ID Flashcards

Question

Antibiotics - cell wall active group, brief

Answer 1

1. Beta lactams a. Penicillins b. Cephalosporins c. Carbapenems d. Monobactams 2. Non-beta lactam a. Glycopeptides

Answer 2

Inhibit cell wall synthesis as inhibit last step of cross linking mucopeptide in cell wall ``` Original penicillins • Phenoxymethylpenicillin • Benzathine penicillin • Procaine penicillin • Benzylpenicillin Coverage - GP – streptococcus, listeria, clostridia, treponemes Side effects/other - Allergic – rash in 2% - Anaphylaxis - ALL renal excretion – 90% tubular ``` ``` Enteric active penicillins (aminopenicillins) • Ampicillin • Amoxicillin Coverage - GP and GN – enterococci (GPC) - No Staph cover Side effects/other - Rash that increases with EBV - Diarrhoea ``` ``` Anti-staph penicillins • Flucloxacillin • Dicloxacillin Coverage - GP – MSSA - GN - No enterococcus Side effects/other - Rash - Hepatitis ``` ``` Anti-pseudomonas penicillins • Ticarcillin • Piperacillin Coverage - GP and GN Side effects/other - Rash - Resistance ``` ``` Extended-spectrum • Augmentin = amox/clav • Timentin = ticarcilllin/clav Tazocin = pip/Taz Coverage - Broad GN and GN cover - Including pseudomonas - Active against penicillinase-producing bacteria – Staph, Strep, Haemo, Morax, EC, Klebsiella Side effects/other - Rash ```

Answer 3

Same action as penicillin due to B-lactam ring (less susceptible to B lactamase) - inhibit cell wall synthesis by blocking cross linking ``` First generation • Cephalexin • Cephalothin • Cephazolin Coverage - GP – MSSA, strep - GN – some E. coli, Klebsiella, Proteus SE/other - Allergy cross reaction with 10% penicillin allergy - Use soft tissue infection ``` ``` Second generation • Cefoxitin • Cefaclor Coverage - GP, GN and anaerobes SE/other - Cefaclor – high incidence serum sickness reaction ``` ``` Third generation • Cefotaxime • Ceftazidime • Ceftriaxone Coverage - GP, GN - Penetrate CNS - NO pseudomonas except ceftazadime SE/other - Able to cross BBB - Ceftriaxone risk of biliary sludging – avoid in neonates Partial biliary excretion ``` ``` Forth generation • Cefepime • Cefpirome Coverage - Gram –ive/+ive/pseudomonas SE/other - Diarrhoea - Vaginal candidiasis ``` e. 5th generation = ceftaroline, ceftobiprole  ANTI-MRSA

Answer 4

Bactericidal; inhibit bacterial cell wall synthesis by preventing formation of peptidoglycan polymers. ``` Eg • Vancomycin • Teicoplanin Coverage - GP – MSSA, MRSA, enterococci - Teicoplanin covers VRE SE/other - 100% renal excretion + nephrotoxic - Red man syndrome - Ototoxic ```

Answer 5

Inhibit bacterial cell wall synthesis by binding to penicillin-binding proteins, the affinities for which differ between the carbapenems and may affect their activity in vitro; usually bactericidal. ``` Eg • Imipenem • Meropenem Coverage - GP, GN (including ESBL, pseudomonas), anaerobes - NOT enterococci, MRSA, VRE - Broadest of all beta lactams SE/other - Limited use due to resistance - Neurotoxicity (fewer seizures with imipenem) - Renal clearance ```

Answer 6

Bactericidal; inhibits bacterial cell wall synthesis by binding to penicillin-binding protein 3 of Gram-negative bacteria. ``` Eg • Aztreonam Coverage - GN ONLY including pseudomonas (especially rods and cocci) - NOT GP or anaerobes SE/other - Rash - Thrombophlebitis - Eosinophilia ```

Answer 7

1. Aminoglycosides 2. Tetracyclines 3. Macrolides 4. Cloramphenicol 5. Lincosamides 6. Oxazolidinones

Answer 8

Gentamicin, tobramycin, amikacin, streptomycin General gent empiric against E. coli, amikacin used in onc patients ``` Action - Bind 30S subunit and prevent protein synthesis in ribosome Coverage • Gentamicin, tobramycin – GN • Synergistic activity with beta lactams for GP organisms (GBS, Listeria, Staphylococci) AE/Comments - Ototoxicity - Nephrotoxicity - Gentamycin – strep most resistant ```

Answer 9

Bind to 50S subunit, inhibit protein synthesis Atypicals Coverage • Roxithromycin (atypicals) • Azithromycin (GP, staph, strep, Hib, atypical) • Erythromycin (GP, mycoplasma, chlamydia) • Clarithromycin (GP, MAC, atypicals) AE/other - Limited use in skin/soft tissue/URTI due to resistance - Use for atypical pneumonia and pertussis - Erythromycin – prokinetic, increased risk pyloric stenosis in infants - Clarithro/Erythro CYP450 3A4

Answer 10

Doxycycline, tetracycline, minocycline Bind to 30S subunit, inhibit protein synthesis ``` Coverage • GP, many GN • Atypical AE/other - Tooth discoloration, bone deformity - Do not prescribe <9years / pregnant. - Photosensitivity - N+V - Benign intracranial hypertension - Hepatitis - Leukopenia/thrombocytopenia ```

Answer 11

Inhibits bacterial protein synthesis by binding to the 50S subunit of the bacterial ribosome and preventing the activity of peptidyltransferase. Conjunctivitis ``` Coverage • GP, GN • Very broad • No pseudomonas AE/other - Use = 3rd world as broad coverage but lots of SE • Grey baby syndrome • Bone marrow suppression • Aplastic anaemia ```

Answer 12

Clindamycin, lincomycin ``` Bind 50S subunit Coverage • Some GP (MRSA, GAS), anaerobes, bacteriodes; no GN • Anti-toxin • Good tissue penetration Other - Clostridium difficile ```

Answer 13

Linezolid Inhibit initiation of protein synthesis by inhibition trna binding to 50S ribosome Coverage • GP – VRE, MRSA, resistant strep • Excellent oral bioavailability AE/other Use only in resistance Pharmacokinetics not altered by hepatic or renal impariment Well tolerated Longer courses - marrow suppression, optic neuritis, peripheral neuropathy (may be irreversible)

Answer 14

Metronidazole Action Inhibit RNA synthesis leading to DNA damage and death Coverage Anaerobes only • 1st line anaerobes • C. difficile AE Teratogenic Disulfiram reaction with ETOH

Answer 15

Norfloxacin, ciprofloxacin Inhibit topoisomerase 2 that blocks DNA gyrase therefore inhibit DNA/RNA synthesis ``` Coverage GN, Atypicals • Enterobacteriaceae • Atypicals • Pseudomonas • Serratia • Some Staph/Strep ``` AE/other Use when no other sensitive. E.g. PO pseudomonas Rx

Answer 16

Inhibits bacterial RNA polymerase Coverage MRSA AE/other Use = TB, leprosy, MRSA, prophylaxis in some UTI

Answer 17

Sulfamethoxazole, trimethoprim, cotrimoxazole Inhibit dihydrofolate synthase and reductase therefore no folic acid or DNA/RNA synthesis ``` Coverage GP and GN • Atypical • Opportunistic – PJP, nocardia • MRSA ``` ``` AE/other Sulphur reactions – • Rash • Erythema multiforme • Stevens-Johnson • BM suppression ```

Answer 18

* Diptheria = phenoxymethylpenicillin * Listeria = Benzylpenicillin * Clostridium difficile = metronidazole/vancomycin

Answer 19

* Streptococci = benzylpenicillin * Enterococci = amp/amoxicillin * Staphylococci = di/flucloxacillin * MRSA = vancomycin/clindamycin

Answer 20

* Pertussis - erythromycin/clarithromycin | * Haemophilus - ceftriaxone

Answer 21

• Neisseria = cefotaxime/cetriaxone

Answer 22

``` • EC/Kleb/Proteus/enterobacteriae - CoT • Salmonella/Shigella = cotrimoxazole (salmonella- cef, Shigella- cipro) • Cholera - tetracycline + TMP • Campylobactor = erythromycin • HP = triple therapy (fluclox/clarithro + metronidazole + PPI) • Pseudomonas = o Ticarcillin/pipercillin o Augmentin/Timentin/Tazocin o 4th gen ceph - ceftazidime o Tobramycin/Amikacin o Ciprofloxacin ```

Answer 23

chlamydia, legionella, mycoplasma * Azithromycin * Roxithromycin

Answer 24

1. Listeria 2. Enterococcus 3. Clostridium 4. Actinomyces 5. Bacillus anthracis 6. Group A strep

Answer 25

1. 4th generation penicillins (piperacillin, ticarcillin) 2. 4th generation cephalosporins (ceftazidime, cefipime) 3. Carbapenems 4. Aztreonam 5. Aminoglycsides – genta, amikacin, tobramycin 6. Ciprofloxacin 7. Tigecycline 8. Colistin

Answer 26

Abdo/necrotic/gasseous infections 1. Metronidazole 2. Carbapenems 3. Tazocin 4. Clindamycin 5. Tigecycline

Answer 27

1. Vancomycin 2. Teicoplanin 3. Clindamycin 4. Bactrim 5. Tetracycline 6. Rifampicin 7. Linezolid

Answer 28

1. Classification a. Endogenous resistance = selection of resistant mutations due to natural selection type processes b. Exogenous resistance = transfer of resistance genes – much more common c. Intrinsic vs acquired 2. Classification of resistance mechanisms a. Molecular mechanisms i. Gene mutations ii. Transfer of plasmids - circular strands of DNA -> autonomous and self-replicating iii. Movement of genetic elements – transposons, integrons, gene cassettes between plasmids/ chromosomes (cannot replicate on their own) b. Biochemical mechanisms i. Enzymatic inactivation ii. Altered/ additional resistant target iii. Altered transport -> reduced intracellular accumulation 3. Intrinsic vs acquired a. Intrinsic i. Predictable resistance – does not require susceptibility testing ii. Intrinsic cellular property of organism or intrinsic mutation iii. Examples 1. Gram negatives = vancomycin not effective against cell wall 2. Pseudomonas aeruginosa = intrinsically resistant to cefotaxime a. Low affinity of cefotaxime to pseudomonal PBPs b. Low permeability 3. Enterococci = intrinsically resistant to cephalosporins a. ALWAYS treat with penicillin, amoxicillin or vancomycin b. Low affinity of cephalosporins for enterococcal PBPs b. Acquired resistance i. Altered site 1. Altered transpeptidases (PBPs) ii. Enzymatic modification of antibiotic – usually plasmid mediated 1. Beta lactamases 2. Aminoglycoside modifying enzymes iii. Decreased access of antibiotic for target 1. Efflux pumps 2. Decreased cell wall permeability

Answer 29

1. Mechanisms a. Alteration of the target site i. Target site for beta-lactams are the PBPs (penicillin-binding proteins) in cytoplasmic membrane ii. Examples 1. Penicillin resistant pneumococci 2. Methicillin resistant staphylococci 3. Bacteria with intrinsic resistance to beta lactams – gonococci, enterococci, haemophilus influenzae b. Inactivation by bacterial enzyme i. May be synthesised constitutively (plasma-mediated) or inducible (chromosomal) ii. Examples = E. coli, Staph aureus iii. Includes 1. Penicillinases – penicillin 2. Cephalosporinases – cephalosporin 3. Beta-lactamases – both 4. Extended-spectrum beta lactamases – resistance to most antibiotics including penicillins, cephalopsorins and monobactam aztreonam iv. Classification 1. Chromosomal = inducible a. Virtually all GNB possess chromosomal beta-lactamase gene; however usually low amounts b. Susceptibility usually determined by plasmid-mediated beta-lactamases c. E coli, Proteus, Salmonella, Shigella, Hib, Klebsiella – primarily penicillinase, therefore more susceptible to cephalosporins d. Enterobacter, Serratia, Citrobacter – inducible chromosomal beta-lactamase AmpC 2. Acquired = constitutive a. Plasmid or transposon c. Mediate resistance to penicillins and first- and some second generation c. Reduced drug entry i. Reduced susceptibility but not usually resistant d. Removal of drug (efflux pump) i. Most often Pseudomonas

Answer 30

a. Produced by GN bacteria b. Definition = resistance to oxyimino-beta-lactam substrates (cefotaxime, ceftazadime, ceftriaxone, cefepime) and the ability of a beta-lactam inhibitor (clavulanate) to block this resistance c. Resistant to = penicillins, cephalosporins, monobactam – RETAIN susceptibility to carbapenems (unless carbapenemase) d. Mechanism i. Either chromosomal (inducible + constitutional) or plasma mediated ii. Most frequently found in Enterobacteriaceae (E. coli, Klebsiella, K pneumoniae, K oxytoca) iv. Risk factors 1. Travel 2. Prolonged hospital stay (especially ICU) 3. Multiple courses of antibiotics – especially 2nd and 3rd generation cephalosporins 4. IDC, ventilation, intubation 5. Malignancy, GIT v. Poorer clinical outcome (delay in appropriate therapy) vi. Oral options limited f. Classes Multiple classes Class A = E. coli, Klebsiella, Salmonella, Shigella, Haemophilus - resistant to broad spectrum cephalosporins Class B = Pseudomonas, Stenotrophomonas, Bacteroides Class C = ESCAPPMs (Enterobacter, Serratia, Citrobacter, Acinetobacter/ Aeromonas, Proteus, Providentia, Morganela) - hydrolyse penicillin, cephalosporin, resistant to beta lactamase inhibitors - treat with carbapenem/cefepime, or SHORT course beta lactam as may initially be sensitive before activating gene for resistance g. Treatment i. Carbapenem treatment of choice (unless carbapenemase) ii. +/- aminoglycosides iii. Some 4th generation cephalosporins (cefepime) can be used iv. NEVER use cephalosporins

Answer 31

Enterobacter, Serratia, Citrobacter, Acinetobacter/ Aeromonas, Proteus, Providentia, Morganela i. Chromosomal coded beta-lactamases ii. May be sensitive in vitro but quickly become resistant iii. Treat with SHORT courses of beta lactams/ beta lactam + another AB / carbapenems

Answer 32

Extended-spectrum beta-lactamase i. Plasmid mediated resistant bugs – any G-ve, classically enterobacteraciae ii. Treat w aminoglycoside/ carbapenem iii. If Carbapenamase resistant  Colistin, fosfomycin

Answer 33

``` MSSA • Flucloxacillin – first line • Cephalexin – alternative oral agent • First generation cephalosporin: cephazolin , cephalexin • Bactrim • Augmentin • Clindamycin – bacteriostatic ``` ``` MRSA • Tetracycline, doxycycline • Glycopeptide – vancomycin, teicoplanin • Erythromycin • Clindamycin • Bactrim • Daptomycin • Linezolid ```

Answer 34

i. Beta lactam resistance 1. Intrinsically resistance to cephalosporins, aztreonam, antistaph penicillins and ticarcillin ii. Aminoglycoside resistance 1. Low level resistance in all strains intrinsically due to poor transport across cell wall iii. Vancomycin resistance = Vancomycin Resistant Enterococci (VRE) 1. Alteration of binding site D-alanyl-D-alanine terminus of peptidoglycan precursors 2. Encoded by cluster of genes referred to as VanA, B, D and M 3. Three major phenotypes – VanA (most common), VanB, VAnD 4. Treat with Linezolid, Daptomycin, Tigecycline, Teicoplanin

Answer 35

i. No resistant strains isolated | ii. Universally susceptible to penicillins and almost all macrolides

Answer 36

i. >90% resistant to penicillins via penicillinase ii. Anti-staph penicillins – different side chain which reduces access of beta-lactamase enzymes iii. Flucloxacillin = main anti-staphylococcal penicillin iv. MRSA = acquisition of mecA gene stops penicillase containing penicillins accessing PBP (will not bind ANY beta lactam drug – therefore resistant to all penicillins + cephalosporins) ix. Clearance = 14 days of mupirocin nasally, antibacterial washes (but poor efficacy) Treatment options for MRSA: erythromycin, clindamycin, doxycycline, cotrimoxazole, gentamicin, vancomycin, linezolid

Answer 37

i. Beta lactam resistance 2. Relatively poor penetration of penicillins into CSF means lower threshold for defining resistance in meningitis than for infections at other sites (ie. chest, otitis media) 3. NO beta lactamase resistance in S pneumoniae (?) 4. Alteration in PBP site – decreases affinity of penicillin ii. Macrolide/ fluoroquinolone resistance = alteration in binding site on RNA/ DNA gyrase respectively iii. Capsular switching

Answer 38

1. Colistin a. Colistemethate = inactive drug, colistin = polymyxin E b. Side effects = renal, neurotoxicity c. Utility i. MDR GNB including pseudomonas, Acinetobacter ii. NDM BMLs – last result d. Complex dosing 2. Fosfomycin a. Interferes with peptidoglycan synthesis disrupts cell wall synthesis b. Utility i. Aerobic gram negative – including UTI ii. Little cross-resistance c. High oral bioavailbility d. Increasing use for community treatment of ESBL UTI 3. Tigelcycline a. Glycylcycline – tetracycline derivative b. Protein synthesis inhibitor c. Active against GP and MDR gram negatives d. Hepatotoxicity, pancreatitis e. Limited paediatric dosing information 4. Daptomycin a. Cyclic lipopeptide/ lipophilic glycopeptide with extensive GP activity b. Effective against MRSA and other GP c. Indication = SSSI (skin and skin structure infections), bacteraemia, endocarditis d. Ineffective for pneumonia as inactivated by lung surfactant e. Emerging issues with resistance f. Lack of paediatric data 5. Ceftaroline fosafmil a. Difficulty managing MRSA with high MIC for vancomycin b. Daptomycin limitations include unsuitability for use in pneumonia (interactions with pulmonary surfactant) and emergence of resistance c. CPT-F is FDA approved for SSTI, CAP d. Haematological toxicity + eosinophilic pneumonitis with prolonged courses e. Paediatric data lacking

Answer 39

a. GPC = Streptococcus, Enterococcus b. GPB = listeria c. GNC = Neisseria meningitis, some haemophilus d. GNB = very few e. Spirochetes (Treponema pallidum = syphilis) f. Anaerobes = GPC and GNB (oral and gut)

Answer 40

methicillin, nafcillin, flucloxacillin -> staphylococci, streptococci (NOT enterococcus)

Answer 41

b. Amoxycillin + clavulanic acid = augmentin (beta-lactamase inhibitor) i. Beta lactamase inhibitor = extends spectrum of activity 1. Binds to the beta lactamase of bacteria to inhibit it 2. Affinity varies – strong for penicillinase of Staph aureus, variable for beta lactamase of gram negatives 3. Examples = clavulanic acid, tazobactam ii. Spectrum 1. Broader gram negative + anaerobic cover (E. coli) 2. Restores activity against staph aureus iii. Good for GIT, UTI

Answer 42

i. Ticarcillin + clavulanic acid = timentin 1. Broad spectrum, including pseudomonas + GP + GN + anaerobes ii. Piperacillin + tazobactam = tazocin 1. Similar spectrum as ticarcillin-clav, improved coverage of pseudomonas spp. and enterococcus

Answer 43

a. Beta lactam drugs b. Same mechanism as penicillins but with differing affinity for PBPs c. RESISTANT to penicillinase e.g. produced by staph aureus d. Cephalasporins do NOT cover enterococci e. Most do NOT cover MRSA 2. Generations = improving GNB activity + worse GPC a. 1st = GPC b. 2nd = GPC + few GNs c. 3rd = lose GP, gain GN (lose staph cover, still have strep) -> targeting GNB d. 4th = includes pseudomonas e. 5th = add MRSA, lose pseudomonas

Answer 44

i. Coverage 1. GN – H. influenzae, enterobacteriaceae (E. coli, Klebs, proteus), Neisseria 2. Lose GP cover – poor staph aureus, but effective against streptococci 3. No antipseudomonal activity 4. Some anaerobic cover (poor) 5. Enterococcus resistant ii. Good CSF penetration iii. Cefotaxime similar to spectrum of ceftriaxone iv. Adverse effects 1. Biliary sludging a. Displaces bilirubin from albumin, may increase risk of bilirubin encephalopathy b. Cefotaxime preferred for Gram-ve septicaemia in neonates c. Contraindicated in preterm neonates up to a postmenstrual age of 41 weeks and in full-term neonates with jaundice or other conditions that might affect bilirubin binding. d. However, single-dose ceftriaxone is used to treat neonatal gonococcal conjunctivitis 2. Calcium precipitation a. Calcium and ceftriaxone are incompatible; calcium ceftriaxone precipitates in the lungs and kidneys of neonates have caused death, -> do not give with IV calcium/same line 3. Pancreatitis 4. Cholecystitis 5. Pseudolithiasis 6. Nephrolithiasis – calcium ceftriaxone renal stones

Answer 45

1. Includes a. Ertapenem b. Imipenem c. Meropenem 2. Spectrum = broadest of beta lactam a. GP – staph (except MRSA), streptococcus b. Most GN (including ESBL) c. Pseudomonas d. Anaerobes e. Some activity against enterococci (but poor) 3. Side effects a. Neurotoxicity – less with meropenem 4. Utility a. Reserved for severe nosocomial (community if high risk resistant bug) sepsis b. Potential for overuse – LRTI, UTI, skin and soft tissue, septicaemia, meningitis, intra-abdo c. Restricted use i. Highly resistant – ESBL ii. Polymicrobial infections where monotherapy advantageous (eg. intra-abdominal) iii. Oncology population iv. Aminoglycoside poorly tolerated 5. Resistance to meropenem a. MRSA – uniformly resistant to beta-lactams b. Pseudomonas – some pseudomonas lack porin proteins used by meropenem to get to target intracellular enzymes c. Emerging global problem i. Carbapenem resistant enterobacteriaceae (CRE) ii. Klebseilla penuoniae carbapenemase (KPC) iii. New Delhi Metallo-beta-lactamase (NDM)

Answer 46

a. Spectrum i. Main use is for MRSA ii. Other = streptococcus, enterococcus – if penicillin allergy or resistant iii. MSSA = if penicillin allergy b. Note i. Poor bactericidal activity ii. INFERIOR to beta lactams for MSSA bacteraemia and endocarditis iii. ‘MIC creep’ among sensitive strains iv. Variable tissue penetration v. Oral vancomycin used to treat pseudomonas colitis (clostridium difficile) no oral absorption acts in bowel c. Side effects i. Red Man’s syndrome – infusion related; NOT an allergy ii. Nephrotoxicity Monitoring: trough levels e. Reactions i. Red man syndrome 1. Most common reaction 2. Not true IgE mediated reaction 3. Psuedoallergic reaction where vancomycin directly activates mast cells – release of histamine and other vasoactive mediators 4. May develop with first administration of vancomycin, occurs with IV route 5. Rate-dependent infusion reaction a. All patients will get reaction if fast enough b. Suggested that infusion rate no higher 10mg/min 6. Clinical features - flushing, erythema, pruritus affecting upper body/face > lower, pain/muscle spasm in back and chest, dyspnea, hypotension. 7. Rarely life threatening, but same clinical presentation as anaphylaxis 8. Management a. Antihistamine premedication if rapid infusion required b. Mild-moderate acute reaction – stop infusion, give antihistamine (H1 and H2), restart infusion half the rate c. Severe reaction (cardiovascular) – stop infusion, give antihistamine, fluid resuscitation, slow infusion further / stop ii. Anaphylaxis

Answer 47

1. Mechanism a. Binds to 30S ribosomal subunit  inhibit protein synthesis b. Bacteriostatic 2. Cover a. Activity against most gram negatives including pseudomonas b. Synergistic against enterococci/streptococci 3. Dosing a. 24 hour dosing recommended including in neonates 4. Monitoring a. TDM essential b. Trough used to evaluate risk of toxicity 5. Significant side effects a. Nephrotoxic (10-20%) = usually reversible b. Ototoxic = cochlear/vestibular permanent i. Cochlear = sudden, irreversible deafness 1. People with genetic predisposition 2. Can also happen in people without predisposing and have high cumulative dose ii. Vestibular = idiosyncratic 1. Can happen with a single dose, even if appropriate dose c. Risk of both increased with loop diuretics 6. Use = empiric sepsis

Answer 48

1. Mechanism = protein synthesis inhibit –binds 30S ribosomal subunit 2. Doxycycline is main one used 3. Cover = atypical pathogens/intracellular pathogens a. Malaria = prophylaxis, treatment b. Rickettsia spp c. Chlamydia spp, Mycoplasma, Legionella d. Spirochetes  Treponema pallidum (syphilis) 4. Use = frequently for CAP atypical cover and pelvic inflammatory diseases 5. Side effects a. Photosensitivity b. Esophagitis, reflux c. Teeth staining

Answer 49

1. Mechanism = affects DNA replication by targeting DNA gyrase 2. Choices a. Ciprofloxacin = excellent bioavailability, given orally i. ONLY ORAL ANTIBIOTIC which has PSEUDOMONAL COVER b. Norfloxacin = not absorbed – GIT/GUT infections c. Moxifloxacin = adds strep cover (particularly pneumococcus), no pseudomonas cover 3. Cover a. Covers most GN, including pseudomonas aeruginosa b. Some activity against staph and mycobacteria c. Poor activity against streptococci and anaerobes d. Pseudomonas rapidly becomes resistant with monotherapy i. Single point mutation to confer resistance to ciprofloxacin  low threshold to resistance ii. Resistance can be induced in vivo iii. Avoiding resistance 1. Can reduce number of bacteria with other antibiotic then change to ciprofloxacin 2. Combination therapy 4. Side effects = Achilles tendon

Answer 50

1. Mechanism = inhibits protein synthesis 2. Clindamycin a. Spectrum i. Gram positive + anaerobes ii. NO gram negative cover b. Note i. Inducible resistance – D zone test (place erythromycin + clindamycin in close proximity) ii. Good oral bioavailable iii. Bacteriostatic  stops bacteria from producing proteins etc. iv. Excellent tissue penetration v. Can be used as adjuvant to block toxin release c. Utility i. Oral/dental infections ii. Skin/soft tissue infections iii. Often used with ciprofloxacin for broad spectrum Tx for diabetic foot infections 1. Clindamycin (GP + anaerobes) + ciprofloxacin (GN)

Answer 51

1. Mechanism = inhibit protein synthesis, 50S ribosomal subunit 2. Azithromycin is main one used 3. Wide spectrum a. GP  streptococcal and staph but increasing resistance b. ‘Atypical’ pathogens = legionella, mycoplasma and chlamydia spp. c. Bordetella pertsusss (whooping cough) 4. Not effective against GNR 5. Major use in community acquired respiratory infections 6. Bioavailability, good ORAL absorption 7. SE = arrhythmias, may lengthen QT interval

Answer 52

1. Mechanism= affects DNA replication 2. Metronidazole is main one used 3. Covers a. Anaerobes  Bacteroides fragilis b. Clostridium difficile (first choice  oral vancomycin) c. Protozoa  Trichomonas vaginalis, giardia lamblia, Entamoeba histolytica 4. Excellent oral bioavailability 5. Side effects a. GI symptoms  nausea, metabolic state b. Disulfiram-like = reaction with alcohol consumption c. Peripheral neuropathy

Answer 53

1. Trimethoprim a. Mechanism = inhibits bacterial DNA synthesis via antifolate activity b. Bacteriostatic c. Cover i. E. coli, simple enterobacteriaceae  ONLY GRAM NEGATIVE ii. Proteus spp. RESISTANT to trimethoprim d. Use = commonly for UTI treatment or prophylaxis 2. Cotrimoxazole = trimethoprim/sulfamethoxazole (BACTRIM) a. Synergist effect b. Beware sulphur allergies c. Cover i. Pneumocystis carinii/jiroveci = MAIN (CD4 <200, prednisolone >15mg for more than 4 week) ii. Listeria monocytogenes iii. Community-associated MRSA iv. Nocardia v. Meliodosis d. Use = treatment and prophylaxis of PJP e. Side effects i. Hypersensitivity reactions are more common  including serious skin reactions Steven Johnson ii. Bone marrow toxicity

Answer 54

1. Overview a. Fungi = eukaryotic cells which lack chlorophyll (cannot generate energy through photosynthesis) i. They require an aerobic environment b. Classification i. Yeast = Candida, Trichosporon, Cryptococcus 1. Unicellular growth form of fungi, reproduce by ‘budding’ 2. Can form long filaments ii. Moulds = Aspergillus, Scedosporium proliferans, Fusarium, Zygomycetes (Rhizopus, Moro) 1. Multicellular colonies that are composed of clumps of hyphae 2. Grow in long filaments that intertwine 3. Eg dermatophytes, Aspergillus iii. Dimorphic = Histoplasma, Blastomyces, Cocciodes 1. Can exist as mould/hyphal/filamentous form or yeast c. Other definition i. Hyphae = tubules composed of fungal cells attached end to end ii. Spores = reproducing bodies of moulds 2. Structure a. Bilayered cell membrane = contains ergosterol b. Cell wall (outside of cell membrane) = mainly carbohydrate + protein (these are the antigens to human immune system) c. Capsule = polysaccharide coating around the cell wall (anti-phagocytic) 3. Types of fungal infections a. Superficial fungal infections i. Pityriasis versicolour ii. Tinea nigra b. Dermatophytoses i. Usually microsporum, trichophyton, epidermophyton ii. Includes tinea corporis, tinea pedis, tinea capitis etc iii. Diagnosed with Wood’s line (will fluoresce green) iv. Usually treated with topical azoles c. Subcutaneous fungal infections d. Systemic infections: i. Histoplasma, Blastomyces, Coccidioides immitis ii. Candidiasis iii. Aspergillosis

Answer 55

• ALL dimorphic fungi • Acquired by inhalation as ‘spores’ (aerosolized from soil, bird droppings, vegetation) • Inhalation  local lung infection  blood stream dissemination • Usually destroyed by cell mediated immune system • Can be diagnosed (like TB) via a delayed type hypersensitivity reaction • Clinical presentations o Asymptomatic o Pneumonia o Disseminated disease (meningitis, granulomas, skin disease) • All need biopsy of affected tissue for diagnosis • Treatment (chronic disease) = itraconazole/ amphotericin

Answer 56

1. Key features a. Histoplasma capsulatum: fungus found in mould form in the environment b. Spread via inhalation of spores, no person-person transmission c. Conidia (spores) reach alveoli and proliferate 2. Clinical manifestations = bronchopneumonia, disseminated disease (w splenic involvement – only in infants + immunocompromised patients) 2. Treatment a. Oral itraconazole b. Amphotericin B for progressive disseminated disease c. Lifelong therapy with itraconazole for HIV / immunocompromised patients

Answer 57

1. Key points a. Group of fungi that grow as mould and produce spores in soil -> convert into pathogenic yeast on inhalation b. Can cause disease in immunocompetent and immunocompromised patients c. Can manifest as subclinical infection, symptomatic pneumonia and disseminated disease d. Skin the most common extrapulmonary manifestation = plaques, ulcers, nodules + bony involvement 2. Diagnosis a. Histopathology: neutrophilic infiltration with noncaseating granulomas b. Urine antigen testing available 3. Treatment = amphotericin B / itraconazole

Answer 58

1. Key points a. Soil dwelling dimorphic fungi b. Grows in environment as mycelial form, inhaled as spores (person to person transmission does not occur)  transform into septated spherules that resist phagocytosis 2. Clinical manifestations a. Primary pulmonary infection = 60% asymptomatic 40% symptomatic b. Pulmonary disease may lead to fibrocavitary disease, empyema c. May be associated with erythema nodosum 3. Diagnosis a. Marked eosinophilia may occur b. Culture is diagnostic but rarely positive c. Coccidioidal galactomannan in urine may be useful d. Serology may be useful (but often negative) 4. Treatment = azole, amphotericin

Answer 59

The term "mucormycosis" was used for years and then was supplanted by "zygomycosis" for several decades. Based on molecular studies, "mucormycosis" is currently again the appropriate term. Devastating rhino-orbital-cerebral and pulmonary infections are the most common syndromes caused by these fungi. 1. Key points a. Fungal infections caused by zygomycetes class of fungi b. Includes = Rhizopus, Mucor, Rhizomucor c. Saprophytic – found in soils 2. Risk factors a. Any immunosuppression b. Diabetes, malignancy c. Steroid or deforoxamine therapy 3. Pathogenesis a. Usually acquired by inhalation of spores b. Disease occurs when there is breakdown in macrophage and neutrophil defences 4. Clinical manifestations a. Sinus and rhino-cerebral infection b. Pulmonary disease c. GI disease is uncommon d. Disseminated – very high mortality rate e. Cutaneous disease – may lead to necrotizing fasciitis 5. Diagnosis = microscopy 6. Treatment a. Surgical debridement b. Amphotericin c. Hyperbaric therapy may be used as an adjunct d. Note – voriconazole + caspofungin are inactive 7. Prognoses a. Rhino-orbital-cerebral mucormycosis 25-60%

Answer 60

1. Microbiology a. Polysaccharide encapsulated yeast, serotypes A, D, and AD b. Species i. Cryptococcus neoformans ii. Cryptococcus gatti 2. Epidemiology a. Distributed in warm climates especially soil contaminated with bird droppings b. Most children > 2 years have been exposed c. Disease is very rare in immunocompetent (pigeon breeders + lab personnel carrier the highest risk) d. <1% of children with HIV affected (5-10% HIV +ve adults) 3. Risk factors a. Immunosuppression b. DM c. Renal failure 4. Pathogenesis a. Most often inhaled as fungal spores, engulfed by macrophages b. Direct GI entry can also occur c. Invades into the body -> latent infection/acute disease d. Cell mediated immunity -> granulomatous inflammation e. Patients with compromised CMI -> invasive disease 5. Clinical features a. Pneumonia b. Disseminate infection c. Cryptococcal meningitis – India ink staining + cryptococcal Ag test i. High mortality of 15-30% d. Can also cause skeletal infection, ocular and lymph node infection 6. Investigations a. Fungal culture b. Latex agglutination test (not a specific test but a means of detecting antigen/antibody): detects cryptococcal antigen in serum and CSF c. India ink stain (less sensitive than culture and antigen detection) 7. Treatment a. Asymptomatic/mild disease in an immunocompetent patient = observation or oral fluconazole b. Cryptococcemia/severe symptoms i. Amphotericin + flucytosine for at least 2 weeks ii. Consolidation phase – oral fluconazole/itraconazole for 6-12 months iii. Immunosuppressed patients usually continue on lifelong fluconazole c. Note – echinocandins do not have evidence against cryptococcal infections d. Monitor with serial cryptococcal antigen levels 8. Prevention a. Fluconazole prophylaxis in patients with AIDS

Answer 61

1. Includes a. Candida albicans b. Candida glabrata c. Candida krusei d. Candida parapsilosis 2. Key points a. Exists in 3 morphologic forms = blastophores (yeast cells), chlamydosphores + pseudomycelium (tissue phase) b. The most common cause of invasive fungal infections in humans 3. Antifungals a. Candida albicans, Candida parapsilosis and Candida tropically = pansensitive = amphotericin, azoles, + echinocandins b. Candida glabrata = amphotericin B i. Many resistant to azoles c. Candida krusei = amphotericin B first line i. Intrinsically resistant to fluconazole ii. Can use voriconazole – but resistance does exist d. Candida lusitaniae = resistant to amphotericin = azoles

Answer 62

a. Oral thrush i. Most commonly due to c. albicans ii. Persistent/recurrent thrush may suggest immunodeficiency – autoimmune polyendocrinopathy-candidiasis (APS-1) b. Intertrigo i. Infection of closely opposed skin surfaces ii. Erythematous, macerated plaques and erosions with peripheral scale, and satellite papulopustules c. Vulvovaginitis i. Risk factors = DM/antibiotic therapy ii. Results in itching, dysuria, vulvar/vaginal erythema d. Balanitis e. Paronychia and onychomycosis i. More often caused by tinea ii. Favours the fingernails >> toenails f. Diaper rash i. Confluent erythematous rash with satellite lesions ii. Topical nystatin +/- steroids g. Oesophagitis i. Rare – primarily occurs if underlying immune defect ii. Hallmark is odynophagia iii. Concomitant thrush may or may not be present iv. Diagnosed endoscopically – mucosal plaque-like lesions

Answer 63

a. Candidaemia + acute disseminated candidiasis i. Candidaemia = candida present in blood ii. Acute disseminated candidiasis = several viscera are infected due to haematogenous spread iii. Populations at risk 1. Neonates 2. Immunocompromised 3. Children in intensive care units iv. Clinical manifestations 1. Fever 2. Fulminant sepsis 3. Chorioretinitis = focal, glistening, white lesions of the retina 4. Skin lesions = clusters of painless pustules on an erythematous base 5. Muscle pain b. Invasive focal infection i. Urinary tract ii. Peritonitis iii. Endophthalmitis iv. Osteoarticular v. Meningitis vi. Endocarditis c. Hepatosplenic or chronic disseminated candidiasis i. Seen in patients with haematological malignancies who have just recovered from neutropenia ii. Clinical manifestations 1. High, spiking fevers in an individual who has just count recovered 2. RUQ pain or discomfort 3. Nausea, vomiting, anorexia iii. Investigations 1. Elevated ALP 2. Abdominal USS = liver, spleen, kidney abscesses 3. Opthal review of eyes

Answer 64

Chronic and severe candida skin and mucous membrane infections Primary defect of T lymphocyte responsiveness to candida May be a/w endocrinopathies, hyperIgE syndrome, autoimmune disorders, HIV, inhaled steroids

Answer 65

1. Includes a. A. fumigatus b. A. flavus c. A. niger d. A. terreus e. A. nidulans 2. Key points a. Ubiquitous fungi, usually found in soil saprophyte (lives on dead/decaying matter) b. Most disease caused by inhalation of airborne conidia (asexual spores) that subsequently germinate into hyphae and invade host c. Manifestations of disease dependent on host response d. Normal immune response i. Macrophage and neutrophil host defences activated ii. Conidia are cleared by phagocytosis 3. Risk factors for disease a. Neutropenia b. Suppressed macrophage function c. Exposure to high dose of conidia 4. Clinical manifestations a. Invasive aspergillosis i. Acute (<1 month) ii. Subacute/ necrotising (1-3 months) b. Chronic aspergillosis (>3 months) i. Chronic cavitatory pulmonary ii. Aspergilloma of lung iii. Chronic fibrosing pulmonary iv. Chronic invasive sinusitis v. Maxillary (sinus) aspergilloma) c. Allergic i. ABPA ii. Extrinsic allergic bronchoalveolitis (EAA) iii. Asthma with fungal sensitisation iv. Allergic aspergillus sinusitis

Answer 66

a. Exacerbation of asthma b. Extrinsic alveolar alveolitis = hypersensitivity pneumonitis -> fever, cough, dyspnoea c. Allergic bronchopulmonary aspergillosis i. Hypersensitivity disease from immunologic sensitization to aspergillus antigens: 1. Starts with non-invasive colonization of bronchial airways 2. Persistent inflammation + hypersensitivity response 3. Immunologic responses lead to wheezing, infiltrates, bronchiectasis and fibrosis ii. Diagnostic criteria: 1. Episodic bronchial obstruction 2. Peripheral eosinophilia 3. Immediate cutaneous reactivity to aspergillus antigens 4. Precipitating antibodies to aspergillus antigen 5. Elevated IgE 6. Pulmonary infiltrates 7. Central bronchiectasis 8. Secondary criteria: sputum detection, coughing up brown plugs/ specks, elevated aspergillus specific IgE antibodies, late skin reaction to aspergillus antigen iii. Treatment 1. Extended course of systemic corticosteroids 2. Antifungal itraconazole to reduce burden and inflammatory stimulus iv. Disease activity monitored with serum IgE levels d. Allergic Aspergillus sinusitis i. Similar to ABPA ii. Symptoms of chronic sinusitis/ recurrent acute sinusitis, congestion, headaches and rhinitis iii. Treatment = surgical drainage, systemic/ inhaled steroids

Answer 67

a. Aspergilloma i. Masses of hyphae, cellular debris and inflammatory cells ii. Proliferate WITHOUT vascular invasion iii. Occur in setting of TB/histoplasmosis or congenitally acquired defects iv. May be associated with fever/cough/haemoptysis v. May require surgical resection b. Chronic pulmonary aspergillosis i. Occurs in immunocompetent/slightly immunosuppressed patients ii. Have chronic cavitatory pulmonary aspergillosis (multiple aspergillus balls), chronic fibrosing pulmonary aspergillosis (develop pulmonary fibrosis) and chronic necrotizing pulmonary aspergillosis (slowly progressive) iii. Treatment = surgical resection or long term antifungal therapy c. Sinusitis d. Otomycosis (ear) i. More often seen in immunocompromised patients ii. Treatment = topical azole creams +/- oral azoles

Answer 68

a. Usually caused by aspergillus fumigatus b. Invasive disease, usually originating in the lung c. Primarily affects immunocompromised host d. Present with persistent fever e. Investigations i. CT 1. Ill-defined nodules 2. Halo sign – haemorrhagic nodule surrounded by ischaemia 3. Air crescent – cavitates during treatment, or with granulocyte activity (count recovery) ii. MRI = target sign (rim enhancing periphery) iii. Conclusive diagnosis = culture iv. Galactomannan assay = ELISA based assay that looks for aspergillus cell wall component 1. Good for serial monitoring of infection 2. High rates of false negativity f. Management i. 1st line = voriconazole ii. Alternatives 1. Amphotericin 2. Posaconazole 3. Echinocandins

Answer 69

1. Key points a. Not clearly a fungus – shares morphologic features with protozoa and fungi i. ‘Yeast-like’ fungus b. Most humans infected with pneumocystis by 4 years of age (usually asymptomatic) c. Disease states occur exclusively in immunocompromised hosts i. Classical presentation is pneumonia in immunosuppressed ii. AIDS-defining illness 2. Pathophysiology a. Found in the alveolar spaces b. Attaches to type I alveolar epithelial cells c. Host response dependent on cell mediated immunity d. Inflammatory changes in immunosuppressed hosts  disrupted surfactant function e. Histopathologic features i. Infantile interstitial plasma cell pneumonitis: extensive infiltration with thickening of the alveolar septum OR ii. Diffuse desquamative alveolar pneumonitis (found in immunocompromised hosts): large numbers of pneumocystis in foamy exudate

Answer 70

3. Clinical features a. Subtle onset of progressive dyspnea, nonproductive cough, and low-grade fever b. Abrupt onset of respiratory insufficiency that may correlate with a tapered or increased dosage of immunosuppressant medications in non-AIDs patients c. History of immunosuppression d. Hypoxia, fever and tachypnoea e. Chest signs not prominent 4. Investigations a. Induced sputum or BAL i. Giemsa and methenamine silver stains (for microscopic visualization of characteristic cystic or trophic forms in respiratory specimens) ii. PCR (highly sensitive, detects colonisation as well as infection) b. Test for HIV and CMV (co-infection is common) c. Consider other causes of immune-suppression (e.g. PCP in the context of a new severe presentation of SLE) d. CXR i. Bilateral, symmetric, reticular (interstitial), or granular opacities ii. Initially perihilar  peripherally (apical areas spared until last) iii. Complications = pneumatocoeles, pneumothorax (may be bilateral) e. HRCT = ground glass opacities (must be present)

Answer 71

5. Treatment a. 1st line = IV bactrim b. 2nd line = pentamidine c. Steroids = suppress the inflammatory response, increase chance for survival in moderate to severe cases of pneumonia 6. Prevention – chemoprophylaxis a. Bactrim b. Alternatives i. Dapsone ii. Atovaquone iii. Aerosolized pentamidine 7. Prognosis a. 10-20% mortality for initial PCP infection in AIDS patients; much higher if requiring mechanical ventilation b. 30-60% mortality for initial PCP infection in patients without AIDS

Answer 72

• Most antifungals work by binding to ergosterol – component of cell membrane present in fungi but not human cells Overview 1. Triazoles = fluconazole, itraconazole, voriconazole, posaconazole  interfere with cell membrane function by inhibiting ergosterol (cell MEMBRANE) synthesis 2. Echinocandins = caspofungin, micafungin  inhibit cell wall synthesis (beta 1,3 D glucan) 3. Polyenes = amphotericin, L-AMB  make holes in cell membrane * Amphotericin = fungicidal + broad spectrum but nephrotoxic * Caspofungin = well tolerated but does NOT penetrate CSF/urine * Fluconazole = candida albicans infection but hepatoxic * Voriconazole = first choice for invasive aspergillosis but hepatotoxic

Answer 73

• Inhibit fungal CP450 (14DM) enzyme preventing ergosterol synthesis -> disrupt permeability of fungal cell membrane • Generations o Second = fluconazole, itraconazole o Third = voriconazole, posaconazole • Azole drug interactions o Decreased plasma concentration of azoles  Rifampicin, rifabutin  AEDs: Carbamazepine, Phenobarbitone, Phenytoin o Increased plasma concentration of co-administered drug  Vinca alkaloids – can result in neurotoxicity (peripheral neuropathy, autonomic neuropathy, seizures)  Tyrosine kinase inhibitors – TKI metabolism reduced increasing risk of QT prolongation  Bortezomib – metabolism reduced, can result in worsening or new neurotoxicity  Sirolimus, tacrolimus, cyclosporin – metabolism reduced increasing drug levels  Diazepam, midazolam – metabolism reduced, increasing risk of toxicity including respiratory depression  Other drugs which prolong QT interval – additive QT prolongation • Adverse effects o Hepatotoxicity – key adverse effect of azoles o Drug interactions

Answer 74

1. Key points a. Fungistatic (concentration independent) b. Broad antifungal coverage, very good for Candida albicans but NOT aspergillus c. Comes in PO/ IV form (O = 90% bioavailability) 2. Pharmacodynamics a. Good systemic access – low lipophilicity + limited plasma protein binding b. Very well absorbed (achieves 90% concentrations CF IV) c. Greatest CSF penetration (80% of serum) d. Penetrates vitreous body well (80% of serum) e. Urinary concentrations 10-20x serum – very good for UTI 3. Dosage = higher doses than required in adults a. Clearance more rapid in children b. Mean half-life 20 hours (CF 30 hours in adult) c. Volume of distribution greater in neonates  require double dosing 4. Indications a. Prophylaxis b. Treatment i. Candida – except candida krusei and glabrata ii. Cryptococcal meningitis

Answer 75

• Covers aspergillus • Increase absorption with acidic rink • High volume of distribution, tissue penetration  this is probably more relevant than system levels • Adverse effects (few) – N+V, transaminitis, peripheral oedema • Indications o Less serious endemic mycoses (histoplasmosis, coccidiodomycosis, blastomycosis) o Prophylaxis

Answer 76

1. Key points a. Second generation triazole b. Fungicidal against aspergillus, fungistatic against candida c. Oral tablet/suspension/IV d. Penetrates eye, brain + CSF (not urine) 2. Pharmacodynamics a. Extensively metabolised by liver – CYP450 b. 90% oral bioavailability c. CYP2C19 polymorphisms may result in slow metabolism d. Linear PK in children at low doses (not in adults) 3. Indications a. Invasive aspergillosis (above amphotericin following recent trial) -> FIRST LINE b. Mucosal + invasive candidiasis (though note its fungistatic) c. Good step down oral treatment for glabarata and krusei 4. Adverse effects a. Visual disturbance b. Elevated hepatic transaminases c. Photosensitization

Answer 77

* Second generation triazole (derivative of itraconazole) * Good for candida, aspergillosis and zygomycetes + mucorales * Only available as oral formulation * Needs to be taken with high fat + may be reduced by PPIs * Adverse effects = transaminitis

Answer 78

• Inhibit 1,3-beta-d-glucan synthase, enzyme involved in fungal wall synthesis • Fungicidal in vitro against candida, fungisatic against aspergillus • Only available IV • Pharmacodynamics o Not metabolised through CYP system (CF with azoles) o Large molecular size (cannot be given orally) • Minimal nephrotoxicity/ myelotoxicity Caspofungin • Indications = refractory aspergillosis , candidaemia • NOT good for cryptococci or filamentous fungi other than aspergillus (eg. Scedosporium, fusarium) • NO active drug in urine, CSF or brain • May not be as effective for Candida parapsilosis • Well tolerated, few interactions • Indications = invasive candidiasis (NOT CNS infection), aspergillus intolerant o other agents Micafungin • May have shorter half-life + more rapid clearance compared to adults • Shown to be better tolerated than liposomal amphotericin B • Used for prophylaxis Anidulafungin • Longest half-life of all echinocandins • Useful for candida • Not hepatotoxic

Answer 79

1. Key points a. Binds to ergosterol in fungal cell membrane, and creates transmembrane channels: this leads to membrane disruption + osmotic lysis of the cell b. Fungicidal (concentration dependent) c. Various forms – liposomal amphotericin B coated with lipid to reduce nephrotoxicity and reactions d. Original form of amphotericin -> amphotericin B deoxycholate (amphotericin mixed with a detergent to enable solubility) 2. Pharmacodynamics a. 24-48 hour distributional half life b. Terminal elimination half-life of up to 15 days 3. Adverse effect a. Most common adverse effect is nephrotoxicity (50% patients will develop acute renal failure) – lipid formulations have reduced nephrotoxicity b. Infusion related toxicity (80% experience either infusion related toxicity/nephrotoxicity) i. Ambisome has shown fewer infusion related events than others 4. Indications a. Candidiasis b. Cryptococcal meningitis c. Severe pneumonia + extrapulmonary blastomycosis, histoplasmosis, coccidodomycosis d. Invasive aspergillosis e. Invasive sporotrichosis f. Mucormycosis 5. Adverse effects (as above renal + infusion reaction) a. Renal toxicity b. Hypokalaemia c. Acute febrile reaction d. Anaemia e. Phlebitis

Answer 80

• Fluorinated analog of cytosine: rapidly converted into 5-FU in fungal cells • Pharmacodynamic features o Highly water soluble o Not protein bound • Resistance develops quickly with monotherapy • May enhance antifungal activity of amphotericin B (esp in places where penetration of amphotericin B is difficult e.g. CSF, heart valves, vitreal body) • Adverse effects o Exacerbates myelosupression in patients with neutropenia o Can reach toxic levels in combination with amphotericin • NOT recommended in premature neonates

Answer 81

``` • Binds to ergosterol • Mainly used topically on skin + mucous membranes • Key indications o Oral thrush o Oesophageal + gastric candidiasis ```

Answer 82

* Blocks ergosterol synthesis * Used for tinea pedis, apitis, corporis * Not metabolised by CP450 system (so has less drug drug interactions)

Answer 83

• Static drug: inhibits growth rather than killing fungi • Adverse effects (uncommon) o Headache, N+V, photosensitivity, confusion o Bone marrow suppression

Answer 84

1. Microbiology a. Gram negative cocco bacillus b. Facultative anaerobe d. Humans only natural hosts – part of normal respiratory flora in 60-90% of healthy children e. Transmitted via direct contact/ inhalation of respiratory droplets f. Exists in capsular and non-capsular forms i. Non-capsular (non-typeable) haemophilus usually colonises URTI -> can also cause invasive disease ii. 6 capsular types A-F associated with invasive disease g. Virulence factors i. Adherence factors – pilus + non-pilus ii. Polysaccharide capsule -> helps evade phagocytosis and other clearance mechanisms h. Children < 2 y unable to mount antibody response to polysaccharide capsule even after invasive infection 2. Epidemiology a. Pre-vaccine: >90% of children <5 years of age b. Invasive disease largely occurs in children <5 c. Invasive disease is RARE in neonates, can be associated with maternal chorioamnionitis d. Cases still occur in vaccinated children 3. Clinical manifestations a. Meningitis i. Previously major cause of meningitis ii. 6% SNHL, 3% mortality iii. 15-30% have serious sequelae b. Epiglottitis c. Septic arthritis d. Cellulitis e. Pneumonia f. Otitis media g. Sinusitis, preseptal cellulitis, orbital cellulitis h. Sepsis (usually associated with focal source) 4. Patients with functional/asplenia a. Uncommon cause of post splenectomy sepsis b. Single vaccine recommended prior to splenectomy if not previously vaccinated c. Ideally perform 2 weeks prior to splenectomy/1 week after 5. Treatment a. Most are susceptible to ampicillin/amoxicillin b. 1/3 produce beta-lactamase conferring resistance (can be treated with augmentin) c. Some strains that produce altered PBP also identified d. Usually susceptible to 3rd generation cephalosporins, Bactrim, quinolones 6. Vaccines a. 2, 4, 6 months (infanrix hexa) b. 18 months (ActHIB)

Answer 85

1. Microbiology a. NOT encapsulated b. Gram negative diplococcus c. Produces endotoxin lipo-oligosaccharide d. Humans specific pathogen – colonizes respiratory tract in infancy e. Virulence factors i. Adhesion molecules ii. Forms biofilms in vitro and in middle ears of children with otitis media 2. Clinical features a. Otitis media = 15-20% of cases b. Sinusitis c. LRTI d. Bacteraemia = rare, usually seeds from respiratory tract 3. Treatment a. Augmentin b. Extended spectrum cephalosporins c. Macrolides d. Bactrim

Answer 86

1. Microbiology a. Gram negative pleomorphic bacillus b. Spread via respiratory droplets c. Highly infectious, 90% spread to unimmunised contacts d. No long term immunity from initial infection (can be reinfected) e. No chronic carriage f. Survives only several hours outside of human support g. Virulence factors i. Pertussis toxin = major virulence protein  can induce histamine sensitivity, insulin secretion, leukocyte dysfunction; Causes lymphocytosis by rerouting lymphocytes to remain in circulating blood pool ii. FHA, agglutinogens, pertactin  important in attachment iii. Tracheal cytotoxic, adenylate cyclase and PT = inhibit clearance of organism and cause local tissue damage  loss of protective respiratory cells  microaspiration and cough 2. Epidemiology a. Pre vaccination: pertussis was the LEADING cause of death due to communicable disease in US children b. Vaccine has led to > 99% decline in infection c. Since vaccine introduction, ongoing steady rise in incidence ?cause

Answer 87

3. Clinical features a. Incubation 1-3 weeks, typically 7-10 days i. Patients are infectious just prior to and for 21 days after the onset of the cough if untreated b. Classic progression i. Catarrhal phase = 1-2 weeks of nonspecific symptoms = congestion, rhinorrhoea, conjunctivitis ii. Paroxysmal phase 1. Paroxysmal cough with inspiratory whoop 2. Post-tussive vomiting or apnoea 3. May be complicated by pneumonia, seizures, encephalopathy 4. Can last for 2-8 weeks iii. Convalescent phase c. Can also present as non-specific persistent cough d. Other family members frequently also have a cough (>70% of household contacts also infected) e. Classic stages not seen in infants: catarrhal fever can be short/ absent. Paroxysmal phase: gagging, gasping, apnoea, vomiting, cyanosis, bradycardia. f. Signs of lower respiratory tract disease are NOT seen unless there is a complicating secondary pneumonia 4. Complications a. Apnoea b. Seizures c. Refractory pneumonia 5. Investigations a. Clinical diagnosis i. Consider in predominant cough (esp if fever/ myalgia/ exanthema LRT findings are absent) ii. Cough > 14 days duration with associated paroxysms/ whoop/ post-tussive vomiting can be used iii. Children < 3 months with gagging, gasping, apnoeas, cyanosis, BRUE b. Investigations i. Laboratory confirmation not necessary for diagnosis, but may be helpful for infection control ii. NPA PCR is the investigation of choice – usually negative after 21 days or 5-7 days after antibiotics iv. FBE = lymphocytosis v. CXR = normal or show subtle abnormalities

Answer 88

6. Management a. Admit any infants < 3 months of age b. Antibiotics = reduce infectivity, but not great evidence that alter course of disease i. Indication 1. Diagnosed in catarrhal or early paroxysmal phase (may reduce severity) 2. Cough <14 days (may reduce spread, reduces school exclusion) 3. Admitted to hospital 4. Pneumonia, cyanosis, apnoea ii. Antibiotics 1. Neonates = azithromycin 10 mg/kg 5 days 2. Children = clarithromycin liquid for 7 days, OR azithromycin for 5 days 3. If macrolides contraindicated – Bactrim for 7 days c. Control of diagnosed case = Isolate until 5 days of abx taken OR coughing > 21 days (respiratory isolation) d. Prophylaxis for contacts i. Prophylaxis is aimed at preventing spread to infants <6 months ii. There is little evidence that antibiotics prevent transmission outside of household settings, and side effects (especially gastrointestinal) are relatively common iii. Transmission requires close contact (exposure < 1m for > 1 h) but can be less for young infants iv. Most school-aged children who are fully vaccinated and do not have symptoms do not require prophylaxis v. Management of immunodeficient contacts should be made on a case by case basis vi. Indications for prophylaxis 1. Close contact while infectious, AND 2. First contact within 14 days, AND 3. Child – age <6 months, <3 doses of pertussis, household member <6 months, attend childcare with children <6 months 4. Adults – expectant mother, HCW, childcare worker, household member <6 months 7. Vaccination a. Acellular vaccine – less side effects than whole cell pertussis (local reactions, fever, anorexia) b. Indications i. Current schedule 1. 2, 4 and 6 months 2. 18 month booster 3. 10-15 year booster ii. Persons in contact with infants or others at increased risk from pertussis 1. Women who are pregnant or post-partum – given during 3rd trimester a. More effective when given DURING pregnancy 2. Other household contacts and carers of infants <6 months 3. Healthcare workers c. Effectiveness i. Clinical efficacy thought to be 80-85% ii. Immunity tends to wane 3-5 years after vaccination, becomes unmeasurable after 12 years iii. Disease can still occur in those who are immunised, but is generally less severe

Answer 89

1. Microbiology a. Gram negative diplococcus, aerobic b. 13 known serogroups - A, B, C, W135 and Y responsible for bulk of disease c. Encapsulated d. Nasopharyngeal commensal, spread via respiratory droplet e. Predisposition to invasive disease is not understood f. Virulence factors i. Pili/fimbria = attachment ii. Opacity proteins (OpA, OpaB, OpaD) = attachment iii. Lipo-oligosaccharide = stimulates cytokines, activating coagulation and bleeding after binding to toll like receptors (TLR4 particularly) - hence petechiae iv. Capsular polysaccharide = physical defence which resists phagocytosis v. Factor H binding protein = down-regulates complement g. Serotypes i. A type – developing countries, most common in Sub Saharan Africa (meningitis belt) ii. B type – increasing in prevalence iii. C type – decreasing since introduction of vaccination iv. W-135 – commonest in developing countries – outbreaks in Australia v. Y type – uncommon outside the USA 2. Epidemiology a. Nasopharyngeal commensal (10% of the population) b. Two peaks of disease i. < 2 years ii. Teenage years (related to kissing etc) c. Seasonal trend in Australia, prominent in winter/spring d. Serotype distribution 3. Risk factors a. Immunodeficiency i. Complement deficiency (5-10,000x risk) – more likely to have recurrence ii. Current or future treatment with eculizumab (Mab against C5) iii. Functional or anatomic Asplenia iv. HIV v. HSCT b. Other = military, university students, indigenous

Answer 90

4. Clinical features a. Incubation = 2-10 days (commonly 3-4 days) b. Onset of disease usually occurs between a few days to a week of organism acquisition c. Meningococcal disease = severe sepsis i. Rapid onset of symptoms (usually) ii. Signs of sepsis iii. Fever, leg pain, altered conscious state (late) iv. Neck stiffness, headache, photophobia, bulging fontanelle (late sign>12 hours) v. Rash: petechiae, purpura (late sign > 12 hours) vi. Complications of severe sepsis 1. Diffuse adrenal haemorrhage (Waterhouse-Friderichsen syndrome) 2. Renal failure, DIC, acidosis d. Meningitis i. 5-10% of children have deafness ii. Seizures and focal signs occur less frequently than in strep/haemophilus meningitis e. Myocarditis f. Pneumonia g. Arthritis – often immune complex mediated 5. Investigations a. Blood culture – prior to antibiotics if possible b. Blood PCR for meningococcal c. CSF – for Gram stain and PCR  only if no contra-indications

Answer 91

6. Management a. Antibiotics i. Ceftriaxone (CNS penetrance) ii. Given immediately – if no IV access within 15 minutes give IM or IO iii. Antibiotics usually continued for 5-7 days b. Other i. Dexamethasone – benefit NOT established in meningococcus meningitis (but is part of empiric meningitis management) ii. Screen for complement deficiency after recovery c. Isolation i. Keep child in droplet precautions for 24 hours after starting therapy d. Prophylaxis i. Prophylaxis should be given to contacts as soon as possible ii. Close household, intimate, and childcare contacts within 7 days prior to disease onset iii. Healthcare workers exposed to respiratory secretions (e.g. intubation without PPE) iv. Antibiotics 1. Infants < 1 month = rifampicin Q12H for 4 doses 2. Children > 1 month = rifampicin Q12H for 4 doses, OR ciprofloxacin single dose 3. Adults = ciprofloxacin single dose 4. Pregnant or contraindication to rifampicin = ceftriaxone IM single dose 7. Outcome a. Overall mortality rate is 5-10%, 10-30% have permanent sequelae b. Myocarditis present in > 50% of patients who die of meningococcal disease 8. Vaccines a. Vaccines available i. Monovalent meningococcal C vaccine (MencCV) – previously on vaccine schedule ii. Quadravalent meningococcal vaccine – ACYW135 iii. MenB vaccine – meningitis B 1. Prophylactic paracetamol recommended due to increased risk of fever b. Current schedule i. Meningogoccal ACYW135 – 12 months c. Indications for others i. MenB = recommended for infants and young children <2 years AND adolescents 15-19 years – however not currently part of the schedule

Answer 92

1. Microbiology a. Gram negative rods b. Aerobic + facultative anaerobic growth c. Various subtypes = salmonella Dublin, s. choleraesuis, s. enteriditis d. Can be killed by heating > 54.4 degrees for one hours AND by gastric pH < 2.0 e. Contain somatic O antigens + flagellar H antigens f. Common virulence factors i. TTS-1 = mediates invasion of intestinal epithelium ii. TTS-2 = mediates survival within macrophages iii. Lipopolysaccharide and flagellin: trigger toll like receptors -> inflammatory response 2. Epidemiology a. Incidence of disease proportional to hygiene, sanitation b. Increasing drug resistance seen – possibly due to farming practice 3. Risk factors a. Neonates b. HIV/AIDS or other immunodeficiency – especially IL-12 c. Malignancies d. Haemolytic anaemia – including sickle cell disease, malaria e. IBD, collagen vascular disease f. Use of antacids

Answer 93

4. Clinical features a. Enteritis i. Incubation period of 6-72 hours ii. Inflammatory enteritis – nausea, vomiting, abdominal pain, mild to severe watery diarrhoea, sometimes containing blood and mucous iii. Usually resolves after 2-7 days b. Bacteremia i. Occurs in 1-5% of patients with salmonella diarrhoea ii. Usually have risk factors c. Extraintestinal infections = skeletal system, meninges, intravascular sites d. Associations with underlying illness i. Reactive arthritis (HLA B27 +ve individuals) ii. Osteomyelitis (sickle cell disease) iii. Overwhelming bacteria ad multi-organ failure (HIV) iv. Toxic megacolon (IBD) 5. Investigations a. Largely based on stool culture - PCR not well established yet 6. Treatment a. Antibiotics NOT recommended for uncomplicated salmonella  can suppress normal flora and prolong excretion, increase risk of chronic carrier state [eTG] b. Recommended in i. Neonates and children <3 months ii. Children aged between 3 and 12 months who are febrile or toxic iii. Patients of any age with severe illness, sepsis or bacteraemia; prosthetic vascular grafts; or haemoglobinopathies iv. Patients of any age who are immunocompromised. c. Azithromycin OR ciprofloxacin 7. Prognosis a. Most recover fully - shed for 5 weeks (median), some children chronic carriers

Answer 94

1. Aetiology a. Salmonella typhi b. Salmonella paratyphi A, B and C – less common 2. Microbiology a. Polysaccharide capsule Vi present in 90% of S. Typhi b. Spread from infected human to human only – has lost ability to cause transmissible disease in animals c. Different to nontyphoid salmonella i. Expresses virulence factors that downregulate host inflammatory response initially ii. Enters via M cells/paracellularly d. Enters the blood stream (first phase of bacteremia asymptomatic) -> seeds in reticuloendothelial system (liver, spleen, gall bladder, bone marrow) e. Replication in macrophages and secondary bacteremia -> clinical symptoms 3. Epidemiology a. Cause more than 200,000 deaths/year b. Mostly affects travellers

Answer 95

4. Clinical features a. Incubation 7-14 days (but can range from 3-30 days) b. Key features i. High grade fever, myalgia, abdominal pain, hepatosplenomegaly, anorexia ii. Diarrhoea may be followed by constipation iii. Maculopapular rash (rose spots) – visible day 7-10 c. Characteristic progression i. Week 1 = fever (100%), abdominal pain, constipation OR diarrhoea (60%), headache, dry cough (30%), malaise, myalgia, epistaxis (25%), delirium ii. Week 2 = fever plateaus, symptoms progress, abdominal distension, delirium/neuropsychiatric iii. Week 3 = symptoms progress, complications (intestinal perforation, intestinal hemorrhages, sepsis, myocarditis, abscesses) d. Examination features i. Relative bradycardia ii. Abdominal tenderness (60%) iii. Hepatosplenomegaly (<40%) iv. Rose spots (20%) 5. Complications a. Hepatitis b. Intestinal haemorrhage/perforation c. Toxic myocarditis d. Delirium/psychosis e. Acute cerebellar ataxia f. Chorea g. Deafness h. GBS 6. Diagnosis a. Based on culture: blood/stool/urine b. Other tests are non specific – leuckocytosis, thrombocytopenia c. Antibody and PCR tests in development d. WCC usually normal or low

Answer 96

Not specific to children Classic reports described the characteristic stages of enteric fever in untreated individuals [34]. In the first week of illness, rising ("stepwise") fever and bacteremia develop [35]. While chills are typical, frank rigors are rare [17]. Relative bradycardia or pulse-temperature dissociation may be observed. In the second week of illness, abdominal pain develops and "rose spots" (faint salmon-colored macules on the trunk and abdomen) may be seen (picture 1). During the third week of illness, hepatosplenomegaly, intestinal bleeding, and perforation due to ileocecal lymphatic hyperplasia of the Peyer's patches may occur, together with secondary bacteremia and peritonitis. Septic shock or an altered level of consciousness may develop; among 300 cases of typhoid fever in Indonesia, these findings were observed in approximately 15 percent of patients [36]. In the absence of acute complications or death from overwhelming sepsis, symptoms gradually resolve over weeks to months.

Answer 97

7. Treatment a. Hydration + antipyretic therapy b. Antibiotic i. PO = azithromycin OR ciprofloxacin (if confirmed susceptibility) ii. IV = ceftriaxone c. RESISTANCE seems to be developing: plasmid mediated resistance seen to ampicillin, chloramphenicol, Bactrim d. Note that fevers continue on appropriate antibiotics for 5-7 days; but the patient will clinically improve 8. Prognosis a. 2-4% children relapse despite initial response to therapy b. <2 % become carriers, excrete for > 3 months 9. Prevention a. Public health measures – sanitation of water, treatment of sewage b. Typhoid vaccine: withdrawn due to high rates of side effects

Answer 98

1. Species a. S. dysenteriae (serogroup A) b. S. flexneri (serogroup B) c. S. boydii (serogrup C) d. S. sonnei (serogroup D) e. Species vary in geographic distribution and antibiotic susceptibility 2. Microbiology a. Gram negative rod b. Facultative anaerobe c. Non-spore forming d. Closely related to E. coli e. Easily transmitted from person to person as inoculum is low f. Virulence factors iv. Some species produce toxin: Shiga toxin and enterotoxins 3. Epidemiology a. Cause of > 1 million deaths/year b. Most common in 2-3rd years of life, 60% of deaths involve children <5 years c. Infection rare in first six month of life ?breast feeding protective d. Spread via contaminated food and water 4. Clinical features a. Dysentery i. Incubation 12 hours – several days ii. Severe abdominal pain, high fever, emesis, painful defecation iii. Small volume, bloody stools b. Neurologic features can occur c. SIADH d. HUS = mediated by Shiga toxin 5. Diagnosis a. Culture of stool = WBC + RBC b. PCR not routinely available 6. Treatment a. Treatment reduces disease transmission b. Treatment recommended for i. Children <6 years ii. People are who are institutionalized iv. Immunocompromised c. Empiric therapy = ciprofloxacin OR Norfloxacin OR Bactrim d. Quinolone resistance is increasing – if concerned = azithromycin e. 5 day course generally recommended

Answer 99

1. Microbiology a. Gram negative bacillus b. Difference in O antigen lead to >150 serogroups - serogroup O1 and O139 result in cholera c. Humans the only known hosts 2. Pathogenesis a. Colonize the small intestine and produce cholera toxin b. Toxin leads to increased chloride secretion by crypt cells -> reduced absorption of sodium and chloride by microvilli -> isotonic fluid is loss through GIT c. Cholera toxin does NOT produce intestinal inflammation 3. Epidemiology a. Now endemic in sub-Saharan Africa, South and southeast Asia b. Rarely seen in Australia c. Few cases seen through ingestion of contaminated water d. Mostly acquired from overseas 4. Risk factors a. Blood group O b. Decreased gastric acidity c. Malnutrition d. Immunocompromised 5. Clinical manifestations a. Diarrhoea disease = painless, profuse watery diarrhoea b. Consequences i. Metabolic acidosis due to loss of bicarbonate ii. Leads to severe dehydration, hypokalemia and hypoglycaemia 6. Diagnosis a. Based on isolation of organism from stool/vomit/rectal swabs b. Note stool will NOT have leukocytes as there is no inflammation 7. Treatment a. Hydration first priority b. Antibiotics – azithromycin OR ciprofloxacin c. Zinc supplementation – shown to shorten duration of diarrhoea and reduce subsequent diarrhoea episodes when given daily for 14 days at time of illness 8. Vaccination a. Oral cholera vaccine available b. Not recommended as the risk to travellers is very low - despite the endemicity of cholera in some countries often visited by Australians (food and water better than vaccine) i. Only considered if increased risk OR humanitarian worker etc.

Answer 100

1. Microbiology a. Campylobacteriacae family b. Multiple species pathogenic for humans – most commonly jejuni c. Gram negative non spore forming rods 2. Epidemiology a. Usually acquired from contaminated poultry/raw milk, farm animals b. Peak in early childhood, then again in 15-44 year age group 3. Clinical manifestation a. Gastroenteritis i. Dysentery type picture, blood often appears in stools 2-4 days after onset of sx ii. Most recover after 1-2 weeks b. Bacteremia i. Mainly occurs in malnourished children, chronic illness and immunodeficiency c. Focal extraintestinal infections i. Rare ii. Mainly in neonates/immunocompromised patients iii. Include = meningitis, pneumonia, thrombophlebitis, pancreatitis, UTI etc. d. Perinatal infections = can occur rarely 4. Treatment a. Antibiotic therapy indicated in severe or prolonged cases, during pregnancy, in immunocompromised people and in infants (NO good guidelines) b. If given = azithromycin OR ciprofloxacin OR Norfloxacin c. Incidence of macrolide and quinolone resistance increasing 5. Complications a. Strong association with GBS i. ?molecular mimicry between C. jejuni and GBS + Miller Fisher variant ii. Estimated rate of 1/3000 C. jejuni infections, stool culture +ve in > 25% of cases b. Reactive arthritis i. Typically migratory involving large joints and resolve without sequelae ii. More likely in HLA B27 +ve patients iii. 5-40 days after onset of diarrhoea c. Erythema nodosum (erythematous, tender nodules on the shins) d. Irritable bowel syndrome

Answer 101

• From family of Enterobacteriaceae • 3 human pathogens: Yersinia enterocolitica, pseudotuberculosis, yersinia pestis o Yersinia pseudotuberculosis = causes mesenteric lymphadenitis, appendicitis like symptoms  8% cases associated with Kawasaki like syndrome o Yersinia pestis = causes plague like syndrome • Can colonize pets

Answer 102

1. Microbiology a. Large gram negative coccobacillus b. Facultative anaerobe c. Transmitted via food, water, animal contacts + vertical d. Usually foodborne e. Pathogenic strains require iron 2. Epidemiology: a. 1/100,000 culture confirmed infection per year b. Affects mostly children < 7 years c. Increased in patients with haemochromatosis, thalassemia, sickle cell disease 3. Clinical features a. Spectrum of disease i. Acute enterocolitis = most common 1. Diarrhoea, fever, abdominal pain 2. Stool may be watery and contain leukocytes, less commonly blood ii. Mesenteric adenitis = more common in older children and adolescents iii. Pharyngitis with or without diarrhoea b. Septicaemia less common, can be complicated by abscess, endocarditis, mycotic aneurysms 4. Diagnosis a. Faecal spec: leukocytes, frank blood and mucous b. Can be cultured in stool for 1-4 weeks c. PCR more sensitive than culture 5. Treatment a. Benefit has not been demonstrated b. Not treated unless immunocompromised or patients with persistent or extra-intestinal disease c. If being treated = ciprofloxacin OR Norfloxacin OR Bactrim d. Bacteraemia treated with prolonged course of ciprofloxacin (3 weeks) 6. Complications a. Post-infectious complications can occur i. Reactive = erythema nodosum, arthritis, uveitis b. Has been associated with Kawasaki disease – some superantigen behaviour

Answer 103

1. Microbiology a. Facultative anaerobic, gram negative bacilli ``` EPEC (enteroPathogenic) - Syndrome: infantile diarrhoea - Non-specific gastro (nausea, vomiting) - Attachment and effacement of the intestinal lining <2 years old - Children in LDCs - 20-30% of infant diarrhoea ETEC (enteroToxigenic) - Syndrome: watery diarrhoea - Explosive watery, non-mucoid, non-bloody diarrhoea - Usually without fever - Self resolves in 1 week - Toxin production: Heat-labile enterotoxin (LT). Heat-stable enterotoxin (ST) - >1 year old and travelers - 10-30% of infant diarrhoea EHEC - Syndrome: HUS and haemorrhagic colitis - Bloody diarrhoea - 5-10% develop HUS - Produces Shiga toxin (shigella producing E. coli = STEC) - Any age; developed countries EIEC (enteroInvasive) - Syndrome: dysentery - Direct invasion - >1 year old - Any age; mainly in LDCs - Usually occurs in outbreaks EAEC (enteroAggregative) - Syndrome: persistent diarrhoea pts with HIV - Watery diarrhoea - Can persist for >14 days - Results in a biofilm on intestinal mucosa, inducing villi shortening and inflammatory changes - Children in LDCs ``` 2. Clinical manifestations a. As above, plus: e. Extra-intestinal i. UTI ii. Neonatal meningitis iii. Septicaemia iv. Wound infection v. Peritonitis vi. Pneumonia 3. Diagnosis a. Culture/ PCR b. Subtype based on identifying specific virulence factors / genotyping 4. Treatment a. Infection with Shiga toxin–producing strains of Escherichia coli (eg 0157:H7 or 0111:H8) may cause bloody diarrhoea and lead to the development of haemolytic uraemic syndrome (HUS) or TTP, particularly in children b. Antibiotic therapy should not be given to children with EHEC who do not have fever or sepsis, as antibiotics appear to increase toxin release and therefore the risk of developing HUS

Answer 104

1. Microbiology a. Gram negative rod, strict aerobe b. Virulence factors i. Exotoxins = cause local necrosis and bacterial invasion ii. TTSS = inserts into host cell membranes, secretes exotoxins directly into cells iii. Formation of biofilms (communities of bacteria encased in an extracellular matrix) -> requires production of an exopolysaccharide to form the matrix, makes more resistant to many antimicrobials 2. Epidemiology a. Tends to cause disease in susceptible patients only: immunosuppressed/neutropenic/impaired mucociliary transport/trauma b. Rate of bacteraemia in children 3.8/1000 patients, 20% mortality rate (Nelsons) c. Colonization following prolonged hospitalisation up to 50-70% 4. Treatment a. Antibiotics active against pseudomonas i. Aminoglycosides ii. Quinolones iii. Cephalasporins – ceftazadime, cefepime (NOT ceftriaxone/cefotaxime) iv. Anti-pseudomonal penicillins – timentin, piptaz v. Carbapenins vi. Polymyxins (polymyxin B and Colistin) 5. Mechanisms of resistance = production of beta-lactamases, drug efflux pumps

Answer 105

a. Skin = characteristic lesion ecthyma gangrenosum – pink macules that progress to haemorrhagic nodules, eventually to ulcers with gangrenous centres with eschar formation surrounded by intense red areola b. Pneumonia i. Abnormal ciliary function (CF) or immune deficiency ii. Colonisation with mucoid subtype associated with morbidity and mortality iii. Can cause nosocomial pneumonia, especially ventilatory related c. Otitis externa i. Swimmer’s ear, humid warm climate ii. Malignant otitis externa – invasive, indolent, febrile toxic destructive lesion in young infants, immunosuppressed, diabetics iii. +/- 7th nerve palsy and mastoiditis d. UTI = suspect if stone/obstruction or IDC related e. GIT i. Immunocomprimised, neutropenia ii. Typhlitis, rectal abscess, ulceration iii. Peritonitis in PD f. Disseminated infection g. Opportunistic infection i. Endocarditis with IVDU ii. CNS infection with trauma, surgery, spread from OM/mastoid etc iii. Contact lens keratitis iv. Endophthalmitis – penetrating injury, trauma v. OM/Septic arthritis – Fracture/surgery/puncture wounds vi. Wound infection – burns, trauma, etc.

Answer 106

1. Microbiology a. Gram negative rod b. Aerobic c. Enterobaceriaecae family 2. Clinical manifestations a. Systemic i. Meningitis/brain abscess ii. Bacteremia iii. Infective endocarditis b. Respiratory i. Nosocomial pneumonia ii. Community acquired pneumonia iii. COPD with secondary infection iv. Lung abscess v. Empyema c. Genitourinary i. Catheter related bacteremia ii. Cystitis & pyelonephritis iii. Renal & perinephric abscess d. GIT i. Liver abscess ii. Splenic abscess iii. Spontaneous bacterial peritonitis e. Cellulitis 3. Treatment a. Dependent on sensitivities

Answer 107

* Gram negative aerobic rods * Bartonella species known to cause disease in humans = B. bacilliformis, B. quintana, and B. henselae Bartonella henslae : 1. Key points a. Common – most have had contact with cats, more common with kittens and known bite / scratch b. Cat scratch disease 2. Clinical manifestations a. Subacute regional lymphadenitis (most commonly) b. Occurs after incubation period of 7-12 days c. 3-5 mm red papules develop at site of inoculation d. Chronic regional lymphadenitis develops i. Axillary / cervical/ submandibular/ preauricular/ epitrochlear/ femoral or inguinal ii. Nodes are tender with overlying erythema but no cellulitis e. Enlarged for 1-2 months 3. Rare presentations = conjunctivitis, hepatosplenomegaly, osteolytic lesions a. Hepatosplenomegaly is an important rare manifestation b. Parinaud oculoglandular syndrome i. 2-8% of patients with CSD (cat scratch disease) ii. Tender regional lymphadenopathy in cervical lymph nodes associated with conjunctival infection (or eyelid/adjacent skin) c. Neuroretinits i. 1-2% of patients with CSD ii. Acute visual loss from optic nerve oedema associated with macular exudates iii. Fever, malaise, and unilateral blurred vision 4. Diagnosis = tissue specimens or serial serology antibody titres 5. Treatment a. Usually self-limiting – most cases do not require treatment b. Indication = immunocompromised patients with unresolved lymphadenopathy (>1 month), lymphadenopathy with morbidity, or systemic organ involvement (liver or eye), or endocarditis c. Antibiotics = azithromycin 6. Complications a. Encephalopathy b. Retinopathy c. Haematological manifestations

Answer 108

Gram-negative facultative anaerobic β-hemolytic coccobacilli a. Part of nasal flora passed from child to child b. Increasingly recognized as the most common aetiology of bone and joint infections in young children – 6 months to 3 years of age c. Other infections = bacteraemia, endocarditis d. Diagnosed by isolation of bacterium or PCR +ve e. Need to consider diagnosis in infant with osteomyelitis who does not respond to flucloxacillin f. Often have normal lab results, an ESR/CRP not particularly elevated g. Blood cultures often negative h. Antibiotic = ceftriaxone (augmentin)

Answer 109

a. Cepacia i. Filamentous gram negative rod ii. Environmental pathogen, mainly seen in CF, CGD iii. Virulence factors – lipopolysaccharide, TTSS (invasion factor) iv. Antibiotic (depends on susceptibility) = ceftazidime, ciprofloxacin, Bactrim, tazocin and meropenam are options b. Mallei (glanders) i. Non motile gram negative bacillus ii. Horse pathogen, occasionally transmitted to human iii. Septicaemia, acute/chronic pneumonitis and haemorrhagic lesions of the skin iv. Treatment = sulfadiazines, tetracyclines, chloramphenicol, streptomycin c. Pseudomallei (meliodosis) i. Inhabitant of soil and water; occurs in NT ii. Infection follows inhalation of dust/ direct contamination of abrasions/ wounds iii. Presentations include: 1. Primary skin lesion – vesicle/ bullae/ urticarial 2. Pulmonary infection 3. Septicaemia iv. Treatment = ceftazadime or meropenem

Answer 110

a. Aerobic gram negative bacilli, non-spore forming b. Facultative intracellular parasites of eukaryotic cells c. Found in water -> risk factors: exposure to cooling towers, residential plumbing repairs d. Clinical manifestations i. Pneumonia (not necessarily atypical) ii. Pontiac fever = fever, myalgia, headache  self-limiting disease associated with legionella seroconversion e. Diagnosis i. Culture/PCR from sputum/respiratory tract/blood ii. Urinary antigen assay f. Treatment = azithromycin OR doxycycline

Answer 111

a. Gram negative bacillus, ubiquitous b. Mainly seen in patients with CF (otherwise can represent colonization) c. Bactrim treatment of choice

Answer 112

a. Aerobic, non-spore forming coccobacilli b. Zoonotic disease, either from life stock / unpasteurized milk products c. Infection occurs through breaches in skin / eye/ inhalation d. Clinical manifestation i. Often presents with PUO ii. Nonspecific, long incubation period  fever, abdominal pain, hepatosplenomegaly, arthritis e. Diagnosis = requires culture, which can take up to 4 weeks f. Treatment = doxycycline, bactrim

Answer 113

a. Gram negative bacillus, aeromonadaceae family b. Infections usually associated with contaminated water c. Causes enteritis, skin and soft tissue infections d. Usually self-limited, does not require abx  can be treated with 3rd gen cephalosporin/ aminoglycoside

Answer 114

a. Gram negative bacillus – facultative anaerobic non spore forming b. Family enterobacteriaceae family c. Found in fresh water d. Thought to cause diarrhoeal illness (not dysentery ) e. Extraintestinal infections rare f. Usually self-limited

Answer 115

Staphylococcus | Streptococcus

Answer 116

``` Bacillus Clostridium Corynebacterium Listeria Actinomyces Norcardia ```

Answer 117

1. Key points a. Protein produced by gram positive bacteria, most commonly staph and strep b. Work in very small concentrations – can trigger immune reaction (eg without septicaemia) 2. Toxin-Mediated Diseases a. Toxic shock syndrome b. Kawasaki disease c. Eczema exacerbations d. Psoriasis e. Does not cause – ARF, scarlet fever, SSSS 3. Pathogenesis a. Superantigen toxin allows the binding of MHC class II with T cell receptors resulting in polyclonal T cell activation - does NOT require processing by antigen presenting cells d. Results in overwhelming cytokine release 4. Clinical manifestations a. Fever b. Rash – sunburnt erythematous rash, blanching c. Conjunctivitis d. Mucous membrane changes e. Hypotension f. End organ damage 5. Management a. Resuscitation b. Remove source if relevant c. Antibiotics = flucloxacillin (has reasonable strep cover) / Vancomycin d. Clindamycin i. Toxin inhibition – this is immunomodulatory, inhibits toxin production AND host protein synthesis ii. Eagle effect – when bacteria reach stationary phase (not dividing as much), harder for penicillin to act as no PBP to act on (penicillin kills during dividing stage)  clindamycin overcomes this effect e. IVIG

Answer 118

``` STAPH Age: 15-35y Sex: Females Local invasive disease: Absent Generalised erythroderma: Present N,V,D: >90% Bacteraemia: Uncommon Toxins implicated: TSST1 Mortality: 3.3% Other: Rash more likely to desquamate (particularly hands and soles (day3-7), hepatic damage, thrombocytopaenia ``` ``` STREP Age: 20-50y Gender: Males + females Local invasive disease: Present Generalised erythroderma: Absent N/V/D: Uncommon Bacteraemia: 60% of patients Toxins: Streptococcal pyrogenic exotoxins A and B Mortality: 30% Other: ARDS, coagulopathy ```

Answer 119

1. Pathogenesis a. TSST1 – produced by Staphylococcus aureus b. Superantigen which activates large number of T cells causing cytokine production 2. Epidemiology a. Menstruating women 15-25 years – tampons or vaginal devices b. Other focus of Staph infection eg. Wound infection, OM, abscess, burns, tracheitis, pneumoniae etc. c. Mortality despite treatment 3-5% d. 30% recurrence if untreated and ongoing source of infection (tampon, local) 3. Clinical manifestations a. High fever b. Vomiting + diarrhoea c. Sore throat, headache, myalgias d. Diffuse, erythematous macular rash e. Hyperemia of pharyngeal, conjunctival, vaginal mucous membrane f. Strawberry tongue 5. Investigations a. Blood cultures – usually negative 6. Complications a. ARDS, myocardial dysfunction, renal failure b. Recovery is associated with desquamation 7. Treatment a. Anti-staphylococcal antibiotic i. Clindamycin + flucloxacillin (or vancomycin if MRSA suspected) b. Remove tampon / source c. Fluid replacement d. IVIG

Answer 120

a. Fever = T>38.9 b. Hypotension = SBP <90 mmHg c. Rash = Diffuse macular erythema d. Desquamation (specially palms and soles) 1-2 weeks after onset e. Multisystem involvement = 3 or more i. Gastrointestinal – vomiting, diarrhoea ii. Muscular – severe myalgia or CK elevation iii. Mucous membrane hyperaemia – vaginal, oral, conjunctival iv. Kidney failure v. Liver failure vi. Thrombocytopaenia vii. CNS involvement (confusion) f. Negative results i. Blood, urine and CSF cultures for other bacteria (apart from S aureus) ii. Negative serology for Rickettsia infection, leptospirosis and measles

Answer 121

1. Key points a. Characterised by multi-organ failure 2. Risk factors a. Minor trauma b. Use of NSAID c. Recent surgery d. Viral infection e. Post-partum 3. Pathogenesis a. GAS releases exotoxins that act as super-antigens b. Group B, C an G have also been associated with toxic shock syndrome 4. Diagnostic criteria a. Isolation of GAS from normally sterile site b. Hypotension c. 2 or more of i. Renal dysfunction ii. Coagulopathy – thrombocytopaenia, DIC iii. Liver dysfunction iv. ARDS v. Erythematous macular rash, may desquamate vi. Soft tissue necrosis (eg. necrotising fasciitis, myositis, or gangrene) 5. Management a. Supportive – treatment of shock b. Surgical debridement of focus c. Antibiotics = high dose IV benpen + clindamycin d. IVIG 6. Prognosis a. Lower rate of mortality in children b. Higher mortality rate than staphylococcal toxic shock syndrome 7. Contact prophylaxis a. Done at RCH

Answer 122

1. Microbiological features a. Aerobic b. Gram positive c. Grow in in pairs and clusters d. Catalase +ve 2. Classification a. Coagulase positive -> Staphylococcus aureus i. Many virulence factors that mediate serious disease b. Coagulase negative -> Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus haemolyticus etc i. Less pathogenic unless indwelling foreign material eg. central line 3. Other points a. Part of normal human flora b. Resistant to heat and drying c. S. aureus produces a yellow or orange pigment and beta-haemolysis on blood agar d. S. epidermidis produces a white pigment with variable haemolysis

Answer 123

1. Key = causes infections in patients with indwelling foreign devices 2. Microbiology a. Normal skin flora = Staph epi consists 65-90% of staph present on skin, mucous membranes b. Exopolysaccharide protective biofilm / slime layer  enhances adhesion, resists phagocytosis 3. Clinical manifestations a. Bacteremia (usually nosocomial) – present in neonates with apnoea & bradycarida, tempearture instability, abdominal distention, meningitis, abscess, +ve blood cultures b. Endocarditis c. Line infection d. CSF shunt infection e. UTI – post-transplant/ urinary catheterization 4. Treatment a. MOST RESISTANT TO FLUCLOXACILLIN b. Vancomycin c. Remove infected device d. Other antibiotics with activity: i. Linezolid ii. Teicoplannin iii. Clindamycin iv. Bactrim

Answer 124

1. Epidemiology a. 20-40% of normal individuals carry 1 strain of S. aureus 2. Risk factors a. Congenital defects in chemotaxis i. HyperIgE ii. Chediak Higashi syndrome iii. Wiskott Aldrich b. Defective phagocytosis and killing i. CGD ii. Neutropenia 3. Pathogenesis a. Many enzymes and proteins which enhance virulence b. Exotoxins i. Exfoliatin  SSSS 1. Produce localized/ generalized dermatologic complications: split the desmosome, alter intracellular matrix in the stratum granulosum ii. Enterotoxins (A/ B/C1/C2/ D/E)  Food poisoning 1. Enterotoxin A and B may be associated with nonmenstural TSS iii. Toxic shock syndrome toxin (TSST-1)  Toxic shock syndrome 1. Found in 20% of staph aureus isolates 4. Clinical manifestations a. Skin and soft tissue infections = cellulitis, impetigo b. Muscle = pyomyositis c. Bone and joint infections = OM, septic arthritis  most common cause d. Respiratory tract infections = pneumonia, empyema, tracheitis i. Often necrotising with pneumatocele, pyopneumothorax e. Bacteraemia f. Endocarditis, pericarditis g. Rarely meningitis without risk factors eg. shunt h. Toxin mediated disease i. Food poisoning – due to enterotoxin A and B, not superantigen ii. Staphlycoccal scarlet fever – not superantigen iii. Scalded syndrome – not superantigen iv. Toxic shock syndrome – due to toxic shock syndrome toxin 1 - superantigen ``` 6. Treatment (MSSA) • Flucloxacillin – first line • Cephalexin – alternative oral agent • First generation cephalosporin: cephazolin , cephalexin • Bactrim • Augmentin • Clindamycin – bacteriostatic (MRSA) • Tetracycline • Glycopeptide – vancomycin, teicoplanin • Clindamycin • Bactrim • Daptomycin • Linezolid ```

Answer 125

1. Microbiological features a. Cocci b. Form strips c. Catalase negative (cf. staph which is catalase positive) 2. Classification a. MANY classification schema b. Historically classified based on haemolytic capability i. Alpha haemolytic = partial haemolyses RBC ii. Beta haemolytic = completely lyses RBCs iii. Gamma haemolytic/non-haemolytic c. Further classified by the presence of Lancefield antigens (A-S) i. Group A = Strep pyogenes ( hemolytic) – serotype 12 throat, serotype 49 skin ii. Group B = Strep agalactiae iii. Group C & D =  haemolytic (similar to strep pyogenes) iv. Group D = Enterococcus + Strep bovis and Strep equinus v. Group E and F =  hemolytic (S pneumoniae, and viridans) ``` Beta haemolytic - GAS, GBS Alpha haemolytic - pneumoniae and viridans Gamma haemolytic - enterococci (formerly group D strep) ```

Answer 126

AKA Strep pyogenes 1. Microbiology a. Gram positive cocci that grow in chains b. Antigenic cell wall components i. C carbohydrate (Lancefield group A) ii. M protein = protects organism from phagocytosis, but also the component that antibodies target c. M protein also used to serotype iii. Note immunity occurs after exposure to specific M type, but does not protect against other M types d. Enzymes i. Streptolysin O = destroys red and WBC, antigenic (inactivated by oxygen) ii. Streptolysin S = also responsible for haemolysis iii. Pyrogenic/ erythrogenic toxin = found in some strains only - contribute to scarlet fever iv. Streptokinase, hyluronidase, DNAses may also be present e. Beta-haemolytic (complete lysis) 2. Epidemiology a. Disease is neonates UNCOMMON b. Pharyngeal infections highest at 5-15 c. Invasive disease highest in very young and older persons i. Most commonly follows SKIN infection (rare post pharyngitis) ii. Risk factors = varicella infection, HIV, DM, IVDU, chronic pulmonary / cardiac disease

Answer 127

i. Strep throat/ pharyngitis 1. Serotypes 1, 2, 3, 4, 5, 12, 28M 2. >2-3years, peaks early school years, declines adolescents 3. Winter peak 4. Clinical presentation a. Rapid onset sore throat, fever, headache b. Absence of cough c. Headache, GIT syndrome (abdominal pain and vomiting) common 5. Examination a. Erythematous pharynx with enlarged tonsils + yellow exudate b. +/- petechiae over palate, uvula may be swollen c. Cervical LN large and tender ii. Skin infections 1. Folliculitis, cellulitis, impetigo (not distinguishable from staph infections) 2. Erysipelas = rare acute GAS infection involving deeper layers of the skin 3. Perianal dermatitis = well-demarcated perianal erythema with anal pruritus, painful defecation and blood streaked stools 4. Clinical features a. Bullous (neonates) – flaccid, transparent bullae <3cm on untraumatized skin, buttocks, trunk b. Non-bullous (more common) – superficial papulovesicular lesions surrounded by areas of redness, amber crust develops, most common on face and extremities iii. Necrotizing fasciitis 1. M proteins that block phagocytosis may allow bacteria to rapidly invade tissue iv. Scarlet fever 1. Syndrome of sore throat, fever and rash (trunk + neck, spares face, may be peeling) 2. Caused by strains of strep A with pyrogenic toxin 3. Rash onset 24-48 hours after onset of symptoms – sandpaper: diffuse, finely papular, erythematous, more intense along crease of the elbows, axillae and groin 4. Desquamates after 3-4 days 5. Tongue has strawberry appearance v. TSS

Answer 128

i. Rheumatic fever 1. Delayed, antibody mediated disease 2. Tends to follow group A strep pharyngitis – typically 2-6 weeks (average 3 weeks) ii. Post-strep GN 1. Can follow group A strep pharyngitis/ skin infections 2. Antigen-antibody complexes deposit in the glomeruli, activation of complement cascade iii. Post streptococcal arthritis (not reaching criteria for rheumatic fever) iv. PANDAS 1. Paediatric autoimmune neuropsychiatric disorders associated with streptococcus pyogenes 2. Obsessive compulsive disorders, tic disorders, Tourette syndrome 3. Controversial entity

Answer 129

4. Investigations a. ASOT (anti-streptolysin O titre) i. Significant result defined as increase in titre of 2 or more dilution increments between acute and convalescent titres ii. Also produced by streptococcal C and G b. Anti-DNAse 5. Treatment a. Very sensitive to penicillin b. Resistant strains have NEVER been encountered

Answer 130

AKA Strep agalactiae 1. Microbiology a. Facultative anaerobic GPC that form chains or diplococci b. Beta-haemolytic on blood agar c. Defined by presence of Lancefield group B carbohydrate antigen e. Capsular polysaccharide = main virulence factor protects organism from opsonophagocytosis f. Other virulence factors g. Four serotypes i. Some serotypes EOS -> pneumonia + septicaemia ii. Some serotypes LOS -> bacteraemia + meningitis 2. Maternal carriage a. 10-30% of women colonised b. 70% of infants born to colonised women are themselves colonised c. <0.1% of infants develop early onset GBS sepsis d. Overall transmission rate ~50% with invasion rate 1-2% i. Note if mum GBS –ve, rate 5% e. Lower intestinal organism (this is the reservoir) f. Risk factors for colonisation = diabetes, teenage, tampon use, <3 pregnancies, ethnicity g. Risk factors for transmission i. Primary risk factor is maternal GBS GU or GI colonisation 1. 50% transmission without use of intrapartum antibiotic prophylaxis 2. Urine culture positive for GBS is a marker for heavy anovaginal colonisation ii. Delivery < 37/40 iii. PROM iv. ROM > 18 hours before delivery v. Chorioamnionitis vi. Maternal fever during labour vii. Early-onset GBS disease in previous pregnancy (routine prophylaxis)

Answer 131

Strep agalactiae a. Early onset neonatal sepsis = <7 days i. 30% premature ii. Bacteraemia, pneumonia iii. Fulminant iv. Mortality 5-20% v. Maternal chemoprophylaxis ↓ incidence by 65% vii. Skin manifestations rarely occur b. Late onset neonatal sepsis = 7 days – 3 months i. Term babies ii. Bacteraemia, meningitis iii. Slowly progressive iv. Serotype III most commonly involved (> 50% ) v. Incidence not affected by maternal chemoprophylaxis c. Other infections i. UTI ii. Bacteraemia iii. Endometritis iv. Chorioamnionitis v. Wound infection

Answer 132

Strep agalactiae 4. Prevention a. >35 weeks (best correlation within 5 days) – anorectal + low vaginal b. Intrapartum antibiotic i. For premature labour / prolonged rupture of membranes ii. Shown to reduce colonization + early onset disease iii. Results in delayed and milder presentation of late onset GBS sepsis iv. Penicillin (or cephazolin / clindamycin/ erythromycin ) if allergic 5. Management algorithm a. Screen at 35-37 weeks gestation i. GBS negative – no intrapartum prophylaxis ii. GBS positive – intrapartum prophylaxis iii. GBS unknown + obstetric RF – intrapartum prophylaxis b. Obstetric factors i. Risk factors 1. Previous infant with EO-GBS 2. GBS bacteriuria 3. Spont onset of labour <37 weeks 4. ROM >=18 hours 5. Intrapartum fever >38 degrees ii. If any of the above are present intrapartum chemoprophylaxis indicated 6. Treatment a. Penicillin – including for meningitis

Answer 133

1. Examples a. Streptococcus sanguinus b. Streptococcus mitis c. Streptococcus intermedius d. Streptococcus mutans 2. Microbiology a. Alpha- haemolytic b. Normal GIT , nasopharynx + gingival flora 3. Clinical manifestations a. Dental infections b. Endocarditis c. Abscesses – largely caused by strep intermedius (look for abscess if found in blood stream)

Answer 134

Formerly group D Strep 1. Microbiology a. Gram positive, catalase negative anaerobes – grow in pairs or short chains b. Non-haemolytic / gamma haemoltyic (some have alpha or beta) c. Only cause disease if there is damaged mucosa/ impaired immune response e. Normal flora of bowel i. E. faecalis = acquired in first week of life ii. E. faecium = less common – present in < 25% 2. Clinical manifestations a. Very common nosocomial infection b. Neonatal sepsis i. Early onset infection = like GBS, often milder ii. Late onset infection = in extreme prem, lines, NEC, post intraabdominal surgery c. UTI – especially nosocomial acquired UTI d. Biliary tract infections – grow very well in bile 3. Treatment a. Ampicillin = most active beta lactam b. Vancomycin = ampicillin resistant enterococci c. Teicoplanin = VRE

Answer 135

a. Beta lactam resistance i. Intrinsic resistance to cephalosporins, aztreonam, antistaph penicillins and ticarcillin ii. Resistance to ampicillin/ penicillin / piperacillin 1. Plasmid encoded beta lactamase -> can be overcome by addition of beta lactamase inhibitor 2. Mutations in PBP 5 -> needs vancomycin/ imipenem b. Aminoglycoside resistance i. Low level resistance in all strains intrinsically due to poor transport across cell wall 1. Improved by cell wall agent (beta lactam/ glycopeptide) ii. High level resistance – modification/ inactivation of aminoglycoside agents or a ribosomal mutation c. Vancomycin resistance = Vancomycin Resistant Enterococci (VRE) i. Alteration of binding site D-alanyl-D-alanine terminus of peptidoglycan precursors ii. Encoded by cluster of genes referred to as VanA, B, D and M iii. Three major phenotypes – VanA, VanB, VAnD 1. VanA a. Most common b. Mediates higher levels of resistance than the other types c. Cross-resistance to teicoplannin d. Can disseminate t other species eg. MRSA 2. VanB a. Second most common type b. Usually teicoplanin susceptible d. Linezolid resistance i. Emerging, due to enzyme modification of ribosomal RNA target

Answer 136

1. Microbiology a. Gram positive, lancet shaped polysaccharide encapsulated diplococcus, occurring individually/in chains b. 90 capsular antigenic types c. Spread via direct contact + resp droplets d. Polysaccharide capsule protects the organism from phagocytosis e. On agar, forms a zone of incomplete alpha haemolysis f. Incubation 1-22 days 2. Epidemiology a. Invasive disease seen in young children and the elderly b. Significant reduction in disease since introduction of 7PV c. S. pneumoniae common flora in the upper respiratory tract - usually from 45 days – 6 months i. Rates of carriage peak between 1st + 2nd year of life, decline gradually thereafter ii. May cause invasive disease through spread to sinuses then blood stream d. Carriage highest during winter

Answer 137

4. High risk groups a. Children more susceptible <2 i. Increased carriage ii. Reduced ability to produce antibody  relies on T cell independent response iii. Decreased effectiveness of polysaccharide vaccines b. Other high risk groups: i. Sickle cell disease – deficient complement activation (properdin pathway) + functional asplenia ii. Asplenia – deficient opsonisation of pneumococci + spleen cannot eradicate bacteria iii. Deficiencies in humoral and complement mediated immunity iv. Acute nephrotic syndrome v. HIV infection, malignancy, chronic disease, CSF leak, cochlear implant 5. Clinical manifestations a. Pneumonia (the classic ‘round’ pneumonia, accounts for 1/3 CAP) b. Meningitis c. Bacteraemia d. URTI = otitis media, sinusitis e. Osteomyelitis (rare) f. Atypical HUS 7. Investigations a. Urinary antigen b. Blood culture – positive in 10-30% of children

Answer 138

1. Treatment a. Antibiotics i. Penicillin ii. Third generation cephalasporin iii. Clindamycin iv. Vancomycin v. Linezolid vi. Clarithromycin/erythromycin vii. Bactrim b. Antibiotic resistance i. Different breakpoints for penicillin susceptibility/ resistance for meningitis/ pneumonia 1. Higher for meningococcal ii. If resistant – vancomycin + ceftriaxone 3. Resistance a. Significant problem - 15-30% of isolates now MDR b. Has developed to beta lactams, macrolides, tetracyclines + folate inhibitors, fluoroquinolones c. Mechanisms of resistance i. Resistance to beta lactams 1. Usually alteration in PBP 2. Intermediate resistance to beta lactams (penicillins/ cephalosporins and carbapenems can be overcome by ↑ doses of antibiotic) 3. Note different breakpoints are used for CNS and LRTI ii. Resistance to macrolides and azalides 1. ermB = alters a site of attachment at RNA level 2. mefA = encodes a pump that expels macrolides iii. Resistance to fluoroquinolone tends to be spontaneous (rather than by clonal spread) 1. Mutations in gyrA/ parC cose altered binding site iv. Capsular switching can also occur 4. Prevention a. Prevenar 13 = pneumococcal CONJUGATE vaccine i. Provides T cell immunity, reduces nasopharyngeal colonization ii. Reduce nasopharyngeal carriage of vaccine serotypes by up to 60-70% b. Pneumovax 23 = pneumococcal POLYSACCHARIDE vaccine i. Contains more capsular types of strep pneumoniae ii. Induces limited immune response in children < 2 years of age + immunosuppressed patients c. Immunisation schedule i. Routine = 13vPCV at 2, 4 and 12 months ii. High risk 1. Extra dose of 13vPCV at 6 months 2. 23vPCV at 4-5 years d. High risk i. Indigenous children ii. Increased risk of disease = asplenia, immunocompromise, CSF leak, intracranial shunt, cochlear implant, chronic cardiac disease, chronic lung disease, DM, Down syndrome, preterm

Answer 139

Gram positive rods 1. Microbiological features a. Aerobic b. Spore forming rods 2. Bacillus ceres – gastroenteritis a. Non-encapsulated bacteria b. Secretes two enterotoxins – one heat labile, another heat stable c. Resistant to penicillin d. Antibiotics do not alter the course of enterotoxin mediated disease 3. Bacillus anthracis – anthrax a. Only bacteria with a protein capsule

Answer 140

1. Microbiology a. Gram positive rod b. Spore forming c. Anaerobic (obligate) d. Lives in soil, dust and GITs of various animals e. Spores can survive boiling f. Bacteria is NOT invasive, but causes disease through effect of a toxin – tetanospasmin 2. Pathophysiology a. Toxin binds at the NMJ, enters motor nerve by endocytosis, exits motor nerve at spinal cord, enters spinal inhibitory interneurons -> prevents release of glycine and GABA: this blocks normal inhibition of antagonistic muscles -> contraction + unable to relax b. Recovery occurs through regeneration of synapses c. Tetanus toxoid is insufficient to produce effective antibody response 3. Epidemiology a. Kills 500,000 infants a year b. At risk group = infants whose mother are not immunized, maternal postpartum infection c. Other cases associated with traumatic injury d. Rare in Australia, case fatality rate ~ 2%

Answer 141

4. Clinical features: a. Incubation period 2-21 days b. Causes generalised/localised disease c. Trismus often the first symptom with headache, restlessness, irritability d. Opisthotonus= abnormal posturing caused by strong muscle spasms e. Laryngeal and respiratory muscle spasm can cause airway obstruction and asphyxiation f. Neonatal disease = difficulty feeding, stiffness, rigidity, often due to infection of umbilical stump

Answer 142

5. Management of acute disease a. Clean wound, excise devitalised tissue b. Penicillin c. Tetanus immunoglobulin AND immunization booster i. Immunoglobulin neutralises toxin, but needs to be given prior to toxin reaching the spinal cord ii. Can give IVIG if tetanus immunoglobulin not available, but dosages unknown iii. Exposure to toxin alone does not induce immunity -> need to give vaccine d. Muscle relaxants 6. Vaccination a. 2, 4, 6 months + booster at 18 months + 4 years + 10-15 years b. Vaccines i. DTPa (childhood concentrations of diphtheria, tetanus and pertussis) ii. dTpa (adult formulations) c. Vaccine stimulates production of antitoxin d. Adsorbed onto aluminium for adjuvant effect (alongside Bordetella pertussis) e. Serum antibody titre > 0.01 U/ mL is considered protective f. 3x doses and 2x boosters usually induces protective levels of antitoxin into middle age g. Boosters previously recommended every 10 years throughout adult life, now only > 50 h. Can rarely cause type III hypersensitivity reactions 7. Treating the exposed patient a. All wounds other than clean minor wounds should be considered tetanus-prone b. Clean wound and debride any necrotic tissue -> anaerobic conditions can predispose to growth c. Summary i. If >=3 doses of vaccine and <5 years since last dose – do not require any further treatment ii. If >=3 doses of vaccine and >5-10 years since last dose – booster vaccine iii. If <3 doses or uncertain – TIG + booster (unless minor wound)

Answer 143

1. Microbiology a. Gram positive rod b. Obligate anaerobe c. Spore producing i. Spores may sometimes persist despite boiling for several hours ii. The toxin itself however is heat labile d. Found in soil, dust, marine sediments + agricultural products e. Similar strains that produce the neurotoxin include clostridium butyricum, clostridium baratii f. Botulinum toxin i. Di-chain protein ii. Various toxin types – A, B, E and F cause human botulism (C+D affect animals) iii. Toxin is endocytosed by cells, and forms a protein that inhibits the release of acetylcholine  blocks neuromuscular transmission iv. Can lead to death through airway + respiratory muscle paralysis 2. Clinical manifestations a. Classic triad i. Symmetrical flaccid ascending paralysis ii. Clear sensorium iii. No fever, no paraesthesias b. Infant botulism i. Only affects the infant in the family ii. Occurs between 3 weeks – 6 months of age iii. M=F iv. Clinical spectrum varies – classically a symmetric, descending, flaccid paralysis beginning with the cranial nerves v. Risk factors = HONEY c. Food botulism i. Caused by ingestion of a food containing the bacteria which has then produced the toxin d. Wound botulism i. Often occurs in adolescent males ii. Can occur with crush injuries (without skin breach) 3. Natural history a. Symptoms improve when new terminal unmyelinated motor neurons ‘sprout’  usually takes ~ 4 weeks 4. Diagnosis a. Identification of botulism toxin in serum / wound material / faeces 5. Treatment a. Human botulism immune globulin b. Antibiotics generally not indicated as the disease is toxin mediated rather than infective

Answer 144

1. Microbiology a. Gram positive rod b. Anaerobic c. Spore forming 2. Pathogenesis a. Produces 1 or both of Toxin A and Toxin B b. Toxins affect intracellular signaling resulting in inflammation and cell death 3. Epidemiology a. Outbreaks of hypervirulent strains (including PCR ribotype 027 and 078) have been reported worldwide inc AUS b. Some outbreaks of these hypervirulent strains have been associated with broad-spectrum quinolone use (eg moxifloxacin) 4. Risk factors a. Antibiotics – fluoroquinolones, cephalasporins, clindamycin (lincosamide) i. Can occur any time during or many months after antibiotics b. Healthcare environment c. Acid suppression medication – PPI d. Chemotherapy 5. Clinical manifestations a. Spectrum of disease i. Mild self-limiting diarrhoea ii. Explosive, watery diarrhoea with occult blood or mucous iii. Pseudomembranous colitis = bloody diarrhoea with fever, abdominal pain/cramps, nausea and vomiting b. Less common i. Small intestinal involvement ii. Bacteraemia iii. Abscess formation iv. Toxic megacolon 6. Diagnosis a. Either i. Colonoscopy or histopathology results that demonstrate pseudomembranous colitis ii. Microbiological evidence of C. Difficile toxin, or toxin-producing C. Difficile, in stools, in a patient who has signs and symptoms of C. Difficile infection in the absence of another cause b. Tests to detect C difficile toxin i. Cell cytotoxicity neutralisation assay (CCNA) = technically demanding and slow, but sensitive and specific ii. Toxigenic culture (ie C. difficile culture with isolate toxin testing) = slow, but sensitive and specific iii. Enzyme immunoassays (EIAs) to detect C. difficile toxins A and B = high specificity but low sensitivity, and should not be used as a stand-alone test 1. Common false positives in children iv. Nucleic acid amplification tests (NAAT) for C. difficile toxin genes have high sensitivity and specificity 7. Treatment a. Mild-moderate = PO or IV metronidazole b. Severe disease = vancomycin via NG c. Faecal microbiota transplant = under investigation

Answer 145

1. Epidemiology a. Virtually disappeared with vaccine b. Last Australian death was in 2011 (imported infection from overseas affecting unimmunised patient) 2. Microbiology a. Aerobic, non-capsulated, non-spore forming b. Pleomorphic gram +ve bacilli c. Exclusively inhabits human mucous membranes and skin : 3-5% carry toxigenic organisms in areas that the bacteria is endemic d. Spread via aerosol transmission or direct contact e. Incubation period 2-5 days, infectivity for 4 weeks 3. Pathogenesis a. Produces an exotoxin that acts locally on URT + skin, producing a ‘pseudomembrane’  inhibits protein synthesis and causes local tissue necrosis b. Also causes paralysis of local palate and hypopharynx c. Systemic effects on myocardium, nervous system and adrenals, kidney, demyelination of nerves, thrombocytopenia

Answer 146

a. Pharyngeal diphtheria i. Pseudomembranous exudate forms on the upper respiratory tract, can cause respiratory obstruction ii. Membrane can be present on the nares/pharynx/upper lip iii. Classic features: extends beyond facial area, cause dysphagia. ‘Bull neck’ swelling iv. Fever is less common v. Leads to hoarseness, stridor, dyspnoea and croupy cough vi. High risks of suffocation due to local edema and airway obstruction b. Cutaneous diphtheria i. Indolent, non-progressive infection ii. Superficial ulcer with grey-brown membrane c. Neuropathy i. Hypesthesia and local paralysis of soft palate (2-3 weeks post onset of infection) ii. 5th week: cranial neuropathies iii. 10 days – 3 months: symmetric polyneuropathy  motor deficits with ↓ reflexes, distal  proximal iv. Recovery is slow but usually complete d. Cardiomyopathy/ myocarditis i. Occurs in 10-25% of patients with respiratory diphtheria ii. Causes 50-60% deaths iii. Presents with tachycardias,ECG changes, dilated/ hypertrophic cardiomyopathy, dysrhythmias

Answer 147

5. Management of (acute disease) a. Antitoxin b. Antibiotics: erythromycin / penicillin c. Prophylaxis for contacts with erythromycin / IM benpen 6. Case fatality – 10% 7. Vaccinations a. Given at 2 months, 4 months, 6 months, 18 months , 4 years, 15 years (DTPa) b. Toxoid treated and adsorbed to aluminium salts c. Protective level 0.01-0.10 IU/ mL

Answer 148

1. Microbiological features a. The only gram positive bacteria that has an ENDOTOXIN b. Anaerobic, nonspore forming, motile gram positive rods c. Catalase positive d. Usually infects via GIT + has tropism for nervous tissue e. Facultative intracellular organism – require cell mediated immunity to be broken down f. Induces granulomatous reactions 2. Pathogenesis a. Pathogenic steps i. Internalization by phagocytosis ii. Escape from the phagocytic vacuole iii. Nucleation of actin filaments iv. Cell to cell spread b. Virulence factors i. Listeriolysin = haemolysis  mediates lysis of vacuoles ii. Locomotion = via cytochalasine sensitive polymerization of actin filaments : extrude bacteria in pseudopods, which are phagocytosed by adjacent cells iii. Protected from humoral arm of immunity = requires T cell mediated activation of monocytes by lymphokines for clearance of infection + establishment of immunity 3. Epidemiology a. Usually traced to animal reservoir b. Occurs in the very young and very old c. Human-human transfer only occurs in maternal – fetal setting d. Environmental sources: soft cheeses, pasteurized milk, uncooked meats

Answer 149

4. Clinical manifestations a. Incubation period usually 21-30 days b. In pregnancy i. Women susceptible due to impaired cell mediated immunity ii. Usually causes flu like illness iii. Placental listeriosis can cause still birth / premature delivery, thorough infants may be unaffected c. Neonatal Listeriosis i. Early onset neonatal disease  usually septicaemia ii. Late onset neonatal disease  usual meningitis d. After neonatal period i. Associated with malignancy/ immunosuppression (T cell deficiency) ii. Usually causes meningitis/ sepsis 5. Investigations a. CSF may be DIFFERENT to typical bacterial infection  can have neutrophil OR lymphocyte predominance 6. Treatment a. Penicillin b. Ampicillin +/- aminoglycoside 7. Prognosis a. Mortality rate > 50% for premature infants infected in utero b. 30% for early onset neonatal sepsis c. 15% for late onset neonatal sepsis

Answer 150

a. Slow growing Gram positive bacteria, look like fungus b. Non spore forming, acid fast, non-motile bacilli c. Clinical manifestations i. Causes granulomatous, suppurative disease ii. Abscesses gradually grow larger over time – may penetrate the surrounding bone and muscle iii. Pus contains characteristic sulphur granules iv. Classic sites = cervicofacial, abdominal pelvic (can mimic appendicitis) and pulmonary d. Treatment i. Debridement ii. Penicillin / tetracycline/ clindamycin / carbapenems

Answer 151

a. Part of the Actinomycetales group b. Only occurs in immunocompromised patients – esp those with CGD c. Microbiology i. Gram Positive ii. Acid fast iii. Environmental saprophytes - ubiquitous in soil + decaying vegetable matter iv. Usually infects via direct contact with soil d. Clinical manifestations i. Pulmonary disease ii. Metastatic lesions (brain abscess, meningitis) iii. Skin, kidneys, GI e. Treatment i. Surgical drainage of abscesses ii. Sulfonamides first line treatment +/- carbapenem/ cephalosporin / amikacin if severely ill iii. Long treatment times recommended f. Prognosis i. Overall mortality > 50%

Answer 152

• Controlled increase in body temperature over normal values • Regulated by thermosensitive neurons in preoptic/anterior hypothalamus (blood temperature) • Resetting of body’s thermostat o Endogenous pyrogens  IL-1, IL-6, TNF-, IFN-, IFN-gamma  Stimulate hypothalamus to produce PGE2 which resets temperature regulatory set point  core temperature o Exogenous pyrogens  Endotoxin can directly affect thermoregulation + stimulate endogenous pyrogen release  Vancomycin, amphotericin B, allopurinol • Fever is an adaptive process BUT O2 consumption, CO2 production, cardiac output

Answer 153

1. Definition = temperature >= 38 degrees for <1 week 2. Differential Diagnosis IMMUNOCOMPETENT ``` Neonates <1 month - Sepsis/meningitis - GBS - E coli - Listeria - Viral = HSV, enterovirus Infants – 1-3 months - Viral most common - Serious bacterial disease (10-15%) - Bacteremia (5%) - UTI (70%) Infants 3mo-3yr - Viral most common - Occult bacteremia (<0.5%) - UTI - Strep pneumoniae - Neisseria - Salmonella ``` ``` IMMUNOCOMPROMISED Sickle cell disease = functional asplenia - Sepsis, pneumonia, meningitis (strep pneumoniae) - Osteomyleitis (salmonella, staph) Asplenia (encapsultaed, NHS/SHiNS) - Strep (pneumo, GBS) - Haemophilus influenzae - Neiserria meningitidis - Salmonella - Klebsiella Complement/properdin deficiency - Sepsis - Neisseria meningitidis AIDS - Strep pneumoniae, HiB, salmonella Congenital heart disease - Infective endocarditis, brain abscess (LR shunt) Central venous line - Staph aureus, CONS, candida Malignancy - Gram –ve, staph aureus, CONS, fungemia (candida, asperigillus) ```

Answer 154

1. Definition: No consensus, anywhere from 5d-3wk, uptodate has 1 week as the cut off from FWS (fever without source) and FUO 2. Differential diagnosis a. Infectious i. Myocoplasma, salmonella, meningococcus ii. Syphilis, cat-scratch disease, brucellosis, leptospirosis iii. TB, rickettsial iv. EBV, CMV, viral hepatitis v. Malaria, toxoplasmosis, histoplasmosis b. Rheumatological i. JIA, SLE, IBD, ii. Rheumatic fever, Kawasaki disease c. Neoplastic d. Periodic fever syndrome e. Drug hypersensitivity 3. Differential diagnosis by age a. Children <6yr most common causes i. Respiratory infections ii. Genitourinary infections iii. Localised infections (abscess, osteomyelitis) iv. Juvenile rheumatoid arthritis v. Leukemia b. Adolescents i. TB ii. IBD iii. Autoimmune process iv. Lymphoma 4. Assessment a. Complete and detailed history i. Possible exposures – animals (leptospirosis), unpasteurised milk, uncooked poultry, ticks, pica or dirt ingestion (Toxoplasma), rabbits (Tularemia), mosquitoes, reptiles (Salmonella) ii. Travel history b. Thorough physical exam c. Blood tests i. FBE ii. CRP or ESR iii. UEC, LFT, uric acid, LDH iv. Urinalysis, urine and blood cultures v. TB skin test, CXR d. ** Most FUO come from atypical presentations of common diseases e. More directed tests i. Bone scan for occult OM ii. BMA for suspected malignancy iii. CT/MRI directed in areas of interest (sinuses, head and neck)

Answer 155

``` Fever alone • Malaria • Typhoid • Dengue • Hepatitis ``` ``` Fever + Diarrhoea • Malaria • Typhoid • Dengue • Hepatitis • Traveller's Diarrhoea • Cholera • Dysentery (bloody diarrhoea) ``` ``` Fever + Respiratory • Malaria • Pneumonia • Influenza • Tuberculosis ``` FEVER PATTERN ``` Fever > 2 weeks • Malaria • Enteric fever • EBV, CMV • Toxoplasmosis • Acute HIV • Schistosomiasis • Brucellosis • TB • Q fever • Visceral leishmaniasis (rare) ``` ``` Fever with normal or low WCC • Dengue • Chikungunya • Zika • Malaria • Rickettsial infections • Enteric fever ``` ``` Fever with onset >6 weeks after travel • Malaria • Acute hepatitis (B, C or E) • TB • Amoebic liver abscess ```

Answer 156

TNF inhibitors (infliximab, adalimumab, etanercept) - Bacterial infections - TB (highest risk/classic) - Fungal - HBV reactivation IL-1 inhibitors (anakinra, cankinumab) - bacterial infections -> pneumonia CD20 or CLA4 B/T lymphocyte inhibitors (rituximab, abatacept) - PJP (not listed elsewhere/classic) - Toxoplasmosis - HBV - PML (progressive multifocal leukoencephalopthy, caused by John Cunningham virus) IL-6 inhibitors (toclizumab) - Respiratory infections - STI - TB reactivation IL-17 inhibitors (Ustekinumab, Secukinumab) - Enteric bacterial + viral infections - Candidiasis - C difficile infections - GU infections - NTBM (non TB mycobacteria) infections Alpha 5 lymphocyte integrin inhibitors (natalizumab) - PML

Answer 157

= Jugular Vein Suppurative Thrombophlebitis • Typically anaerobic gram –ve rod – Fusobacterium necrophorum oral flora • Begins as pharyngitis or tonsillitis -> thrombophlebitis -> seeding of multiple organs with septic emboli particularly lungs • Acute fever, hypoxia, tachypnea, WOB • CXR – multiple cavities • Pneumonia may lead to respiratory failure in untreated cases • Anaerobic BC, USS of jugular veins CT of chest -> Dx

Answer 158

``` • Divided into 2 main groups taxonomically o Protozoans (unicellular) o Helminths (multicellular) ``` Strongyloidiasis • Waxing and waning GI, cutaneous or pulmonary symptoms over years • Isolated eosinophilia • Immunocompromised -> hyperinfection syndrome (massive dissemination) - Treatment: Ivermectin single dose with fatty food; repeat in 7-14 days, Albendazole If immunocompromised; prolonged ivermectin course Schistosomiasis • “Swimmer’s itch” • Systemic hypersensitivity reaction Treatment: Praziquantel Entamoeba histolytica • 1-3 weeks diarrhoea • Fulminant colitis can occur Treatment: Metronidazole, Tinidazole Giardia lamblia • Diarrhoea, malaise, abdo pain and weight loss • Malabsorption Treatment: Metronidazole, Tinidazole Cryptosporidium • Diarrhoea • May have biliary tract involvement Treatment: Supportive

Answer 159

* Blastocystis hominis * Endolimax nana * Chilomastix mesnili * Entamoeba coli + hartmanni * Lodamoeba buestchilii

Answer 160

1. Microbiology a. Flagellated protozoa b. Life cycle consists of trophozites and cysts c. Infection occurs after ingestion of cysts d. Cysts produce trophozoites, colonize the duodenum and jejunum then multiply by binary fission e. They then detach from intestinal tract and become encysted which are excreted in stools 2. Life-cycle a. Cause of water born and food borne diseases – cysts are the infectious form of the parasite b. Humans ingest cysts (10-100), each ingested cyst then makes 2 trophozoites c. These trophozoites colonize the lumen of the duodenum, and proximal jejunum, where they attach to brush border and multiply via binary fission d. Trophozoites that do not adhere to SI then pass through the gut, where they join back together to make cysts – excreted into environment and are infectious e. These cysts remain viable in water for 2 months 3. Epidemiology a. More common in children than adults b. Endemic in countries with poor sanitation c. Higher rates in children with immunodeficiencies (humoral + IgA deficiency) , cystic fibrosis and malnutrition d. Transmission rates higher in day care centres, travellers, MSM e. Can be spread via contaminated water or faecal-oral contact

Answer 161

4. Clinical manifestations a. Incubation period 1-2 weeks b. Broad spectrum of clinical manifestations i. Most infections clear in absence of clinical symptoms – 50% ii. Asymptomatic – 5-15% shed cysts in stool iii. Acute infectious diarrhoea – 35-45% 1. Diarrhoea (90%), Malaise (85%), foul smelling & fatty stools (70%), abdo cramps and bloating (70%), flatulence, nausea, weight loss (60%), vomiting (30%), fever (10-15%) 2. Symptoms may last 2-4 weeks!! iv. Chronic diarrhoea with GIT symptoms – alone or follows acute phase 1. Loose stools, steatorrhea, profound weight loss (10-20%), malabsorption, malaise, fatigue, depression c. Symptoms occur more often in children than adults d. Stools may be initially watery  greasy, foul smelling and may float e. Stools do NOT contain blood, mucus or fecal WCC f. Varying degrees of malabsorption occur – sugars, fats and fat soluble vitamins g. Osmotic and secretory diarrhoea 5. Diagnosis a. Stool enzyme immune assay/direct fluorescent antibody test b. Trophozoites can be visualized on wet mount – 90% diagnosed with 3 stool specimens c. Fatty acid crystals common – malabsorption 6. Treatment a. Indicated for children with FTT/ malabsorption/ chronic diarrhea b. Tinidazole OR metronidazole

Answer 162

1. Microbiology a. Obligate intracellular protozoan b. Multiplies ONLY in living cells c. Multiple in cysts that can contain thousands of parasites and remain in tissues for life of the host d. Often found in cat faeces, infected meats 2. Lifecycle a. Mature/sporulated oocyst eaten  parasite burrows its way through the intestinal wall  phagocytosed by macrophages  replicates inside macrophages (tachyzoites)  rupture  releases many tachyzoites b. This generally goes on for about 2 weeks; as the immune system responds the parasite slows in its growth and you get development of pseudocysts c. Not cysts as intracellular; get slowly dividing parasites called bradyzoites in pseudocysts d. Pseudocysts can persist for life 3. Transmission a. Eat poorly cooked meat containing the pseudocyst (OR cut yourself when cutting meat) b. Transmits transplacentally to a fetus c. Organ transplant or blood transfusion d. Reactivation

Answer 163

4. Clinical manifestations a. CONGENITAL TOXOPLASMOSIS i. Usually occurs when women has primary infection whilst pregnant ii. Wide range of presentations: from hydrops + perinatal death  SGA, prematurity, retinal scars, jaundice, thrombocytopenia iii. Characteristic triad: chorioretinitis, hydrocephalus, cerebral calcifications (Only congenital/TORCH infection p/w hydrocephalus) iv. Symptoms may manifest later in life (> 50% normal in the perinatal period) v. CSF may show protein level > 1 g/ dL vi. Almost all develop chorioretinitis b. ACUTE ACQUIRED INFECTION i. Usually asymptomatic (80-90%) ii. Cause lymphadenopathy, fever, myalgia, arthralgia, maculopapular rash, hepatitis, meningitis, brain abscess, encephalitis, confusion etc. iii. Most patients recover without specific therapy c. OCULAR TOXOPLASMOSIS i. Posterior uveitis ii. Present with blurred vision, floaters, photophobia, epiphora, loss of central vision (NOT typically with pain) d. INFECTION IN IMMUNOCOMPROMISED PATIENTS i. Can develop disseminated disease - encephalitis, pneumonitis, chorioretinitis, hepatitis etc 5. Investigations a. Central imaging: USS/ CT/ MRI may show calcifications (propensity for caudate nucleus, basal ganglia, choroid plexus and subependyma) b. Culture from blood / body fluids c. Tachyzoites can be seen in tissue fluids/ amniotic fluid/ placenta on special stains d. Serology i. Various IgG and IgM tests ii. Acquired toxo is suggested by 2 tube increase in IgG titre 3 weeks apart iii. Avidity test can suggest time frame of infection: high avidity suggests infection > 16 weeks ago (though low avidity may persist for a long period of time) e. PCR

Answer 164

6. Treatment a. Pyrimethamine + sulfadiazine are synergistic b. Pyrimethamine i. Inhibits dihydrofolate reductase  can produce bone marrow depression ii. Contraindicated in first trimester of pregnancy iii. Given concomitantly with folinic acid c. Sulfadiazine i. Bacteriostatic agent: inhibits bacterial folate production ii. Give for toxoplasma and nocardia (in conjunction with pyrimethamine) iii. RFx – allergies (sulfur), may worsen SLE, folate deficiency, G6PD deficiency d. Spiramycin i. Used to prevent vertical transmission e. Managements i. Congenital toxo  pyrimethamine + sulfadiazine + folinic acid ii. Antenatal toxo  spiramycin + pyrimethamine from >18 weeks iii. Acquired  no specific treatment required, if immunosuppressed: pyrimethamine/ sulfadiazine can be given 7. Prognosis a. Congenital toxo i. Early treatment often cure active manifestations ii. Hydrocephalus may worsen despite treatment iii. Treatment probably ↓ cognitive and developmental problems 8. Prevention a. Avoid undercooked meats, cats b. Hand hygiene c. Prophylaxis i. Allogeneic HSCT recipients who are positive for Toxoplasma gondii IgG pretransplant and who are highly immunosuppressed ii. Heart transplant recipients who are IgG negative pretransplant and receive an organ from an IgG-positive donor

Answer 165

``` Falciparum - incubation: 10-14 days • Results in bulk of disease • Found worldwide • High level of blood stage parasites • Severe disease ``` ``` Vivax - incubation: 2-3 weeks • Milder disease • Recurrent – has dormant liver stage • Predominantly found in Asia ``` Ovale + Malariae • Limited distribution • Mild disease Knowlsei - incubation: 10-14 days • Primarily zoonotic – found in macaques throughout SE Asia • Can be severe disease

Answer 166

1. Microbiology a. Caused by intracellular plasmodium protozoa b. P. falciparum causes the bulk of disease c. Transmitted by female Anopheles mosquitoes (very specific to infect humans) d. Note – sickle erythrocytes, HbF and ovalocytes are resistant to plasmodium falciparum 2. Key points a. Severe malaria is largely caused by P. falciparum; children with vivax + knowlesi malaria can also be seriously ill b. Liver hypnozoite eradication eliminates the Plasmodium forms that lie dormant in the liver that can cause relapse of illness months to years later  Only P. vivax and P. ovale produce hyponozoite forms i. P. vivax, P. ovale, or an unknown species = treat with a course of primaquine to prevent relapse 3. Life cycle a. Sexual phase in the mosquito + asexual phase in the human host b. Marked amplification of plasmodium occurs from 100  10^14 during 2 step process: i. Exoerythrocytic phase 1. Sporozoite enter blood stream from mosquito, then enter hepatocytes 2. Asexual reproduction in the liver 3. After 1-2 weeks, hepatocytes rupture and release merozoites into the circulation ii. Erythrocytic phase 1. Merozoites penetrate erythrocytes 2. Inside the erythrocyte, the parasite transforms into ring form, and then a trophozoite 3. Asexual reproduction to form small merozoites  released into the blood stream, associated with fever iii. During time in blood stream, can be ingested by mosquito

Answer 167

4. Clinical features a. Incubation period varies from 8-40 days depending on species b. Prodrome: headache, fever, anorexia, myalgia + arthralgia c. Classic features = paroxysmal fever: i. 48 hours – vivax, ovale ii. 72 hours – malariae d. Relapse can occur due to i. Survival of erythrocyte forms in blood stream ii. Release of merozoites from the liver e. Complications i. Severe anaemia ii. Cerebral malaria – seizures, hypoglycaemia, 25% have long term cognitive impairment 1. More common in children <5 years of age iii. Tropical splenomegaly syndrome f. Differences between species i. Falciparum = the most serious, tends to cause cerebral malaria, bleeding diasthesis (a constitutional predisposition toward a particular state or condition and especially one that is abnormal or diseased) ii. Malariae = mildest, but can be associated with nephrotic syndrome poorly response to treatment iii. Vivax + Ovale = results in dormant liver stage 5. Diagnosis a. Thick and thin film i. Thick film = confirm the presence of parasites and percentage of erythrocytes containing parasites ii. Thin film = identify Plasmodium species b. Malaria antigen/ICT = detects P. falciparum with >90% sensitivity, but is insensitive for other species or when there is a low level of parasitaemia

Answer 168

6. Basic treatment a. Depends on species and patterns of resistance and whether the child has severe or uncomplicated malaria b. Uncomplicated malaria i. P falciparum or unidentified species 1. Artemether-lumefantrine (coartem, riamet) = 1st line 2. Atovaquone-proguanil (malarone) = 2nd line 3. Quinine + clindamycin = 3rd line 4. Primaquine = to eradicate liver hypnozoites if species unknown 5. Quinine used if severe disease ii. P vivax, P ovale, P malariase, P knowlesi 1. Chloroquine OR hydroxychloroquine OR artemether-lumefantrine (coartem, riamet) 2. Primaquine = to eradicate liver hypnozoites if vivax or ovale c. Complicated malaria i. Artesunate IV ii. Quinidine dihydrochloride IV iii. Artemether-lumefantrine d. Management of complications i. Hypovolaemia + acidosis ii. Severe anaemia iii. Seizure control 7. Options for prevention a. Mosquito avoidance b. Drugs – malarone (Atovaquone-proguanil), mefloquine, doxycycline (not in children < 8 years)

Answer 169

1. Primary amebic meningoencephalitis a. Naegleria, Acanthamoeba, Balamuthia, and Sappina – small, free-living amoebas that cause human amebic meningoencephalitis b. Clinical manifestations i. Amebic meningitis 1. Caused by Naegleria 2. Occurs in previously well children and young adults 3. Usually fatal ii. Granulomatous amebic meningoencephalitis 1. Caused by Acanthamoeba, Balamuthia, and Sappina iii. Acanthamoeba keratitis 2. Amebiasis a. Entamoeba species infect or colonize up to 10% of the world population b. Entamoeba histolytica is the only invasive species c. Clinical manifestations i. Asymptomatic cyst passage ii. Amebic colitis iii. Amebic liver abscess

Answer 170

Protozoan infection 1. Key points a. Leading protozoal cause of diarrhoea in children worldwide b. Can occur in outbreaks c. Significant pathogen in immunocompromised d. Transmission i. Close contact with infected animals ii. Person to person iii. Environmentally contaminated water 2. Pathogenesis a. Oocytes enter GIT b. Excystation in small bowel c. Release sporosoites which are motile and attach to bowel wall d. Mature and release intraluminal merozoites – can cause autoinfection or reform oocytes that are excreted into the environment e. Oocytes remain infectious and survive many months in environment f. Mechanism of diarrhoea i. Mild villous blunting ii. Dissacharidase deficiency iii. Primarily SECRETORY diarrhoea 3. Clinical manifestations a. Incubation 2-14 days b. Profuse, watery, non-bloody diarrhoea c. Associated crampy abdominal pain, nausea and vomiting d. Usually self-limiting and subsides over 5-10 days e. Chronic diarrhoea can occur in immunocompromised individuals f. Assocated with profuse, watery, nonbloody diarrhoea +/- vomiting, abdo pain, nausea, anorexia, myalgia, weakness, headache, low grade fever 4. Diagnosis a. Monoclonal antibody based assay 5. Treatment a. Treatment only required if symptomatic b. If symptomatic - Nitazoxanide 6. NOTE: immunocompromised a. Usually self limiting in immunocompetent patients 10-14days, although diarrhoea may persist for several weeks (oocyst shedding may persist many weeks after symptoms resolve) b. In immunocompromsied, can cause chronic debilitating illness with wasting and persistent diarrhoea, and acutely can affect biliary tract (cholecystitis, cholangitis, hepaitits, pancreatitis) – untreated 50% chronic disease

Answer 171

Protozoan • Sexually transmitted infection • Results in vulvovaginitis – malodorous, grey, frothy vaginal discharge, vulvovaginal irritation, dysuria and dyspareunia

Answer 172

• Diverse group of disease caused by the intracellular protozoan parasite Leishmania • Common in refugees • Clinical manifestations o Localised cutaneous leishmaniasis  Acquired through bite of infected sand-fly  Erythematous papule to nodule to ulcerating lesion with raised indurated borders  May spontaneously resolve over months/years o Diffuse cutaneous leishmaniasis o Mucosal leishmaniasis o Visceral leishmaniasis • Investigations = biopsy • Treatment = various o No good evidence

Answer 173

= Roundworms * Major pathogens of humans and livestock animals * All have developmental Egg, L1, L2, L3, L4, adult (male + female)  L3 is the ONLY infective stage * Most free-living

Answer 174

Pinworm (nematode, roundworm) a. Most children infected at some time (30%), highly infectious but does not usually cause significant pathology b. Affects children 5-14 years c. Transmission = faecal oral route d. Pre-patent period 4-6 weeks (4-6 weeks from when you eat eggs to excrete eggs) e. Lifecycle = ingest egg  small intestine  large intestine  male and female worms develop  female crawls to the anus and uterus explodes  eggs released Symptoms/pathology • Most asymptomatic • Perianal itching, vaginal infection – particularly at night Diagnostic procedures • Detection of eggs (sticky tape on anus) • Eosinophilia – but not usually required Treatments • Albendazole • Pyrantel

Answer 175

Roundworm, nematode a. Infects 25% of the world’s population b. Faecal-oral transmission  infected by eating embryonated egg c. Undergoes broncho-tracheal migration d. Female lays 200,000 highly resistant eggs each day e. Embryonation occurs in the soil, requires 2-4 weeks f. Lifecycle = eat embryonated egg  worm burrows out in the intestine to enter blood  portal system  lungs  crawl into the air space and are swallowed  back into the intestine ``` Symptoms/pathology • Many asymptomatic • Pneumonitis (larval migration) • Intestinal obstruction – perforation, malabsorption, pancreatitis, cholangitis Diagnostic procedures • Characteristic eggs in faeces Treatments • Albendazole • Mebendazole ```

Answer 176

Roundworm, nematode a. Infection by skin penetration b. Undergoes broncho-tracheal migration c. Auto-infection occurs d. Immunosuppression may lead to hyper infection/dissemination  larval stages throughout the body ``` Symptoms/pathology • Many asymptomatic • Pneumonitis (larval migration) • Diarrhoea • Disseminated infection (secondary bacterial infections) Diagnostic procedures • Characteristic larval stages (not eggs) in faeces Treatments • Ivermectin • Albendazole ```

Answer 177

Flatworms a. 5 species that infect humans i. Schistosoma haemobium ii. Schistosoma mansoni iii. Shistosoma japnicum iv. Shistosma intercalatum v. Shistosoma mekongi b. Clinical manifestations i. Asymptomatic ii. Pruritic rash – swimmer’s itch iii. Acute schistosomiasis = Katayama syndrome 1. Serum-sickness like syndrome manifested by acute onset of fever, cough, chills sweating, abdominal pain, lymphadenopathy, hepatosplenomegaly and eosinophilia iv. Chronic schistosomiasis 1. Genitourinary disease a. Cause = S. haematobium b. Can result in infertility, increases risk of HIV infection c. Microscopic or macroscopic haematuria 2. Gastrointestinal disease a. Cause = S. mansoni, S japnoicum, S intercalatum, S mekongi b. Chronic or intermittent abdominal pain, poor appetite, diarrhoea c. Chronic ulceration resulting in bleeding and IDA 3. Hepatosplenic a. Cause = S. mansoni, S japnoicum, S intercalatum, S mekongi b. Non-fibrotic granulomatous inflammation around trapped eggs in the presinusoidal periportal spaces of the liver c. Can develop into periportal fibrosis 4. Pulmonary a. Cause = S. mansoni, S japoncium, S haemtobium b. Eggs lodge in pulmonary arterioles and produce pulmonary endarteritis  pulmonary hypertension and cor pulmonale 5. CNS disease = neuroschistosomiasis a. Can involve spinal cord or brain b. May result in single or multiple intracerebral lesions c. Investigations i. Eosinophilia ii. Anaemia = if GI or urinary blood loss iii. Thrombocytopaenia = if splenomegaly iv. Serology v. Microscopy = stool or urine vi. PCR = determine species d. Treatment i. Goals 1. Reversing acute or early chronic disease 2. Prevent complications of chronic infection 3. Preventing neuroschistosomiasis ii. Swimmer’s itch = no treatment iii. Acute schistosomiasis = corticosteroids, praziquantel iv. Chronic infection = praziquantel

Answer 178

Flatworms a. Zoonotic infection b. Humans are accidental intermediate hosts c. Proliferation internally in cysts producing infective prostoscoleces d. Secondary infection may occur after escape of prostoscoleces e. Lifecycle = ingested egg  larval form is released in intestine  enters the blood  moves to liver and lungs  hydatid cyst forms f. Epidemiology of hydatid disease in AUS i. Endemic in NSW, ACT, WLD, VIC, SA and WA, eradicated in Tasmania ii. Victoria approx 100 current cases, 230 cases in last 5 years in NSW iii. Two interrelated lifecycles: domestic and sylvatic g. Clinical manifestations i. Initial phase of primary infection always asymptomatic ii. Latent periods of up to 50 years before symptoms reported iii. Clinical presentation depends on cysts and size iv. Possible manifestations 1. Liver = cysts, hepatomegaly, biliary obstruction 2. Lung = cough, chest pain, dyspnoea, haemoptysis, secondary bacterial infection 3. Heart = mechanical rupture, tamponade 4. CNS = raised ICP 5. Kidney = haematuria, flank pain h. Investigations i. Imaging ii. Serology i. Treatment i. Surgery = management of complicated cysts (cyst rupture, biliary fistulae, compressing vital structures, secondary haemorrhage) ii. Pharmacological = albendazole, mebendazole j. Prevention i. Prevention of infection in dogs, public education, personal hygiene, quarantine of infected livestock, vaccination in livestock ii. No immunity to reinfection in dogs

Answer 179

Pork tapeworm a. Zoonotic infection b. Humans can be both definitive and intermediate hosts c. Tapeworm up to 10m long, produces about 300,000 eggs per day d. Lifecycle = eggs ingested by pig and enters the blood then muscle  meat eaten by humans  tapeworm grows inside humans  have sex and produce eggs inside human  eggs are immediately infective e. Clinical manifestations i. Neurocysticercosis 1. Major cause of neurological disease in endemic countries (acquired epilepsy) 2. NOTE: the natural history of parenchymal lesions is to resolve with or without antiparasitic drugs but this process is prolonged (months-years) ii. Other tissues can also be affected f. Investigations i. MRI brain = solitary parenchymal cyst with or without contrast enhancement is the most common finding in children ii. Serology g. Treatment i. Neurocysticercosis 1. Initial management should focus on symptomatic therapy for seizures and/or hydrocephalus 2. Seizures can be controlled using standard anti-epileptic drugs 3. Antiparasitic drugs can decrease the frequency of recurrent seizures 4. Albendazole +/- praziquantel

Answer 180

1. Key points a. Most frequent skin disease among travellers returning from tropical countries b. Contact is made with sand containing dog hookworm eggs expelled in dog faces c. Most common site is the foot 2. Aetiology a. Animal hookworms – contact with dog/cat faeces i. Ancylostoma braziliense (cat) ii. Ancylostoma caninum (dog) 3. Clinical manifestations a. Short incubation period b. Advancing serpiginous tracts in skin with associated intense pruritis c. Eventually self-limiting 4. Treatment a. Albendazole b. Ivermectin 5. Complications a. Impetigo b. Local and generalised allergic reaction c. Hypereosinophilia

Answer 181

Mites + ticks • Rickettsia – scrub typhus, Lyme disease Fleas • Plague Bugs • Reduviid bug – trypanosomiasis Sand-fly • Cutaneous leishmaniasis ``` Mosquito • Malaria • Dengue fever • Ross River • Murray Valley • Barmah forest • Filariasis/elaphantitis ```

Answer 182

1. Clinical features of congenital infection a. General = SGA b. GIT = hepatosplenomegaly, conjugated jaundice c. Skin = petechiae, purpura i. Syphilis – peeling of hands and feet ii. Blueberry muffin spots – intradermal erythropoiesis 1. Typical of rubella but can occur in any infection 2. DDx – haematological, malignancy, haemolysis, Langerhans cell histiocytosis, vascular abnormality d. CNS = microcephaly, hydrocephalus, intracranial calcification, meningoencephalitis e. Haematological = haemolytic anaemia f. Eye = chorioretinitis, keratoconjunctivitis, cataracts, glaucoma g. Resp = pneumonitis h. CVS = myocarditis, congenital heart disease 2. Differentiating a. Rubella = heart b. CMV = intracranial Calfication c. Toxo = hydrocephalus d. Syphilis = bones 3. Golden rules a. Ask ID consultant b. Full blown disease is rare c. Very few specific features of congenital infections d. Take a careful maternal history  if well – CMV e. Ophthal and audiology f. LFT, FBE, imaging (head and bone) g. Previously taken specimen helpful i. Mum’s antenatal bloods ii. Guthrie – can do CMV PCR on Guthrie card h. PCR has replaced culture, and is replacing serology i. Always check the placenta – for histopath and micro j. Pathogen specific i. Early positive CMV PCR in urine = congenital infection (under 2-3 weeks of age) 1. Incubation period is 2-3 weeks so could NOT be acquired ii. Resp and skin specimens for syphilis

Answer 183

1. Early onset sepsis a. GBS b. E coli c. Listeria d. Enterovirus i. Hand foot mouth disease ii. Aseptic meningitis iii. Sepsis-like disease 2. Viral transmission a. VZV b. HSV c. Enterovirus i. Hand foot mouth disease ii. Aseptic meningitis iii. Sepsis-like disease 3. Late onset sepsis a. LOS >48 hours i. EOS bugs (GBS, E. coli, Listeria) ii. Plus nosocomial iii. +/- CONS b. Other nosocomial pathogens – enterococci, candida, pseudomonas

Answer 184

* Thrombocytopenia * Periventricular intracranial calcifications * Microcephaly * Hepatosplenomegaly * Sensorineural hearing loss First six months of pregnancy

Answer 185

* Intracranial calcifications (diffuse) * Hydrocephalus * Chorioretinitis * Otherwise unexplained mononuclear CSF pleocytosis or elevated CSF protein Throughout the pregnancy

Answer 186

* Skeletal abnormalities (osteochondritis and periostitis) * Pseudoparalysis * Persistent rhinitis * Maculopapular rash (particularly on palms and soles or in diaper area) Throughout the pregnancy

Answer 187

* Cataracts, congenital glaucoma, pigmentary retinopathy * Congenital heart disease (most commonly patent ductus arteriosus or peripheral pulmonary artery stenosis) * Radiolucent bone disease * Sensorineural hearing loss Up to 16 weeks although more significant in the first two months of pregnancy

Answer 188

``` Perinatally acquired HSV infection • Mucocutaneous vesicles • CSF pleocytosis • Thrombocytopenia • Elevated liver transaminases • Conjunctivitis or keratoconjuctivitis ``` In utero acquisition • Skin vesicles, ulcerations, or scarring • Eye abnormalities (eg, micro-ophthalmia) • Brain abnormalities (eg, hydranencephaly, microcephaly) Throughout the pregnancy

Answer 189

* Cicatricial or vesicular skin lesions * Microcephaly First trimester

Answer 190

* Microcephaly * Intracranial calcifications * Arthrogryposis (congenital contractures) * Hypertonia/spasticity * Ocular abnormalities * Sensorineural hearing loss Up to 20 weeks gestation

Answer 191

* Stillbirth * Hydrops Up to 20 weeks gestation

Answer 192

1. Key points a. Seroprevalence is inversely related to country’s socioeconomic development b. Most common congenital infection c. CMV infection in pregnancy is common (3-12%) (pregnancy relatively immunocomprimised state) i. Maternal infection is asymptomatic in >80% d. Most common cause of non-hereditary sensorineural hearing loss (SNHL) e. 0.1-0.2% of births f. Definitions i. Symptomatic = one or more symptoms at birth ii. Asymptomatic = apparently no symptoms at birth, may develop hearing loss or subtle symptoms g. Incubation = 3-12 weeks h. Transmission = close contacts, sexual, blood or tissue, occupational [low transmissibility] i. Types of infections i. Non-immune mother (primary infection) ii. Immune mother (recurrent infection) Overall transmission 30-50% - 90% asymptomatic -> 5-10% develop SNHL by 5-7 - 10% symptomatic -> 50% deaf 2. Neonatal transmission + outcome a. Key points i. Risk of severe adverse neuroglial outcome is more likely with primary infection in the first half of pregnancy ii. A fetus infected late in pregnancy is more likely to have acute visceral disease (hepatitis, pneumonia, purpura, severe thrombocytopaenia) b. Maternal primary infection = 30% risk of transmission i. Symptomatic congenital CMV = 10-15% 1. Risk of sequelae 50% 2. Normal 50% ii. Asymptomatic congenital CMV = 85-90% 1. Risk of sequelae 10-15% 2. Normal 85-90% c. Maternal non-primary infection (re-infection or reactivation) = 1% risk of transmission i. Symptomatic congenital CMV <1% ii. Asymptomatic congenital CMV >99% iii. Risk of sequelae <10%

Answer 193

3. Clinical manifestations a. Symptomatic congenital CMV infection i. Neonatal features 1. Petechiae 2. Jaundice 3. Hepatosplenomegaly 4. SGA, microcephaly, SNHL ii. Long-term 1. Early mortality (first 3 months) = 5-10% 2. Neurological sequelae a. Microcephaly (35-50%) b. Seizures (10%) c. Chorioretinitis (10-20%) d. Developmental delay (<70%) 3. SNHL (25-50%) – progression in half (mainly first 2 years) b. Asymptomatic congenital CMV i. Sensorineural hearing loss (5%) – progression in half ii. Ocular manifestations (retinal lesions, strabismus (1-2%)) 5. Neonatal management a. Asymptomatic i. No specific treatment ii. Audiology follow-up b. Symptomatic = ganciclovir (IV), valganciclovir (PO) i. Duration of treatment – 6 months 1. If unwell – first 2 weeks IV ganciclovir 2. Following this treatment continued with oral valganciclovir ii. Monitoring for toxicity 1. FBE – drug-induced neutropenia and thrombocytopaenia 2. LFT – drug-induced hepatitis 3. UEC – drug-induced nephrotoxicity iii. Assessing treatment response 1. Clinical evaluation 2. Viraemia levels – goal non-detectable levels iv. Antiviral resistance should be suspected in infants with progressive end-organ disease despite adequate treatment, rising levels over the first two weeks, or a sustained increase after an initial decline v. Alternative if resistance – foscarnet

Answer 194

a. Mother i. Primary infection = new positive IgG, IgM ii. Reactivation = IgM iii. AVIDITY – low avidity indicates recent infection iv. NB. Primary CMV only diagnosed in 20-25% of IgM positive mothers b. Fetus i. Fetal USS – many features 1. Microcephaly, ascites, oligo or polyhydramnios 2. Abdominal calcification, hydrocephalus, intracranial calcification 3. Hydrops fetalis, pleural or pericardial effusion 4. Hepatomegaly, hyperechogenic bowel ii. Amniocentesis for PCR – poor sensitivity but 100% specificity 1. Cannot predict degree of fetal damage c. Neonate i. Diagnosis of congenital CMV 1. Patients with congenital CMV have very high viral load in urine, saliva and blood 2. Must test <=3 weeks of birth 3. Options a. Urinary CMV PCR b. Blood PCR (viral load) c. Gurthrie PCR 4. Can be retrospectively diagnosed using Guthrie spot PCR ii. Other investigations 1. FBE = thrombocytopaenia 2. LFT = elevated transaminases, elevated conjugated + unconjugated bilirubin 3. Ophthalmology = chorioretinitis 4. CRUSS = hydrocephalus 5. MRI = intracranial calcification (usually periventricular), ventriculomegaly, lenticulostriate vasculopathy, cerebral atrophy, migrational abnormalities (focal polymicrogyria, pachygyria, lissencephaly) iii. If any investigations are abnormal  ‘symptomatic’ CMV iv. If investigations are normal  ‘asymptomatic’ CMV

Answer 195

* Usually self-limiting infection in pregnant women * Maternal HAV does not increase risk of congenital malformations, still births, IUGR or spontaneous abortions * Increased risk of premature labour and PROM * Acquired neonatal disease rare

Answer 196

1. Key points a. Risk of chronic infection and subsequent liver disease is inversely proportional to age at time of infection b. Acute HBV infection during pregnancy is not severe or associated with teratogenicity c. 90-95% of HBV infections <1 year old result in chronic liver disease 2. Maternal screening a. Routine maternal screening with HBsAg b. Overall risk of transmission 90% - reduced by 95% with management c. Risk of transmission on maternal status i. sAg +ve = carrier (5-20% vertical transmission) ii. eAg +ve = higher risk carrier (90% transmission) 3. Clinical manifestations a. Newborn infants with HBV rarely show any clinical or biochemical evidence of disease b. Mild persistent elevation of transaminases 2-6 months of age (immune tolerant phase) c. Very small number develop acute hepatitis by 2 months of age 4. Acute management a. Maternal i. Check HBV DNA in mother, if HBV DNA >107 IU/ml -> treat with lamivudine, tenofovir or telbivudine from 30 weeks ii. Monitor for flare during pregnancy b. Neonate i. All neonates = Hepatitis B vaccine + Ig (within 12 hours)  prevents 95% (even if mother eAg +ve) ii. Give within 12 hours iii. Usual vaccines at 2, 4 and 6 months c. NOTE i. No evidence that offering LUSCS reduces risk ii. Breastfeeding is recommended iii. Consider minimising invasive procedures antenatally and intrapartum particularly in women with high viral lode 5. Long-term management a. Follow-up i. Serology a 9-12 months including HBsAg and anti-HBs ii. If negative anti-HBs (<10 IU/ml)  consider repeat doses of vaccine iii. If anti-HBs (>10 IU/ml) and HBsAg ve –ve  no further management iv. If HBsAg positive  referral to paediatric GI/infectious disease physician b. Note i. If vertical transmission does not occur, chance of horizontal transmission until 5 year old ii. Vaccinate household contacts and sexual partners

Answer 197

1. Key points a. Vertical transmission is the primary source of paediatric infection 2. Maternal screening a. Hepatitis C antibody b. If positive -> HCV RNA and LFTs i. HCV RNA negative = false positive, past cleared infection, past successful treatment, or low level of viraemia ii. If positive = risk of perinatal transmission only 5% 3. Clinical manifestations a. Asymptomatic b. Mild elevation in ALT c. Infections acquired during infancy often clear spontaneously – typically by 3 years of age 4. Maternal management a. Treatment of HCV contraindicated during pregnancy b. No effective interventions to reduce transmission c. Consider minimising invasive procedures d. No clear evidence that maternal LUSCS reduces transmission e. No increased risk with breastfeeding – however consider expressing and discarding milk if nipples cracked and bleeding 5. Neonate management a. HCV RNA test at 3/12 b. HCV Ab test at 12-18 months – most uninfected infants are antibody negative by 12 months (maternal Ab until this time therefore cannot infer neonate infection) i. HCV Ab +ve  HCV RNA and LFTs ii. HCV Ab –ve  not infected

Answer 198

 HSV1 = usually oral  HSV2 = usually genital Classification • Congenital = intrauterine – 5% • Intrapartum = perinatal (infected secretions) – 85-90% • Postnatal = caregiver with HSV – 5-10%

Answer 199

1. Key points a. True intra-uterine infection accounts for <5% of reported cases b. Usually occurs in women with newly acquired infection 2. Pathogenesis a. Maternal primary HSV and viraemia results in placental infarcts and inflammation of umbilical cord 3. Manifestations a. Hydrops fetalis b. Fetal in utero demise c. Congenital malformations i. Triad 1. Skin vesicles, ulcerations or scarring 2. Eye damage 3. Severe CNS manifestations – microcephaly, hydrancephaly ii. Other 1. Chorioretinitis 2. Micropthalmia

Answer 200

1. Risk factors a. Type of maternal infection = primary, reactivation with symptoms/reactivation without symptoms b. History of herpes labialis c. Transmission of maternal Ab d. Duration of ROM e. Fetal scalp electrode  increases risk of transmission f. Method of delivery  C/S reduces risk of transmission 2. Vertical transmission a. First episode primary = 50-65% i. New acquisition of either HSV serotype (1 or 2) without prior exposure (ie. seronegative) b. First episode non-primary = 25% i. Acquisition of a new HSV serotype, with evidence of exposure to another serotype (already had 1, now has 2, or vice versa) ii. Non-specific Ab to other HSV virus provides partial infection c. Recurrent <2% i. Maternal Ab pass to fetus d. Note: i. Most genital HSV infections (primary, non-primary OR recurrent) are asymptomatic ii. Therefore most mothers of infants with neonatal HSV were previously unaware of their own infection iii. 2% of pregnant women acquire genital HSV in pregnancy, 70% of primary cases are asymptomatic 3. Paradox of symptomatic disease at labour and delivery a. Most symptomatic women have RECURRENT disease (lower risk) b. Therefore women with symptoms have lower risk i. Antibody passage to baby ii. Preventative regimens instituted eg. C/S

Answer 201

4. Maternal management a. History of genital herpes i. Consider use of suppressive antiviral therapy from 36 weeks ii. Careful speculum examination in labour 1. No active lesions -> vaginal delivery 2. Active lesions -> management of newborn as below b. No history of genital herpes i. First genital HSV infection diagnosed during pregnancy 1. HSV serology + type specific HSV PCR 2. Recurrent infection (HSV Ab+ve to same HSV from genital swab) -> same as for history of herpes above 3. New infection (HSV Ab –ve to same HSV from genital swab) a. Diagnosis made early in pregnancy (first or second trimester) -> same as for history of genital herpes above b. Diagnosis made late in pregnancy (ie third trimester) i. Consider suppressive antiviral from 36 weeks ii. Delivery by LUSCS ii. First genital HSV infection diagnosed during labour 1. Delivery by LUSCS 2. HSV type specific PCR on genital swab 3. Management of newborn as below 5. Neonatal management a. Risk stratification i. Low risk 1. Mother with recurrent genital infection, OR 2. Mother with primary infection seroconverted well prior to delivery, AND 3. Without genital lesions at delivery ii. High risk 1. Mother with primary genital infection close to delivery, OR 2. Infant born through birth canal with active HSV disease to mother with no prior history of active genital HSV iii. ‘Symptomatic neonate’ 1. Vesicular lesions or atypically pustular or bullous lesions 2. Seizures 3. Unexplained sepsis 4. Low platelets, elevated LFTs, DIC 5. Respiratory distress 6. Corneal ulceration, keratitis b. Management of low risk i. Transmission rare in this setting ii. Practice varies between centres c. Management of high risk + symptomatic neonate i. Investigations 1. LP 2. FBE – thrombocytopaenia 3. LFTs 4. HSV PCR on blood 5. Surface swabs – eye, throat, umbilicus, rectum, urine ii. Treatment = aciclovir

Answer 202

a. Skin eye mouth (dx of EXCLUSION) - 45% i. 10-12 days of life – can present any time during first 6 weeks ii. High risk of progression to CNS or disseminated disease if not treated iii. Skin 1. Localised skin disease associated with coalescing or clustering of vesicular lesions with an erythematous base 2. May begin at presenting part of the body, or sites of trauma 3. Note skin lesions can occur late in the course of disseminated disease iv. Eye 1. Excessive watering of eye, crying from eye pain, conjunctival erythema, periorbital skin vesicles 2. HSV keratoconjunctivitis may progress to cataracts and chorioretinitis – permanent visual impairment v. Mouth 1. Local ulcerative lesions of the mouth, palate and tongue 2. Differentiate from other causes of oral lesions (eg. trauma, enterovirus) 80% skin lesions, mortality 10% Swabs (>90% pos), blood (75% pos), CSF (negative) b. CNS - 30%, mortality 50% i. 16-19 days of life – can present any time during first 6 weeks ii. Can result from retrograde spread from the nasopharynx and olfactory nerves to the brain or haematogenous spread in neonates with disseminated disease iii. May occur with or without disseminated/SEM disease iv. Clinical manifestations 1. Lethargy, irritability, tremors 2. Seizures (60%) – focal or generalised 3. Poor feeding, temperature instability 4. Full anterior fontanelle Skin lesions present 60-70% Swabs (>90% pos), blood (65% pos), CSF (75-100% pos) EEG+MRI c. Disseminated - 25%, mortality 80% i. 10-12 days of life ii. Sepsis like presentation involving multiple organs iii. Clinical manifestations 1. Liver = hepatitis, ascites, jaundice, liver failure requiring transplantation 2. Lungs = pneumonia, haemorrhagic pneumonitis, effusion, respiratory failure 3. CNS = as above 4. Heart = myocarditis 5. Adrenal glands 6. Bone marrow + coagulation = DIC, thrombocytopaenia, neutropenia 7. GI = necrotising enterocolitis Skin lesions 60-80% CNS involvement 60-75% Seizures 60% Swabs >90% pos, blood 100% pos, CSF >90% pos

Answer 203

1. Key points a. >95% of HIV infected children have acquired it vertically b. Exposure through pregnancy, birth or breast-feeding c. Can be transmitted early in gestation BUT MOST occur near or at delivery i. In utero transmission if HIV PCR positive <48hrs after delivery ii. Peripartum transmission HIV PCR positive >48hours age d. Transmission risk in developed countries in the ABSENCE of preventative strategies i. Breastfed infants = 40% ii. Non-breastfed infants = 20% e. Rate of vertical transmission IN ABSENCE OF ART = 20-30% f. ART in HIV pregnant women has decreased vertical transmission, rate now <2% g. Transmission risk if mother is on HAART and breastfeeds = 1-5% 2. Maternal screening a. Part of routine antenatal screening – HIV antibody i. Screen with ELISA ii. Confirmed with Western Blot b. HIV +ve  multidisciplinary care c. HIV –ve  repeat in 4/52 if high likelihood

Answer 204

3. Vertical transmission a. Intrauterine (before delivery) = PCR +ve at <48 hours of age i. 20-30% of infected newborns are infected in utero (PCR positive in first week of life) b. Intrapartum (during delivery) = PCR +ve at >48 hours of age i. Higher percentage of HIV-infected children acquire virus intrapartum – 70-80% of infected infants do not demonstrate detectable virus until >1 week of age ii. Through exposure to infected blood + cervicovaginal secretions iii. Elective LUSC ↓ transmission by 87% in conjunction with zidovudine (benefit likely negligible if viral load < 1000) c. After delivery via breastfeeding i. Breastfeeding LEAST common route of vertical transmission in industrialized nations, but as much as 40% of perinatal infections in resource-limited countries ii. Risk 9-16% in women with established infection iii. Risk 29-53% in women who acquire HIV postnatally 4. Risk of transmission a. Majority of in utero transmission likely occur late in gestation – vascular integrity of the placenta weakens and microtransfusions across the maternal-fetal circulation occur b. Maternal i. High viral load ii. Low CD4 count iii. Non-compliance/incomplete treatment c. Delivery i. Preterm delivery (<34 weeks) ii. ROM >4hours (doubles risk) iii. Vaginal vs. C/S d. Baby i. BW <2.5kg (doubles risk)

Answer 205

a. Maternal i. Effective HAART important ii. Vial load <50 copies/ml at 36 weeks gestation 1. If yes a. No intrapartum zidovudine b. Vaginal delivery if no obstetric contraindications 2. If no a. Intrapartum zidovudine b. Planned LUSCS b. Neonatal i. Avoid use of scalp clips in labour ii. Infant ALWAYS fed with formula in developed countries (BF in developing countries) iii. Commence antiretroviral prophylaxis (4/52) – varies based on the risk to the neonate 1. Low risk (<2%) a. Zidovudine monotherapy within 6-12 hours for 4 weeks 2. High risk (>2%) a. Lamivudine + neviarpine + zidovudine b. PJP prophylaxis iv. Testing infant 1. HIV PCR (DNA or RNA) 2. HIV antibody (only >=18 months of age) 3. Occur at least 2 weeks and 2 months after antiretroviral prophylaxis is ceased

Answer 206

1. Key points a. Pregnancy does NOT increase risk of inactive TB becoming active b. Routine screening for TB in pregnancy is not standard practice 2. Vertical transmission a. Airborne spread post-delivery = most common i. Isolation from mother NOT recommended b. Risk stratification i. High risk 1. Maternal TB with haematogenous spread (disseminated or miliary TB) 2. Active pulmonary TB – mother infectious (sputum smear positive) at time of delivery ii. Low risk 1. Mother on anti-TB treatment – not infectious 2. Mother completed anti-TB treatment during pregnancy – not infectious 3. Clinical manifestations a. Respiratory distress b. Hepatosplenomegaly c. Fever d. Poor feeding

Answer 207

4. Maternal management a. Proven maternal TB should be treated b. Active TB requires immediate treatment c. All anti-TB drugs cross placenta i. Isoniazid, rifampicin + ethambutol – safe during pregnancy 1. Isoniazid has a higher risk of hepatotoxicity – require close monitoring ii. Pyrazinamide – less data; recommended by WHO iii. Streptomycin is contraindicated in pregnancy 5. Management of neonate a. High risk i. Assess neonate for clinical evidence of TB 1. Absent a. Investigations = CXR and gastric aspirates x3 b. Management i. No evidence of TB  INH (isoniazid) for 6 months ii. TB  treatment 2. Present a. Investigations i. CXR, gastric aspirates x3 and LP ii. Placental examination b. Management = TB treatment b. Low risk i. Assess neonate for evidence of TB (as above) 1. Absent a. INH for 6 months b. TST at 3 months and 6 months 2. Present – as above ii. If TST (TB skin test) is positive at any time  treatment c. BCG – should be considered if there is any possibility of future exposure to TB 6. Note a. If another close contact of newborn has TB – separation is preferable, if not possible should be given INH prophylaxis until the culture has been culture-negative for 3 months b. TST positivity can be delayed for up to 6 months – INH must be continued until this time

Answer 208

1. Key points a. B19 viraemia begins 6 days after exposure and lasts for one week – contagious prior to symptoms (5-10 days) 2. Maternal infection a. 60% of pregnant women are immune b. Risk of infection if susceptible i. Exposure at home – 50% ii. Exposure at school/ child care = 20-30% iii. Exposure in community = <20% c. Note i. It is not practicable to prevent exposure at home ii. Exclusion from work of pregnant school teachers/CCW child not recommended during parvovirus epidemics, which are often very prolonged (nor is exclusion of infected children) iii. Routine antenatal screening is not indicated 3. Vertical transmission a. Risk of transmission to neonate = 50% b. Outcome if maternal infection i. < 20 weeks = 10% fetal loss ii. 9-20 weeks = 3% hydrops 1. Spontaneous resolution 32% (usually within 8 weeks) 2. Death without intrauterine transfusion 33% 3. Resolution after intrauterine transfusion 27% 4. Death after intrauterine transfusion 6% c. NO long-term neurodevelopmental sequelae of infected children

Answer 209

4. Diagnosis a. Maternal i. IgM is detectable within 1-3 weeks of exposure and usually remains detectable for 2-3 months ii. Serology 1. IgG +ve, IgM –ve = immune 2. IgG –ve, IgM –ve = susceptible 3. IgG-ve, IgM +ve = ? recent infection 4. IgG +ve, IgM +ve = recent infection iii. If susceptible or possible recent infection 1. Repeat IgG in 2-4 weeks 2. IgG –ve = false positive IgM  no further action 3. IgG +ve = recent infection b. Fetal i. Fetal infection may be identified by using (non-quantitative) PCR on amniotic fluid or fetal cord blood ii. HOWEVER amniocentesis for diagnosis of asymptomatic intrauterine fetal infection is NOT recommended iii. Doppler assessment of the fetal middle cerebral artery peak systolic velocity is an accurate tool for the determination of fetal anemia and provides a noninvasive alternative to cord blood sampling 5. Management of fetus a. No intervention is available to prevent fetal infection or damage b. Termination is not indicated because of low risk of fetal damage c. Confirmed maternal infection <20 weeks gestation i. USS at 1-2 weekly intervals for 12 weeks ii. No fetal abnormality after 30 weeks gestation  no further action iii. Fetal anaemia  fetal blood sampling +/- intrauterine transfusion

Answer 210

1. Key points a. Reduction in incidence since MMR introduced – up to 10% susceptible b. Re-infection occurs in around 2% - usually subclinical 2. Risk of transmission a. Primary infection i. Risk of fetal infection +/- damage related to timing ii. 1-12 weeks = 80% infection, 85% congenital defects iii. 13-16 weeks = 50% infection, 35% congenital defects iv. 17-22 weeks = 36% infection, congenital defects rare v. 23-30 weeks = 30% infection, congenital defects rare vi. 31-36 weeks = 60% infection, congenital defects rare vii. >36 weeks = 100% infection, congenital defects rare b. Re-infection i. If asymptomatic reinfection with a good history of previous positive serology, then risk of fetal infection is <10% ii. Risk of fetal injury is difficult to quantify and has been reported to be <5% iii. Thus, CRS following maternal reinfection is considered to be rare, particularly if reinfection is after 12 weeks of gestation

Answer 211

3. Clinical manifestations a. <12 weeks = congenital rubella syndrome i. At birth or early manifestations 1. Deafness – sensorineural 2. CNS dysfunction – mental retardation, dev delay, microcephaly 3. Heart defects – PS, PDA 4. Ophthal abnormalities – cataracts, microphthalmos, retinopathy, glaucoma, strabismus, cloudy cornea 5. Other – IUGR, haematological abnormalities, GIT abnormalities, pneumonitis and osteitis ii. Late manifestations 1. Deafness – sensorineural 2. Neurological deficiencies 3. Epilepsy 4. Retinopathy 5. Other – tooth defects, growth retardation 6. IDDM, thyroid dysfunction 7. Panencephalitis b. 12-18 weeks = sensorineural deafness c. >18 weeks = rare 4. Diagnosis a. Maternal i. Positive IgM ii. Rising IgG titre iii. IgG seroconversion iv. Note: Positive IgM persist for 2/12 after primary infection b. Fetal i. Serology (IgM), PCR (urine, eye and throat swab)

Answer 212

5. Maternal management a. Consider TOP if maternal infection in first trimester b. If maternal infection in second trimester, consider fetal testing i. Cord blood IgM or PCR of amniotic fluid c. Maternal infection > 20 weeks is rarely associated with CRS 6. Neonatal management a. Symptomatic infected infant OR asymptomatic infected infant (risk of late onset disease months or years after birth) i. Nonspecific management ii. Breastfeeding not contra-indicated iii. Audiometry – deafness may be progressive iv. Ophthal – progressive retinal damage v. Endocrine problems long term – diabetes, hypothyroidism vi. Cardiac investigation and management b. Infant probably not infected i. No specific management 7. Rubella prevention a. Vaccine (live attenuated) -> 95% immunogenic, 90% lifelong protection b. Seronegative women vaccinated postpartum – avoid vaccination during pregnancy

Answer 213

1. Key points a. Toxoplasma gondii = protozoan parasite b. Zoonosis – domestic animal esp cats  eat oocyst in cat faeces or infected meat c. Incidence – 0.2-10 per 1000 pregnancies d. Most women asymptomatic – can have flu-like illness or lymphadenopathy 2. Vertical transmission a. Risk to fetus greatest in first trimester b. Risk assessment = highest risk of infection 3rd trimester, highest risk of fetal damage 1st trimester i. First trimester 1. Fetal infection = low risk 4-15% 2. If infected = high risk (34-85%)  likely to be severe fetal damage ii. Second trimester 1. Fetal infection = intermediate risk 25-44% 2. If infected = intermediate risk (18-33%)  likely to be less severe iii. Third trimester 1. Fetal infection = high risk 30-75% 2. If infected = low risk (4-17%)  usually asymptomatic at birth

Answer 214

3. Clinical manifestations – congenital toxoplasmosis a. Classic tetrad i. Chorioretinitis ii. Hydrocephalus/ microcephaly iii. Convulsions iv. Intracranial calcification b. Generalised – lethargy, malaise, poor feeding, vomiting, diarrhoea, temp instability, jaundice c. Haematopoietic – hydrops, rash due to TTP, blueberry muffin, lymphadenopathy, hepatosplenomegaly d. Neurological – convulsion, hydrocephalus, microcephaly, chorioretinitis 4. Diagnosis a. Maternal i. Antenatal screening NOT routine in Australia, but often done ii. IgG –ve, IgM +ve = recent toxoplasmosis iii. IgG +ve, IgM –ve = past infection, no further action iv. IgG +ve or –ve, IgM +ve = probable recent infection 1. Recheck IgM and IgG 2. Check IgG avidity 3. If asymptomatic and/or inconsistent/low IgM, IgA –ve or high IgG avidity  low risk b. Fetal i. Intra-uterine fetal testing 1. USS +/- fetal MRI confirmation 2. T. gondii PCR on amniotic fluid at 18-20 weeks gestation or >=4 weeks after maternal infection has high sensitivity and specificity ii. PCR and USS negative = fetus not infected 1. Continue maternal treatment if certain iii. PCR +ve with or without abnormal USS 1. Consider termination 2. Treat mother

Answer 215

5. Management a. Maternal/fetal i. Consider treatment – depending on gestation and certainty of diagnosis ii. <=18 weeks – spiramycin 1. Goal is to prevent vertical transmission iii. >= 18 weeks – pyramethamine + sulfadiazine + folinic acid 1. Goal to treat fetus 2. Not safe in first trimester b. Neonatal i. Treatment = Pyrimethamine + sulphadoxine +/- spiramycin for one year ii. Investigations 1. Infant blood IgM and/or IgA 2. Maternal blood and infant IgG 3. Placental histology/PCR 4. Blood +/- CSF PCR iii. IgM +ve and/or IgA and/or PCR +ve and/or fetal IgG higher than mothers 1. Further investigations a. Full clinical examination b. Imaging c. Ophthal review d. Audiology 2. If abnormal = symptomatic congenital toxoplasmosis 3. If normal = asymptomatic congenital toxoplasmosis [MAJORITY] iv. Fetal, infant Ix and placental Ix normal 1. Still do full workup as above 2. If abnormal commence treatment if signs consistent with congenital toxoplasmosis 6. Long-term outcome a. Infants symptomatic at birth have significant disability i. Chorioretinitis ii. Developmental delay iii. Seizures iv. Microcephaly v. Deafness

Answer 216

1. Key points a. Significant issue – affects 1 million pregnancies/year 2. Vertical transmission a. Intrauterine = transplacental transmission of spirochetes in maternal blood stream; most common i. Occurs with increasing frequency as gestation advances ii. Untreated primary or secondary fetuses most likely to transmit b. Intrapartum = occasionally due to contact with infectious lesion during delivery c. NOT transmitted in breast milk

Answer 217

a. Transplacental spread i. Abortion ii. Fetal death iii. Hydrops fetalis iv. Preterm labour v. IUGR b. Congenital syphilis i. Early features 1. Wide spectrum, including fulminant sepsis 2. Maculopapular rash on back, legs, palms, soles 3. Bullous/desquamation 4. Rhinitis/snuffles 1/52-3/12 5. Lymphadenopathy + HSM 6. Osteitis 7. Jaundice, pancytopenia, edema ii. Untreated, late features 1. Facial features = frontal bossing, saddle nose, short maxilla, protruberant mandible 2. Ophthal = interstitial keratitis, chorioretinitis, secondary glaucoma, corneal scarring, optic atrophy 3. Ears = SNHL 4. Oropharynx = Hutchinson teeth, mulberry molars, perforation of hard palate 5. Cutaneous = rhagades, gummas 6. CNS = ID, arrested hydrocephalus, seizures, paresis 7. Skeletal = saber shins (anterior bowing), Higoumenakis sign (enlargement of sternoclavicular portion of clavicle), Clutton joints (painless arthritis), scaphoid scapula ``` STAGES Primary - Chancre - Transmission risk: High Secondary - Systemic illness including fever, rash, hepatitis, lymphadenitis, meningoencephalitis - Transmission: Moderate Latent - Asymptomatic, <2 years – early, >2 years – late - Transmission: Low Tertiary - Cardiovascular - Neurological - Gummatous lesions - Transmission: Negligible ```

Answer 218

4. Screening tests a. Non-treponemal test = RPR, VDRL i. Non-specific cardiolipin  detect antibodies against phospholipid antigens on the treponemal surface that cross react with mammalian cardiolipin lecithin cholesterol antigens ii. Useful for screening iii. Sensitive (negative = ruled out) but not specific tests (positive = not ruled in) iv. Positive results may indicate syphilis but confirmatory tests are required v. Correlate with active disease – usually become nonreactive within 1 year of adequate therapy / 2 years of adequate therapy for secondary disease b. Treponemal test = TPPA, TPHA, EIA i. Become positive after initial infection ii. Usually remain positive for life – do NOT correlate with disease activity iii. Useful for diagnosis of first episode, distinguishing false +ve results of non-treponemal antibody test iv. FTA-Abs = fluorescent treponemal antibody test v. TPPA = treponema pallidum particle agglutination assay vi. TPHA = treponemal pallidum hamagluttination assay vii. EIA = enzyme immunoassay 5. Maternal screening a. Screening with non-specific treponemal tests (RPR and VDRL titre) i. Highly sensitive, but NOT specific ii. If positive, then specific TPHA/ FTA Abs titre iii. At booking – and then at 28-32/40 if high risk b. Benefits of antenatal i. Prevent congenital infection ii. Prevent further sexual transmission iii. Prevent progression to tertiary syphilis c. If positive – determine stage d. Maternal treatment = benzathine penicillin or procaine penicillin e. Repeat VDRL or RPR monthly until delivery i. Negative or 4 fold drop in titre = successful treatment f. If treatment not successful – consider higher risk of congenital syphilis

Answer 219

a. If suspected congenital syphilis i. Infant serology = IgM, RPR – run in parallel with maternal serology ii. Full clinical examination 1. Rash 2. Mucosal lesions 3. Hepatomegaly 4. Nasal discharge 5. Bony tenderness 6. Eye lesions iii. Placental histology +/- PCR if available b. If serology abnormal, abnormal examination, or placental investigations possible  further investigations i. FBE, LFT, UEC ii. CXR iii. LP/CSF c. Congenital syphilis or abnormal CSF = treat for 10 days with benzylpenicillin or procaine penicillin

Answer 220

1. Risk of transmission a. <12 weeks gestation = 0.4% b. 12-18 weeks gestation = 2% c. >28 weeks gestation = no cases 2. Clinical manifestations a. IUGR b. Cicatricial skin scarring (zigzag dermatomal) c. Limb hypoplasia d. Neurological – microcephaly, cortical atrophy, seizures, DD e. Eye – chorioretinitis, microphthalmia, cataracts f. Renal – hydroureter/nephrosis g. ANS – neurogenic bladder, swallowing dysfunction, aspiration 3. Pregnant lady exposed to varicella – TWO key questions a. Past Hx of chickenpox b. Past vaccine of chickenpox c.  varicella serology 4. Maternal varicella exposure a. Previous maternal chickenpox or vaccination  no action required b. Uncertain  check serology urgently c. If seronegative (or serology not available) – assess time of exposure i. Exposure <= 96 hours earlier = ZIG ii. Exposure >= 96 hours earlier = no ZIG, consider oral aciclovir post-exposure prophylaxis if at risk (second half of pregnancy, underlying lung disease, immunocompromised, smoker) 5. Management a. Fetal USS is recommended for 5/52 after primary infection b. If abnormal consider fetal MRI c. VZV fetal serology unhelpful d. Amniocentesis not advised

Answer 221

Period of risk is -7 to +2 days from delivery 1. Transmission a. Neonatal varicella has high mortality – up to 30% i. WORST situation is VZV spreading via placental route b. Incubation period 14 days (max 21 days) c. IgG (from mum) takes 5 days to be produced and transmitted to babies d. Therefore, most risk of varicella occurs if: i. Mother has rash 5 days before birth (not time for IgG to cross), or ii. Mother develops rash 2 days after birth (because of 48 hours infectivity prior to appearance of rash) e. NOTE: exception is the premature neonate because no IgG crosses 2. Management of maternal chickenpox a. Dependent on timing of maternal chickenpox – in all cases breastfeeding encouraged and NO isolation b. Maternal chickenpox > 7 days before delivery  no intervention c. Maternal chickenpox 7 days before to 2 days after delivery  ZIG d. Maternal chickenpox >2-28 days after delivery  dependent on neonatal risk factors i. If infant <28 weeks gestation or <1000g birth weight give ZIG within 96 hours but can be given up to 10 days post maternal rash ii. Discharge term infants as soon as possible iii. Some experts give ZIG to term babies >2-28 days of age when mother develops chickenpox but little data to support this e. Newborn develops chickenpox i. Very-pre term infant in nursery  IV aciclovir ii. Term infant at home or on post-natal ward 1. Mild disease and ZIG given <24 hours after birth = observe, treat with IV aciclovir if respiratory symptoms 2. Severe disease or ZIG given >24 hours after birth = treat with IV aciclovir 3. Term neonate exposed to chickenpox a. Mother vaccinated  no further intervention b. Unsure or no maternal vaccine i. Positive serology  no further intervention ii. Seronegative or serology unavailable  consider ZIG to infant (ideally within 96 hours but can be given up to 10 days later)

Answer 222

1. Key points a. Arthropod-borne flavivirus b. Transmitted by mosquitos c. Discovered in Africa in 1947 d. Epidemics through the pacific since 2007 e. 2015 outbreak in Brazil found association with Zika infection with microcephaly f. Highly neurotropic virus g. No specific treatment h. Association with Guillane Barre 2. Transmission a. Spread via Aedes mosquito b. Sexual transmission reported c. Greatest risk with first trimester infection 3. Diagnosis a. Prenatal i. USS ii. Amniotic fluid PCR – predictive of fetal viral exposure but not infection

Answer 223

a. Mother i. Incubation 3-12 days ii. Symptomatic in 20% of cases iii. ‘Influenza like syndrome’ 1. Low grade fever 2. Arthralgia especially hands and feet 3. Myalgia 4. Headche, retro-ocular headache 5. Conjunctivitis 6. Maculopupalr rash 7. Post-infection asthenia b. Neonate i. Neurological 1. Microcephaly 2. Intracranial calcifications 3. Ventriculomegaly, porencephaly, hydrancephaly 4. Abnormal gyral pattern 5. Cerebral atrophy 6. Cortical atrophy and malformation, cerebellum hypoplasia 7. Delayed myelination 8. Thinning or hypoplasia of corpus callosum ii. Ocular findings 1. Chorioretinal atrophy or scarring, microphthalmia 2. Pigmentary changes, coloboma, cataract 3. Optic nerve hypoplasia, optic disc pallor, increased cupping 4. Haemorrhageic retinopathy, abnormal retinal vasculature iii. Consequences of CNS dysfunction 1. Congenital deafness 2. Orthopaedics – clubfoot, arthrogryposis Unique features: congenital contractures, severe microcephaly with partially collapsed skull, thin cerebral cortices with subcortical calcification, macular scarring, marked hypertonia

Answer 224

5. Management a. Nil b. Breastfeeding not contraindicated 6. Prevention a. Pregnant women should i. Avoid travel to areas with known mosquito transmission ii. Mosquito protection iii. Avoid unprotected sex with a partner in high risk area iv. Avoid blood donation

Answer 225

1. Key points a. Breast infection (mastitis or breast abscess) typically occurs in infants younger than two months of age (infant mastitis) and lactating women b. Equal M:F ratio 1st 2 weeks of life 2. Microbiology a. Staphylococcus aureus b. Less common - gram-negative enteric organisms (eg, Escherichia coli, Salmonella), anaerobes, and group B streptococcus (S. agalactiae) 3. Clinical features a. Marked erythema, tenderness, and induration of the affected breast bud b. Purulent nipple discharge and breast abscess may be present (20%) c. The axillary lymph nodes may be enlarged and tender d. One-quarter of patients may also have fever (>101ºF (38.3ºC)

Answer 226

1. Key points a. Potential cause of blindness - EMERGENCY 2. Clinical manifestations a. Chemosis of the conjunctiva (swelling) b. Oedema of the eyelids c. Discharge which may be purulent 3. Aetiology a. Chlamydia trachomatis – most common cause (GN coccobacillus, typically 5-15 days) b. Neisseria gonorrhea (GN diplococci, w/i 5 days) c. HSV d. Staph, strep and GN species 4. Investigations a. Swab – MCS and PCR

Answer 227

a. Neisseria gonorrhoea i. Involves cornea ii. Vertical transmission from maternal birth canal iii. Classically presents in 1st week of life – 2-5 days incubation iv. Classically a hyper-purulent discharge v. Gonococcal conjunctivitis is a true ocular emergency vi. Complications 1. Corneal ulceration 2. Perforation 3. Anterior synechiae (adhesions of the iris to ocular structures) 4. Pan-ophthalmitis vii. Treatment 1. IV ceftriaxone 2. Eye irrigation b. Chlamydia trahcomatis i. Involves tarsal conjunctiva ii. Vertical transmission iii. 5-14 days incubation iv. Also check for pharyngitis, otitis media and pneumonia v. Treatment 1. Oral azithromycin 3 days 2. Treat the parents vi. 5-30% get delayed onset pneumonia at 2-4 weeks – staccato cough c. HSV i. Vertical transmission from maternal birth canal ii. HSV may affect skin, eyes or mouth BUT in most patients it affects CNS, liver, or lungs iii. High risk of neonatal infection if mother has primary infection & NVD occurs iv. Risk is lower when mother has recurrent disease BUT most is asymptomatic v. Can causes conjunctivitis, keratitis, retinochoroiditis and cataract vi. Treat with IV aciclovir and topical antivirals vii. Confirmed by virus culture/PCR/antigen testing in swabs, blood and CSF

Answer 228

GN coccobacillus 1. Key points a. Most common cause of STI b. Infants born vaginally to infected mothers with genital disease at risk of acquiring Chlamydia 2. Transmission a. Via exposure to infected mother’s genital flora during transmission b. Risk of transmission 50% in women with active cervicitis c. Rate of symptomatic infection i. Conjunctivitis 15-50% ii. Pneumonia 5-20% 3. Clinical manifestations a. Conjunctivitis i. Most frequent clinical manifestation ii. Incubation period 5-14 days – presentation <5 days is unusual iii. Clinical findings = range; mild swelling with watery eye discharge which becomes mucopurulent to marked swelling of the eyelids with red and thickened conjunctiva, a pseudomembrane may form, may be bloody discharge from friable conjunctiva iv. Untreated infants may have persistent conjunctivitis for months that may result in corneal and conjunctival scarring b. Pneumonia i. 50% of infants with chlamydia pneumonia have a history of conjunctivitis ii. Affects babies between 4 and 12 weeks of age iii. Some infants have upper respiratory tract symptoms from 2/52 of age iv. Clinical manifestations 1. URTI symptoms from 2/52 of age 2. Cough and nasal congestion without significant discharge 3. Otitis media may be present 4. Usually afebrile or minimal fever 5. Characteristic features = staccato cough that may occur in paroxysms, tachypnoea 4. Investigations a. Culture + PCR b. CXR = hyperinflation with bilateral symmetrical infiltrates 5. Treatment a. Maternal screening of pregnant women b. Treat conjunctivitis based on culture = PO azithromycin c. Treat pneumonia based on presumptive diagnosis = IV azithromycin

Answer 229

1. Key points a. 3rd most common bloodstream infection in premature infants b. Occurs in < 0.3% infants > 2.5kg, 12 % infants < 750g BW c. 10% of full term infants colonized via vertical transmission, increasing to 50% among infants admitted to NICU by 1 month of age 2. Risk factors for invasive disease a. Prematurity b. LBW c. Broad spectrum ABX d. Abdominal surgery e. CVC 3. Clinical manifestations a. Sepsis b. CNS disease c. Endopthalmitis (< 5%) , increases risk of severe ROP d. Renal involvement also common 4. Diagnosis = requires histologic examination of sterile fluid a. Skin scrapings for skin lesions b. Thrombocytopenia occurs in > 80% of infants but is nonspecific 5. Management a. Remove any lines b. Check eyes, head, LP and kidney , echo c. Antifungal therapy – treat for 21 days post last +ve culture i. Amphotericin B = the mainstay of Rx ii. Fluconazole (esp if evidence of urinary tract infection) iii. Echinocandins – consider if C. krusei/ C. glabrata

Answer 230

1. Key points a. >90% enteroviral infections in adults either asymptomatic or cause non-specific febrile illness 2. Transmission a. In utero transmission in late gestation has been described b. Intrapartum exposure to maternal blood, genital secretions and stool c. Postnatal exposure to oropharyngeal secretions from mother and other contacts 3. Clinical manifestations a. Wide spectrum of clinical presentations i. Fever, irritability, poor feeding, lethargy ii. Maculopapular rash 50% iii. Respiratory symptoms 50% iv. GIT symptoms 20% v. Hepatitis 50% vi. May have myocarditis, meningoencephalitis 4. Investigations a. PCR i. Rapid, sensitive and specific ii. Isolation from stool not specific, can be shed in stool for several weeks iii. Detection in blood, CSF and tissue most reliable 5. Treatment a. No currently available treatment b. IVIG may be of benefit

Answer 231

1. Key points a. Primary disease = occurring directly after initial infection (more common in children) b. Reactivation disease = occurring after latent period (more common in adolescents + adults) c. Following exposure risk of progression to TB is highest in young children (<5 years, particularly <2 years) d. Most commonly pulmonary disease – 85% in adults + 75% in children e. Children more likely to develop disseminated or non-pulmonary TB than adults – infants particularly prone to miliary TB + TB meningitis f. Children largely have smear NEGATIVE disease 2. SUMMARY: child vs. adults a. More likely acquired form close family contact b. Unlikely to be the first case -> need to look for index case c. Nonspecific symptoms (less often pulmonary) d. Rarely infectious – pattern of disease, low bacillary load + lack of coughing force e. < 2 years old; tend to get more severe disease  dissemination + meningitis 3. Microbiology a. Non-spore forming, non-motile, pleomorphic weakly gram positive curved rods b. Obligate aerobes c. Acid fast = forms stable complexes with certain dyes, resist decolouration with acid d. Lipid rich cell wall makes it resistant to antibody and complement 4. Epidemiology a. Largely in immigrant population in Australia b. Prevalence in refugees from Africa, Europe + Middle East 25-55% c. Approximately 10% infection develop disease d. Worldwide 2.3 billion infected, ~ 7 million develop disease e. Most paediatric cases <5 years of age f. Most disease occurs within 2 years after exposure/ infection g. Smear positive disease more common in children h. A person with TB will infect 15 people a year if untreated

Answer 232

5. Pathophysiology a. Respiratory spread by ‘droplet nuclei’ small (1-5 microns) particles coughed that have dried (survive due to waxy coat) and can remain airborne and float to be inhaled by a susceptible individual b. Small particle ends in peripheral small airways alveoli = particularly UPPER parts of lungs (more air, less immunology)  frequent apical disease c. After infection, tubercle bacilli replicate in free alveolar spaces and inactivated alveolar macrophages d. Sulfatides in the mycobacterial cell wall inhibit fusion of the macrophage phagosome with lysosomes e. Cell mediated immunity develops 2-12 weeks after infection : i. Lymphocytes recognise mycobacterial antigens, proliferate and secrete lymphokines ii. Some lymphokines activate macrophages iii. This response limits the initial infection, with resultant granuloma formation 6. Risk factors a. For infection i. Close and prolonged contact with source contact 1. Gender of contact - female contact more likely to produce infection 2. Smear positivity 3. CXR ii. Living in high TB endemic country b. For disease i. Young age 1-2 years ii. HIV infection iii. Malnutrition iv. NO BCG vaccination

Answer 233

Because pulmonary TB in children typically presents with paucibacillary, noncavitary pulmonary disease, bacteriologic confirmation is achievable in less than 50 percent of children and 75 percent of infants; in such cases, pulmonary TB is diagnosed by other clinical criteria. A diagnosis of TB (pulmonary or extrapulmonary) in a child is often based on the presence of the classic triad: (1) recent close contact with an infectious case, (2) a positive tuberculin skin test (TST) or interferon-gamma release assay (IGRA), and (3) suggestive symptoms and findings on chest radiograph or physical examination. Most experts recommend that children <12 months who are suspected of having pulmonary or extrapulmonary TB undergo lumbar puncture, regardless of whether neurological symptoms are present. 7. Screening a. TB screening requires history, examination + TB screening test b. Positive screening test does not distinguish between TB infection + disease c. Negative screening test does not exclude TB infection or disease d. Assessment i. Contacts/ previous screening ii. Symptoms iii. Comorbidities 1. Low vitamin D, HIV – risk for disease progression 2. Hepatitis, H pylori, poor nutrition – risk for intolerance of treatment iv. Social circumstance v. Examination 1. BCG sites – deltoid, forearm, thigh, scapulae 2. TB in LN = >1cm in neck, >1.5cm in axilla, >2cm in groin, and do not improve within 1 week of anti-staphylococcal antibiotics e. TST (tuberculin skin test) i. Preferred first line screening test in children <5 years (less reliable in those <6 months) ii. False negative 1. Recent exposure 2. Active disease 3. Immunosuppression 4. Within 4 weeks of live viral vaccines iii. False positive 1. Previous BCG – particularly if given in early infancy a. False positive with BCG - < 50% infants TST +ve 9-12 months post vaccination 2. Exposure to NTM iv. Suggests infection but not necessarily disease v. Hallmark of primary TB infection (more likely to signify infection if in an endemic area than elsewhere) vi. Contraindicated if previous TB disease (causes large reaction) or previous large reaction to TST vii. Interpretation 1. >=5 mm in children who have household contacts 2. >=10 mm in children with history of close contact or endemic area 3. >=15 mm in all other children f. Quantiferon i. NOT used as screening test in young children ii. Positive control (mitogen response) iii. Less useful in young children – use with confidence in > 15 year olds iv. Dos not react to prior BCG or most ATM 8. Diagnosis a. CXR = all children with positive TST need CXR i. NOTE: children with respiratory symptoms and normal CXR may require CT b. Culture i. Most sensitive ii. Acid fast bacilli iii. Can take up to 6 weeks for diagnosis iv. Getting a sample 1. Sputum x3 early morning samples 2. BAL c. GeneXpert: real time PCR, higher sensitive in smear +ve disease i. 2 hours ii. Susceptibility d. ROFB = rifampicin sensitivity detection

Answer 234

a. Asymptomatic (80-95%) infected children, 40-50% infected infants b. Primary pulmonary TB i. Adenopathy with small parenchymal foci ii. Signs/ symptoms infrequent, non-specific c. Progressive pulmonary disease i. Extension of primary focus +/- cavitation ii. Present with severe pneumonia + respiratory distress d. Chronic pulmonary disease i. More typical of adult reactivation type ii. 6-7% paediatric patients iii. TB usually acquired > 7 years of age e. Pleural effusion i. AFB + GenExpert often negative from pleural fluid f. Pericarditis i. Very rare in children ii. Occurs from direct invasion from lymph nodes iii. Nonspecific signs and symptoms g. Miliary disease i. > 2 organs affected ii. Early complication of primary infection iii. Due to massive release of organisms iv. Fever, weight loss, anorexia, malaise, HSM, generalised lymphadenopathy, respiratory distress v. CXR- diffuse, bilateral, micronodular pattern h. Meningitis i. Children < 4 years of age ii. Early complication iii. Gradual onset (rapid in infants) iv. Mortality high - 10% with treatment, morbidity high (seizures, hemiparesis, cranial nerve palsy) v. TST – in 40% vi. CSF: cell count 10-100, glucose low, protein high i. Osteitis i. Ponchet’s disease ii. Well defined sclerotic margins on X-ray iii. Thick , inflammatory synovium  invades articular surface iv. More common in school age group v. Spinal TB  vertebral body destruction, deformity

Answer 235

a. BCG Vaccination i. Live vaccine, Mycobacterium bovis ii. Most effective against miliary TB + TB meningitis iii. Not very effective against pulmonary TB in adults iv. If possible prior contact with TB need to have TST first v. Indications 1. ATSI in high prevalence area 2. Children <5 years who are travelling for extended periods to countries with high risk of TB 3. Babies whose mothers have TB vi. Contraindications 1. Past history of TB (already immune/exposed, more side effects likely and little benefit) 2. Positive Mantoux 3. HIV infection 4. Pregnant b. TB disease in family/household member i. If initial screen is negative children <5 years typically start isoniazid preventative therapy ii. TST repeated after 10 weeks to 3 months (break of contact) to look for conversion iii. In children <2 years a complete course of prevention therapy may be given regardless of the break of contact TST result iv. Consider BCG immunisations in children with negative break of contact screening v. Children <6 months should be placed on isoniazid and have a TST at 6 months c. Latent TB in family/household member i. Screen other family members ii. Children <16 months with negative screening and who have not had BCG – consider vaccination d. Other i. Improving diagnosis of active TB ii. Preventing HIV infection

Answer 236

1. Latent TB a. 6 months with isoniazid b. Prevents TB disease by 50-90% c. Consider B6 i. Breastfed infants ii. Adolescents iii. Children with poor nutrition 2. Active TB a. Indications for urgent treatment i. Child < 2 ii. Suspicion of meningitis iii. Otherwise, there is no necessary urgency to commence treatment b. Children vs adult i. Standard short course therapy appropriate ii. Children require higher mg/kg of antituberculosis drugs to achieve effective serum concentrations iii. Adverse effects rare in children c. Standard short course = 2 months RIPE  4 months RI i. Rifampicin = sterilizing activity to eradicate persistent subpopulations ii. Isoniazid = bactericidal agent with high activity iii. Pyriazinamide = agent to kill extracellular microbes in acid vacuoles iv. Ethambutol = agent to reduce risk of development of resistance d. Addition of pyridoxine (B6) i. Malnourished ii. Pregnant adolescents iii. MDR f. Steroids i. Indications = compressive lymphadenitis, severe military disease, pericardial/ pleural effusions, endobronchial disease, abdominal TB ii. Pred 1-2 mg/kg x 4-6 weeks g. Resistance i. Multidrug resistant TB = resistant to isoniazid and rifampicin ii. XDR TB = resistant to isoniazid, rifampicin, fluoroquinolones and 1 of 1. Amikacin 2. Capreomycin 3. Kanamycin iii. Building a regimen for MDR 1. Add first line agents that are sensitive 2. Add injectable 3. Add fluoroquinolone 4. Add ethionamide (unless INH mutation- may have cross reactivity) 5. All MDR patients should have pyridoxine 6. Treat for 18 months or 15 months if paucibacillary/ mild 3. Other Aspects a. Check for HIV b. Need to monitor growth

Answer 237

1. Key points a. Environmental organisms that occasionally cause respiratory, cutaneous or disseminated infection b. Rarely spread person-to-person c. Include m. avium, m. kansaii 2. Organisms a. Mycobacerium avium i. Cervical lymphadenitis – most common in children 1. Can have purplish discolouration 2. Treated with excision of node 3. 3-6 months of macrolide therapy if complicated ii. Pulmonary disease – occurs in several forms iii. Disseminated disease – if immunocompromised b. Mycobacerium kansaii i. Chronic pulmonary infection which resembles MTB c. Mycobacerium ulcerans i. Skin and soft tissue infection – begins as painless dermal papule or SC nodule which breaks down over months to form a necrotic ulcer with undermined edges ii. Most common in coastal Victoria, FNQ and QLD iii. Treatment with 8-12 weeks of antibiotics +/- surgery iv. Usually treated with rifampicin + quinolone or clarithromycin 3. Risk factors a. Younger age group (exposure to soils) b. Interferon gamma receptor/ Il12 receptor deficiencies 4. Pathology a. Caseating granulomas (can be non caseating) b. Interferon gamma, IL 12 and TNF alpha often involved 5. Diagnosis a. Culture/ PCR of excised node

Answer 238

• Many antibiotics do not penetrate eukaryotic cells ``` • Intracellular pathogens o Listeria monocytogenes o Salmonella o Brucella, o Legionella o Mycobacterium o Rickettsia o Toxoplasma o Coxiella - Chalmydia pneumomniae ``` • Treatment o Antibiotics usually enter cells via diffusion (lipid soluble), pinocytosis or carrier mediated transport o Effective antibiotics  Clindamycin + macrolide  tropic for lysozomes  Quinolones

Answer 239

1. Microbiology a. Gram negative envelope without peptidoglycan b. Obligate intracellular organisms c. Serologically classified by different major outer membrane proteins (MOMP/ OmpA) d. Primarily a human respiratory pathogen (can affect koalas, horses, reptiles) e. Transmitted via respiratory droplets f. Exist in two forms – elementary bodies (EB) + reticulate bodies (RB) i. Following infection, EBS attached to host cell, taken up via endocytosis ii. EB remains within host cell as a phagosome iii. EB differentiates into RB  binary fission, differentiate into EB iv. After 48 hours, they are released by cytolysis/exocytosis, leaving host cell intact 2. Epidemiology a. Affects all ages 3. Clinical features: a. Pneumonia (2-19%) b. Asthma exacerbation c. Bronchitis d. Pharyngitis e. Can cause prolonged, persistent infection as it stays in persistent state within host cells 4. Diagnosis a. Presents similarly to other atypical pneumonia b. CXR = often worse than patient’s clinical status: mild, diffuse involvement/lobar infiltrates c. Needs to be cultured/identified via PCR d. Can also look at changes in IgG titre (4 fold increase) or IgM titre > 16 5. Treatment (Mycoplasma pneumoniae, Chlamydia pneumoniae, Chlamydia psittaci) a. Doxycycline OR azithromycin OR clarithromycin b. Therapy usually for 7-10 days (except azithromycin which is used for 3-5 days) c. Duration depends on clinical response

Answer 240

Psittacocis • Most often infects birds (budgies) • Usually results in prominent systemic manifestations and some respiratory symptoms • Most common in young and middle-aged men • Clinical manifestations o Results in abrupt onset fever, pronounced headache, dry cough o Respiratory symptoms of dyspnoea, chest pain and haemoptysis sin 25% o Infection can also be asymptomatic o Usually have a history bird exposure • Rare in immunocompromised

Answer 241

1. Microbiology a. Lack a cell wall, have double stranded DNA b. The smallest self-replicating biologic system  rely on host cells for precursors c. Part of URT flora, transmitted by droplet spread d. Incubation period 1-3 weeks 2. Pathogenesis a. Have specialised tip organelles that mediate interactions with host cells: surface parasites on host cells acquire essential biosynthetic precursors +/- cell entry and intracellularly survival b. Cause damage via production of hydrogen peroxide and superoxide c. Immune mechanism that protect against disease not well defined 3. Epidemiology a. Overt illness rare before 3 b. Children < 5 – mild upper respiratory tract involvement, vomiting and diarrhoea c. Peak LRT illness occurs in school aged children d. Causes 20% of pneumonias in middle and high school students, up to 50% in college students and military recruits

Answer 242

4. Clinical manifestations a. LRTI i. Usual clinical course = headache, malaise, fever, sore throat  lower respiratory symptoms ii. Cough is the clinical hallmark – usually worsens in the first week of the illness and symptoms generally resolve by 2 weeks; can last up to 4 weeks iii. Coryza usually present iv. Bronchopneumonia v. Examination findings do not appear until late in the disease 1. May develop crackles and wheeze b. URTI – pharyngitis/ sinusitis/ croup/ bronchiolitis 5. Complications a. Skin lesions = SJS, erythema multiform b. Neurologic complications = meningoencephalitis, transverse myelitis, aseptic meningitis, cerebellar ataxia, Bell palsy, deafness c. Haematologic complications = haemolysis (DAT +ve ), cold antibody mediated disease 6. Investigations a. CXR i. Commonly appears WORSE than clinical examination ii. Interstitial / bronchopneumonia iii. Lower lobe more commonly involved iv. 1/3 have hilar lymphadenopathy

Answer 243

7. Diagnosis a. Consider in school aged children and young adults with pneumonia b. Difficult to culture (takes 2-3 weeks) - not usually cultured c. IgM may suggest diagnosis but stays +ve for 6-12 months post infection i. 4 fold increase in IgG between acute and convalescent serum 10days – 3weeks after onset of illness d. PCR of M. pneumonia DNA is specific , but sensitivity only 50-70% (may suggest asymptomatic carriage also) 5. Treatment (Mycoplasma pneumoniae, Chlamydia pneumoniae, Chlamydia psittaci) a. Doxycycline OR azithromycin OR clarithromycin b. Therapy usually for 7-10 days (except azithromycin which is used for 3-5 days) c. Duration depends on clinical response

Answer 244

Hominis, genitalium, ureaplasma, urealyticum 1. Species a. Mycoplasma hominis b. Urease urealtyicum 2. Transmission a. Via sexual contact b. Vertical transmission in 25-60% colonized women 3. Clinical manifestations: a. Sexually transmitted disease: non gonococcal urethritis i. Most common in young adults ii. Discharge, dysuria , vaginal/ penile discomfort iii. Can rarely cause epidydimitis and proctitis b. Neonates i. Urease urealyticum can cause chorioamnionitis 4. Diagnosis a. Difficult due to colonisation b. Requires presence of leukocytes 5. Treatment a. Azithromycin / doxycycline

Answer 245

Spirochaetes 1. Epidemiology + transmission a. Tropical or subtropical countries b. Survive days-weeks in warm/damp environmental conditions (water and moist soil) c. Infected animals excrete spirochetes in their urine for prolonged periods (ie dog and rat) d. Enter through mucous membranes (eyes, nose, and mouth)/abraded skin OR by ingestion of contaminated water e. After penetration  circulate in the bloodstream to all body organs  endothelial lining damage of small blood vessels with secondary ischemic damage to end organs 2. Clinical manifestations a. Spectrum – asymptomatic (most cases) to severe disease (multiorgan dysfunction and death) b. Abrupt onset c. Anicteric or icteric d. Biphasic course i. Incubation period of 7-12 days ii. Initial or septicemic phase = 2-7 days (isolate from blood, CSF, other tissues) iii. Asymptomatic phase iv. Second symptomatic immune or leptospiruric phase 1. Appearance of circulating IgM, disappearance of organisms from the blood and CSF 2. Appearance of signs associated with localization of leptospires in tissues 3. The immune phase can last for several weeks 3. Anicteric a. No mortality b. Septicemic phase i. Abrupt onset of flu-like symptoms = fever, shaking chills, lethargy, severe headache, malaise, nausea, vomiting, and severe debilitating myalgia ii. Circulatory collapse uncommon iii. +/- conjunctival suffusion – photophobia, orbital pain (in absence of chemosis and purulent exudate) iv. +/- generalized lymphadenopathy v. +/- hepatosplenomegaly vi. +/- transient (<24 hr) erythematous maculopapular, urticarial, petechial, purpuric, or desquamating rash (10%) vii. Rarer– pharyngitis, pneumonitis, arthritis, carditis, cholecystitis, and orchitis. c. Second/immune phase i. Recurrence of fever and aseptic meningitis. 1. Although 80% of infected children have abnormal CSF profiles, only 50% have clinical meningeal manifestations. ii. Unilateral or bilateral uveitis iii. Central nervous system symptoms usually resolve spontaneously within 1 wk 4. Icteric leptospirosis (Weil syndrome) a. Rare (<10% of cases) severe form of leptospirosis – mortality 10-15% b. Seen more commonly in adults (>30 yr) than in children. c. Septicemic phase – similar to those described for anicteric d. Immune phase i. Jaundice, renal failure, thrombocytopenia, hemorrhage and cardiovascular collapse ii. Hepatic = RUQ pain, hepatomegaly, elevated liver enzymes and bilirubin iii. Renal = haematuria, proteinuria, AKI (principle cause of death) iv. Cardiac = abnormal ECG, CHD v. Haematology = transient thrombocytopaenia; haemorrhagic manifestations (pulmonary, gastrointestinal, adrenal haemorrhage)

Answer 246

1. Virology a. Genus erythrovirus, family parvoviridae b. Small DNA viruses c. B19 only a human pathogen f. Needs to propagate in erythropoietic cells 2. Epidemiology a. Common – 5-10% children aged 2-5 are seropositive b. 70% of cases occur in patients between 5-15 years of age c. Seasonal peaks in winter and spring 3. Pathogenesis a. Virus infects erythroid precursors near pronormoblast stage -> produces cell lysis, depleting erythroid precursors i. Erythrocyte P blood group antigen is the primary cell receptor for virus ii. Also found on endothelial cells, placental cells and myocardial cells

Answer 247

4. Clinical manifestations a. Transmission = most often transmitted via droplet spread (can also be transmitted via blood products) b. Incubation = 4-28 days c. Infectious period = infectious in days PRECEDING rash/arthropathy d. Symptoms and signs i. Prodromal phase = viraemia 1. Fever, headache, URTI 2. If underlying haemolysis – severe anaemia occurs at this time ii. Immune-mediated rash (Ag-Ig immune complex) 1. Slapped cheek flushing 2. Spreads to trunk and proximal extremities as diffuse macular erythema rash 3. Central clearing of lesions then causes a lacy reticulated appearance 4. Rash disappears over 1-3 week can recur with exposure to sunlight, heat, exercise and stress e. Other features i. Transient aplastic crisis = occurs in individuals with haematological abnormalities 1. Increased RBC destruction – sickle cell disease, HS, chronic haemolysis 2. Decreased RBC production – IDA ii. Arthropathy = arthritis and arthralgia can occur – most often in the hands, wrists, knees and ankles 1. Usually 17-18 days after inoculation iii. Myocarditis iv. Other cutaneous manifestations = atypical skin eruptions  petechial, purpuric; evidence of vasculitis on biopsy v. Many rare associations/complications = aseptic meningitis, encephalitis, peripheral neuropathy, stroke in children with sickle cell, HLH 5. Complications a. Chronic haemolytic anaemia (E.g. sickle/thal) = severe aplasia ii. Sick cell may also have vasoocclusive pain crisis b. Impaired humoral immunity = at risk of serious/ persistent infection with B19  anaemia, neutropenia, thrombocytopenia and marrow failure c. Perinatal infections = fetal anaemia  high output CO + hydrops fetalis

Answer 248

6. Investigations a. Diagnosis is most often clinical b. Serology = IgM remains detectable for months, appears after 1-2 days of infection i. Testing unreliable in immunocompromised persons c. PCR = low levels detectable 4 months after infection d. Prenatal diagnosis can be made by viral DNA in fetal blood/ amniotic fluid 7. Treatment a. Supportive b. IVIG IF aplasia c. Affected foetuses have been managed with intrauterine blood transfusions 8. Public health a. Children not likely to be infectious at presentation as rash and arthopathy are immune mediated, post infectious b. Most contagious few days before rash c. School isolation therefore unnecessary after diagnosis d. Children with B19 induced RBC aplasia are infectious upon presentation as they are viraemic – hospital/school exclusion for at least 1 week after fever

Answer 249

Human Herpes Virus 6 1. Virology a. DNA virus c. Enters different types of cells via CD46 regulatory protein d. After primary infection, herpes virus establishes latency in monocytes/macrophages (can be reactivated during bone marrow transplant) 2. Epidemiology a. Most children have primary infection after maternal antibodies lost b. Peak age 6-9 months, 95% affected by age of 2 c. Can be acquired from saliva / congenital infection d. 1% newborns have vertical transmission of HHV-6 3. Clinical manifestations a. Transmission = oral secretions b. Incubation = 9 days incubation c. Symptoms and signs i. High fever, resolving after 72 hours ii. Rash appears as fever subsides iii. Morbilliform rash on trunk, lasting 1-3 days (morbilliform = rose-red flat (macular) or slightly elevated (maculopapular) eruption) d. Immunocompromised hosts: interstitial pneumonitis, gastroenteritis, marrow suppression encephalitis 4. Investigations (?none needed) a. Leukopenia is common b. Virus can be detected by PCR 5. Treatment a. Supportive b. Antivirals are used in immunocompromised patients 6. Complications: a. 1/3 have febrile convulsions b. Higher rate of complex seizures including post ictal paralysis

Answer 250

Human herpes virus 8 1. Virology a. Gamma-2 human herpes virus, very similar to EBV b. Large DNA genome 2. Key points a. Endemic in parts of Africa and South America – tends to be low-prevalence in Aus b. Can be transmitted via saliva, sexual contact, blood transfusion c. Contains multiple factors that interfere with cell cycle regulation 3. Clinical manifestations a. Primary infection usually fever + rash b. Kaposi sarcoma = multifocal angiogenic lesions in lower extremities, can vary to widespread cutaneous lesions 4. Complications a. Kaposi sarcoma b. Multicentric Castleman disease c. Primary effusion based lymphoma

Answer 251

Kaposi sarcoma (KS) is an angioproliferative disorder that requires infection with human herpes virus 8 (HHV-8), also known as Kaposi sarcoma-associated herpes virus (KSHV), for its development. KS is classified into four types based on the clinical circumstances in which it develops: classic (the type originally described by Kaposi, which typically presents in middle or old age), endemic (several forms described in sub-Saharan indigenous Africans prior to the acquired immunodeficiency syndrome [AIDS] epidemic), iatrogenic (a type associated with immunosuppressive drug therapy, typically seen in renal allograft recipients), and AIDS associated (epidemic KS). Skin lesions — Classic KS is characterized by the appearance of purplish, reddish blue, or dark brown/black macules, plaques, and nodules on the skin. The dermatology literature contains reference to at least 10 different morphologic variants of the cutaneous lesions of KS.

Answer 252

1. Virology a. Togavirus family, rubivirus genus b. Single stranded RNA virus with lipid envelope c. Humans = the only known host 2. Epidemiology a. Pre-vaccine – major epidemics every 6-9 years in preschool and school age children b. Brief resurgence in infections in 1989-1991  introduction of 2 dose rubella vaccine 3. Clinical manifestations a. Transmission = respiratory droplet b. Incubation = 14-21 days c. Infectious period = 10 days after infection – up to 2 weeks post rash i. Sheds from 5 days before to 6 days after rash - less infectious than measles d. Symptoms and signs i. Causes mild disease: fever, myalgia, headache, sore threat, read eyes, lymphadenopathy (sub occipital, postauricular and anterior cervical lymph nodes) ii. Specific features: 1. Pinpoint petechiae on soft palate 2. Rash on trunk, hands and feet (begins on face and neck) a. Usually lasts 3 days, resolves without desquamation 7. Complications a. Arthralgia/arthritis = distal, symmetrical rarely occurs in children b. Neuro = encephalitis is RARE, but can be severe i. Either acute or years post infectious c. Thrombocytopenia = occurs in 1/3000 cases : may cause petechiae, epistaxis, GI bleeding and haematuria d. Haemolytic anaemia e. Myocarditis 8. Vaccine a. Given at 12 months (MMR) and 18 months (MMR-V) b. Not given to immunocompromised patients c. Can be given for post exposure prophylaxis 3 days post exposure d. Common reactions: fever 5-15%, arthralgia and arthritis (more common in adults) e. Single dose produces antibody response in over 95% of recipients 9. Public heath a. Isolation up to 7 days post rash b. Congenital – up to 1 year of age (unless cultures persistently negative)

Answer 253

Lesions with bluish white spots in the centre on buccal mucosa Pathognomonic of measles

Answer 254

1. Virology a. Paramyxovirus family, genus morbillivirus b. Single stranded, enveloped RNA virus c. Important virulence factors are the envelope proteins: haemagluttinin (H) protein and fusion (F) protein  antibodies to these factors limit infection 2. Clinical manifestations a. Transmission = respiratory secretions (survives 2 hours in air) i. VERY contagious: 90% of household contacts will be infected if non immunised b. Incubation = 10-14 days c. Infectious period = 3 days prior to 4 days after the rash d. Symptoms and signs i. Prodromal illness 1. Fever, malaise, cough, coryza, conjunctivitis, otitis media, Koplik spots a. Koplik spots = lesions with bluish white spots in the centre on buccal mucosa 2. Usually 3-5 days ii. Rash = maculopapular, begins behind ears face, neck, generalised. Fades over 7 days iii. Recovery = cough tends to persist the longest 3. Complications a. Acute otitis media = most common complications b. Pneumonia = often staph aureus/ strep / haemophilus, may lead to bronchiolitis obliterans c. Cardiac = myocarditis, pericarditis d. Encephalitis (post infectious phenomena) = 1/1000, usually occurs during exanthema i. If affected, 25% will have some sort of ongoing deficit + 15 % die e. Subacute sclerosing panencephalitis i. Can present up to 7 years post disease ii. Often fatal iii. 0.6/100,000 iv. Management – supportive, death 1-3years from onset v. Measles Ab in CSF with characteristic EEG findings + virus isolated from brain biopsy

Answer 255

4. Investigations a. Leukopenia, thrombocytopaenia b. Serology – IgM detectable for about 1 month c. NP immunofluorescence d. Pathological features – Warthin Finkeldey giant cells (fusion of infected cells causing MNGC(multinucleated giant cells)) are pathognomic 5. Prognosis a. Morbidity and mortality worst in children < 5 years of age b. Much worse in children who are immunosuppressed and malnourished (low retinol = poor outcomes) 6. Treatment a. Supportive b. Vitamin A (maintains mucosal integrity) if children hospitalized, have risk factor (malabsorption, malnutrition, immunodeficiency) 7. Vaccination a. Routine doses at 12 months + 18 months b. For susceptible contacts within 72 hours c. Contacts – 1 dose of MMR d. 5% of recipients will fail to develop immunity to measles e. Contraindications: immunocompromised f. Note 2 doses in each birth cohort > 95% for herd immunity g. CAN be given to people with egg allergy 8. Immunoglobulin a. IM injection within 7 days of exposure b. > 9 months if MMR contraindicated AND non-immune pregnant c. If vaccine is declined, need to exclude from school for 14 days

Answer 256

1. Virology a. Paramyxovirus family, rubulavirus genus b. Single stranded RNA virus with lipoprotein envelop 2. Epidemiology a. Uncommon in developed nations due to vaccination b. Used to occur in epidemics over winter/spring every 4 years at 5-9years c. Post-vaccination – older children, adolescents, adults 3. Clinical manifestations a. Transmission = respiratory b. Incubation = 15-25 days c. Infectious period i. 2 days before onset of illness  4 days after ii. 6 days prior to parotid swelling  9 days post d. Symptoms and signs i. 30% asymptomatic ii. Constitutional symptoms iii. Parotitis – 60-70% iv. Rare complications: sensorineural deafness, orchitis 4. Complications a. Meningitis +/- encephalitis b. Orchitis and oophoritis  orchitis affects 30-40% males post puberty (sterility is rare) c. Myocarditis, pancreatitis, arthritis, thyroiditis all reported d. Perinatal infection i. Can cause IUGR ii. Not associated with fetal malformation iii. May cause spontaneous abortion in 1st trimester 5. Diagnosis a. Elevated serum amylase – parotitis b. Leukopenia with lymphocytosis c. Viral PCR – blood/ urine / CSF or serology (may cross react with parainfluenza) 6. Vaccine a. 12 and 18 months b. Side effects - parotitis and orchitis have been reported rarely c. 1 dose seroconversion 60 – 90%

Answer 257

1. Virology a. Neurotropic human herpes virus (alpha herpes virus) b. Double stranded DNA genome , enveloped c. Subclinical viraemia: virus spreads to reticuloendothelial system: widespread cutaneous lesions during 2nd viraemic phase lasting 3-7 days d. Cell mediated immunity largely responsible for containing virus e. Establishes latent infection in the dorsal root ganglia a. Transmission = droplet/ direct contact b. Incubation period = 20-21 days c. Infectious period = 1-2 days before rash until rash crusts i. 80-90% attack rate within house holds 3. Investigations a. Leukopenia – Day 1-3 from onset of rash b. Absolute lymphocytosis c. LFT elevated d. CSF – lymphocytic pleocytosis (increased cell count) if CNS involvement e. VZV PCR or IF on vesicular fluid diagnostic f. VZV IgG – 4 x rise diagnostic (IgM unreliable assay) 4. Complications a. More common in infants, those > 15 years and immunocompromised b. Include i. Secondary infection = strep pyogenes + staph ii. Pneumonitis (25 x more common in adults) iii. Acute cerebellar ataxia (1/4000) iv. Acute encephalitis ( 1/100,000) v. Shingles vi. Thrombocytopenia 1-2 % vii. Reye syndrome

Answer 258

i. Acute varicella 1. Low grade fever, headache, malaise, anorexia 2. Itchy, vesicular rash (centripetal spread = greatest concentration of lesions on the trunk, fewest lesions on distal extremities)  200-500 lesions normal a. Initially papules  vesicles  crust (usually fully crusted by 10 days) 3. Usually begins on the scalp/ face/ trunk  central/ centripetal (compared to smallpox, more prominent on extremities) 4. Can also occur on the conjunctivae ii. Progressive/disseminated varicella 1. Complications of visceral organ involvement, coagulopathy , severe haemorrhage 2. Increased risk in children with cellular immune deficiency iii. Neonatal varicella 1. Mortality is very high 2. Risk is highest for mothers who develop varicella from five days prior  2 days afterward 3. Infants generally symptomatic by first week – second week of life 4. Treatment = ZIG  50% will still develop varicella but it is usually mild a. Then treated with acyclovir 10 mg/kg tds if lesions develop iv. Congenital varicella syndrome 1. 0.4% of infants < 13 weeks of gestation 2. 2% of infants 13-20 weeks of gestation 3. Features a. Cicatricial skin scarring b. Limb hypoplasia c. Neurologic features: microcepahly, cortical atrophy, seizures, mental retardation , d. Eyes – chroioretinitis, micropthalmai, cataracts e. Renal – hydroureter + hydronephrosis f. ANS abnormalities 4. Maternal treatment with Varicella IgG / Aciclovir – benefit unknown v. Herpes zoster = shingles 1. Uncommon in childhood 2. No seasonal variation in incidence 3. Lifetime risk is 10-20% 75% occur after 45 years 4. Relates to waning of cell mediated immunity 5. In children, more common in infants infected < 1 year OR those who are immunocompromised (malignancy, anti-TNF therapy) 6. May spread over more than one dermatome – usually milder than adults and post-herpetic neuralgia less common 7. Clinical manifestations a. Prodrome: burning pain b. Clusters of vesicular lesions in a dermatomal distribution on an erythematous base c. Timeline: erupts over 1 week, self resolves over 1-2 weeks d. In immunocompromised patients, systemic symptoms and a multi-dermatomal rash can complicate infection 8. Treatment a. Aciclovir = within 72 hours of onset of the rash to reduce duration of illness – in all immunocompromised patients regardless of duration of the rash i. PO acyclovir 20mg/kg 5 times daily for 7 days ii. IV acyclovir 500mg/m2 Q8hrly in the case of immunocompromised with disseminated disease b. Children not traditionally treated BUT – may be worth considering oral antivirals to prevent post herpetic neuralgia 9. Complications a. Risk of transverse myelitis b. Post-herpetic neuralgia

Answer 259

5. Treatment a. Supportive b. Calamine lotion, cool compress, antihistamines c. Aciclovir i. Indications 1. Impaired immunity, some neonates, and possibly severe eczema 2. Severe disease = pneumonitis, encephalitis, hepatitis ii. Key issues with use 1. Should be initiated between 24 hours of onset of exanthema – 72 hours after onset 2. Does not interfere with immunity 3. Safety and efficacy in pregnancy not well defined iii. If treating disseminated disease, pneumonia, thrombocytopenia, encephalitis  7-10 day course 6. Prognosis a. Mortality rate is 2-3/100,000 b. 7-8 deaths, 1500 hospitalizations per year in Australia pre vaccine 7. Post exposure a. Vaccination i. Vaccinate within 72 hours (up to 5 days) ii. Household contacts with impaired immunity iii. Health care workers – unvaccinated/ uncertain history. Or isolate D10-21 iv. CAN cause latent infection and reactivate as herpes zoster BUT risk is much lower than with natural VZV infection b. Immunoglobulin i. Pregnant women within 96 hours if susceptible ii. To neonate of mother who gets VZV from 5 days prior to 2 days after delivery iii. To neonates in first 30 days if mother has no history / negative serology iv. Premature infants < 28 weeks (no passive transfer, usually at 30 weeks) v. Immunocompromised patients where vaccine is compromised

Answer 260

8. Vaccination a. VZV vaccine b. Live attenuated c. Given TWICE  18 months (as part of MMRV) and during 10-15 year old school program d. Effective 3-5 days post exposure e. Contraindicated in pregnant women, immunosuppressed patients 9. Public health a. School exclusion until lesions crusted b. Avoid high risk (children Rx malignancy, immunosuppressed, pregnant women) c. Post – exposure prophylaxis ZIG if: i. Immunocomprimised ii. Pregnant women without evidence of immunity iii. Newborns whose mother develops VZV 5 days prior to 2 days after delivery iv. Neonates <30days if mother no history or negative serology v. Newborns <28weeks exposed regardless of maternal immunity (passive transfer begins 30 weeks) vi. Vaccine within 3-5days of exposure – effective in preventing or modifying disease d. Healthcare workers i. History of infection/vaccination – watch for rash 3 weeks ii. Unsure vaccine history – vaccinate iii. If doesn’t consent to vaccine – leave for 21days

Answer 261

1. Virology a. HSV-1 and HSV-2: double stranded DNA genome, contained within an icosadeltahedral capsid, surrounded by an outer lipid bilayer envelope b. 12 viral glycoproteins present in envelop: major targets for humoral immunity c. Key proteins: viral DNA polymerase + thymidine kinase d. Main difference between HSV-1 and HSV-2 = different glycoprotein G genes 2. Types a. HSV 1 i. Oral infection, can cause genital - usually transmitted by oral secretions ii. 65% by age 40 iii. Decreased risk of recurrent infection b. HSV 2 i. Genital infection, can cause oral - usually transmitted by genital secretions ii. 25% by age 40 iii. Increased risk of recurrent infection 3. Epidemiology a. Ubiquitous, no seasonal variation b. Only natural host is humans; transferred via direct mucocutaneous surface exposure 4. Classification of infections a. Primary infections i. Often severe ii. HSV then establishes latent infection in regional sensory ganglion neurons b. Non-primary infections i. Infections with the other type (eg HSV-2 in an individual with HSV01) c. Recurrent infection i. Tend to be less severe, shorter duration the primary infections ii. Traditionally – HSV-1 associated with oral lesions, HSV-2 associated with anogenital contact

Answer 262

a. Neonatal herpes i. Severe, potentially fatal infection ii. Estimated rate is 1/3000-1/50000 iii. Most common portals of entry: conjunctivae, mucosal epithelium, scalp electrode / forceps delivery iv. Risk for transmission 1. Primary / non-primary infection (30-50%) 2. Recurrent infection < 2% 3. Increases risk of HIV transmission if mother is HIV positive b. Encephalitis i. 1/250 cases in the US ii. Tends to affect the frontal/ temporal/ limbic region iii. Fever, headache, nuchal rigidity, nausea and vomiting, seizures, altered consciousness, focal features iv. Untreated  mortality up to 75% v. CSF analysis = moderate number of mononuclear cells + leukocytes 1. HSV PCR may be negative if performed in first 48 hours of symptoms c. Acute oropharyngeal infections/gingivostomatitis i. Most common in 6 months – 5 years ii. Mouth pain, drooling, high fevers, vesicles in oral cavity / skin iii. Vesicles more extensively distributed than with herpangina iv. Resolves over 7-14 days v. Treat with PO aciclovir d. Herpes labialis (cold sores) i. Classically caused by HSV -1 ii. Most common site: vermilion border of the lip, nose, chin , cheek, oral mucosa iii. Burning, tingling, itching before development of lesion iv. Complete healing occurs over 6-10 days e. Cutaneous infections i. Multiple lesions, often over larger surface area than cold sores ii. Herpes whitlow = HSV infection of fingers/ toes/ paronychia, can be due to thumb sucking with oral HSV-1 infection f. Other i. Genital herpes ii. Ocular herpes = vesicular lesions evident, corneal involvement is rare iii. Disseminated infections (in immunocompromised patients) 1. Invasive disease 2. Mucocutaneous, mucositis/oesophagitis, deep extension 3. Tracheobronchitis, pneumonitis, anogenital 4. DIC + shock

Answer 263

6. Investigations a. HSV PCR 7. Treatment a. Antiviral options: i. Aciclovir = oral/ IV  poor bioavailability; 5x per day dosing ii. Valaciclovir = prodrug of acyclovir iii. Famciclovir = prodrug of penciclovir iv. Good safety profiles in paediatric patients v. Resistance is rare in immunocompetent individuals b. Acute mucocutaneous infections i. Gingiovostomatitis = oral acyclovir beneficial within 72 hours of onset ii. Herpes labilias = oral treatment > topical 1. Shortens duration of episode 2. Long term daily use of acyclovir/ valaciclvoir may prevent recurrences iii. Eczema herpeticum = often requires IV treatment c. Genital herpes i. Treatment of initial infection reduces severity and duration of antiviral therapy ii. Ongoing treatment can be episodic/ suppressive iii. Suppressive treatment reduces recurrences but does not eliminate risk of sexual transmission d. CNS = IV aciclovir e. Perinatal infections: high dose IV aciclovir immediately i. 14 day course for SEM disease ii. 21 days for disseminated/ CNS disease 8. Prevention a. Prevention of perinatal disease i. Active genital herpes  deliver via LUSCS (reduces but does not eliminate risk of disease) ii. Antiviral suppression in last 4 weeks of pregnancy b. Work up for perinatal disease i. Swab eye/ nasopharynx/ umbilicus ii. Treat if suspected until cultures negative

Answer 264

1. Virology a. Largest herpes virus, ds DNA virus b. Enclosed in icosahedral capsid 2. Epidemiology a. 60-70% Seroprevalence , increases with age b. Second peak in adolescence from sexual transmission c. General risk of infection is 1-3% ( 10-20% if in childcare) a. Transmission = oral secretions, breast milk, vaginal secretions, urine, semen, blood and organ transplants i. Often acquired postnatally via breast milk / from childcare centre b. Infectious duration = virus can be shed for years after infection

Answer 265

i. Congenital disease ii. Perinatal disease 1. 3 weeks – 6 months 2. Acquired through cervicovaginal secretions/ breast milk / horizontally 3. Breast milk is +ve for virus in 96% of seropositive mothers 4. Increased risk of < 1500g (little maternal antibodies) 5. Can continue to secrete virus in saliva/ urine for years 6. Clinical features a. Usually asymptomatic b. Occasionally can cause sepsis like syndrome (assoc HSmegaly, lymphopenia, neutropenia, thrombocytopenia, abnormal transminates and pneumonitis) c. Does NOT increase risk of hearing loss/ chorioretinitis/ microcephaly iii. Acquired CMV infections 1. Mostly asymptomatic/ self-resolving over 2-3 weeks 2. 10% - fever, fatigue, pharyngitis, adenopathy, hepatitis 3. Other manifestations = pneumonitis, hepatomegaly, petechial rashes 4. Older children = mononucleosis like syndrome, atypical lymphocytosis 5. Disease can be due to primary / reactivation of latent infection, but primary infection most commonly associated with disease iv. CMV in immunocompromised patients 1. Causes significant morbidity + mortality 2. Can have pneumonitis, retinitis and GI disease 3. Transplantation - risk factors a. CMV seropositive donor – seronegative recipient b. Decreased T cell function (immunosuppressive drugs) c. Transplanting an organ with viraemia 4. Fever, malaise, leupenia, rash 5. Graft loss (renal), pneumonitis, GIT disease, CMV retinitis (HIV) v. Transmission via blood transfusion 1. Risk estimated at 2.7% per unit of whole blood (higher risk with leukocyte transfusions) 2. Risk is greater in children who are seronegative / immunocompromised

Answer 266

4. Investigations (mostly seen urine PCR) a. Congenital = viral culture/ PCR from urine/ saliva / Guthrie within first 3 weeks of life b. Otherwise, PCR positivity more useful than serology – suggests active disease c. Serology i. MOST of the population is IgG positive ii. IgM is NOT a useful tool for acute infection - usually develops after 4-16 weeks iii. Avidity of IgG is typically LOW for the first 4-5 months following infection 5. Treatment (mostly seen ganciclovir) a. Antiviral options = ganciclovir, famciclovir (foscarnet), cidofovir  all inhibit viral DNA polymerase b. Main indication is for immunosuppressed patient: i. Ganciclovir + IVIG may be used for severe infections ii. Toxicity = neutropenia, thrombocytopenia, liver dysfunction, ↓spermatogenesis, GI and renal abnormalities c. Other options i. Oral valganciclovir (ganciclovir prodrug) ii. Foscarnet d. Prophylaxis (valaciclovir) given to prevent CMV disease 6. Prevention a. CMV negative blood products for immunosuppressed/ premature newborns

Answer 267

1. Virology a. Member of human herpes virus family b. Two distinct types characterised – no type specific disease manifestations 2. Epidemiology a. Affects 95% of the world’s population, 50% infected by age 5 3. Pathogenesis a. Establish infection in oropharyngeal epithelial cells + memory B cells b. Atypical lymphocytes produced in response to B cell infection a. Transmission = oral and genital secretions b. Incubation = 30-50 days c. Infective duration = > 6 months after acute infection then intermittently for life 1. Investigations a. FBE – lymphocytosis, atypical lymphocytes +/- low platelets i. Leucocytosis present in > 90% of cases b. MONOSPOT – tests for Heterophile antibody, usually +ve after 2-9 weeks after infection c. ?EBV serology used in Australia… i. Heterophile antibodies = agglutinate cells from species different from those in the source serum

Answer 268

d. Clinical features i. Most cases are asymptomatic ii. Acute illness 1. Fever 1-2 weeks, sore throat 2. Lymphadenopathy (particularly epitrochlear), tonsillitis 3. Hepato-splenomegaly 4. Rash 5. Eyelid edema (MCQ) iii. Resolution phase = 3-4 weeks with ongoing enlarged nodes and severe fatigue (NO clear CFS) iv. Reactivation is usually asymptomatic 5. Complications a. Rash = with amoxicillin (most antibiotics in fact will cause rash) b. Splenic rupture = rare < 0.5% adults, less in children c. Lymphoproliferative disorders i. HLH (fever, pancytopenia, splenomegaly, haemophagocytosis) ii. Lymphoid granulomatosis iii. X linked lymphoproliferative disease iv. Post-transplant lymphoproliferative disease d. Other malignancy i. Nasopharyngeal CA ii. Leiomyosarcoma iii. Hodgkin disease iv. Burkitt lymphoma e. In immunosuppressed patients i. Oral hairy leukoplakia (white corrugated painless plaques that CANNOT be scraped off) ii. Lymphoid interstitial pneumonitis

Answer 269

1. Virology b. RNA virus – single stranded genome , enveloped c. Replicates in the cytoplasm of infected cells entirely d. Matures by budding from apical surface of the cell membrane e. Does not undergo antigenic shift 2. Epidemiology a. Occurs in yearly epidemics b. Transplacental antibodies partially protective d. Breastfeeding partially protective e. Highest incidence 6 weeks- 7 months of age f. Infection almost universal by 2 years 3. Clinical manifestations a. Bronchiolitis b. Otitis media c. Co-infection with metapneumovirus tends to cause more severe disease 4. Diagnosis a. CXR: 30% normal, 70% hyperexpansion of the chest, peribronchial thickening, interstitial infiltrates b. Fever an inconstant sign c. Apnoea tends to be due to alterations in central control of breathing d. If interstitial infiltrates are prominent, consider chlamydia trachomatis infection -> macrolide therapy 5. Treatment a. Ribavirin = not commonly used, modest beneficial effect, some reduction in mechanical ventilation and hospitalization 6. Prevention a. Palivizumab = monoclonal antibody i. Given monthly during peak seasons ii. For high risk children 1. CLD 2. Congenital heart disease if < 2 3. Extremely premature < 28 weeks iii. Given IM monthly for five doses iv. Discontinue if admitted with RSV infection 7. Prognosis a. Low mortality rate b. 30-50% infants with severe bronchiolitis develop recurrent wheeze

Answer 270

1. Virology b. Double stranded DNA viruses c. Non enveloped viruses with icosahedral protein capsid d. Seven species, cause distinct infections 2. Epidemiology a. Occurs in annual epidemics similar to RSV b. 2nd most common cause of LRTI in children 3. Clinical manifestations a. Transmission = respiratory b. Incubation = 3-5 days c. Infectious duration = several weeks after primary infection d. Clinical features i. Lower respiratory tract infection, otitis media 1. 50% of LRT occur in the first six month of life 2. Bronchiolitis, pneumonia, croup ii. Ocular infections iii. GI iv. Haemorrhagic cystitis v. Immunocompromised  pneumonia, hepatitis, gastroenteritis and disseminated disease 4. Diagnosis = NPA 5. Treatment a. Mainly supportive

Answer 271

1. Virology a. Double stranded DNA genome contained within the particle complexed with several viral proteins b. More than 50 serotypes in 8 species 2. Epidemiology a. Outbreaks occur in communities and closed populations (eg. military) b. Shed from the GIT for prolonged periods and can establish chronic low-level infection of the tonsils and adenoids c. Circulate worldwide and cause endemic infections year-round in immunocompetent hosts 3. Clinical manifestations a. Asymptomatic infections common – 1/3 of infections results in clinically apparent disease b. Classically results in conjunctivitis c. Acute respiratory distress = bronchiolitis, pneumonia i. May have features typical of bacterial disease (lobular infiltrates, high fever, parapneumonic effusions) ii. Pharyngitis, coryza, sore throat, fever d. Follicular conjunctivitis i. Pharyngoconjunctival fever = high temperature, pharyngitis, non-purulent conjunctivitis, lymphadenopathy e. Gastrointestinal infection = diarrhoea, usually self-limiting f. Haemorrhagic cystitis g. Rare manifestations i. Myocarditis ii. Hepatitis iii. Meningoencephalitis 4. Immunocompromised individuals a. Severe disease – particularly HSCT and solid organ recipients b. Patient may have primary infection or reactivation of endogenous virus in a transplant recipient or transmission of virus from donor organ c. Organ failure as a consequence of pneumonia, hepatitis, gastroenteritis and disseminated infection can occur 5. Diagnosis = PCR 6. Treatment a. No specific antivirals b. Vaccines for HAV type 4 and 7 – for military use c. Cidofivir = used for systemic infections in immunocompromised i. Highly nephrotoxic ii. No good evidence

Answer 272

1. Virology a. Picorniviridae family , more than 100 serotypes 2. Clinical manifestations a. Virus can be shed for up to 3 weeks after infection b. Most common cause of the common cold c. Infective exacerbation of airways disease d. Fever less common than with other viruses e. 15% asymptomatic 3. Complications a. Sinusitis b. Otitis media c. Asthma d. Bronchiolitis

Answer 273

= poliovirus, coxckie virus (group A and B), echovirus, enterovirus 1. Virology a. Non-enveloped, single stranded viruses - picornaviridae family (small RNA virus) b. > 100 types identified, with 10-15 accounting for the majority of disease c. Paraechovirus share similar characteristics but are classified as a separate genus 2. Epidemiology a. Predominant in summer/ autumn b. Humans the only natural hosts 3. Clinical manifestations a. Transmission = faecal oral (major), respiratory, vertical, vomits b. Incubation = 3-6 days c. Infections period = sheds for 1-3 weeks (if respiratory), 7-11 weeks (if faecal) 4. Diagnosis = PCR 5. Treatment a. Largely supportive IVIG, steroids, and antivirals either inconclusive or being investigated

Answer 274

= poliovirus, coxsackie viruses group A and B, echovirus, enterovirus i. Non-specific febrile illnesses 1. Fever, malaise, irritability, headache, sore throat 2. VARIABLE rash - macular, papular, urticarial, vesicular, petechial ii. Hand-foot and mouth disease 1. Coxsackie A16 + enterovirus 71 2. Pharyngitis + vesicles on oral mucosal 3. Maculopapular/vesicular/papular lesions on hands, fingers, feet and buttocks 4. Fever usually mild 5. Blistering usually resolves after 1 weeks 6. Can be complicated by neurological disease – encephalomyelitis (particularly enterovirus) 7. Exclude from school until blisters have dried – viral shedding can persist iii. Herpangina 1. Coxsackie A and enterovirus 71 2. Fevers + vesicles/ ulcers in the mouth iv. Acute haemorrhagic conjunctivitis 1. Enterovirus 70 and coxsackie virus A24 2. Usually spread via eye-hand-fomite-eye transmission 3. Sudden eye pain, photophobia, blurred vision, lacrimation + conjunctival erythema/congestion 4. Mucopurulent eye discharge 5. Systemic symptoms are rare v. Myocarditis/ pericarditis 1. Cause 25-35% cases of myocarditis and pericarditis 2. Coxsackie B most commonly implicated vi. Meningitis 1. Most common cause of viral meningitis (post mumps vaccine) + >20% causes of encephalitis 2. More common in infant, esp < 3months of age 3. Caused by coxsackie B viruses, echoviruses, parechoviruses, enteroviruses 4. CSF = pleocytosis, predominant PMN cells in the first 48 hours  mimics bacterial vii. Polio 1. Enterovirus P, V1, V2 and 3 2. Faecal-oral transmission, multiplies in pharynx + GIT 3. Incubation period 3-21 days 4. Infectivity 7-10 days prior  7-10 days after symptoms 5. 90% asymptomatic, but can cause aseptic meningitis with asymmetrical paralysis viii. Neonatal disease 1. Outbreaks of Paraechovirus recently in infants <3 months – presenting with ‘sepsis-like’ illness often with seizures due to CNS involvement 2. Sibling <2 years increases risk 3. Majority of severe infections caused by Paraechovirus serotype 3

Answer 275

1. Virology a. Non-enveloped, RNA viruses b. Picornaviridae family  genus enterovirus c. 3 serotypes 1-3 d. Adsorb to poliovirus receptor, penetrates cell and releases viral RNA e. RNA is translated to produce proteins f. Primary site of replication is usually in the GIT 2. Clinical manifestations a. Transmitted = via faecal oral route (humans only reservoir) b. Clinical features i. 90-95% infections are inapparent ii. Paralysis occurs in 1/1000 infections in infants, 1/100 infants in adolescents iii. Abortive poliomyelitis = nonspecific illness only iv. Nonparalytic poliomyelitis = nonspecific illness followed by nuchal and spinal rigidity, loss of reflexes v. Paralytic poliomyelitis = can be spinal, bulbar and polioencephalitis vi. Aseptic meningitis = rarely associated with paralysis 3. Diagnosis a. Faecal specimen b. Serology testing for IgG increase between acute phase  6 weeks later 4. Treatment = supportive 5. Prognosis depends on type a. Abortive polio + aseptic meningitis = usually benign b. Severe bulbar poliomyelitis = mortality rates up to 60% i. Maximum paralysis is usually 2-3 days after onset of paralytic phase c. Post-polio syndrome = following paralytic poliomyelitis, there may be intermittent weakness and muscle pain 6. Vaccination a. Given at 2, 4, 6 months + booster at 4 years b. IPV given in Australian regimen  better at inducing high serum IgG titres i. HOWEVER OPV improves mucosal IgA immunity c. Oral vaccine strains can develop neurophenotype and cause paralysis 7-14 days (risk 1/ 6.2 million doses) d. As of 2006, only present still in Afghanistan, India, Nigeria, Pakistan

Answer 276

1. Virology a. Orthomyxoviridae family b. Large single stranded RNA viruses – segmented genome encased in a lipid envelope c. Antigenically classified into A, B, C (C tends not to cause severe disease in humans) d. Structure i. Two spike glycoproteins 1. Haemagluttinin (HA) = agglutinates RBCs (nothing to do with pathogenicity), binds to sialic acid portion of the host glycoprotein receptor on resp epithelium for entry – trimer of identical subunits 2. Neuraminidase (NA) = releases virus from cells – tetramer of identical subunits 3. Membrane channel protein M2 = involved in the influx of protons allowing uncoating e. Lifecycle i. Attaches to cells via HA, endocytosis into the endosomal membrane ii. Releases viral RNA into the cytoplasm  nucleus, transcribed iii. Viral replication usually occurs for 10-14 days f. Pathogenesis i. Lytic infection of respiratory epithelium  loss of ciliary function, decreased mucous production and desquamation of the epithelial layer (predisposes to viral infection) g. Immune response i. Stimulates humoral and cell mediated immunity 2. Antigenic shift + drift a. Antigenic drift = minor changes = point mutations in respective gene (H or N) (made by RNA-dependent RNA polymerase – no proof reading/correction of mistakes) i. Results in ‘variant’ becoming the predominant virus  interpandemic influenza / seasonal variant ii. Occurs in influenza A, B, and C b. Antigenic shift = major changes = not accounted by point mutation = sudden appearance of new HA subtype (may or may not be accompanied by NA subtype) i. As there are now new surface Ag, there is no recognition or neutralization by the immune response ii. Only occurs with influenza A virus iii. Outcome = pandemic influenza eg. 1957 H2H2, 1968 H3N2, 1977 H1N1 1. Associated with high morbidity and mortality 3. Epidemiology a. Have avian and mammalian hosts b. Segmented nature of genome allows reassortment

Answer 277

4. Clinical manifestations a. Transmission = droplet b. Incubation = 1-7 days c. Infectious period = highly contagious; shedding is slightly shorter for influenza A d. Symptoms and signs i. Fever 2-3 days ii. Chills, headache, myalgia iii. +/- pneumonia/ GI symptom 5. Complications a. Otitis media – up to 25% b. Pneumonia – inc secondary bacterial infection c. Myocarditis d. Toxic shock syndrome 6. Management a. Amantadine (A) i. NOT effective against influenza B ii. Drug resistance evolves quickly iii. NOT commonly used b. Oseltamivir (A/B) - neuraminidase inhibitor i. Reduces duration of symptoms by 1 day on average - must be started within 48 h of symptom onset ii. Adverse effects – nausea, and vomiting iii. Offer treatment to all individuals with established complications or to patients requiring admission to hospital for management of influenza iv. Consider treatment for individuals at high risk for poor outcomes 1. Adults >65 years 2. Comorbidities 3. ATSI 4. Children <5 years 7. Vaccinations a. Indications i. Children <5 years ii. Pregnant women iii. Comorbidities = congenital heart disease, Down syndrome, obesity, chronic respiratory/ neurological conditions and immunocompromised patients

Answer 278

1. Virology a. Paramyxviridae family b. Nonsegmented, single stranded RNA virus c. Four subtypes that cause disease 2. Epidemiology a. Very common – most infected by age 5 3. Clinical manifestations a. Transmission = spread via respiratory tract b. Incubation = 2-6 days c. Infectious duration = 2-3 weeks (months in immunocompromised patients) d. Clinical features i. URT infections - croup (50% hospitalization), bronchiolitis, pneumonia, parotitis ii. Disease more severe in patients with compromised cell mediated immunity 4. Complications a. Sinusitis, bacterial pneumonia b. Rare = aseptic meningitis, encephalitis, rhabdomyloysis, myocarditis 5. Treatment a. No specific treatments available b. Vaccines being investigated

Answer 279

1. Virology a. Contain 2 surface proteins: VP7 (G glycoprotein) + VP4 (protease cleaved P protein) – these are the targets of antibodies 2. Clinical manifestations a. Incubation = 1-3 days b. Clinical features i. Recurrent infections throughout life, but first most likely to cause severe symptom ii. Results in severe diarrhoea 3. Vaccines a. Two oral vaccines available – given at 2, 4, and 6 months i. Both are live oral attenuated ii. Rotarix: contains one strain of attenuated human rotavirus  protects against non G1 serotypes iii. RotaTeq: contains five human bovine rotavirus + human serotypes G, G2, G3, G4, PqA and G6 and P7 b. Efficacy of vaccine i. Since 2007, > 70% in rotavirus specific and hospital presentations has been reported ii. Prevents gastroenteritis in approximately 70% of recipients iii. Prevents severe gastroenteritis and hospitalisation for 85-100% of recipients for up to 3 years c. Rotavirus and intussusception i. Initial vaccine found to be associated with increased risk ii. Large scale safety studies of Rotarix and RotaTeq : risk of intussusception similar to placebo iii. On post marketing study showed 4-5 fold increase in IS in the 7 days following first dose of Rotarix and RotaTeq d. Contraindications i. Anaphylaxis ii. Previous hx of intussusception / anatomical anomaly that increases risk iii. SCID iv. Note immunocompromise is NOT a contraindication to rotavirus vaccine

Answer 280

1. Virology a. Small circular stranded DNA viruses b. Spread via direct contact c. Infect and replicate within cutaneous and mucosal tissues d. More than 100 genotypes identified 2. Epidemiology a. Most prevalent viral STI  up to 70% of women acquire HPV thorugh sexual intercourse 3. Clinical features a. Most common manifestation is latent infection b. Genital warts (types 6, 11) c. Cervical cancer (types 16, 18) i. 70% of cases: infection induces epithelial change (cervical intraepithelial neoplasia), small number of which may progress to cervical cancer ii. HSIL occur in 0.4-3% of sexually active women iii. Invasive cervical CA occurs in 8/100,000 adult women iv. 5-15% untreated CIN3 lesions thought to progress to cervical cancer d. Recurrent papillomatosis – can be acquired vertically e. Warts tend to recur despite treatment 4. Pathogenesis a. Viral invasion of the basal cells of the epithelium (enhanced by trauma/ inflammation) b. Early regulation proteins E6 and E7 perturb normal cellular DNA synthesis: usually disruption of tumour suppressor genes p53 and retinoblastoma 5. Vaccine a. 3 dose schedule to both males and females at 12- 13 years b. Contain virus like particles c. Prevents HPV types 6, 11, 16 and 18

Answer 281

1. Epidemiology a. 180 children in Australia living with HIV b. 2.5 million children worldwide in 2009 2. Virology a. RNA viruses of the retroviridae viruses – HIV-1 and HIV-2 b. HIV-1 i. 2x single stranded RNA ii. Long terminal repeats at each end of the genome contain regulation and expression genes iii. Three other major sections: 1. GAG region -> STRUCTURAL 2. POL region -> ENZYMES 3. ENV region -> ENVELOPE iv. Other regulatory proteins involved in transactivation, viral messenger RNA expression, viral replication, induction of cell cycle arrest c. HIV-2 i. Similar lifecycle to HIV-1 ii. Differs in accessory genes iii. More prevalent in Western Africa Pathogenesis a. Most infected through mucosal – rectal or vaginal b. Mix of quasi species – R5 and X4 i. Most transmission occurs with R5 ii. Only one virus gets across c. First cell the virus sees is a DC – binds R5 virus d. Transports virus to the lymph node e. Activated CD4+ T cells – become infected f. Within days there is spread of infection to activated CD4+ lymphocytes g. Entry of virus infected blood cells into the bloodstream – high levels of virus in the blood h. Favourite sites of HIV to infect is the GIT – lots of activated CD4+ T cells i. Within weeks – significant deletion of CD4+ T cells in the GIT j. The immune system response to HIV i. CD8 T cells = suppress HIV replication by preventing virus binding to co receptors (eg CCR5) ii. Humoral response = formation of HIV antibodies

Answer 282

3. Lifecycle a. CD4 binding (CD4+ T cells) i. Gp120 present in the envelope, associated with transmembrane protein glycoprotein gp41 ii. Gp120 binds to CD4 iii. Coreceptor binding = CXCR4 or CCR5  Critical for viral entry b. Fusion i. After attachment, gp120 and CD4 undergo conformational change  gp 41 interacts with fusion receptor on the cell surface ii. Virus membrane fuses with the host cell membrane  Allows entry of RNA into the cell iii. RNA reverse transcribes (reverse transcriptase from HIV) →DNA 1. HIV-1 reverse transcriptase = error prone  lots of mutations and genetic variation iv. DNA moves into the nucleus and integrates into the host DNA v. Can sit dormant OR can complete viral lifecycle by forming viral RNA and RNA required for proteins which allow for assembly c. Budding  maturation  new HIV virion d. NOTE: There are two major co-receptors for HIV = CCR5, CXCR4 e. One strain use CCR5 and another strain use CXCR4 i. R5 = CCR5 – enter cells that express CCR5 which is commonly expressed on activated T cells ii. X4 = CXCR4 – expressed predominantly on resting CD4 T cells 4. Transmission a. Vertical transmission = the primary route of paediatric infection (<2% with effective treatment) i. Intrauterine = 30-40% pregnancies infected in utero (evidenced by HIV PCR +ve in first week of life) ii. Intrapartum = occurs in 60-70% of pregnancies without treatment 1. Through exposure to infected blood + cervicovaginal secretions 2. Elective LUSC ↓ transmission by 87% in conjunction with zidovudine (benefit likely negligible if viral load < 1000) iii. Post-partum 1. Breastfeeding LEAST common route of vertical transmission in industrialized nations, but as much as 40% of perinatal infections in resource-limited countries 2. Risk 9-16% in women with established infection 3. Risk 29-53% in women who acquire HIV postnatally b. Via blood transfusions i. Nucleic amplification testing now used to reduce risk of donations made prior to seroconversion c. Sexual transmission

Answer 283

6. Natural history a. Primary infection with seroconversion i. Mononucleosis like syndrome – 3-6 weeks after infection with viraemia 1. 50-70% adults 2. Fever, rash, lyphadenopathy, arthraligia ii. Primary HIV infection confirmed by antibodies to HIV – 6-12 weeks post infection iii. Antibodies against HIV-1 – include p24, gp120 and gp41 iv. IgG antibodies usually persist for life b. Clinical latency i. No findings on physical exam except for lymphadenopathy ii. Despite lack of symptoms, high rate of HIV replication and CD4 destruction may be occurring c. Early symptomatic disease d. AIDS 7. Clinical manifestations a. Adult disease i. Seroconversion illness: flu like symptoms 3-6 weeks following infection ii. Period of clinical latency 1. Associated with high turnover of virus + CD4 lymphocytes 2. Gradual deterioration of immune system b. Children – 3 patterns observed i. Rapid disease course 1. Onset of AIDS and symptoms within first few months of life  survival of 6-8 months 2. HIV-1 culture/ virus detectable in first 48 hours of life 3. Viral load rapidly increases, peaking by 2-3 months of life ii. Slower progression disease 1. More likely infected intrapartum 2. Median survival of 6 years 3. Viral load peaks by 2-3 months, then declines slowly over 24 months iii. Long term survivors 1. Minimal or no progression of disease: normal CD4 counts and low viral loads for > 8 years 2. May relate to effective humoral immunity , host genetic factors or defective gene viruses 8. General clinical finding a. Mild symptoms = lymphadenopathy, parotitis, hepatomegaly, splenomegaly, dermatitis, recurrent / persistent sinusitis/ otitis media b. Moderate symptoms = lymphocytic interstitial pneumonitis, oropharyngeal thrush, recurrent or chronic diarrhoea , persistent fever > 1 month , recurrent HSV stomatitis/ oesophagitis/ pneumonitis, disseminated varicella, cardiomegaly, nephropathy c. Severe symptoms = opportunistic infections – oesophageal/ lower respiratory tract candida, cryptosporidiosis, disseminated mycobacterial or CMV infection, PJP, toxoplasmosis

Answer 284

* Invasive candidiasis: bronchi/ trachea/ lungs/ oesophageal * Disseminated/ extarpulmonary coccidiodomycosis * Cryptococcus * CMV disease/ retinopathy * HSV – bronchitis/ pneumonitis/ esophagitis * MAC * PJP * Cerebral toxoplasmosis * Malignancies: cervical cancer, Kaposi sarcoma, lymphoma * Wasting syndrome * CD4 T lymphocyte count < 15% (absolute count < 200) a. PJP pneumonia i. ½ of all AIDS defining conditions diagnosed in 1st year of life ii. Low grade fever, tachypnea, non productive cough, dyspnea, poor feeding, diarrhea & weight loss iii. CXR – bilateral perihilar interstitial infiltrates iv. BAL or lung biopsy to confirm diagnosis v. Mortality rate ranges from 5-40% vi. Rx with TMP-SMX, Prophylaxis with the same if CD4 count <200 b. Lymphoid interstitial pneumonia/pulmonary lymphoid hyperplasia i. Affects older children, mean age 14 months ii. LIP/PLH onset is insidious, chronic cough & tachypnea iii. Generalised lymphadenopathy, HSM, painless parotid enlargement iv. Digital clubbing in advance stages v. CXR: symmetric bilateral reticulonodular interstitial infiltrates vi. CT shows micronodules vii. EBV has been implicated in development of it viii. Management is supportive, Abx for acute pulmonary infections & inhaled bronchodilators c. Recurrent bacterial infections i. Streptococcal pneumoniae, salmonella, staphylococcus, HiB are most frequently isolated ii. Pseudomonas is associated with late stage disease & severe immunosuppression d. Wasting syndrome i. Persistent weight loss >10% of baseline ii. Downward crossing of 2 or more major centile lines iii. Less than 5th percentile weight-for-height + chronic diarrhea or documented fever iv. Loss of lean body mass or wasting is well recognised AIDS defining condition e. HIV encephalopathy i. Failure to attain or loss of developmental milestones or loss of cognitive ability ii. Impaired brain growth or acquired microcephaly, or brain atrophy on CT or MRI iii. Acquired symmetric motor deficits – paresis, pathologic reflexes, ataxia or gait disturbances iv. Can be either static or progressive v. Static is more common  involves significant global cognitive & motor deficits with normal rate of learning vi. Progressive  developmental delay or regression vii. Associated with severe disease f. Candida esophagitis i. Risk factors  oral candidiasis, low CD4 count, and receiving Abx ii. Present with odynophagia, retrosternal pain, fever, N & V, drooling or dehydration and GIT bleeding & hoarseness g. CMV disease i. Can present with pneumonia, colitis or retinitis

Answer 285

10. Investigations/ diagnosis a. Serology i. HIV Ab may be present at birth due to maternal antibody ii. Most uninfected infants will lose antibody between 6-12 months iii. Note IgA and IgM do not cross placenta and would represent infection (but are not used clinically) b. Other diagnostic testing i. Screen with ELISA ii. Western blot testing c. Viral diagnostic assays = HIV DNA/ RNA PCR or HIV culture i. HIV DNA PCR the preferred virological assay – however RNA assay more commonly used ii. Should be performed within first 12-24 hours of life , 1-2 months and 4-6 months of age (check ASID guideline) d. CD4 lymphocyte count i. Value of < 1500 in children < 1 year of age suggests severe depletion ii. Value of < 200 CD 4 cells/ mm3 used in adults e. NOTE: i. Magnitude of viral load predicts the rate of disease progression ii. CD4 cell count reflects risk of opportunistic infections and HIV complications 12. Prognosis a. 50% of untreated children will die within first 2 years of life b. Risk factors for rapid progression i. High viral burden ii. Depletion of infected CD 4 lymphocytes iii. Opportunistic infections, encephalopathy or wasting syndrome c. Mean age of death > 18 years in 2006

Answer 286

a. Key aspects = 1) prevent vertical transmission 2) manage infection if +ve b. Preventing transmission i. Maternal ART = until undetectable ii. Appropriate mode of delivery iii. Formula feed (developed); breastfed (developing) iv. Baby receives PEP – varies depending on risk to neonate v. Testing - HIV PCR or HIV antibody >18months c. Treatment of HIV positive children i. When to start treatment - threshold is now ANY CD4 count ii. Adherence is a much greater issue - consider risks of breeding resistant strains iii. Medication = usually give 3 types to reduce risk of resistance 1. Treat children with symptoms/ evidence of immune dysfunction 2. Children < 1 are treated as they are at high risk of progression, regardless of viral load/ investigations 3. Treatment of children > 1 is controversial d. Classes of medication i. Preventers of viral entrance into CD4T cells 1. Fusion inhibitor: enfuvirtide, binds to gp41 (given subcutaneously) 2. CCR4 receptor blocker: maraviroc ii. Reverse transcriptase inhibitors 1. Nucleoside / nucleotide reverse transcriptase inhibitors (NRTIs): structure similar to DNA building blocks  incorporated into DNA and stop further transcriptions. Include: a. Thymidine analogues: stavudine, zidovudine b. Nonthymidine analoges: didanosine, lamivudine c. Classic side effects: lactic acidosis + hepatic steatosis (zidovudine also causes lipodystrophy) 2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs): attach to reverse transcriptase and restrict its motility: a. Examples: nevirapine, efavirenze, etravirine b. Classic side effects = rash iii. Protease enzymes inhibitors 1. Bind to the site where long polypeptides are cut to functional core proteins that produce infectious virions 2. Include: Ritonavir, Nelfinavir, Fosamprenavir, Tipranvair, Lopinavir 3. Classic side effects: hyperglycaemia, hyperlipidemia, lipodystrophy, lots of drug interactions (mostly metabolised by CYP3A4) iv. Drugs inhibiting integration of virus into human DNA 1. Integrase ihibitors: raltegavir e. Other management aspects i. Vaccines  avoid live vaccines 1. Rotavirus depending on risk ii. Prophylactic regimens 1. Pneumocystis a. Infants = PJP prophylaxis regardless of CD4 count b. Children > 1 = prophylaxis according to CD4 count 2. MAC = if advanced immunosuppression iii. Yearly TST testing

Answer 287

1. Key points a. Caused by multiple arthropod borne viruses – dengue virus (falviviridae vrus) + togavirus (chikungunya and West Nile fever) b. Spread via mosquitoes c. Incubation period 1-7 days d. Four strains – DENV-1 to DENV-4 e. Second dengue infection is more severe f. Viraemia peaks on day 2-3 then drops 2. Clinical features a. Fever, sore throat, rhinitis and cough – characteristic features are high fever + retro-orbital pain b. After defervescence: generalized morbilliform rash on the palms and soles c. Fever is classically biphasic d. Tourniquet test – causing petechiae e. 3 clinical phases i. Febrile ii. Critical iii. Recovery f. Dengue haemorrhagic fever i. Can be complicated by infection enhancing antibodies that lead to haemorrhagic fever ii. Rapid activation of the complement system also occurs with mild DIC and thrombocytopenia iii. Suggested by presence of petechiae iv. Circumoral and peripheral cyanosis v. Hepatomegaly vi. 20-30% cases complicated by shock 3. Investigations a. Serology and PCR available -> diagnosis b. Haemoconcentration (increase of > 20% in haematocrit) c. Thrombocytopenia d. Moderately decreased prothrombin level e. Pleural effusions common in dengue shock syndrome 4. Treatment is supportive 5. Prognosis – 40-50% with shock die

Answer 288

1. Virology a. Single stranded RNA virus b. Rhabdovirus family, lyssavirus genus c. 7 genotypes d. Dog and bats the most common reservoirs, transmitted via infected saliva i. NOTE: Australia has bat lyssavirus 2. Pathogenesis a. Virus enters the peripheral motor nerve via the nicotinic acetylcholine receptor, then disseminates through the brain and spinal cord, concentrates in the brain stem b. Clumped viral nucleocapsid seen pathologically as a negri body c. Deficiency of BH4 (neuronal nitric oxide synthase cofactor) underlies problems: i. Causes deficiencies in dopamine, noradrenalin and serotonin metabolism ii. Leads to spasm of the basilar arteries 3. Clinical features a. Incubation period 1-3 months b. Fever, sore throat, malaise, weakness c. Paraesthesias and pruritus d. Severe encephalitis e. Hydrophobia and aerophobia f. Findings of brainstem coma g. Paralytic form: fevers and ascending motor weakness 4. Diagnosis = based on PCR, most patients die while seronegative 5. Treatment a. Post exposure prophylaxis = immediate immunization and immunoglobulin