ID Flashcards
Immunisations - birth
Hepatitis B
Vitamin K
Immunisations - 2&4 months
Diptheria, Tetanus, Pertussis, Poliomyelitis, Hepatitis B, Haemophilus influenzae type B (Infanrix hexa)
Rotavirus (Rotarix)
Pneumococcal (Prevenar 13)
ATSI: Meningococcal B
Immunisations - 6 months
Infanrix hexa (diptheria, tetanus, pertussis, poliomyelitis, hepatitis B, haemophilus influenzae type B)
ATSI/High risk: Pneumococcal (Prevenar 13)
Immunisations - 12 months
MMR (measles, mumps, rubella)
Meningococcal ACWY (Nimenrix)
Pneumococcal (Prevenar 13)
ATSI: Meningococcal B, Hepatitis A
Immunisations - 18 months
Measles, mumps, rubella, varicella (Priorix-tetra)
Haemophilus influenzae type B
DTP (diptheria, tetanus, pertussis - infanrix)
ATSI: Hep A
Immunisations - 4 years
DTPP (diptheria, pertussis, tetanus, poliomyelitis) - infanrix IPV
ATSI/high risk: Pneumococcal (Prevenar 23)
Immunisations - 10-15 years
HPV (human papilloma virus) - generally year 7 and then 6-12months boost
DTP boost
Meningococcal ACWY boost
Live Vaccines (examples)
- Bacille Calmette-Guérin (BCG)
- Live attenuated oral poliovirus vaccine
- Measles, mumps, rubella, and varicella vaccine
- Oral typhoid vaccine (IPV also exists – on schedule)
- Rotavirus vaccine
- Smallpox vaccine
- Yellow fever vaccine
Toxoid Vaccines (examples)
- Diphtheria
* Tetanus
Vaccine AEs - general
- Common
a. Local reaction
i. Pain, redness, itching, swelling or burning
ii. Usually mild, last for 1-2 days
b. Injection site nodule
i. Fibrous remnant of body’s interaction with vaccine components
ii. May remain for many weeks and do not require treatment
c. Low-grade fever and malaise
i. Prophylactic paracetamol is NOT recommended except MenB
ii. If temperature >38.5 following vaccination can give paracetamol - Uncommon
a. Febrile convulsions
i. 3% of all children experience febrile convulsion
ii. Occur more commonly after some vaccines
iii. MMR/MMRV – associated with increased risk of febrile convulsion 7-12 days after vaccine
iv. 2010 – high incidence of febrile convulsions and fevers following a particular influenza vaccine
b. Brachial neuritis
i. Described following tetanus toxoid containing vaccines
ii. Occurs in 0.5-100 000 doses in adults
c. Intussusception
i. Oral rotavirus vaccine associated with small increase
ii. Appears to be particularly in 7 days following the first vaccine
iii. Children who have had IS or have congenital anomalies increasing risk should not receive rotavirus vaccine
d. Anaphylaxis
i. Generally occurs very rarely
e. Hypotonic-Hyporesponsive Episode (HHE)
i. Sudden onset of pallor or cyanosis, limpness (muscle hypotonia) and reduced responsiveness or unresponsiveness occurring after vaccination
ii. No other cause identified – not vasovagal or anaphylaxis
iii. No long term side effects
f. Guillain-Barre syndrome (GBS)
i. Small increase occurred following influenza vaccine in 1976
ii. Very low risk
g. Complex regional pain syndrome
i. Reports of possible link
Vaccines in preterm infants
- Vaccinate as per CHRONOLOGICAL AGE (including rotavirus) not corrected age
- Close contacts should have = influenzae, pertussis
- Note risk of apnoea in infants born <28 weeks – if previous apnoea following immunisations in hospital readmit for next vaccination and place on respiratory monitoring for 48-72 hours
• Hepatitis B
o 3 doses at 2, 4 and 6 months of age
o Booster at 12 months of age
• Pneumococcal
o Extra 13vPPV at 6 months
o 23vPCV at 4-5 years
• Influenza vaccine
o >6 months if chronic lung disease
o Prevention may be improved by maternal vaccination
• Rotavirus vaccine
o Give at chronological age without correction for prematurity
Vaccination in immunocompromised patients
BCG
• Always contraindicated
MMR and VZV
• Should not be given to persons with severe immunocompromise
• Includes:
o Active leukaemia or lymphoma
o Generalised malignancy
o Aplastic anaemia
o GVHD
o Congenital immunodeficiency
• Also includes:
o Those who have received recent chemotherapy
o Solid organ or bone transplant (within 2 years)
o Transplant recipients taking immunosuppression
o Steroids immunosuppressive - >= 2 mg/kg/day for more than 1 week OR
1 mg/kg/day for >=4 weeks
o Others on high dose immunosuppressive therapy
Oral typhoid • Contraindicated Yellow fever • Contraindicated Rotavirus • Indicated EXCEPT SCID
Household Contacts
• To best protect immunocompromised persons – household and other close contacts should be fully vaccinated
• Use of live attenuated viral vaccines in contacts (MMRV, rotavirus) is safe and strongly recommended to reduce the likelihood of contacts infecting the immunocompromised person
Rotavirus vaccine - general
- Key points
a. Two oral rotavirus vaccines available in Australia
b. Both live attenuated vaccines administered orally to vaccine
c. Recommended for all infants in the first half of the 1st year of life
d. Vaccination of older infants, children and adults is not recommended
e. Rotarix = monovalent human G1P1A strain – protects against non-G1 serotypes on the basis of other shared epitopes - Efficacy
a. Prevents rotavirus gastroenteritis of any severity in approximately 70% of recipients
b. Prevents severe rotavirus gastroenteritis and rotavirus hospitalisation for 85 to 100% of recipients for up to 3 years - Contraindication
a. Anaphylaxis to previous rotavirus vaccination
b. Previous history of intussusception or a congenital abnormality that may predispose to intussusception
c. SCID - prolonged vaccine virus-associated gastrointestinal disease reported - Intussuception
a. Clinical trials did NOT find association between vaccination and intussusception
b. Post-marketing study in Australia found a 4- to 5- fold increase in the risk of intussusception in the 7 days of either rotavirus vaccination
c. HOWEVER, no overall increase in the risk of intussusception was detected over the first 9 months of life
d. The increased risk of IS following rotavirus vaccination, from the most recent Australian study, is estimated as approximately 6 additional cases of intussusception among every 100 000 infants vaccinated, or 14 additional cases per year in Australia
e. This estimate assumes that infants in which an episode of IS occurs shortly after vaccination would not have otherwise experienced a ‘natural’ episode of intussusception; however, cannot be determined from current data
f. Rotavirus vaccine should not be given to an infant who has had a confirmed intussusception because there may be an increased risk of the condition recurring - NOTE
a. Unexpected benefit in reducing childhood seizures
Measles vaccine - general
- Key points
a. Cases of measles in Australia continue to occur – primarily in returning non-immune travellers
b. To ensure herd immunity + maintenance of elimination – 2 dose vaccine coverage in each birth cohort >95% - Schedule
a. 12 months – MMR, 18 months – MMRV - Adverse effects
a. Fever (with malaise and/or rash – non-infectious) may occur after MMR vaccine
iv. Risk of febrile seizures
b. Anaphylaxis (very rare)
c. Thrombocytopaenia (very rare)
d. Encephalopathy (unclear, infrequent)
e. Transient lymphadenopathy
f. Transient arthralgia
g. Parotitis - Rubella vaccine in pregnancy
a. Rubella vaccine virus may cross the placenta and infect the foetus
b. No cases of congenital rubella syndrome reported in women inadvertently vaccinated during early pregnancy
c. Theoretical risk to foetus so women advised to avoid pregnancy for 3 months following vaccination
d. Given prior to pregnancy, and retested 6-8 weeks post for seroconversion. If not converted 2nd dose - Efficacy
a. Measles immunity induced by 1-dose vaccination provides long-term immunity in most recipients.
b. However, approximately 5% of recipients fail to develop immunity to measles after 1 dose
c. Following a 2nd vaccine dose, approximately 99% of subjects overall will be immune to measles
BCG Vaccine - general
= Bacillus Calmette–Guérin (named after inventors)
- Key points
a. Attenuated live vaccine - Efficacy
a. 80% protection in the first 15 years of life; reduces subsequently
b. Greatest benefit in preventing miliary tuberculosis and tuberculosis meningitis in children, and pulmonary TB in adults
c. Best efficacy in newborns and infants not previously exposed - Adverse effects
a. Osteitis
b. Osteomyelitis
c. Disseminated infection; commonly in setting of HIV infection or other immunosuppression - Neonatal BCG indications
a. Living in a house or family with a person with either current or past history of TB
b. Household members who within the last 5 years have lived 6 months or longer in countries with high TB rates
c. For first 5 years will be spending >3 months in high-incidence country - Contraindications
a. Immunocompromise – drug-induced or disease
b. Infected HIV
c. Generalised skin conditions
d. Previous TB
e. Mantoux test >5mm
f. Mother received anti-TNF therapy in pregnancy (BCG delayed)
g. Pregnancy
Hepatitis A vaccine - general
- Efficacy
a. Almost universal seroconversion 4 weeks after vaccine
b. Single dose provides immunity for at least 1 year
c. Second dose recommended to prolong duration of protection - Serology
a. Titres are usually below detection limits of the routinely available commercial tests for anti-HAV serological testing to assess immunity after vaccination is NOT required - Recommendation
a. All travelers >=1 year of age travelling to endemic areas (all developing countries)
Pertussis vaccine - general
- Key points
a. Pertussis remains highly prevalent in Australia
b. Least well controlled of all vaccine-preventable diseases
c. Epidemics occur every 3 to 4 years
d. Maximal risk of infection and severe morbidity is before infants are old enough to have received at least 2 vaccine doses
e. Many cases of pertussis have occurred in adults + adolescents due to waning of immunity – reservoir of infection
i. Household contacts and carers are frequently the source of infection - Parents identified as the source for more than 50% of cases
ii. Siblings are a significant source of infant infections - Vaccine strategies
a. Indirect protection from immunisation of household contacts and carers of newborn infants, known as the ‘cocoon’ strategy
b. Direct protection from immunisation of the mother during the last trimester of pregnancy - Vaccine schedule
a. Children
i. 3 dose primary schedule = 2, 4, 6 months
ii. Booster doses - Two booster doses of pertussis-containing vaccine are recommended during childhood to provide ongoing protection against pertussis through to early adolescence
- 18 months
- 4 years
b. Adolescents = dTpa (reduced Ag content) booster between 10-17 years
c. Household contacts and carers
i. Age-appropriately immunised
ii. A booster dose of dTpa is recommended if 10 years have elapsed since a previous dose
d. Pregnancy
i. Third trimester of each pregnancy – passive protection to the newborn
Varicella immunisation - general
- Active immunisation
a. Active immunization within 3-5 days of exposure prevention of infection among susceptible persons and lessening of disease severity
b. Indication = healthy but susceptible adults and children who were exposed but have not received full course
c. Contraindications = immunocompromised - Passive immunisation
a. Indications
i. Immunocompromised who lack evidence of immunity to VZV
ii. Neoplastic disease
iii. Newborns of mothers with varicella shortly before or after delivery (ie, five days before to two days after delivery)
iv. Premature ≥28 weeks AND mothers lack immunity
v. Premature <28 weeks/weigh ≤1000 g at birth REGARDLESS of mothers’ immunity
vi. Pregnant women who lack evidence of immunity to VZV
b. NOT indicated if two prior doses varicella vaccine that preceded onset of immunocompromise
c. Efficacy of VariZIG has only been studied within 10 days of varicella exposure
d. Patients who receive VariZIG for post-exposure prophylaxis should be monitored for varicella for 28 days after exposure since passive immunization may prolong the incubation period
HPV vaccination - general
- HPV (human papilloma virus)
a. 16 + 18: 63% of cervical cancers
b. 6 + 11: 90% genital warts - Vaccine
a. Quadrivalent HPV vaccine funded since 2007
b. Recombinant virus-like particles (VLPs) = composed of L1 protein (outer virus layer) mimicking outer structure of HPV virion
c. Do NOT contain viral DNA and CANNOT cause infection
d. Two vaccines:
i. Cervarix (16, 18)
ii. Gardasil (16, 18, 6, 11) - Vaccine schedule
a. Boys and girls 12-13 years ?3 x doses – 0, ?2 and 6 months (check most recent schedule)
b. Immunocompromised = recommended
c. Pregnancy = not recommended
d. Contraindication = anaphylaxis
Meningococcal vaccine - general
- Available vaccines
a. Monovalent meningococcal C vaccine (also produced in combination with Hib) previously on schedule
b. Quadrivalent meningococcal conjugate vaccines (4vMenCV) ACWY now on schedule
c. Meningococcal B vaccine (recombinant) MenBV optional extra - Meningococcal B vaccine
a. MenB responsible for most cases of invasive disease
b. Development of vaccine challenging as MenB polysaccharide capsule similar to fetal nerve cells and therefore poorly immunogenic (PAST MCQ)
Vaccine allergy - general
- Key points
a. Vaccines rarely produce allergy or anaphylaxis
b. Risk of anaphylaxis after a single vaccine estimated to be <1 case per 1 million - Allergens
a. Antibiotics, gelatin and egg proteins are the components most often implicated
b. Yeast rarely associated with reaction
c. Latex allergy – presence of latex in the equipment use to hold the vaccine and plungers - Antibiotic allergy
a. This is frequently NOT a contraindication to vaccination
b. Beta-lactam or related antibiotic allergy = NOT a contra-indication to vaccines containing neomycin, polymyxin B or gentamicin
c. Previous reactions to neomycin that involve the skin only = NOT risk factor for severe allergic reaction - Egg allergy
a. 2nd most common food allergy in infants and young children (milk is the most common)
b. IgE antibody-mediated allergy
c. Safe vaccines
i. Influenza vaccine - History of anaphylaxis or serious reaction to egg previously absolute contraindication to influenza vaccine
- However many studies indicating it can be safely given current guidelines suggest giving
- Should be given in facility with staff able to recognize and treat anaphylaxis
- Allergy testing prior to vaccine NOT recommended
ii. MMR - NOT a contraindication to MMR (even anphaylaxis)
- MMR vaccine contains only a negligible quantity of egg ovalbumin
d. Contra-indicated vaccines
i. Yellow fever and Q fever – contain higher amounts of ovalbumin and are contraindicated
Pregnancy and vaccines - general
- Recommended vaccines during pregnancy
a. Influenza
b. dTpa
Influenza
• Recommended for all pregnant women at any stage of pregnancy, particularly those who will be in the second or third trimester during the influenza season
• Influenza immunisation protects the mother, as pregnancy increases her risk of severe influenza, and also protects her newborn baby in the first few months after birth
dTpa
• dTpa recommended as a single dose during the third trimester of each pregnancy (ideally at 28–32 weeks)
• Pertussis vaccination during the third trimester of pregnancy has been shown to be more effective in reducing the risk of infant pertussis than maternal vaccination post partum
- Contraindicated vaccines = ALL live vaccines
a. Due to hypothetical risk of harm should vaccine virus replication occur in the fetus
b. If a live attenuated viral vaccine is inadvertently given to a pregnant woman, or if a woman becomes pregnant within 28 days of vaccination, she should be counselled about the potential for adverse effects, albeit extremely unlikely, to the fetus
Vaccine efficacy (HepB, DTP, MMR, Hib)
- Hep B (birth, 2 mo, 4 mo, 12 mo) = 98% after 3 vaccines
- DTPa (2mo, 4 mo, 6 mo) = 95% efficacy after 6 month vaccine but wanes 50% in 5yrs; of these pertussis is the least effective which is why you give a booster at 4yrs and with pregnancy etc.
- MMR (12 mo) = 95% respond after 1 dose (98% after 2 doses)
- Hib (2mo, 4 mo, 12 mo) = 95% effectiveness
Basic reproductive number
• Basic reproduction number = “R0.”
o How many people in an unprotected population one infected person could pass the disease along to
• Measles has highest R0 closely followed by pertussis
Antibiotics - cell wall active group, brief
- Beta lactams
a. Penicillins
b. Cephalosporins
c. Carbapenems
d. Monobactams - Non-beta lactam
a. Glycopeptides
Penicillins - summary
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
Cephalosporins - summary
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
Glycopeptides - summary
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
Carbapenems - summary
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
Monobactams - summary
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
Antibiotics - protein synthesis group, brief
- Aminoglycosides
- Tetracyclines
- Macrolides
- Cloramphenicol
- Lincosamides
- Oxazolidinones
Aminoglycosides
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
Macrolides
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
Tetracyclines
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
Chloramphenicol
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
Lincosamides
Clindamycin, lincomycin
Bind 50S subunit Coverage • Some GP (MRSA, GAS), anaerobes, bacteriodes; no GN • Anti-toxin • Good tissue penetration Other - Clostridium difficile
Oxazalidinones
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)
Nitromidazoles
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
Fluoroquinolones
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
Rifampicin
Inhibits bacterial RNA polymerase
Coverage
MRSA
AE/other
Use = TB, leprosy, MRSA, prophylaxis in some UTI
Sulphonamides and trimethroprim
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
Antibiotics for GPB
- Diptheria = phenoxymethylpenicillin
- Listeria = Benzylpenicillin
- Clostridium difficile = metronidazole/vancomycin
Antibiotics for GPC
- Streptococci = benzylpenicillin
- Enterococci = amp/amoxicillin
- Staphylococci = di/flucloxacillin
- MRSA = vancomycin/clindamycin
Antibiotics for GN coccobacilli
- Pertussis - erythromycin/clarithromycin
* Haemophilus - ceftriaxone
Antibiotics for GN cocci
• Neisseria = cefotaxime/cetriaxone
Antibiotics for GNB
• 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
Antibiotics for atypicals
chlamydia, legionella, mycoplasma
- Azithromycin
- Roxithromycin
Bacteria treated with penicillin not flucloxacillin
- Listeria
- Enterococcus
- Clostridium
- Actinomyces
- Bacillus anthracis
- Group A strep
Antibiotics for pseudomonas
- 4th generation penicillins (piperacillin, ticarcillin)
- 4th generation cephalosporins (ceftazidime, cefipime)
- Carbapenems
- Aztreonam
- Aminoglycsides – genta, amikacin, tobramycin
- Ciprofloxacin
- Tigecycline
- Colistin
Antibiotics for anaerobes
Abdo/necrotic/gasseous infections
- Metronidazole
- Carbapenems
- Tazocin
- Clindamycin
- Tigecycline
Antibiotics for MRSA
- Vancomycin
- Teicoplanin
- Clindamycin
- Bactrim
- Tetracycline
- Rifampicin
- Linezolid
Bacterial resistance to antibiotics - general
- 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 - 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 - Intrinsic vs acquired
a. Intrinsic
i. Predictable resistance – does not require susceptibility testing
ii. Intrinsic cellular property of organism or intrinsic mutation
iii. Examples - Gram negatives = vancomycin not effective against cell wall
- Pseudomonas aeruginosa = intrinsically resistant to cefotaxime
a. Low affinity of cefotaxime to pseudomonal PBPs
b. Low permeability - 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 - Altered transpeptidases (PBPs)
ii. Enzymatic modification of antibiotic – usually plasmid mediated - Beta lactamases
- Aminoglycoside modifying enzymes
iii. Decreased access of antibiotic for target - Efflux pumps
- Decreased cell wall permeability
Beta lactam resistance - mechanisms
- Mechanisms
a. Alteration of the target site
i. Target site for beta-lactams are the PBPs (penicillin-binding proteins) in cytoplasmic membrane
ii. Examples - Penicillin resistant pneumococci
- Methicillin resistant staphylococci
- 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
Extended-spectrum beta-lactamases
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
ESCAPPM organisms and resistance
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
ESBLs and resistance
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
MSSA and MRSA antibiotic options
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
Enterococci - antibiotic resistance
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
Group A Strep - antibiotic resistance
i. No resistant strains isolated
ii. Universally susceptible to penicillins and almost all macrolides
Staph - antibiotic resistance
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
Strep pneumo - antibiotic resistance
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
New antibiotic classes (colistin, fosfomycin, tigelcycline, daptomycin, ceftaroline fosafmil)
- 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 - 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 - 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 - 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 - 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
Pencillins - spectrum
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)
Penicillinase-resistant penicillins
methicillin, nafcillin, flucloxacillin -> staphylococci, streptococci (NOT enterococcus)
Augmentin
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
Extended spectrum penicillins
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
Cephalosporins - key points
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
- 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
Ceftriaxone
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
Carbapenems
- Includes
a. Ertapenem
b. Imipenem
c. Meropenem - 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) - Side effects
a. Neurotoxicity – less with meropenem - 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 - 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)
Vancomycin
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
Aminoglycosides
- Mechanism
a. Binds to 30S ribosomal subunit inhibit protein synthesis
b. Bacteriostatic - Cover
a. Activity against most gram negatives including pseudomonas
b. Synergistic against enterococci/streptococci - Dosing
a. 24 hour dosing recommended including in neonates - Monitoring
a. TDM essential
b. Trough used to evaluate risk of toxicity - Significant side effects
a. Nephrotoxic (10-20%) = usually reversible
b. Ototoxic = cochlear/vestibular permanent
i. Cochlear = sudden, irreversible deafness - People with genetic predisposition
- Can also happen in people without predisposing and have high cumulative dose
ii. Vestibular = idiosyncratic - Can happen with a single dose, even if appropriate dose
c. Risk of both increased with loop diuretics - Use = empiric sepsis
Tetracyclines
- Mechanism = protein synthesis inhibit –binds 30S ribosomal subunit
- Doxycycline is main one used
- Cover = atypical pathogens/intracellular pathogens
a. Malaria = prophylaxis, treatment
b. Rickettsia spp
c. Chlamydia spp, Mycoplasma, Legionella
d. Spirochetes Treponema pallidum (syphilis) - Use = frequently for CAP atypical cover and pelvic inflammatory diseases
- Side effects
a. Photosensitivity
b. Esophagitis, reflux
c. Teeth staining
Fluoroquinolones
- Mechanism = affects DNA replication by targeting DNA gyrase
- 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 - 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 - Can reduce number of bacteria with other antibiotic then change to ciprofloxacin
- Combination therapy
- Side effects = Achilles tendon
Lincosamides
- Mechanism = inhibits protein synthesis
- 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 - Clindamycin (GP + anaerobes) + ciprofloxacin (GN)
Macrolides
- Mechanism = inhibit protein synthesis, 50S ribosomal subunit
- Azithromycin is main one used
- Wide spectrum
a. GP streptococcal and staph but increasing resistance
b. ‘Atypical’ pathogens = legionella, mycoplasma and chlamydia spp.
c. Bordetella pertsusss (whooping cough) - Not effective against GNR
- Major use in community acquired respiratory infections
- Bioavailability, good ORAL absorption
- SE = arrhythmias, may lengthen QT interval
Nitroimidazoles
- Mechanism= affects DNA replication
- Metronidazole is main one used
- Covers
a. Anaerobes Bacteroides fragilis
b. Clostridium difficile (first choice oral vancomycin)
c. Protozoa Trichomonas vaginalis, giardia lamblia, Entamoeba histolytica - Excellent oral bioavailability
- Side effects
a. GI symptoms nausea, metabolic state
b. Disulfiram-like = reaction with alcohol consumption
c. Peripheral neuropathy
TMP+Bactrim
- 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 - 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
Fungal infections - overview/general
- 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 - Unicellular growth form of fungi, reproduce by ‘budding’
- Can form long filaments
ii. Moulds = Aspergillus, Scedosporium proliferans, Fusarium, Zygomycetes (Rhizopus, Moro) - Multicellular colonies that are composed of clumps of hyphae
- Grow in long filaments that intertwine
- Eg dermatophytes, Aspergillus
iii. Dimorphic = Histoplasma, Blastomyces, Cocciodes - 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 - 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) - 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
Systemic fungal infections - general/overview
• 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
Histoplasmosis - general
- 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 - Clinical manifestations = bronchopneumonia, disseminated disease (w splenic involvement – only in infants + immunocompromised patients)
- Treatment
a. Oral itraconazole
b. Amphotericin B for progressive disseminated disease
c. Lifelong therapy with itraconazole for HIV / immunocompromised patients
Blastomycosis - general
- 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 - Diagnosis
a. Histopathology: neutrophilic infiltration with noncaseating granulomas
b. Urine antigen testing available - Treatment = amphotericin B / itraconazole
Coccidioidomycosis - general
- 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 - 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 - 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) - Treatment = azole, amphotericin
Zygomycosis - general
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.
- Key points
a. Fungal infections caused by zygomycetes class of fungi
b. Includes = Rhizopus, Mucor, Rhizomucor
c. Saprophytic – found in soils - Risk factors
a. Any immunosuppression
b. Diabetes, malignancy
c. Steroid or deforoxamine therapy - Pathogenesis
a. Usually acquired by inhalation of spores
b. Disease occurs when there is breakdown in macrophage and neutrophil defences - 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 - Diagnosis = microscopy
- Treatment
a. Surgical debridement
b. Amphotericin
c. Hyperbaric therapy may be used as an adjunct
d. Note – voriconazole + caspofungin are inactive - Prognoses
a. Rhino-orbital-cerebral mucormycosis 25-60%
Cryptococcus - general
- Microbiology
a. Polysaccharide encapsulated yeast, serotypes A, D, and AD
b. Species
i. Cryptococcus neoformans
ii. Cryptococcus gatti - 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) - Risk factors
a. Immunosuppression
b. DM
c. Renal failure - 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 - 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 - 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) - 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 - Prevention
a. Fluconazole prophylaxis in patients with AIDS
Candida - background and antifungals
- Includes
a. Candida albicans
b. Candida glabrata
c. Candida krusei
d. Candida parapsilosis - 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 - 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
Candida - superficial disease
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»_space; 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
Candida - Invasive candidiasis
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
Chronic mucocutaneous candidiasis
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
Aspergillus - background and manifestations
- Includes
a. A. fumigatus
b. A. flavus
c. A. niger
d. A. terreus
e. A. nidulans - 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 - Risk factors for disease
a. Neutropenia
b. Suppressed macrophage function
c. Exposure to high dose of conidia - 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
Aspergillus - allergic disease
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
Aspergillus - non invasive
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
Aspergillus - invasive
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
Pneumocystis jirovecii PJP - background
- 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 - 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
Pneumocystis jirovecci PJP - manifestations/ix
- 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 - 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)
Pneumocystis jirovecii PJP - rx/prognosis
- 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 - Prevention – chemoprophylaxis
a. Bactrim
b. Alternatives
i. Dapsone
ii. Atovaquone
iii. Aerosolized pentamidine - 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
Antifungals - overview
• Most antifungals work by binding to ergosterol – component of cell membrane present in fungi but not human cells
Overview
- Triazoles = fluconazole, itraconazole, voriconazole, posaconazole interfere with cell membrane function by inhibiting ergosterol (cell MEMBRANE) synthesis
- Echinocandins = caspofungin, micafungin inhibit cell wall synthesis (beta 1,3 D glucan)
- 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
Triazoles - general
• 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
Fluconazole - general
- 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) - 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 - 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 - Indications
a. Prophylaxis
b. Treatment
i. Candida – except candida krusei and glabrata
ii. Cryptococcal meningitis
Itraconazole - general
• 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
Voriconazole - general
- 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) - 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) - 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 - Adverse effects
a. Visual disturbance
b. Elevated hepatic transaminases
c. Photosensitization
Posaconazole - general
- 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
Echinocandins - general + examples
• 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
Amphotericin - general
- 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) - Pharmacodynamics
a. 24-48 hour distributional half life
b. Terminal elimination half-life of up to 15 days - 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 - Indications
a. Candidiasis
b. Cryptococcal meningitis
c. Severe pneumonia + extrapulmonary blastomycosis, histoplasmosis, coccidodomycosis
d. Invasive aspergillosis
e. Invasive sporotrichosis
f. Mucormycosis - Adverse effects (as above renal + infusion reaction)
a. Renal toxicity
b. Hypokalaemia
c. Acute febrile reaction
d. Anaemia
e. Phlebitis
5-flurocytosine - general
• 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
Nystatin - general
• Binds to ergosterol • Mainly used topically on skin + mucous membranes • Key indications o Oral thrush o Oesophageal + gastric candidiasis
Terbinafine - general
- Blocks ergosterol synthesis
- Used for tinea pedis, apitis, corporis
- Not metabolised by CP450 system (so has less drug drug interactions)
Griseofulvin - general
• Static drug: inhibits growth rather than killing fungi
• Adverse effects (uncommon)
o Headache, N+V, photosensitivity, confusion
o Bone marrow suppression
Haemophilus influenzae type B - general
- 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 - 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 - 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) - 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 - 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 - Vaccines
a. 2, 4, 6 months (infanrix hexa)
b. 18 months (ActHIB)
Moraxella catarrhalis - general
- 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 - Clinical features
a. Otitis media = 15-20% of cases
b. Sinusitis
c. LRTI
d. Bacteraemia = rare, usually seeds from respiratory tract - Treatment
a. Augmentin
b. Extended spectrum cephalosporins
c. Macrolides
d. Bactrim
Bordetella pertussis - background
- 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 - 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
Bordetella pertussis - sx/ix
- 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 - Paroxysmal cough with inspiratory whoop
- Post-tussive vomiting or apnoea
- May be complicated by pneumonia, seizures, encephalopathy
- 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 - Complications
a. Apnoea
b. Seizures
c. Refractory pneumonia - 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
Bordetella pertussis - management
- Management
a. Admit any infants < 3 months of age
b. Antibiotics = reduce infectivity, but not great evidence that alter course of disease
i. Indication - Diagnosed in catarrhal or early paroxysmal phase (may reduce severity)
- Cough <14 days (may reduce spread, reduces school exclusion)
- Admitted to hospital
- Pneumonia, cyanosis, apnoea
ii. Antibiotics - Neonates = azithromycin 10 mg/kg 5 days
- Children = clarithromycin liquid for 7 days, OR azithromycin for 5 days
- 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 - Close contact while infectious, AND
- First contact within 14 days, AND
- Child – age <6 months, <3 doses of pertussis, household member <6 months, attend childcare with children <6 months
- Adults – expectant mother, HCW, childcare worker, household member <6 months
- Vaccination
a. Acellular vaccine – less side effects than whole cell pertussis (local reactions, fever, anorexia)
b. Indications
i. Current schedule - 2, 4 and 6 months
- 18 month booster
- 10-15 year booster
ii. Persons in contact with infants or others at increased risk from pertussis - Women who are pregnant or post-partum – given during 3rd trimester
a. More effective when given DURING pregnancy - Other household contacts and carers of infants <6 months
- 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
Neisseria meningitidis - background, RFs
- 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 - 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 - 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
Neisseria meningitidis - sx/ix
- 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 - Diffuse adrenal haemorrhage (Waterhouse-Friderichsen syndrome)
- 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 - 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
Neisseria meningitidis - rx, prognosis
- 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 - Infants < 1 month = rifampicin Q12H for 4 doses
- Children > 1 month = rifampicin Q12H for 4 doses, OR ciprofloxacin single dose
- Adults = ciprofloxacin single dose
- Pregnant or contraindication to rifampicin = ceftriaxone IM single dose
- 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 - Vaccines
a. Vaccines available
i. Monovalent meningococcal C vaccine (MencCV) – previously on vaccine schedule
ii. Quadravalent meningococcal vaccine – ACYW135
iii. MenB vaccine – meningitis B - 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
Non-Typhoid Salmonella - background
- 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 - Epidemiology
a. Incidence of disease proportional to hygiene, sanitation
b. Increasing drug resistance seen – possibly due to farming practice - 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
Non-Typhoid Salmonella - sx/ix/rx
- 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) - Investigations
a. Largely based on stool culture - PCR not well established yet - 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 - Prognosis
a. Most recover fully - shed for 5 weeks (median), some children chronic carriers
Typhoid Fever - background
- Aetiology
a. Salmonella typhi
b. Salmonella paratyphi A, B and C – less common - 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 - Epidemiology
a. Cause more than 200,000 deaths/year
b. Mostly affects travellers
Typhoid Fever - sx/ix
- 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%) - Complications
a. Hepatitis
b. Intestinal haemorrhage/perforation
c. Toxic myocarditis
d. Delirium/psychosis
e. Acute cerebellar ataxia
f. Chorea
g. Deafness
h. GBS - 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
Typhoid Fever - classic presentation (uptodate)
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.
Typhoid Fever - rx/prognosis
- 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 - Prognosis
a. 2-4% children relapse despite initial response to therapy
b. <2 % become carriers, excrete for > 3 months - Prevention
a. Public health measures – sanitation of water, treatment of sewage
b. Typhoid vaccine: withdrawn due to high rates of side effects
Shigella - general
- 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 - 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 - 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 - 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 - Diagnosis
a. Culture of stool = WBC + RBC
b. PCR not routinely available - 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
Cholera - general
- 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 - 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 - 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 - Risk factors
a. Blood group O
b. Decreased gastric acidity
c. Malnutrition
d. Immunocompromised - 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 - Diagnosis
a. Based on isolation of organism from stool/vomit/rectal swabs
b. Note stool will NOT have leukocytes as there is no inflammation - 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 - 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.
Campylobacter - general
- Microbiology
a. Campylobacteriacae family
b. Multiple species pathogenic for humans – most commonly jejuni
c. Gram negative non spore forming rods - Epidemiology
a. Usually acquired from contaminated poultry/raw milk, farm animals
b. Peak in early childhood, then again in 15-44 year age group - 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 - 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 - 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
