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Pathology > Microbiology > Flashcards

Microbiology Flashcards

1
Q

Routes of entry of CNS infections

A

haematogenous spread (through blood-brain barrier)
direct implantation (instrumentation: sharp objects)
local extension (eg. through ears) - secondary to established infections
PNS into CNS (ascend along axonal structures) - viruses (rabies)

most common: haematogenous spread

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2
Q

Meningitis

A

inflammatory process of meninges and CSF
neurological damage caused by: direct bacterial toxicity, indirect inflammatory process and cytokine release and oedema, shock, seizures, cerebral hypoperfusion

mortality approx 10%
morbidity approx 5% (deafness)

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3
Q

Meningitis classification

A
  1. Acute: within days max, usually bacterial meningitis
  2. Chronic: symptoms for couple of weeks - months, usually TB, spirochetes, cryptococcus
  3. Aseptic: usually acute viral meningitis
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4
Q

Meningitis symptoms

A

vomiting
fever
headache
stiff neck
light aversion/photophobia
drowsiness
joint pain
fitting
non-blanching petechial rash (can use bp cuff if don’t have glass)

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5
Q

acute meningitis commonest causes

A

neisseria meningitidis (meningococcus) (10%)
strep pneumoniae (33%)
haemophilus influenzae (25%)
what they all have in common: commensal in naso and oropharynx commonly

Less common:
listeria monocytogenes
group b strep
E. coli
many more

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6
Q

N. meningitidis

A

50% have meningitis
7-10% have septicaemia
40% have septicaemia AND meningitis

clinical difference: those with septicaemia have lower prognosis, no LP in septicaemia due to DIC (need to optimise first)

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7
Q

Chronic meningitis

A

fever, headache, neck stiffness
on CT: thickening of dura mater, may have space-occupying lesions (TB)

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8
Q

Chronic tuberculous meningitis

A

incidence: 544 per 100,000 in Africa
more common in immunosuppressed
mortality: 5.5 per 100,000
involves meninges and basal cisterns of brain and spinal cord
can result in tuberculous granulomas, tuberculous abscesses, or cerebritis

NB: 25% of population is exposed to TB but most continue normal life course, of those who develop TB 50% have pulmonary TB, want to diagnose TB meningitis v quickly

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9
Q

Aseptic meningitis

A

most common infection of CNS
headache, stiff neck, photophobia (fever less common)
enteroviruses responsible for 80-90% cases (feacal-oral route or saliva)
most frequent in children <1 year
clinical course: self-limited and resolves in 1-2 weeks

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10
Q

Encephalitis

A

inflammation of brain parenchyma
25% death, 20% morbidity
causes are most commonly viral
transmission commonly person to person or through vectors (mosquitoes, lice, ticks)
West nile virus becoming a leading cause after enteroviruses and herpes (can test both of those but need to advocate for testing WNV)

other infectious causes: bacterial (listeria monocytogenes)
amoebic (naegleria fowleria, habitat - warm weather, acanthamoeba species and balamuthia mandrillaris) - cause brain abscess, aseptic or chronic meningitis
toxoplasmosis (immunocompromised): affected organs include the gray and white matter of the brain, retinas, alveolar lining of the lungs, heart, skeletal muscle

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11
Q

Focal CNS infections

A

Brain abscess (pathophysiology: otitis media, mastoiditis, paranasal sinuses, endocarditis, haematogenously) (microbiology: strep, staph)

Spinal infections (post-surgical or trauma or staph aureus from infected cannulas)

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12
Q

Investigations for CNS infections

A

thorough history (incl travel and contact)
Bloods: FBC, renal, liver, inflamm markers (CRP), coagulation, culture, PCR
throat swab
MRI > CT for detecting parenchymal abnormalities such as abscesses and infarctions (NB: normal imaging in acute meningitis)
CSF sample

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13
Q

CSF studies

A

colour/clarity
cell counts
chemistry (protein/glucose)
stains (gram/auramine [ZN]/ india ink)
cultures +/- antigens
PCR

neutrophils –> bacteria
lymphocytes –> viral or TB

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14
Q

Gram positive diplococci, alpha haemolysed (partially haemolysed)

A

Streptococcus pneumoniae

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15
Q

Gram negative diplococci, non-haemolytic

A

Neisseria meningitidis

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16
Q

Gram positive rods in immunocompromised (old age, diabetes)

A

Listeria monocytogenes

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17
Q

positive india ink stain, fungal growth, immunocompromised

A

cryptococcus

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18
Q

Management of CNS infections

A

Initial: ceftriaxone (2g IV BD) for meningitis (amox (2g IV 4hourly) if immunocompromised or >50), aciclovir (10mg/kg IV TDS) or ceftriaxone(2g IV BD) for meningo-encephalitis - amox if immunocompromised or >50

adjust Abx accordingly after investigation results

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19
Q

How do we diagnose viral infections in the lab?

A

Detection of host response:
Serology assays – Antibody detection
IgM Ab: current or recent infection
IgG Ab: chronic infection, past infection or immunity

Detection of viral DNA/RNA:
“Molecular” assays
Nucleic acid tests (PCR etc.)

Detection of viral antigens:
Serology assays
Lateral flow assays – rapid antigen tests

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20
Q

Hepatitis A

A

Family:
Family picornaviridae
Genus hepatoviridae
ssRNA

Transmission:
Faecal-oral route
Person-to-Person contact
Contaminated food or drink

Incubation period:
2-6 weeks
usually 28-30 days

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21
Q

Symptoms of acute hepatitis

A

Non-specific:
fever
malaise
fatigue
loss of appetite
abdo pain (RUQ due to distended liver)

Elevated bilirubin:
jaundice
dark urine
pale, grey or white stools
pruritus

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22
Q

Diagnosing Hep A

A

Clinically + raised ALT

Acute infection: Anti-HAV IgM
May be negative the first week of symptoms
Immunity (past infection OR vaccination): Anti-HAV IgG (or total Anti-HAV Ab)
HAV RNA PCR performed by the reference lab for confirmation of acute cases
Do not request Anti-HAV IgM unless ALT>500 u/L (too early or too late)

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23
Q

Hep A infectious period

A

2 weeks pre-symptom onset and for 1 week after onset of jaundice
Advice for patient: isolate for 7 days from onset symptoms

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24
Q

Hep A treatment

A

Mainly supportive
Mortality increases with age

NB: notifiable disease, must be reported to UKHSA

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25
Q

Vaccine indications for Hep A

A

Travel to endemic country
Chronic liver disease
Chronic hepatitis B/C
Haemophilia
People who inject drugs ‘PWID’
MSM
Occupational risk: lab, residential facilities, sewage work

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26
Q

Hepatitis B

A

Family:
Hepadnaviridae, dsDNA virus
8 genotypes

Transmission:
Parenteral
Sexual
Vertical

Incubation period:
2-6 months

Notifiable

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27
Q

Hep B acute infection

A

<5 years old:
Asymptomatic
90% progress to chronic hepatitis B virus infection

Adults:
20-40% symptomatic
10% progress to chronic hepatitis B virus infection

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28
Q

Hep B chronic infection

A

Mostly asymptomatic

Complications:
Cirrhosis
Hepatocellular carcinoma
Extra-hepatic manifestations

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29
Q

Hep B serology markers

A

HBsAg = surface antigen –> current infection
HBeAg = E antigen –> high viral replication/infectivity
HBcIgM = core IgM antibody –> acute infection
AntiHBc = total/IgG core antibody –> exposure to HBV infection past or present
AntiHBe = E antibody –> immune control: imminent or already achieved eAg clearance
AntiHBs = surface antibody –> Immunity
Natural (past infection) or Induced (vaccination)

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30
Q

Complications of Hep B

A

Cirrhosis:
Clinical: Child-Pugh score
Radiological: coarse echotexture, nodularity, portal HTN – splenomegaly
Transient elastography: >12.5 kPa
Histopathological: gold std

Hepatocellular carcinoma:
Alpha-fetoprotein
Imaging

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31
Q

Hep B treatment

A

Pegylated IFN-apha:
Strategy: induce long term immune control: eAg, sAg loss
s.c. injections 48 weeks
low tolerability, lots of contraindications

Nucleotide analogues:
Strategy: inhibit viral replication by inhibiting viral DNA polymerase
Entecavir
Tenofovir
long-term oral treatment (until HBsAg loss)

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32
Q

Hep B prevention

A

Vaccine: routine imms in UK since 2017: 2, 3, 4 months

Screening in pregnancy: HBsAg positive, eAg negative –> vaccine at birth + routine schedule, HBsAg positive, eAg positive –> vaccine at birth PLUS HBIG within 48 hours

Blood screening

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33
Q

Hepatitis C

A

Family:
Flaviviridae
ssRNA virus
6 genotypes (type 1 and 3 most common)

Transmission:
Mainly blood products
Sharing of needles
Sharing banknotes to insufflate (snort) recreational drugs

Incubation period:
2 weeks-6 months

Notifiable

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34
Q

Hep C acute infection

A

Mostly asymptomatic
20-40% will spontaneously clear the infection
40-60% progress to chronicity

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35
Q

Hep C chronic infection

A

Incidental finding
Complications:
CLD/cirrhosis
Hepatocellular carcinoma

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36
Q

Hep C diagnosis

A

Clinical + raised ALT

AntiHCV Ab becomes reactive >4 weeks after infection
HCV RNA should be requested if acute infection is suspected

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37
Q

Hep C treatment

A

Direct acting antivirals (DAA) have revolutionized treatment
Hepatitis C is now considered a curable disease
Every patient should be considered for treatment
12-week treatment course with a daily pill
Very good results against all genotypes

‘-previr’ e.g. bocepravir
‘-asvir’ e.g. velpatasvir
‘-buvir’ e.g. sofosbuvir

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38
Q

Hep C prevention

A

no vaccine
screening of blood, organs, tissue products
Needle exchange programs & similar risk-reduction strategies

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39
Q

Hepatitis D

A

Delta is a defective virus – small genome of ss RNA
Can only exist WITH hepatitis B virus
uses machinery of Hep B to destroy liver cells (makes Hep B hepatotoxic)

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40
Q

HBV-HDV co-infection

A

severe acute disease with very high ALT, possibly leading to hepatic failure
unlikely to become chronic

serology: HDV RNA, IgM anti-HDV, HBsAg

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41
Q

HBV-HDV super-infection

A

usually leads to chronic infection with very high risk of severe liver disease

Serology: ALT, total anti-HDV, IgM anti-HDV, HDV RNA and HbsAg

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42
Q

Hep D prevention

A

prevent Hep B infection:
Vaccination
Post-exposure prophylaxis

Educate patients with HBV re: risky behaviours (parenteral/sexual)

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43
Q

Hep D treatment

A

pegylated IFN-alpha

New agent: Bivalirutide

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44
Q

Hepatitis E

A

Family: Hepeviridae
RNA virus

4 genotypes infect humans:
GT 1 and 2:
Natural host: human
Transmission: faecal-oral
30% mortality in pregnant women

GT 3 and 4:
Natural host: pig/wild boar
Transmission:
Zoonotic – undercooked meat
Organ transplantation
Blood transfusion
asymptomatic in 95% adults, tends to affect older males

Incubation period: 2-8 weeks

Chronic infection rare and only occurs in severely immunocompromised

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45
Q

Hep E serology

A

Immunocompetent: HEV IgM and IgG
Immunocompromised: HEV RNA (Ab often undetectable)
‘Chronic infection’ = HEV RNA positive > 3 months

HEV RNA becomes detectable in stool and serum during the incubation period
Subsequent appearance of the IgM and IgG anti-HEV antibodies. The level of IgM antibody peaks early and becomes undetectable during recovery, whereas the level of the IgG antibody continues to increase and persists in the long term.
Clinical symptoms (fatigue, nausea, and jaundice) begin shortly after elevations in serum alanine aminotransferase (ALT) levels.
HEV RNA disappears from serum with recovery, whereas detectable virus usually persists longer in stool (arrows).

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46
Q

Extra-hepatic manifestations of Hep E

A

Haematological:
thrombocytopenia
red cell aplasia

Neurological:
encephalitis
ataxia
brachial neuritis
GBS

Muscular:
proximal myopathy
necrotising myositis

Renal:
membranoproliferative glomerulonephritis
IgA nephropathy

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47
Q

Hep E treatment and prevention

A

Treatment:
Supportive
Acute, severe hepatitis – consider ribavirin
Chronic hepatitis in immunocompromise: 3/12 Rx course

Vaccination:
Vaccine has been developed, only licensed in China
Screen blood products
Avoid undercooked meat (pork, wild boar, venison)

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48
Q

Inhibitors of cell wall synthesis

A

(a) beta-lactam antibiotics (penicillins, cephalosporins and carbapenems)
- safe in pregnancy
- broad-spec
- can cross damaged BBB and be used in meningitis
- need to clarify penicillin allergies

(b) Glycopeptides (Vancomycin and Teicoplanin)
- used for MRSA

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49
Q

Gram-positive vs gram-negative bacteria

A

Gram-positive have cytoplasmic membrane and thick peptidoglycan layer

Gram-negative have cytoplasmic membrane and thin peptidoglycan layer then a thick outer membrane so harder to get into

Both have peptidoglycan layer so can be targeted with beta-lactams and glycopeptides

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50
Q

Beta-lactams

A

Inactivate the enzymes that are involved in the terminal stages of cell wall synthesis (transpeptidases also known as penicillin binding proteins) – β-lactam is a structural analogue of the enzyme substrate
Bactericidal - weakened cell wall causes cell lysis
Active against rapidly-dividing bacteria only
Ineffective against bacteria that lack peptidoglycan cell walls (e.g. Mycoplasma or Chlamydia)

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51
Q

Beta-lactam penicillins antibiotics (examples)

A

penicillin - Gram positive organisms, Streptococci, Clostridia; broken down by an enzyme (β-lactamase) produced by S. aureus

amoxicillin – Broad spectrum penicillin, extends coverage to Enterococci and Gram negative organisms ; broken down by β-lactamase produced by S. aureus and many Gram negative organisms

flucloxacillin- Similar to penicillin although less active. Stable to β-lactamase produced by S. aureus.

piperacillin – similar to amoxicillin, extends coverage to Pseudomonas and other non-enteric Gram negatives; broken down by β-lactamase produced by S. aureus and many Gram negative organisms

clavulanic acid and tazobactam – β-lactamase inhibitors. Protect penicillins from enzymatic breakdown and increase coverage to include S. aureus, Gram negatives and anaerobes

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52
Q

Cephalosporins generations

A

1st, 2nd, 3rd
Increasing generation = increasing activity against gram-negative bacilli

examples: 1st - cephalexin
2nd - cefuroxime
3rd - ceftriaxone, cefotaxime, ceftazidime

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53
Q

Beta-lactam Cephalosporins examples

A

cefuroxime – Stable to many β-lactamases produced by Gram negatives. Similar cover to co-amoxiclav but less active against anaerobes

ceftriaxone – 3rd generation cephalosporin. Associated with C. difficile

ceftazidime – anti-Pseudomonas

Extended Spectrum β-lactamase (ESBL) producing organisms are resistant to all cephalosporins regardless of in vitro results

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54
Q

Beta-lactam carbapenems examples

A

Stable to Extended Spectrum β-lactamase (ESBL) enzymes
Meropenem, Imipenem, Ertapenem

Carbapenemase enzymes becoming more widespread. Multi drug resistant Acinetobacter and Klebsiella species.

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55
Q

Beta-lactams key features

A

Relatively non-toxic

Renally excreted (so ↓dose if renal impairment)

Short half life

Will not cross intact blood-brain barrier

Cross-allergenic (penicillins approx 10% cross-reactivity with cephalosporins or carbapenems)

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56
Q

Glycopeptides

A

Large molecules, unable to penetrate Gram –ve outer cell wall
Active against Gram +ve organisms
Inhibit cell wall synthesis
Important for treating serious MRSA infections (iv only)
Oral vancomycin can be used to treat serious C. difficile infection
Vancomycin and Teicoplanin are examples of glycopeptides
Slowly bactericidal
Nephrotoxic – hence important to monitor drug levels to prevent accumulation

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57
Q

Inhibitors of protein synthesis

A

Aminoglycosides (e.g. gentamicin, amikacin,tobramycin)

Tetracyclines

Macrolides (e.g. erythromycin) / Lincosamides (clindamycin) / Streptogramins (Synercid) – The MSL group

Chloramphenicol

Oxazolidinones (e.g. Linezolid)

all bind to ribosome or different parts of ribosome

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58
Q

Aminoglycosides

A

Bind to amino-acyl site of the 30S ribosomal subunit
Rapid, concentration-dependent bactericidal action
Require specific transport mechanisms to enter cells (accounts for some intrinsic R)
Ototoxic & nephrotoxic, therefore must monitor levels
Gentamicin & tobramycin particularly active vs. Ps. aeruginosa
Synergistic combination with beta-lactams (used in endocarditis)
No activity vs. anaerobes

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59
Q

Aminoglycosides mechanisms of action

A

Prevent elongation of the polypeptide chain

Cause misreading of the codons along the mRNA

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60
Q

Tetracyclines

A

Broad-spectrum agents with activity against intracellular pathogens (e.g. chlamydiae, rickettsiae & mycoplasmas) as well as most conventional bacteria

Bacteriostatic (not good for bacteraemias/sepsis)

Widespread resistance limits usefulness to certain defined situations

Do not give to children or pregnant women (stain teeth and deposit in bone)

Light-sensitive rash

Uses: soft-tissue infections, returner’s diarrhoea etc.

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61
Q

Tetracyclines mechanisms of actions

A

Reversibly bind to the ribosomal 30S subunit
Prevent binding of aminoacyl-tRNA to the ribosomal acceptor site, so inhibiting protein synthesis.

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62
Q

Macrolides

A

Bacteriostatic

Minimal activity against Gram –ve bacteria

Useful for diarrhoea in a returning traveller, shigella and salmonella

Useful agent for treating mild Staphylococcal or Streptococcal infections in penicillin-allergic patients

Also active against Campylobacter sp and Legionella. Pneumophila, mycoplasmas, chlamydia

Newer agents include clarithromycin & azithromycin with improved pharmacological properties

Used for cellulitis in penicillin-allergic patients

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63
Q

Macrolides mechanism of action

A

binds to 50S subunit of ribosome:

  1. interfere with translocation
  2. stimulate dissociation of peptidyl-tRNA
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64
Q

Chloramphenicol

A

Bacteriostatic

Very broad antibacterial activity

Rarely used (apart from eye preparations and special indications) because risk of aplastic anaemia (1/25,000 – 1/45,000 patients) and grey baby syndrome in neonates because of an inability to metabolise the drug

used in meningococcal meningitis if penicillin-allergic

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65
Q

Chloramphenicol mechanism of action

A

binds to the peptidyl transferase of the 50S ribosomal subunit and inhibits the formation of peptide bonds during translation

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66
Q

Oxazolidinones (Linezolid)

A

Binds to the 23S component of the 50S subunit to prevent the formation of a functional 70S initiation complex (required for the translation process to occur).

Highly active against Gram positive organisms, including MRSA and VRE. Not active against most Gram negatives.

May cause thrombocytopenia and optic neuritis and should be used only with Infectious Diseases approval

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67
Q

Inhibitors of DNA synthesis

A

Quinolones e.g. Ciprofloxacin, Levofloxacin, Moxifloxacin
- associated with c diff and severe side effects (esp. tendonitis), lower threshold for seizures
- levo used sometimes in penicillin-allergy

Nitroimidazoles e.g. Metronidazole & Tinidazole
- used for amoebas

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68
Q

Fluoroquinolones

A

Act on alpha-subunit of DNA gyrase predominantly, but, together with other antibacterial actions, are essentially bactericidal

Broad antibacterial activity, especially vs Gram –ve organisms, including Pseudomonas aeruginosa

Newer agents (e.g. levofloxacin, moxifloxacin) high activity vs G +ves and intracellular bacteria, e.g. Chlamydia spp

Well absorbed following oral administration

Use for UTIs, pneumonia, atypical pneumonia & bacterial gastroenteritis

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69
Q

Nitroimidazoles

A

Include the antimicrobial agents metronidazole & tinidazole

Under anaerobic conditions, an active intermediate is produced which causes DNA strand breakage

Rapidly bactericidal

Active against anaerobic bacteria and protozoa (e.g. Giardia)

Nitrofurans are related compounds: nitrofurantoin is useful for treating simple UTIs (not pyelonephritis)
- should be taken after emptying bladder

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70
Q

Inhibitors of RNA synthesis

A

Rifamycins, e.g. rifampicin & rifabutin
- mainly used for TB
- can be used post-joint surgeries
- resistance can develop very quickly so should only be used in combination

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71
Q

Rifampicin

A

Inhibits protein synthesis by binding to DNA-dependent RNA polymerase thereby inhibiting initiation

Bactericidal

Active against certain bacteria, including Mycobacteria & Chlamydiae

Monitor LFTs

Beware of interactions with other drugs that are metabolised in the liver (e.g oral contraceptives)

May turn urine (& contact lenses) orange

Except for short-term prophylaxis (vs. meningococcal infection) you should NEVER use as single agent because resistance develops rapidly

Resistance is due to chromosomal mutation.

This causes a single amino acid change in the ß subunit of RNA polymerase which then fails to bind Rifampicin.

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72
Q

Cell membrane toxins

A

Daptomycin – a cyclic lipopeptide with activity limited to G+ve pathogens. It is a recently-licenced antibiotic likely to be used for treating MRSA and VRE infections as an alternative to linezolid and Synercid

Colistin – a polymyxin antibiotic that is active against Gram negative organisms, including Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella. pneumoniae. It is not absorbed by mouth. It is nephrotoxic and should be reserved for use against multi-resistant organisms

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73
Q

Inhibitors of folate metabolism

A

Sulfonamides

Diaminopyrimidines (e.g. trimethoprim)

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74
Q

Sulfonamides & Diaminopyrimidines

A

Act indirectly on DNA through interference with folic acid metabolism

Synergistic action between the two drug classes because they act on sequential stages in the same pathway

Sulphonamide resistance is common, but the combination of sulphamethoxazole+trimethoprim (Co-trimoxazole) is a valuable antimicrobial in certain situations (e.g. Treating Pneumocystis jiroveci pneumonia)

Trimethoprim is used for Rx community-acquired UTIs

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75
Q

Mechanisms of antibiotic resistance

A

Chemical modification or inactivation of the antibiotic
Modification or replacement of target
Reduced antibiotic accumulation
1) Impaired uptake
2)Enhanced efflux
Bypass antibiotic sensitive step

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76
Q

Beta-lactams inactivation

A

ß Lactamases are a major mechanism of resistance to ß Lactam antibiotics in Staphylococcus aureus and Gram Negative Bacilli (Coliforms).

NOT the mechanism of resistance in penicillin resistant Pneumococci and MRSA.

Penicillin resistance not reported in Group A (S. pyogenes), B, C, or G ß haemolytic Streptococci.

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77
Q

Beta-lactams altered targets

A

Methicillin Resistant Staphylococcus aureus (MRSA):
mecA gene encodes a novel PBP (2a).
Low affinity for binding ß Lactams.
Substitutes for the essential functions of high affinity PBPs at otherwise lethal concentrations of antibiotic.

Streptococcus pneumoniae:
Penicillin resistance is the result of the acquisition of a series of stepwise mutations in PBP genes.
Lower level resistance can be overcome by increasing the dose of penicillin used.
(for meningitis: add vancomycin)

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78
Q

Extended spectrum beta-lactamases (ESBLs)

A

Able to break down cephalosporins (cefotaxime, ceftazidime, cefuroxime)
Becoming more common in E. coli and Klebsiella species.
Treatment failures reported with ß Lactam/ ß Lactamase inhibitor combinations (eg. Augmentin/Tazocin).

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79
Q

Recommended treatment course lengths for particular infections

A

N. meningitidis meningitis: 7 days
Acute osteomyelitis (adult): 6 weeks
Bacterial endocarditis: 4-6 weeks
Group A strep pharyngitis: 10 days
Simple cystitis (women): 3 days

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80
Q

TB transmission

A

TB is spread person to person through the air via droplet nuclei

M. tuberculosis may be expelled when an infectious person:
Coughs
Sneezes
Speaks
Sings

Transmission occurs when another person inhales droplet nuclei

Whether TB will be transmitted depends on:
Infectiousness of person with TB disease
Environment in which exposure occurred
Length of exposure
Virulence (strength) of the tubercle bacilli

The best way to stop transmission is to:
Isolate infectious persons
Provide effective treatment to infectious persons as soon as possible

requires around 8 hours of exposure

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81
Q

Latent TB

A

About ¼ to 1/3 of world’s population estimated to have a latent TB infection,
So risk of developing active TB disease
Post TB infection, 10% lifetime risk for active TB =dogma; 30-50% active TB if HIV positive
Latent infection: prevent active TB = diagnosis +chemoprophylaxis
Fever+Wt loss+Night sweats+cough (2-3 wks), haemoptysis (rare, very advanced disease)
Disease can occur decades later but rare

Diagnosis: Mantoux with PPD or Interferon gamma release assays (IGRA)

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82
Q

Drug sensitive TB treatment

A

Isoniazid, Rifampicin, Pyrazinamide +/- Ethambutol for 2 months
Then
Rifampicin and Isoniazid for 4 months
(95% cure rate)

Daily therapy (or 3 x weekly), orally
Total 6 months
12 months for TB meningitis
Baseline checks incl CXR, LFT, FBC, U&E, CRP

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83
Q

TB diagnosis

A

Microscopy ZN stain (quickest)
Microscopy auramine stain
Xpert MTB/RIF assay
MGIT (liquid culture)
Solid culture (best)

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84
Q

Rapid diagnosis of resistance to RIF and INH

A

Molecular line probe assays:
DNA extraction from cultures and clinical specimens (sputum);
PCR amplification of fragments of genes associated with drug resistance;
Hybridization with the DNA probes on membranes;
Development, reading and interpretation of results

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85
Q

Viral infections in pregnancy

A

Hep E: maternal infection
Measles: miscarriage/stillbirth
Zika: teratogenicity
CMV: IUGR/Prematurity
Parvovirus: congenital disease
HBV: vertical transmission

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86
Q

Rashes in pregnant women

A

Vesicular:
VZV
HSV
enterovirus
(monkey pox)

Maculopapular:
Parvovirus B19
Measles
Rubella
(Dengue/Zika/Yellow Fever, HIV)

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87
Q

Herpes viruses

A

HSV
VZV
CMV
EBV

These are DNA viruses
Once exposed they will cause lifelong infection (often latent)
Have the capacity to reactivate under stress/ immunosuppression etc

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88
Q

VZV (chickenpox) & Herpes zoster (shingles)

A

Transmission: respiratory (isolate!)
70% infection rate in those who are susceptible
Incubation: 7-13 days (mean 14 days)
Rash will be precipitated by prodromal illness

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89
Q

Foetal varicella syndrome

A

Neurological – intellectual disability, microcephaly , hydrocephalus, seizures, Horner’s syndrome
Occular abnormalities – optic nerve atrophy, cataracts, chorioretinities, micropthalmost, nystagmus
Limb abnormalities – hypoplasia , atrophy, paresis
GI – GORD, atretic or stenotic bowel
Skin scarring

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90
Q

VZV in pregnancy

A

MATERNAL VARICELLA
10-20% of women of childbearing age are susceptible
10-20% of pregnant women with varicella will have varicella pneumonia.
Encephalitis is rare but mortality is 5-10%

CONGENITAL (foetal) VARICELLA SYNDROME
0.4% if maternal infection weeks 0-12
2% if weeks12-20

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91
Q

What to do with maternal VZV?

A

Ask if previous exposure to VZV
If had previous chickenpox/shingles infection or had the vaccine: sufficient evidence of immunity
If no previous exposure: Urgent antibody testing on recent blood sample
If VZV IgG <100 mIU/ml offer PEP - aciclovir (start 7 days after exposure due to replication cycle)

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92
Q

HSV 1&2

A

Transmission : via close contact

Incubation:
Oropharyngeal/ oro-facial 2-12 days
Genital infection 4-7 days

Latency: established in nerve cells

Symptoms:
Asymptomatic
Painful vesicular rash
Lymphadenopathy
Fever

Diagnosis:
Viral detection – lesion swab for PCR
Serology

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93
Q

HSV in pregnancy

A

Foetal infection: ascending infection in PROM (premature rupture of membranes)

Neonatal infection
Direct contact with infected maternal secretions during delivery (usually C-section recommended)
Oral herpes : kissing baby
Non familial transmission: other relatives, hospital staff etc

VERTICAL TRANSMISSION
Greatest risk of transmission is primary genital infection in the 3rd trimester
If active HSV in final 6 weeks before delivery then C-section is recommended

IN UTERO INFECTION (rare but severe)
Primary infection only
Miscarriage
Congenital abnormalities ( ventriculomegaly, CNS abnormalities)
Preterm birth
IUGR

Non-primary and recurrent have antibodies that can pass onto neonate

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94
Q

HSV in pregnancy - what to do?

A

GUM clinic referral
Aciclvoir
HSV anti-body testing
Consider planned C-section if within 6 weeks before delivery

If gets recurrent outbreaks:
May not treat recurrence
Consider suppressive therapy from 36 weeks
Maternal antibody will offer some protection (but may not prevent transmission)
Avoid prolonged rupture of membranes / invasive foetal monitoring

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95
Q

Neonatal HSV

A

Untreated -> mortality >80% and severe neurological involvement is common

Skin, Eye, Mouth:
45% of cases
Initially benign
High risk of progression to CNS
MUST be treated
Usually first 14 days
Up to 6 weeks

CNS involvement:
30% of cases
Weeks 2-3 of life (up to 6)
Seizures
Lethargy
Irritability
Poor feeding
Fevers
Need CSF!

Disseminated:
Presents like sepsis
Often in 1st week of life
Multi-organ involvement (liver, lungs, CNS, heart, GI tract, renal tract, bone marrow)

Treat with aciclovir

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96
Q

Rubella

A

Rubella is a Togavirus – RNA virus . AKA German measles

Transmission: respiratory (isolate!)

Incubation 12-21 days

Symptoms
20-50% are subclinical
May be a prodrome (more likely in adult infection) – coryza, sore throat , cough, headache (1-5 days pre rash)
Fine, macular rash. Mildly pruritic. Starts on face and spreads to trunk / limbs (within hours)
Lymphadenopathy – tender, postauricular/ cervical/ suboccipital

Diagnosis:
Viral detection (PCR)
Serology

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97
Q

Rubella in pregnancy

A

In well vaccinated countries immigrants form the burden of CRS (congenital rubella syndrome)
Risk of this rising with vaccine avoidance CRS can be catastrophic
Greatest risk is in the 1st trimester
If infection before 8 weeks -> 20% spont abortion
If infection before 10 weeks 90% incidence of fetal defects
If infection after 18-18 weeks -> hearing defects and retinopathy
If infection after 20 weeks risk is much lower

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98
Q

Measles

A

Rash starts at hairline / behind ears and spreads cephalocaudally over 3 days

Paramyxovirus – RNA virus

Transmission: respiratory (isolate!) , conjunctiva

Incubation 7-18 days (mean 10 days)

Symptoms
Prodrome 2-4 days
Conjunctivitis
Koplick spots
Rash

Complications for mother:
Secondary bacterial infection
Otitis media / pneumonia / gastrointestinal
Encephalitis

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98
Q

Congenital Rubella syndrome

A

Manifest in infancy:
bone lesions
microcephaly
cataracts
retinopathy
meningioencephalitis
cardiac (PDA, PS)
purpura
hepatosplenomegaly

later manifestation:
panencephalitis
hearing loss
intellectual disability
diabetes mellitus
thyroid dysfunction

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99
Q

Measles in pregnancy

A

foetal loss
preterm delivery
no congenital abnormalities
SSPE – subacute sclerosing panencephalitis – fatal, progressive degenerative disease of CNS. Occcurs 7-10 years after natural infection.

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100
Q

Parvovirus 19

A

DNA virus
30-60% of adults have antibodies

Transmission: Respiratory, blood products

Incubation: 6-8 days

Symptoms
Mostly asymptomatic
Erythema infectiosum/ slapped cheek/5ths disease
Polyarthropathy
Transient aplastic crisis

Diagnosis
Virus detection (PCR)
Serology

Infectious: 6 days post exposure – 1 week.
You are infectious before symptoms commence

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101
Q

Parvovirus in pregnancy

A

Before 20 weeks
Transmission 33%
9% risk of infection
3% hydrops fetalis if infection)
1% fetal anomalies
7% fetal loss
(refer to foetal medicine for monitoring, may need intrauterine blood transfusions)

Fetal hydrops
Cytotoxic to fetal red blood precursor cells
-> anaemia
-> accumulation of fluid in soft tissues and serous cavities.
-> can rapidly cause fetal death
(acites, pleural effusion, skin edema, hydopic placenta, pericardial effusion, cardiomegaly, polyhydramnos, oligohydramnos
RX: intrauterine transfusion
50% of fetal infections result in interuterine death)

After 20 weeks: no documented risk

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102
Q

Enterovirus

A

Transmission: respiratory +/- faecal

Incubation: 2-40 days

Symptoms:
Hand, foot and mouth disease
Rash
Encephalitis
Myocarditis

Not generally associated with severe outcomes
Coxsakie virus presents main risk
Perinatal newborn infection can occur in last week of pregnancy
Neonates are at risk of myocarditis, fulminant hepatitis , encephalitis , bleeding and multi-organ failure.

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103
Q

CMV

A

Common early childhood infection
2-6% of infants infected by 6 months, 40% by 16yrs.

Transmission: salvia/ resp secretions/ urine

Incubation: 4-8 weeks
Virus persists lifelong

Symptoms
Mostly asymptomatic
Maculopapular rash, infectious mononucleosis-like illness

Test:
PCR of urine/ saliva / amniotic fluid/ tissue
Serology

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104
Q

CMV in pregnancy

A

If maternal CMV infection is suspected then check serology (compare booking to repeat sample)
Is seroconversion suspected (aka infection during pregnancy) then refer to fetal medicine unit for USS +/- amniocentesis
No treatment available
Neonates are investigated – urine and saliva CMV PCR within 1st 21 days.

Foetus:
microcephaly
encephalitis
ventriculomegaly
choriorenitis
hepatosplenomegaly
thrombocytopenia
jaundice

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105
Q

Zika virus

A

mosquito vector
no vaccine
incubation period: 5-7 days

in pregnancy:
microcephaly
visual and hearing problems
seizures
feeding problems
movement problems

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106
Q

Zika infection in pregnancy (advice)

A

Current advice:
All travellers – bite avoidance
Pregnant women – avoid travel to areas with current transmission
Avoid conception for 2 – 6 months after travel (prolonged viral shedding in semen)
Testing only if symptomatic or abnormalities identified on antenatal USS

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107
Q

Hepatitis B in pregnancy

A

pt monitored through hepatology
HBV can be transmitted from infected mothers (perinatal transmission)
- increased risk of becoming chronically infected with the virus
vaccination at birth can prevent 90% perinatal transmission
neonate given extra vaccine dose +/- immunoglobulin

Normal vaccination schedule:
8,12,16 weeks

If mother is HBV infected then given additional doses:
24 hours, 4 weeks, 1 year

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108
Q

HIV in pregnancy

A

birth plan managed through MDT
viral load cervicovaginal vertical transmission of HIV
review plasma viral load at 36 weeks
- c-section>
- intrapartum IV infusion of cART
viral load implications for duration of neonatal treatment

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109
Q

Clinical features of HIV infection

A

HSV infection
progressive encephalopathy
anaemia
frequent nose bleeds
thrush
pnuemonia
pneumocystis, TB
diarrhoea
bruising
enlarged parotids
lymphadenopathy
suppurative infections
hepatosplenomegaly
clubbing
nappy rash (severe)
failure to thrive

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110
Q

Major pathogens in surgical site infections (SSIs)

A

Staph.aureus (MSSA and MRSA)
E.coli
Pseudomonas aeruginosa

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111
Q

SSIs pathogenesis

A

If surgical site is contaminated with
> 10 5 microorganisms per gram of tissue, risk of SSI is increased.
The dose of contaminating bacteria required to cause infection is much lower if there is foreign material present e.g silk suture

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112
Q

Levels of SSI

A

Superficial incisional- affect skin and subcutaneous tissue

Deep incisional- affect fascial and muscle layers

Organ/space infection- any part of anatomy other than incision

113
Q

SSIs contributing factors

A

Age ; over 75 in hip replacement
ASA score of 3 or more
Diabetes – two to three fold increased risk. Association with post-op hyperglycaemia. Control blood glucose. HbA1C < 7
Radiotherapy and steroid use. Taper steroids
Rheumatoid arthritis. Stop disease modifying agents for 4 weeks before and 8 weeks post-op.
Obesity 2-7 increased risk if BMI> 35
Smoking- delayed wound healing and vasoconstrictive effect

114
Q

Septic arthritis risk factors

A

Rheumatoid arthritis , osteoarthritis, crystal induced arthritis
Joint prosthesis
Intravenous drug abuse
Diabetes, chronic renal disease, chronic liver disease
Immunosuppression- steroids
Trauma- intra-articular injection, penetrating injury

115
Q

Septic arthritis pathophysiology

A

Organisms adhere to the synovial membrane, bacterial proliferation in the synovial fluid with generation of host inflammatory response.
Joint damage leads to exposure of host derived proteins such as fibronectin to which bacteria adhere

BACTERIAL FACTORS
S.aureus has receptors such as fibronectin binding protein that recognise selected host proteins.
Kingella kingae synovial adherence is via bacterial pili
Some strains produce the cytotoxin PVL ( Panton-Valentine Leucocidin) which have been associated with fulminant infections.

HOST FACTORS
Leucocyte derived proteases and cytokines can lead to cartilage degradation and bone loss.
Raised intra-articular pressure can hamper capillary blood flow and lead to cartilage and bone ischaemia and necrosis.
Genetic variation in expression of cytokines may lead to differential susceptibility to septic arthritis.

116
Q

Causative organisms of septic arthritis

A

Staph. aureus 46%
- Coagulase negative staphylococci 4%
Streptococci 22%
Streptococcus pyogenes
Streptococcus pneumoniae
Streptococcus agalactiae
Gram negative organisms
-E.coli
- Haemophilus influezae
- Neisseria gonorrhoeae
- Salmonella
Rare- Lyme, brucellosis, mycobacteria, fungi

117
Q

Septic arthritis presentation

A

1-2 week history of red, painful, swollen restricted joint
Monoarticular in 90%
Knee is involved in 50%

Patients with rheumatoid arthritis may show more subtle signs of joint infection

118
Q

Investigations for septic arthritis

A

Blood culture before antibiotics are given

Synovial fluid aspiration for microscopy and culture
ESR,CRP
-Traditionally a synovial count> 50,000 cells/mm3 used to suggest septic arthritis
(Negative culture result does not exclude septic arthritis)
US- confirm effusion and guide needle aspiration
MRI- joint effusion, articular cartilage destruction, abscess, contiguous osteomyelitis

119
Q

Septic arthritis management

A

Arthroscopic washout

Antibiotics- iv Cephalosporin or Flucloxacillin
- may need to add vancomycin if at high risk of MRSA
Intravenous antibiotics for 2 weeks and review; then upto four weeks orally

120
Q

Vertebral osteomyelitis causative organisms & localisation

A

S.aureus- 48.3%
CNS- 6.7%
GNR- 23.1%
Strep- 43.1%

cervical- 10.6%
cervico-thoraco- 0.4%
lumbar 43.1%

121
Q

Vertebral osteomyelitis presentation

A

Back pain
Fever
Neuro impairment

122
Q

Vertebral osteomyelitis diagnosis

A

MRI: 90% sensitive
Blood cultures
CT/ open biopsy

123
Q

Vertebral osteomyelitis management

A

Six weeks of treatment (IV & PO Abx)
Longer treatment if undrained abscesses/implant associated
Surgery if there is spinal cord compression

124
Q

Signs/Symptoms of Prosthetic joint infections (PJIs)

A

Pain
Patient complains that the joint was ‘never right’
Early failure
Sinus tract

125
Q

PJIs causative organisms

A

Gram positive cocci
-coagulase negative staphylococci
-staphylococus aureus
Streptococci sp
Enterococci sp

Aerobic gram negative bacilli
Enterobacteriaceae
Pseudomonas aeruginosa

Anaerobes
Polymicrobial
Culture negative
Fungi

126
Q

PJIs diagnosis

A

Symptoms
CRP
Synovial fluid analysis: Leukocytes, PMN, alpha defensin
Aspiration fluid culture
Intraoperative tissue culture
Histology
Nuclear imaging

127
Q

Intraoperative microbiological sampling

A

Tissue specimens from at least 5 sites around the implant
Histopathology – infection defined as >5 neutrophils per high power field.
If 3 or more specimens yield identical organisms, this is highly predictive of infection (sensitivity 65%, specificity 99%)

128
Q

PJI management revision stages

A

Single stage revision:
Remove all foreign material and dead bone
Change gloves, drapes etc
Re-implant new prosthesis with antibiotic impregnated cement and give iv antibiotics

Two stage revision:
Remove prosthesis
Take samples for microbiology and histology
Period of iv antibiotics (6weeks). Stop antibiotics for 2 weeks
Re-debride and sample at second stage
Re-implantation with antibiotic impregnated cement
No further antibiotics if samples clear
OPAT

129
Q

DAIR

A

= debridement, antibiotics and implant retention
Within 3 weeks of operation
Tissue sampling
Radical debridement
Exchange of modular components
Antibiotics

130
Q

Streptococcus pneumoniae

A

Gram positive diplococci
30-50% of CAP
Acute onset
Severe pneumonia
Fever, rigors
Lobar consolidation
Almost always penicillin sensitive (increasing resistance in southern europe so important to obtain travel history and to check sensitivities)

131
Q

Pneumonia

A

Inflammation of the lung alveoli
Patients are sick- mortality 5-10%, 20-40% admitted to hospital
Presentation
Fever
Cough
Pleuritic chest pain
Shortness of breath
Often localising signs and abnormal CXR

Classification:
- community acquired
- hospital acquired

132
Q

Community acquired pneumonia

A

No microbiological ID made in most cases
Main organisms:
- Streptococcus pneumoniae
- Haemophilus influenzae
- Moraxella catarrhalis
- Staphylococcus aureus
- Klebsiella pneumoniae

133
Q

Pneumonia pathogens by age group

A

0-1 mths- E.coli, GBS, Listeria
1-6mths- Chlamydia trachomatis, S aureus, RSV
6mths-5yrs- Mycolpasma, Influenza
16-30yrs-M pneumoniae, S pneumoniae

134
Q

Pneumonia signs and symptoms

A

SOB
Cough +/- sputum
Fever
Rigors
Pleuritic chest pain
Malaise, nausea & vomiting

Pyrexia
Tachycardia
Tachypnoea
Cyanosis
Dullness to percussion, tactile vocal fremitus
Bronchial breathing
Crackles

135
Q

CURB-65 score

A

used to assess severity of pneumonia
score 2-5 = manage as severe

Confusion
Urea >7 mmol/l
RR >30
BP <90 systolic <60 diastolic
>65 years

136
Q

Bronchitis

A

Inflammation of medium sized airways.
Mainly in smokers
Cough, fever, increased sputum production, increased shortness of breath.
CXR: normal
Organisms:
viruses
S. pneumoniae
H. influenzae
M. catarrhalis
Bronchodilation; Physiotherapy +/- Abx

137
Q

Haemophilus influenzae

A

Gram –ve coccobacillus
15-35% of CAP
More common with pre-existing lung disease (older individuals)
May produce β-lactamase

138
Q

Legionella pneumophilia

A

Inhalation of infected water droplets
Can cause mild disease upto multi-organ failure
Requires special culture: buffered charcoal yeast extract

Aerosol spread
Environmental outbreaks
Associated with confusion, abdo pain, diarrhoea
Lymphopenia, hyponatremia
Dx by antigen in urine/serum
Sensitive to macrolides

139
Q

Atypical pneumonia

A

Pneumonia caused by organisms without a cell wall
- Mycoplasma
- Legionella
- Chlamydia
- Coxiella
Cell-wall active antibiotics e.g. penicillins don’t work
Need agents that work on protein synthesis
- Macrolides (clarithromycin / erythromycin)
- Tetracyclines (doxycycline)
Extrapulmonary features – e.g. hepatitis; low sodium

~20% of CAP
Flu-like prodrome before fever & pneumonia

140
Q

Coxiella burnetii

A

Common in domestic/farm animals
Transmitted by aerosol or milk
Dx by serology
Sensitive to macrolides

141
Q

Chlamydia psittaci

A

Spread from birds by inhalation
Dx by serology
Sensitive to macrolides

142
Q

Causes of failure to improve on treatment for pneumonia

A

Empyema / abscess
Proximal obstruction (tumour)
Resistant organism (incl. Tb)
Not receiving / absorbing Abx
Immunosuppression
Other diagnosis
Lung cancer
Cryptogenic organising pneumonia

143
Q

Quad PCR

A

influenza A
influenza B
RSV
SARS-CoV-2

everyone admitted usually gets one

144
Q

Tuberculosis

A

(mycobacterium tb)
“The white plague”
Must always be considered in differential. (great mimic - doesn’t always present with resp symptoms due to extrapulmon features)
Clues:
- Ethnicity
- Prolonged prodrome
- Fevers
- Weight loss
- Haemoptysis
CXR: Classically upper lobe cavitation (but can vary considerably)

Auramine and ZN stain
TB culture

145
Q

Hospital acquired pneumonia

A

> 48 hours in hospital.
Often previous antibiotics; +/- ventilator Infectious vs Non-infectious causes of abnormal CXR / lung function.
Bronchial lavage desirable to differentiate upper respiratory from lower respiratory flora

146
Q

Hospital acquired pneumonia pathogens

A

Staphylococcus aureus 19%
Enterobacteriaciae 31%
Pseudomonas spp 17%
Acinetobacter baumanii 6%
Fungi (Candida sp.)
7%

147
Q

Pneumocystis jirovecii

A

Protozoan
Ubiquitous in environment
Insidious onset
Dry cough, weight loss, SOB, malaise
CXR “bat’s wing”
Dx Immunofluorescence on BAL/PCR, silver stain (cytology lab)
desaturation on walking up and down corridor
Rx Septrin (Co-trimoxazole)
Prophylaxis Septrin

(usually seen in pts with HIV, or immunosuppressed due to medications)

148
Q

Aspergillus fumigatus

A

Allergic bronchopulmonary aspergillosis
- Chronic wheeze, eosinophilia
- Bronchiectasis

Aspergilloma
- Fungal ball often in pre-existing cavity
- May cause haemoptysis

Invasive aspergillosis
- Immunocompromised
- Rx Amphotericin B

149
Q

Immunosuppression & LRTI

A

HIV: PCP, TB, atypical mycobacteria

Neutropenia: fungi e.g. Aspergillus spp

Bone marrow transplant: CMV

Splenectomy: encapsulated organisms
e.g. S. pneumoniae, H. influenzae

150
Q

CAP: empirical therapy

A

Each hospital has its own guideline
Mild-moderate:
- Amoxicillin
- Or erthromycin / clarithromycin
Moderate-severe:
- Needing hospital admission: Augmentin (co-amoxiclav) AND clarithromycin.
- Allergic: Cefuroxime AND clarithromycin.

151
Q

HAP: antibiotics

A

First line: Ceftazidime/Ciprofloxacin +/- vancomycin.

Second line/ITU: Piperacillin/tazobactam AND vancomycin

Specific therapy:
MRSA: Vancomycin.
Pseudomonas: Piperacillin/tazobactam or Ciprofloxacin +/- gentamicin.

152
Q

Pyrexia of unknown origin definition

A

Petersdorf 1961
Fever >38.3C
Lasting > 3 weeks
Uncertain diagnosis after 7 days in hospital

Durack 1991
Prescriptive set of mandatory investigations
3 days of hospital investigation or 3 OP visits

Knockaert 2003
Pragmatic
3 days of Hospital investigation with no diagnosis

153
Q

Causes of PUO

A

Infection
Inflammation
Malignancy
Other

154
Q

History components for PUO

A

B-symptoms, localising symptoms
Medications - doses and initiation date
Contact history, pets / animal exposures
Injecting drug use, sexual history
Foreign travel

155
Q

PUO examination

A

True multisystem diseases
Fundoscopy – roth spots (endocarditis)
ENT – sinusitis, OM, or oropharyngeal candidiasis - ?HIV
SSTI – OM, ticks - annular lesions (lyme disease), erythema migrans
Neuro and spinal exam

156
Q

PUO investigations

A

Routine admission tests:
FBC
U&E
LFT
CRP
CXR
Blood cultures
Urine dip

PUO initial tests:
2 x more blood cultures
Urine culture
Stool cultures + OCP
CMV /EBV serology
HIV/HBV/HCV
CK
Ferritin
LDH
ANA
ANCA
RhF
TFT

FDG-PET CT scan
Echocardiogram

Biopsies
Lumbar puncture
Bone marrow aspirate

157
Q

IgM vs IgG

A

IgM = pentamer in acute phase
IgG = dimer after IgM production has stopped (chronic phase) - during clearance of infection

158
Q

PET-CT in PUO

A

Fluoro-D-Glucose accumulates in cells with an increased rate of glycolysis
All activated leukocytes demonstrate increased FDG uptake

Allows metabolic correlation to anatomical scan

Useful in endocarditis and vascular infections / inflammation

Caution in those with poor glucose control

Ensure patient fasted appropriately

159
Q

Infective causes of PUO

A

Viral
CMV / EBV
HIV
Hepatitis A,B,C,D,E

Parasites
Malaria
Amoebic liver abscess
Schistosomiasis
Toxoplasmosis
Trypanosomiasis

Fungal
Cryptococcosis
Histoplasmosis
Coccidioides

Bacterial
Q-Fever, Bartonella, Brucella.
Mycobacteria
TB/NTM
Enteric fevers
Zoonoses

160
Q

Inflammatory causes of PUO

A

Connective tissue diseases:
Adult onset stills diseases (rule out using ferritin, salmon pink rash)
SLE
Polymyalgia rheumatica
RA
Sjogrens

Vasculitis syndromes:
Giant cell arteritis (rule out using ESR)
Wegener disease
Polyarteritis nodosa

161
Q

Giant cell arteritis

A

Age >50
Headache
- Not needed for diagnosis – but should raise suspicion
Jaw claudication
ESR > 45
- need to adjust for age
- Not raised in 7-20% in case series
- CRP adds sensitivity
50% will have change if vision on presentation
- Often minor / fluctuating
High risk of sight impairment / stroke
Temporal biopsy gold standard
PET CT useful
Treat immediately – involve rheumatologist.

162
Q

Malignant causes of PUO

A

Lymphoma – especially non-Hodgkin’s
Often advanced disease with aggressive subtype
Raised LDH, weight loss, lymph nodes

Leukaemia
Bone marrow biopsy

Renal Cell Carcinoma
20% of cases present with fever, haematuria can occur

Hepatocellular carcinoma or other tumours metastatic to the liver

Often identified on axial imaging

163
Q

Miscellaneous causes of PUO

A

Subacute thyroiditis
Addison’s
Dressler syndrome
PE
Habitual hyperthermia
Drugs
Factitious fever

164
Q

Indications for urgent treatment in PUO

A

Infective endocarditis
Disseminated TB
CNS TB
GCA
Clinical signs of sepsis

165
Q

Zoonoses

A

Diseases that pass between people and animals.

> 70% of emerging human infectious diseases come from animals.
Examples of new emerging infectious diseases:
VHF
respiratory diseases
novel influenza viruses

166
Q

Zoonotic transmission

A

Every day contact with animals
- Scratches or bites
By-products (feces/urine)
- Contaminated soil
- Litter
Foodstuffs
- Carcass processing
- Milk and milking
- Raw/undercooked meats

167
Q

Source animals in zoonoses

A

Farm/wild:
Campylobacter
Salmonella
Brucella
Coxiella
Rabies
VHF

Companion:
Bartonella
Toxoplasmosis
Ringworm
Psitticosis
Rabies
Tick-borne diseases
Spirilum minus

168
Q

Campylobacter

A

Reservoir:
poultry
cattle

Transmission:
contaminated food (80% from raw chicken)

also found in: red meat, unpasteurised milk and untreated water

Clinical presentation:
Diarrhoea
Bloating
Cramps

Ix:
stool culture

Mx:
supportive

169
Q

Salmonella

A

Reservoir:
poultry
reptiles/amphibians

Transmission:
contaminated food
poor hand hygiene

Presentation:
Diarrhoea
Vomiting
Fever

Ix:
stool culture

Mx:
Supportive
(Ciprofloxacin, azithromycin)

169
Q

Bartonella henselae

A

= slightly curved gram neg rod

Reservoir:
kittens > cats

Transmission:
Scratches
Bites
Licks of open wounds
Fleas

Causes two diseases:
Cat Scratch Disease
Bacillary angiomatosis

170
Q

Cat scratch disease

A

Presentation:
Macule at site of innoculation
Becomes pustular
Regional adenopathy
Systemic symptoms

Ix:
serology

Mx:
Erythromycin
doxycycline

171
Q

Bacilliary angiomatosis

A

Presentation:
Occurs in immunocompromised
Skin papules
Disseminated multi-organ and vasculature involvement

Ix:
Histopathology
Serology

Mx:
erythromycin
doxycycline
PLUS rifampicin

172
Q

Toxoplasmosis

A

Reservoir:
cats
sheep

Transmission:
infected meat
faecal contamination

Presentation:
Fever
Adenopathy
Still-birth
Progressive visual, hearing, motor, & cognitive issues
Seizures
Neuropathies

Ix:
Serology

Mx:
spiramycin
pyrimethamine plus sulfadiazine

173
Q

Brucellosis

A

Reservoir:
cattle
goats

Transmission:
Unpasteurised milk
Undercooked meat
Mucosal splash
Aerosolisation/inhalation

Presentation:
Fever
chills, headache, myalgia, arthralgia, anorexia, fatigue, lymphadenopathy and splenomagaly
Back pain
Orchitis
Focal abscesses (Psoas, liver etc)

Ix:
blood/pus culture
serology

Mx:
doxycycline PLUS
gentamicin or rifampicin

Incubation period- usually 30 days but can be up to 5 months

(often presents like TB)

174
Q

Coxiella burnetii - Q fever

A

Reservoir:
goats
sheep
cattle

Transmission:
Aerosolisation/inhalation of secretions, waste, or milk of infected animals
Unpasteurised milk

Presentation:
Fever
‘Flu-like illness
Pneumonia
Hepatitis
Endocarditis
Focal abscesses (Para-vertebral/discitis etc)

Ix:
serology

Mx:
doxycycline
(hydroxychloroquine)

175
Q

Rabies (Lyssa virus)

A

Reservoir:
dogs
cats
bats

Transmission:
bites
scratches
contact with infected fluid

Presentation:
Seizures
Excessive salivation
Agitation
Confusion
Fever
Headache

Ix:
serology
brain biopsy
(USA saliva PCR)

Mx:
(too late if neuro symptoms)
Ig
Vaccine

176
Q

Rat bite fever

A

Reservoir:
rats

Transmission:
bites
contact with infected urine or droppings

Responsible agents either: Streptobacillus moniliformis or Spirillum minus

Presentation:
Fevers
Polyarthralgia
Maculopapular progressing to purpuric rash
Can progress to endocarditis

Ix:
Joint fluid microscopy & culture
blood culture

Mx:
penicillins

177
Q

Hantavirus pulmonary syndrome

A

Reservoir:
Deer mouse; Sin Nombre virus
White footed mouse; Sin Nombre virus
Cotton rat; Black canal virus
Rice rat; Bayou virus

Transmission:
contact with infected urine or droppings
aerosolisation

Presentation:
Fever
Myalgia
‘Flu-like illness
Respiratory failure
Bleeding
Renal failure

Ix:
serology
PCR

Mx:
supportive

178
Q

Viral haemorrhagic fever

A

Reservoir:
Ebola - ? Bats
Marburg - ? Bats
Lassa – Rats
CCHF - ticks

Transmission:
contact with fluids of infected

Viruses:
Lassa, Marburg, Ebola, and Congo-Crimean Hemorrhagic Fever

Presentation:
Fever
Myalgia
‘Flulike illness
Bleeding

Ix:
serology
PCR

Mx:
supportive

179
Q

Virus classification

A

Baltimore: depends on replicative life cycle
All viruses produce a positive sense messenger RNA to generate proteins for their replication. The nature of their genomes means different classes achieve this through differing mechanisms. This has implications for their life cycle, diagnosis and treatment

180
Q

Opportunistic infections

A

An infection caused by an organism that does not normally cause disease
…Or symptomatology may be altered in the immunocompromised compared to immunocompetent
May be “endogenous”
Latent viruses that reactivate in the absence of a normal immune system
Acquired in the past prior to immune suppression – eg Varicella Zoster (VZV)
May be “exogenous”
Viruses which are acquired from the environment
Increased severity in the immunocompromised – eg influenza, SARS-CoV-2.. Or even primary acquisition of VZV

181
Q

Causes of AIDS defining illness

A

Candidiasis of the esophagus, bronchi, trachea, or lungs
Cervical cancer, invasive
Coccidioidomycosis, disseminated or extrapulmonary
Cryptococcosis, extrapulmonary
Cryptosporidiosis, chronic intestinal (greater than one month’s duration)
Cytomegalovirus disease (other than liver, spleen, or nodes)
Cytomegalovirus retinitis (with loss of vision)
Encephalopathy, HIV related
Herpes simplex: chronic ulcer(s) (more than 1 month in duration); or bronchitis, pneumonitis, or esophagitis
Histoplasmosis, disseminated or extrapulmonary
Isosporiasis, chronic intestinal (more than 1 month in duration)
Kaposi sarcoma
Lymphoma, Burkitt’s (or equivalent term)
Lymphoma, immunoblastic (or equivalent term)
Lymphoma, primary, of brain
Mycobacterium avium complex or M kansasii, disseminated or extrapulmonary
Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary)
Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
Pneumocystis jiroveci pneumonia
Pneumonia, recurrent
Progressive multifocal leukoencephalopathy
Salmonella septicemia, recurrent
Toxoplasmosis of brain
Wasting syndrome due to HIV

182
Q

Diagnosing viruses

A

Viruses are challenging to grow – they require human cells + dangerous
Therefore, we look for indirect or direct evidence of their presence

Indirect detection:
Useful to see whether you have ever had the infection
Response of the immune system to the virus (IgM and IgG)

Direct detection:
Useful to see whether you currently have the infection
Viral proteins (lateral flow/antigen tests)
Viral genetic material (virus genetic material is present with patient sample)
Polymerase Chain Reaction, PCR
used in immunosuppressed as cannot detect immune response in these people

183
Q

Viral serology

A

(Indirect activation)
Measure levels of antibody in patients serum

+++ IgM indicate Active or Resolving infection

+++ IgG indicates past infection > 6 weeks ago

Antibody levels ↓↓↓ reduced in Immunosuppressed

Serological course may differ depending upon virus

184
Q

Viral PCR

A

(direct detection)
Polymerase chain reaction

Detect viral genome in samples via amplification

Highly sensitive and specific

Performed on many different sample types

Viral load can be used to monitor infection

May remain positive after infection resolved (lingering DNA)

185
Q

Diagnostic virology in immunocompromised individuals

A

Immune system = non functional → Serology useless

1.Screen prior to immunosuppression
Identify previous viral exposure that may reactivate
Guide the use of antiviral prophylaxis

2.Monitor using PCR
Identify viral reactivation promptly → Rx
Detect infection

186
Q

Diagnostic protocols in immunosuppressed

A

Serological screening (before):
HIV Ag/Ab
HBV surface antigen
HBV core antibody
HBV surface antibody
HCV antibody
EBV antibody
CMV antibody
HSV antibody
VZV antibody
HTLV antibody

Monitoring (during):
CMV monitoring PCR or prophylaxis
EBV monitoring PCR
BK monitoring PCR (Renal & BMT)
Adenovirus monitoring PCR (Paediatric BMT)
HSV prophylaxis if indicated

187
Q

Relative risk of opportunistic viral infections with immunosuppression

A

(increasing to decreasing risk)

Allogeneic stem cell transplant

Advanced HIV infection (CD4 dep)

Solid organ transplant

Various monoclonal antibody therapies

Cytotoxic chemotherapy

DMARDs and steroids

188
Q

Transplant immunosuppression

A

Stem cells:
Before: conditioning regime (eg. total body irradiation or cyclophosphamide)
Engraftment
During: ongoing immunosuppression and graft vs host prophylaxis

Solid organ:
Before: induction immunosuppression
During: maintenance immunosuppression

189
Q

Sources of viral infections in transplant recipients

A

Viruses acquired from graft eg. HBV
Viral reactivation from host eg. HSV
Novel infection from infected individual eg. VZV

190
Q

Anti-viral therapy in immunosuppressed

A

Therapeutically challenging
Pre-emptive treatment
Prophylaxis
Increased doses
Longer duration
Combination therapy
↑ Opportunity antiviral resistance
↑ Toxicity of antivirals

191
Q

Viral infections different in immunocompromised

A

Present differently
Disseminated
Different organs
More severe
Oncogenic
Lack of immune mediated symptoms

192
Q

Herpes simplex (1&2) in immunosuppressed

A

Increased frequency
Increased severity /risk of dissemination
More organs can be involved (pneumonitis, eosophagitis, hepatitis); NB: not enceph!
Increased risk of acyclovir resistance

Management:
HIV/AIDS
CD4 <200

Prophylaxis:
Test for HSV IgG
Bone marrow
- 1 month (until engraftment)
Solid organ
- 3-6 months
- And if treated for rejection

193
Q

Varicella Zoster (VZV) in immunocompromised

A

Varicella:
Pneumonitis
Encephalitis
Hepatitis
Purpura fulminans in neonate

Zoster (shingles):
Multi-dermatomal / disseminated
Often a late presenting immunosuppression

194
Q

VZV management in immunocompromised

A

Prevention:
Prophylaxis (prolonged if post-bone marrow)
PEP
Vaccination

Treatment:
Varicella
Anti-viral for 7-10 days
IV until no new lesions; PO until all crusted

Zoster
Anti-viral (IV if disseminated) + analgesia
If Ramsay-Hunt: add steroids
If HZO (ophthalmic): add topical steroids

195
Q

EBV in immunocompromised

A

Issues:
Oncogenesis
- B cell latency, high turn-over
- T-cells monitor/control this
B-cell lymphomas
PTLD (post-transplant lympho-proliferative disorder

Post-transplant lymphoproliferative disease (PTLD) :
Latently infected B cells – polyclonal activation
Predisposes to lymphoma
Occurs in solid organ or allogenic haematopoietic cell transplants
Related to the level of immunosuppression
Suspicion on rising EBV viral load (> 105 c/ml) and CT scan
Confirmation with biopsy of lymph nodes

Management:
Monitor EBV levels (proactive monitoring)
Ix for lymphoma as needed
Rx: ?Rituximab
Rx: reduce immunosuppression (if possible)

196
Q

CMV in immunocompromised

A

HIV/AIDS: CD4 <50
- Ocular (retinitis)
- Polyradiculopathy
- Pneumonitis
- GI tract
SOT
- Allograft disease (function of transplant organ reduced)
- GI tract (i.e. renal)

Histology: inclusion bodies

Management:
Prophylaxis (i.e. lung transplant)
Pre-emptive treatment (i.e. renal transplant / HSCT)
Treat if disease (HIV/AIDS)
Rx: Ganciclovir / Valganciclovir (pro-drug)
Rx: Reduce immunosuppression (if possible)

197
Q

SOT vs HSCT with CMV

A

SOT:
Donor + / Recipient –
Immunosuppressed patient gets given some CMV for the first time (reactivation from donor)

HSCT:
Donor - / Recipient +
Patient with CMV has immune system replaced with one that hasn’t seen CMV

198
Q

CMV prevention strategies post-transplant

A

HSCT:
CMV viral load measured twice weekly, treat if virus reactivated until suppressed (pre-emptive therapy)

SOT:
valganciclovir prophylaxis for 100 days

199
Q

CMV treatment

A

Ganciclovir (IV): bone marrow suppression
Valganciclovir: oral
Foscarnet (IV) (nephrotoxicity)
Cidofovir (nephrotoxicity)
IVIg (with another drug for pneumonitis)

200
Q

John Cunningham virus

A

JC virus is a polyomavirus

Progressive multifocal leukoencephalopathy

Effective antiretroviral therapy has drastically reduced PML incidence in HIV+ve patient

PML can be seen in other types of immunosuppressed
- humanised monoclonal antibodies
- Natalizumab (for treatment of multiple sclerosis)

201
Q

Progressive multifocal leukoencephalopathy

A

Cognitive disturbance, personality change, motor deficits other focal neurological signs

Demyelination of white matter
→neurological deficits

Diagnosis: MRI and PCR on CSF

202
Q

BK virus

A

Polyomavirus
Double stranded DNA
BK cystitis post SCT
BK nephropathy post Renal Tx

203
Q

Respiratory viruses in immunocompromised

A

Increased risk of complications (pneumonitis) and high mortality associated particularly with:
Influenza A and B
Parainfluenza 1, 2, 3 and 4
Respiratory Syncytial Virus (RSV) Adenovirus
SARS-CoV-2

Influenza A and B →Oseltamivir (oral drug) for 5 days
If resistance/severe/immunosuppressed →zanamivir (inhalation or IV)

SARS-CoV-2
Paxlovid
Rituximab

204
Q

Hepatitis viruses in immunocompromised

A

Hep A: more severe, vaccinate

Hep B: re-activation, vaccinate/prophylaxis

Hep C: ?increased fibrosis, Rx direct-acting antiviral

Hep E: chronic infection, reduce immunosuppression

205
Q

Hep B in immunocompromised

A

Two things can happen:
1. Carriers may have flare of disease.
2. Those who have had past infection can reactivate

Reactivation ↑ B-cell depleting therapies (i.e Rituximab)
- IL-6 inhibitor COVID also a risk

Prevention:
Nucleoside (lamivudine) nucleotide (tenofovir, entecavir)
Prophylaxis
HIV makes control more difficult

206
Q

What are fungi?

A
  • Eukaryotic organisms
  • Possess chitinous cell walls, plasma membranes containing ergosterol, 80S RNA

Can be divided into 2:
* Yeasts – single celled, reproduce by budding
– Candida
– Cryptococcus
– Histoplasma (dimorphic)

  • Moulds – multicellular hyphae, grow by branching and extension
    – Dermatophytes
    – Aspergillus
    – Agents of mucormycoses

Dimorphic fungi: exist as moulds at lower temperatures and yeasts at higher temperatures

Both positive on gram stain

207
Q

Candida spp.

A
  • A yeast and the commonest fungal infection
  • > 150 Candida spp., but < 10 are human pathogens
  • Clinical manifestations
    – Acute, subacute, chronic, episodic
    – Superficial or systemic/invasive
208
Q

Superficial candida infections

A
  • Oral thrush
  • Candida oesophagitis
  • Vulvovaginitis
  • Cutaneous
    – Localised or generalised

very common

treatment:
* Topical
– Oral thrush: nystatin
– Vulvovaginitis: cotrimazole
– Localised cutaneous: cotrimazole
* Oral
– Vulvovaginitis: fluconazole
– Oesophagitis: fluconazole

209
Q

Candidaemia

A

RFs
– Malignancies, esp haematological
– Burns patients
– Complicated post-op courses (eg Tx or GIT Sx)
– Long lines

Management
* Look for source and signs of dissemination
– Imaging
– Serology for beta-D-glucan
– ECHO
– Fundoscopy
* Antifungals for at least 2/52 (from date of first –ve BC)
– Echinocandin (broad spec cover) eg anidulafungin (whilst a/w identification and susceptibilities)
* BC every 48 hours
* REMOVE ANY LINES/PROSTHETIC MATERIAL

210
Q

Invasive candida infections

A
  • Candidaemia
  • CNS
    – Dissemination, trauma, Sx
  • Rx: Ambisome/voriconazole
  • Endocarditis
    – Abnormal valves/prosthetic valves, long
    lines, IVDU
  • Rx: Ambisome/voriconazole, Sx
  • Urinary tract
    – Vulvovaginits, catheters
  • Rx: Fluconazole
  • Bone and joint
    – Dissemination. Trauma
  • Rx: Ambisome/voriconazle, Sx
  • Intra-abdominal
    – Peritoneal dialysis, Sx, perforation
  • Rx: Echinocandin/Fluconazole
211
Q

Cryptococcosis

A
  • Encapsulated yeast
    – Serotypes A&D = C neoformans
    (immunodeficient)
    – Serotypes B&C = C gattii
    (immunocompetent)
  • Transmission by inhalation of aerosolised organisms
  • Chronic, subacute to acute pulmonary, meningitic or systemic disease

associated with pigeons

212
Q

Cryptococcosis risk factors

A
  • Impaired T-cell immunity
    – E.g patients with HIV, who have reduced CD4 helper T-cell numbers (typically
    less than 200/ml)
  • Patients taking T-cell immunosuppressants for solid organ transplant also have a 6%
    lifetime risk
213
Q

C gattii

A
  • Causes a meningitis in apparently immunocompetent individuals in tropical
    latitudes, esp. SE Asia and Australia
  • Outbreak in Vancouver Island 2004
  • High incidence of space-occupying lesions in brain and lung
  • Increased resistance to amphotericin B clinically
214
Q

Cryptococcosis diagnosis

A
  • Typical clinical history/features
    – Immunosuppressed host
  • Imaging
  • India ink staining of CSF
  • Serum/CSF cryptococcal Ag (CRAG)
  • Can culture from blood/body fluids
215
Q

Cryptococcosis management

A
  • Induction:
    – Amphotericin B + flucytosine (at least 2/52)
  • Consolidation:
    – High dose fluconazole (at least 8/52)
  • Maintenance:
    – Low dose fluconazole (at least 1 year)
  • Repeat LP for pressure management
  • Pulmonary disease:
    – If mild, fluconazole alone
216
Q

Aspergillosis

A
  • A mould with worldwide distribution
  • Causes a spectrum of disease in helath and immunocompromised patients
    – Mycotoxicosis - ingestion of contaminated foods
    – Allergy and sequelae - presence of conidia/transient growth of the organism in body orifices
    – Colonization - in preformed cavities and debilitated tissues
    – invasive, inflammatory, granulomatous, necrotizing disease of lungs, and other organs
    – systemic and fatal disseminated disease
  • type of disease and severity depends upon the physiologic state of the host and the species
217
Q

Aspergillosis diagnosis & management

A

Dx
* Imaging
* Sputum/BAL – MC&S, Ag testing
* Aspergillus Abs (precipitans)
* Galactomannan (surface antigens)
* Bx – histology, MC&S

Mx
* Voriconazole
* Ambisome
* Duration based on host/radiological/mycological factors
– At least 6/52

Complications:
- aspergillomas
- invasive fungal disease

218
Q

Pneumocystis jiroveci

A
  • Ubiquitous in the environment and distributed worldwide
  • Lacks ergosterol in it’s cell wall
  • Acquisition by airborne route
    – Pneumonia
    – Extrapulmonary disease = rare
  • RFs
    – Immunodeficiency
    – Immunosuppressive drugs
    – Debilitated infants
    – Severe protein malnutrition
219
Q

Pneumocystis jiroveci diagnosis & management

A
  • Dx
    – Microscopy
    – PCR
    – Beta-D-glucan
  • Mx
    – High dose cotrimoxazole 2-3/52
    – Alternatives: atovaquone, clindamycin + primaquine
    – Steroids if hypoxia present
220
Q

Mucormycosis

A
  • Clinical syndrome caused by a number of fungal species belonging to the order
    Mucorales eg Rhizopus, Rhizomucor, Mucor
  • Inoculation via inhalation of spores or primary cutaneous inoculation
  • Favours immunosuppressed/diabetic patients

Clinical features
* Rhinocerebral => CNS
– Cellulitis of the orbit and face progress with discharge of black pus from the palate and
nose.
– Retro-orbital extension produces proptosis, chemosis, ophthalmoplegias and blindness.
– As the brain is involved, there are decreasing levels of consciousness.

  • Pulmonary
  • Cutaneous
221
Q

Mucormycosis diagnosis & management

A
  • Dx
    – Isolation from tissue Bx
  • Mx
    – Ambisome/Posaconazole
    – Sx
    – Rx guided by response
222
Q

Dermatophytes

A
  • A group of fungi capable of ivading dead keratin of skin, hair and nails
  • Classified by site infected e.g tinea capitis
  • Spread via contact with desquamated skin scales
  • RFs
    – Moisture
    – Deficiencies in cell mediated immunity
    – Genetic predisposition

tinea pedis: foot
tinea capitis: scalp
tinea cruris: groin
tinea corporis: abdomen

223
Q

Dermatophytes diagnosis & management

A
  • Dx
    – Skin scrapings, nail specimens and plucked hairs
  • MC&S
  • Mx
    – Topical eg clotrimazole, ketoconazole
    – Oral eg griseofulvin, terbinafine, itraconazole
224
Q

Side effects of antifungals

A

Azoles: abnormal LFTs
Polyenes: nephrotoxicity
Echinocandins: relatively innocuous
Pyrimidine analogues: blood disorders

225
Q

Targets for antifungal therapy

A

Cell membrane:
Fungi use principally ergosterol
instead of cholesterol

Cell Wall:
Unlike mammalian cells, fungi have a
cell wall

DNA Synthesis:
Some compounds may be selectively
activated by fungi, arresting DNA
synthesis

226
Q

Cell membrane active antifungals

A
  • Polyene antibiotics
  • Amphotericin B, lipid
    formulations
  • Nystatin (topical)
  • Azole antifungals
  • Ketoconazole
  • Itraconazole
  • Fluconazole
  • Voriconazole
  • Miconazole, clotrimazole (and
    other topicals)
227
Q

Azoles

A
  • In fungi, the cytochrome P450-enzyme lanosterol 14-a demethylase is responsible for
    the conversion of lanosterol to ergosterol
  • Azoles bind to lanosterol 14a-demethylase inhibiting the production of ergosterol
    – Some cross-reactivity is seen with mammalian cytochrome p450 enzymes
  • Drug Interactions
  • Impairment of steroidneogenesis (ketoconazole, itraconazole)
228
Q

Polyenes - Amphotericin B

A
  • Polyene antibiotic
  • Fermentation product of Streptomyces nodusus
  • Binds sterols in fungal cell membrane
  • Creates transmembrane channel and electrolyte leakage
  • Active against most fungi except Aspergillus terreus, Scedosporium spp.

Nephrotoxicity
* Most significant delayed toxicity
* Renovascular and tubular mechanisms
– Vascular-decrease in renal blood flow leading to drop in GFR, azotemia
– Tubular-distal tubular ischemia, wasting of potassium, sodium, and magnesium
* Enhanced in patients who are volume depleted or who are on concomitant
nephrotoxic agents

  • Less toxic preparations:
    1) Liposomal amphotericin B
    2) Amphotericin B colloidal dispersion
    3) Amphotericin B lipid complex
229
Q

Cell Wall active antifungals

A
  • Echinocandins
    -Caspofungin acetate (Cancidas)
230
Q

Echinocandins

A
  • Cyclic lipopeptide antibiotics that interfere with fungal cell wall synthesis by
    inhibition of ß-(1,3) D-glucan synthase
  • Loss of cell wall glucan results in osmotic fragility
  • Spectrum:
    – Candida species including non-albicans isolates resistant to fluconazole
    – Aspergillus spp. but not activity against other moulds (Fusarium, Zygomycosis)
    – No coverage of Cryptococcus neoformans
231
Q

Antifungals targeting DNA/RNA synthesis

A
  • Pyrimidine analogues
  • Flucytosine
232
Q

Flucytosine

A
  • Restricted spectrum of activity
  • Acquired Resistance
    – result of monotherapy
    – rapid onset
  • Due to:
    – Decreased uptake (permease activity)
    – Altered 5-FC metabolism (cytosine deaminase or UMP pyrophosphorylase activity)

Uses and side effects
* Limited
– Candida and cryptococcosis
* In combination with Ambisome/fluconazole
* Ses
– Infrequent – include D&V, alterations in liver function tests and blood disorders.
* Blood concentrations need monitoring when used in conjunction with Amphotericin B

233
Q

Viral pathogens with potential to cause pandemics

A

Influenza
SARS-CoV-2
Nipah
West Nile virus
Dengue
Zika

234
Q

Mechanisms of GI infections

A

No fever and no white blood cells in stool –> secretory diarrhoea
(cholera, E coli)

Fever and white blood cells in stool sample (neutrophils) –> inflammatory diarrhoea
(campylobacter, shigella, salmonella)

Fever and mononuclear cells in stool sample –> enteric fever
(typhoidal salmonella, yersinia, brucells)

235
Q

Organisms causing GI infections (incubation periods)

A

Campylobacter: 1-10 days incubation, duration 2-20 days, poultry

E coli 0157: 1-5 days incubation, 1-4 days duration

Shigella, Salmonella, Vibro 2-3 days incubation period

Staph aureus 2-6 hours incubation period

236
Q

Secretory diarrhoea mechanism

A

superantigen binding directly to T-cell receptors and MHC molecules (outside peptide binding site)
causes massive cytokine release (systemic toxicity)

237
Q

Mechanism of inflammatory diarrhoea

A

excess inflammatory response and bacteraemia
can be managed in immunocompetent but immune suppressed will have enteric picture

238
Q

Staph aureus food poisoning

A

spread by skin lesions on food handlers
catalase and coagulase positive
produces enterotoxin, causes prominent vomiting and watery (non-bloody) diarrhoea
self-limiting

239
Q

Bacillus cereus food poisoning

A

reheated rice
gram positive rod-spores
has heat stable emetic toxin (not destroyed by reheating)
heat labile diarrhoeal toxin (food not cooked to high enough temp)

watery, non-bloody diarrhoea
self-limiting
rare cause of bacteraemia in vulnerable population
can cause cerebral abscesses

240
Q

Clostridia organisms

A

gram-positive anaerobe

C. botulinum: botulism
source in canned or vacuum-packed food (honey in infants)
ingestion of preformed toxin (inactivated by cooking)
blocks ACh release from peripheral nerve synapses (present with paralysis)
treatment: antitoxin

C. pefringens: food poisoning
Source: reheated food (meat)
normal flora of colon but not small bowel is where enterotoxin acts (superantigen)
Incubation: 8-16 hours
watery diarrhoea, cramps, little vomiting lasting 24 hrs

C difficile: pseudomembranous colitis
HAI
children and >65s carry it in gut so don’t commonly test for it in these groups
antibiotic related colitis (any but mainly cephalosporins, cipro, clindamycin etc.)
Infection control
Mx: PO metronidazole, vancomycin (stop Abx where possible)

241
Q

Listeria monocytogenes

A

outbreaks of febrile gastroenteritis
beta-haemolytic, aesculin positive with tumbling motility
Source: refrigerated food, unpasteurised dairy, vegetables
grows at 4 degrees
Watery diarrhoea, cramps, headache, fever, little vomiting
perinatal infection (can cause miscarriage), immunocompromised patient
Mx: ampicillin

242
Q

Enterobacteria

A

facultative anaerobes, glucose/lactose fermenters, oxidase negative

E. coli:
traveller’s diarrhoea
source: food/water contaminated with human faeces
Enterotoxins:
- heat labile stimulate adenyl cyclase and cAMP
- heat stable stimulates guanylate cyclase
- act on the jejunum and ileum, not colon

243
Q

Types of E coli

A

ETEC: toxigenic, main cause of traveller’s diarrhoea

EPEC: pathogenic, infantile diarrhoea

EIEC: invasive, dysentery

EHEC: haemorrhagic, 0157:H7 EHEC: shiga-like verocytotoxin causes HUS

(avoid antibiotics - could exacerbate)

244
Q

Salmonella

A

non-lactose fermenters
H2S producers
TSI agar and XLD agar, selenite F broth

Antigens:
- cell wall O (groups A-I)
- flagellar H
- capsular Vi (virulence, antiphagocytic)

3 species:
- S. typhi (and paratyphi)
- S. enteritidis
- S. cholerasuis

Sources: poultry and meat, pets (reptiles)

245
Q

S. enteritidis

A

Enterocolitis

transmitted from poultry, eggs, meat

invasion of epi- and sub-epithelial tissue of small and large bowel
fever and bacteraemia infrequent
self-limited
non-bloody diarrhoea
usually no treatment
stool positivity

246
Q

S. typhi

A

Typhoid (enteric) fever)

transmitted only by humans
multiples in Payer’s patches
spreads via endoreticular system (ERS) –> bacteraemia (sickle cell and prosthetic materials increase risk)

slow onset, fever and constipation, splenomegaly, rose spots
anaemia and leucopenia
bradycardia, haemorrhage, perforation
blood culture positive
Mx: ceftriaxone

247
Q

Shigella

A

non-lactose fermenters
non H2S producers
non motile

Antigens:
- cell wall O antigens
- polysaccharide (groups A-D): S. sonnei, S. dysenteriae, S. flexneri (MSM)

most effective enteric pathogen (low ID 50)
no animal reservoir
no carrier state
Dysentery: invading cells of mucosa of distal ileum and colon, producting enterotoxin (shiga)

usually self-limiting
avoid Abx (ciprofloxacin if required)

248
Q

Vibrios

A

curved, comma shaped, late lactose fermenters, oxidase positive

Vibrio cholerae
Vibrio parahaemolyticus
Vibrio vulnificus

249
Q

Vibrio cholerae

A
  • O1 group: epidemics
  • Non O1 group: sporadic or non pathogens
  • transmitted by contamination of water and food from human feaces
  • colonisation of small bowel and secretion of enterotoxin with A and B subunit, causing persistent stimulation of adenylate cyclase
    causes massive diarrhoea (rice water stool) without inflammatory cells
    treat the losses (fluid resus)
250
Q

Vibrio parahaemolyticus

A

ingestion of raw or undercooked seafood
major cause of diarrhoea in Japan or when cruising in Carribean
self-limiting: 3 days
grows in salty 8.5% NaCl
treat with doxycycline

251
Q

Vibrio vulnificus

A

cellulitis in shellfish handlers
fatal septicaemia with D+V in HIV patients
treat with doxycycline

252
Q

Campylobacter

A

curved, comma or S shaped
Microaerophilic
C. jejuni at 42 degrees
oxidase positive, motile
self-limiting but symptom can last for weeks (20 days)
only treat if immunocompromised (macrolides)

transmitted via contaminated food and water with animal faeces (poultry, meat, unpasteurised milk)

Enterotoxin –> watery diarrhoea
Invasion –> bacteraemia
watery, foul-smelling diarrhoea, bloody stool, fever and severe abdo pain
treat with erythromycin or cipro if in first 4-5 days (otherwise self-limiting)

can cause guillan-barre, reactive arthritis and Reiter’s

253
Q

Yersinia enterocolitica

A

non-lactose fermenter, prefers 4 degrees
transmitted via contaminated food with domestic animals excreta (farms)
enterocolitis or mesenteric adenitis
associated with reactive arthritis and Reiter’s

254
Q

Mycobacteria

A

(tuberculosis, avium, intracellulare)

will appear as gram variable
always think of TB

255
Q

Entamoeba histolytica

A

(protozoa)
motile trophozoite in diarrhoea
non-motile cyst in non-diarrhoeal illness
killed by boiling, removed by water filters
4 nuclei
no animal reservoir

ingestion of cysts –> trophos in ileum –> colonise caecum, colon –> flask-shaped ulcer

dysentery, flatulence, tenesmus
chronic: weight loss +/- diarrhoea
liver abscess

Diagnosis:
stool micro (wet mount, iodine and trichrome)
serology in invasive disease

Mx: metronidazole and paromomycin in luminal disease

256
Q

Giardia lamblia

A

(protozoa)
trophozoite pear-shaped
2 nuclei
4 flagellas and a suction disk (attachment)

ingestion of cyst from faecally contaminated water and food

excystation at duodenum
tropho attaches
no invasion
malabsorption of protein and fat

travellers, hikers, day care, mental hospitals, MSM

foul smelling, non-bloody diarrhoea
cramps, flatulence, no fever

Diagnosis: stool micro, ELISA, string test

Mx: metronidazole

257
Q

Cryptosporidium parvum

A

(protozoa)
infects the jejunum
severe diarrhoea in immunocompromised
oocysts seen in stool by modified Kinyoun acid fast stain
Mx: reconstitution of immune system (self-limiting)

258
Q

Norovirus

A

outbreaks
low infectious dose (18-1000 viral particles)
environmental resilience (0-60 degrees)
no long-term immunity
GII.4 currently predominant strain

259
Q

Rotavirus

A

dsRNA wheel-like virus
replicates in mucosa of small intestine
secretory diarrhoea, no inflammation
can get watery diarrhoea by stimulation of enteric nervous system

by age 6, most children have antibodies to at least one type
exposure twice confers lifelong immunity

260
Q

Adenovirus

A

Types 40 and 42 cause non-bloody diarrhoea (<2yrs of age)
any type in immunocompromised
diagnosis: stool EM, antigen detection, PCR

261
Q

Other faeco-orally transmitted viruses

A

polio
entero
hepatitis A

262
Q

GI infection vaccines

A

Cholera: inactivated whole cell or live attenuated (if travelling to endemic area)
Campylobacter: military, infants, travellers
ETEC: inactivated and live vaccines in trials
Salmonella typhi: Vi capsular PS (IM) and live (PO)
Rotavirus: 3 types, age 6-12 weeks

NB: all gastroenteritis is notifiable

263
Q

Prion diseases

A

Protein-only infectious agent

Rapidly infect existing prions in cells and cause them to switch to abnormal isoforms which triggers neurodegeneration

Rare transmissable spongiform encephalopathies in humans + animals

Rapid neuro-degeneration (max survival from first symptom to death is 6 months)

Currently untreatable

264
Q

Normal prion protein

A

normal prion protein gene on chromosome 20 - thought to be involved in copper metabolism and binding
Codon 129 polymorphism: MM, MV, VV (MM predisposes to prion disease)

265
Q

Prion protein structure

A

PrP: Alpha-helical configuration
Protease sensitive

PrPsc: Beta-sheet configuration
Protease/radiation resistant
(abnormal isoform)

266
Q

Prion protein replication

A

Seed of PrPSc acts as a template
which promotes irreversible
conversion of PrP to insoluble PrPSc

ie. conformational change in PrP

The trigger for this process
remains unclear in sporadic cases

267
Q

Prion disease classification

A

Sporadic Creutzfeldt-Jakob Disease (80%)

Acquired (<5%):
- Kuru (cannibalism)
- variant CJD (mad cow epidemic, young people)
- iatrogenic CJD:
*GH
*Blood
*Surgery

Genetic (15%):
- PRNP mutations
eg. Gerstmann-Straussler-Sheinker syndrome
Familial Fatal Insomnia

268
Q

Sporadic CJD

A

Rapid dementia with:
- myoclonus
- cortical blindness
- akinetic mutism
- LMN signs (anterior horn cells –> signs consistent with MND)

Mean age onset 65 yrs
(range 45-75 yrs)
Incidence 1/million/year
Death within 6/12
Cause uncertain
? somatic PRNP mutation
? spontaneous conversion of PrPc to PrPsc
?? Environmental exposure to prions

269
Q

Sporadic CJD diagnosis

A

EEG (electroencephalography)
- periodic, triphasic complexes (non-specific: can also be caused by hepatic encephalopathy and lithium use but would be able to rule this out using history and blood tests)
- 2/3 abnormal

MRI
- basal ganglia – increased signal
- cortical/striatal signal change on DWI MRI

CSF  14-3-3 protein, S100

Neurogenetics to r/o genetic cause

Tonsillar biopsy NOT useful

Brain biopsy (cannot reuse equipment): spongiform vacuolation(water) (basal ganglia and cortical structures), amyloid plaques

Autopsy – by experienced pathologist

270
Q

Varian CJD presentation

A

Younger age of onset (median age 26 yrs)
Median survival time 14 months
Psychiatric onset:
- dysphoria, anxiety, paranoia, hallucinations
Then neurological:
- peripheral sensory symptoms
- ataxia
- myoclonus
- chorea
- dementia

First appeared during BSE (mad cow disease) epidemic due to poor practices in food chain

271
Q

Variant CJD diagnosis

A

MRI brain - positive pulvinar sign (high signal in posterior thalamus aka putamen)
EEG – non-specific slow waves
CSF – 14.3.3, S100 not useful (usually normal)
Neurogenetics (almost 100% are MM at codon 129 so far)
Tonsil biopsy 100% sensitive and specific (prions find way into lymphoid tissue)
(Brain biopsy) - no need if tonsil biopsy positive
Autopsy
PrPSc type 4t detectable in CNS + most lympo-reticular tissues

272
Q

Tonsillar biopsy in vCJD

A

100% sensitivity and specificity for vCJD
Early clinical diagnosis
Eliminates need for further investigation
(e.g. brain biopsy to exclude other treatable causes)
Important for therapeutic trials and early treatment
May be positive during incubation period before clinical onset
(sheep scrapie, mouse models)
Histology: florid plaques and areas of vacuolation

273
Q

Iatrogenic CJD

A

Human cadaveric growth hormone (in past)
Corneal transplants
Neurosurgical procedures eg. dural grafts, pre-1991
Blood transfusions, other blood products
Other surgical procedures
? appendicectomy and tonsillectomy in vCJD

274
Q

Clinical features of iatrogenic CJD

A

Progressive ataxia initially

Dementia and myoclonus later stages

Speed of progression depends on route of inoculation (CNS inoculation fastest)

275
Q

Prion genetics

A

3 Aspects:

  • Codon 129 polymorphism
    Methionine – Methionine (MM)
    Methionine – Valine (MV)
    Valine – Valine (VV)
  • Specific PRNP mutations (~30 so far)
  • Consider other neuro-genetic conditions eg. Huntington’s, spinocerebellar ataxia

prion protein mutations are all autosomal dominant

276
Q

Familial prion disease

A

(GSS, FFI, CJD)

F.H. crucial:
Dementia
“MS”
Ataxia
Psychiatric

EEG – non-specific
MRI – basal ganglia: sometimes high signal
Neurogenetics crucial
If negative: SCA / Huntington’s
Autopsy

277
Q

Gerstmann-Straussler-Scheinker syndrome (GSS)

A

Slowly progressive ataxia
Diminished reflexes
Dementia
Onset age 30-70 years
Survival 2-10 years
PRNP P102L, but several other mutations

278
Q

Fatal Familial Insomnia (FFI)

A

Untreatable insomnia
Dysautonomia
Ataxia
(thalamic degeneration)
PRNP D178N
+/-pyramidal/extrapyramidal signs
late cognitive decline

279
Q

Kuru

A

(Papua New Guinea)
Foré tribes – Papua New Guinea highlands
Epidemic 1950’s / 1960’s
- Women
- Children
Last endo-cannibalistic feast 1957
Longest incubation: up to 45 years
No MM’s left
Progressive cerebellar syndrome:
- death within 2 years
Dementia late or absent

280
Q

CJD treatment

A

Symptomatic: clonazepam – myoclonus
(valproate, levetiracetam, piracetam)

Delaying prion conversion:
quinacrine
pentosan (intra-ventricular administration)
tetracycline

Anti-prion antibody (prevents peripheral prion replication and blocks progression to disease in infected mice but does not get into CNS)

Depletion of neuronal cellular prion protein (prevents onset of disease in mice and blocks neuronal cell loss + reverses early spongiosis)

Pathology (5 decks)

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