Infectious diseases Flashcards
CYP3A4 inducers (i.e. will decrease efficacy of other medications)
St John’s Wart
Glucoocorticoids
Carbamazepine
Phenytoin
Phenobarbital
Rifampicin
CYP3A4 inhibitors (will lead to higher levels of the drug)
HIV protease inhibitors - ritonavir, cobicistat
Grapefruit juice
Verapamil, diltizam
? Amiodarone
Clarithyromycin, erythromycin
Itraconazole, ketoconazole
Antibiotic mechanism of action
Mechanisms of antimicrobial resistance in Pseudomonas Aeruginosa
- gram negative aerobic rod
- important cause of VAP - Pseudomonas VAP has highest mortality of all hospital acquired infections
- most common cause of respiratory failure in CF ; Pts with CF often colonised with MDR Pseudomonas with loss of virulence traits
- lipopolysaccharide may play a role in virulence - found in outer membrane of gram negative bacteria & protects from complement activity, triggers cytokine pathways, leads to septic shock
Mechanisms of antimicrobial resistance - both acquired & chromosomally encoded
1. Beta-lactamases
-> AmpC - inducible chromosomal beta-lactamase. Found in ESCAPPM. Hydrolyses extended spectrum (class C) cephalosporins
-> ESBL (class A)
-> Metallo beta-lactamase - less common (class B)
- Reduced permeability - downregulation of outer membrane protein OprD, which is a carbapenem-specific porin -> resistance to carbapenems, particularly imipenem
- Active efflux
- Ability to fomr a biofirm
- Aminoglycoside modifying enzymes
Define MDR
- Multi-drug resistance (MDR): non-susceptible to at least one agent in three or more antibiotic classes
- Extensively drug-resistant (XDR): non-susceptible to at least one agent in all but two or fewer antibiotic classes
Pan-drug resistant: non-susceptible to all agents
What antibiotics are effective in Pseudomonas infections?
- Penicillins
Piperacillin - tazobactam
Ceftazidime - avibactram - Fluoroquinolones - only antibiotic with oral formulation which is reliably active against Pseudomonas. Cipro 750mg PO BD or 400mg IV TDS. Levofloxacin 750mg PO daily. Moxi NOT effective
- 3rd generation cephalosporins
Cefepime, ceftazidime, (cefoperazone), not ceftriaxone - Carbapenems - meropenem
- Aminoglycosides - gentamicin. Do not usually use as monotherapy due to inadequate efficacy
- Polymyxins - colitin & polymyxin B - effective for MDR pseudomonas including metallo beta lactamase producing Pseudomonas
Side effects - renal impairment & neurotoxicity
Combination therapy of beta lactam PLUS aminoglycoside may be helpful in serious infections as empiric therapy but not much data
What are the differences between typable and non-typeable Haemophilus influenzae?
- H. influenzae broadly divided into typeable (typically encapsulated) & non-typeable (typically without capsule)
- typeable A-F are more virulent - type B is most virulent
- non-typeable strains are less virulent
- in places where Hib vaccination uncommon -> leading cause of meningitis & epiglottitis in children & pneumonia in adults
- non-typeable typically causes non-invasive mucosal infections in elderly & children e.g. otitis media & respiratory tract infections (IECOPD, bronchitis, rhinosinusitis, pneumonia).
-rarely non-typable NTHi causes locally invasive genital infections e.g. endometritis, amnionitis, Bartholin gland abscess
-invasive Haemophilus typically occurs in extremes of age & more common with Hib -e.g. meningitis, bacteraemia, epiglottitis etc.
What are the virulence factors associated with haemophilus influenzae?
Most invasive haemophilus infections are due to haemophilus influenza type B -> capsule contains **polyribitol ribose phosphate **which mediates invasion
Other virulence factors
-adhesins - mediate attachment to respiratory mucosa - pilli, fimbriae, high molecular weight factors HMW1, HMW2
-cell wall lipoproteins e.g. lipo-oligosaccharide - impair ciliar function
-biofilm formation
-IgA proteases
**- non-type haemophilus **can survive **intra-cellularly **
- typeable strains have a dense polysaccharide capsule -> renders greater resistance to **complement mediated killing & phagocytosis **
How does the antibody response for typeable vs non-typeable Haemophilus influenzae differ?
Strong antibody response against non-typeable haemophilus influenzae
Ab response is strong & bactericidal with formation of MAC
What is the most common organism identified in pyogenic liver abscess?
Klebsiella (seen in 40%)
What are the virulence factors associated with Klebsiella?
- Capsular serotype - some capsules lack antigens that can be recognised by macrophages / neutrophils - K1, K2, K25
- Hypermucoviscosity - hyperviscous exopolysaccharide web - resists complement mediated serum killing. Associated with magA and rmpA genes - seen disproportionately in Klebsiella forming liver abscess
- Lipopolysaccharide (LPS O side chain can impede C1q or C3b from binding)
- Siderophores - aerobactin binds iron which is an essential growth factors for enterobactericae
- Pili - type 3 fimbrial adhesion protein (MrkD adhesin) plays a key role in virulence of Klebsiella pneumoniae
What proportion of Klebsiella expresses an ESBL?
30% community acquired
44% hospital acquired
Rx meropenem -> step down to cipro
Consider nitrofurantoin / fosfomycin for uncomplicated cystitis
What proportion of E.coli is resistant to penicillin & 3rd gen cephalosporins like ceftriaxone?
12% E.coli produces ESBL - encoded by CTX-M
0.1% E.coli produce a carbapenamase
What features of E.coli make the urinary tract more susceptible to infection?
E.coli causes vast majority of UTIs - up to 95% in people with normal anatomy
P. fimbriae (pyelonephritis associated pilli) is an adhesion that attaches to the D-galactose D-galactose moiety expressed on urothelial cells & RBCs
-also promote persistence of infection by binding to renal basement membrane & Bowman’s capsule, impair ureteric contractility allowing ascend of bacteria from bladder
What are the key features of ETEC?
Enterotoxigenic E.coli = travellers diarrhoea
- incubation period is 1-3 days with rapid onset of Sx
- profuse watery, secretory diarrhoea
- can produce a heat labile (i.e sensitive to heat) and heat stable toxin. Heat labile activates adenylate cyclase -> incr. intracellular caMP -> secretion of chloride
Heat stable activates cGMP -> Cl secretion & inhibition of NaCl absorption
What are the key features of EPEC?
Enteropathogenic E.coli
-profuse watery, secretory diarrhoea & vomiting
-can cause very severe disease & fatal dehydration
-expresses intimin which allows adhesion -> causes re-arrangement of actin in host cell -> “attaching and effacing” effect.
Locus of enterocyte effacement island - 20 protein toxins that are injected directly into the target epithelial cell
What are the differences between enteroaggregative E.coli (EAEC) vs enteroinvasive E.coli (EIEC)?
EAEC - causes both acute & chronic diarrhoea in resource-poor and rich settings. Not invasive - no fever.
EIEC - uncommon; begins as watery diarrhoea & progresses to bloody diarrhoea & frank dysentery WITH FEVER. Closely related to Shigella and causes a colitis similar to shigellosis
What are the features of STEC?
Shiga-toxin producing E.coli
= enterohaemorrhagic E.coli
e.g. O157:H7
- small infectious dose ; large outbreaks
- incubation period around 3 days
- causes bloody diarrhoea without fever
- STEC rarely invades extra-intestinal sites or bloodstream - systemic injury is due to toxinaemia
- key complication is haemolytic uraemic syndrome - complicates STEC infection in about 15% children, less common in adults
- antibiotic treatment for STEC can trigger HUS
- key features - microangiopathic haemolytic anaemia, thrombocytopenia, renal failure
- HUS develops day 7 when diarrhoea is improving
**- decrease in platelet count is the first sign of HUS **
**
If the platelet count is increasing in middle or late phase of illness - risk has passed
STEC patients should be admitted for aggressive fluid resuscitation - aim for haemodilution
Ambler classification of beta lactamases
Are EBSLs plasmid-mediated or chromosomally-encoded?
Plasmid mediated
What is the most common gene encoding ESBL?
CTX-M
What types of bacteria producing ESBLs?
Gram negative aerobic bacteria
What resistance pattern defines ESBL?
- Resistance to 3rd generation cephalosporins e.g. ceftriaxone, ceftazidime
- Resistance to penicillins
- Resistance to aztreonam
- Resistance to 1st & 2nd gen cephalosporins
*Resistance to aminoglycosides & Bactrim often carried on the same plasmid
What are the differences between ESBL & ampC?
- ESBL is plasmid-mediated (constitutively expressed) vs ampC chromsomally encoded & induced
- ampC is sensitive to cefepime - one of the first ways in which lab distinguishes between ESBL & ampC
- ampC is resistant to beta-lactamase inhibitors (except the novel 2nd generation beta lactamase inhibitor avibactam); ESBL is inhibited by beta-lactamase inhibitors, however, this is not clinically useful
- ampC is usually resistant to cefoxitin (2nd gen cephalosporin), but ESBL often appear sensitive in vitro
What are the treatment options for organisms that produce ESBLs?
- Carbapenems
- Ceftazidime - avibactam
- Ceftolozane - tazobactam
- Aminoglycosides e.g. gentamicin, amikacin
- Bactrim
- Fluoroquinolones
What is the preferred treatment for an uncomplicated UTI caused by an ESBL producing organism?
- Nitrofurantoin is 1st line if susceptible & renal funcion ok - eGFR >40
- PO fosfomycin
- PO pivmecillinam
- Bactrim or fluoroquinolones
What are the ESCAPPM organisms?
Enterobacter
Serratia
Citrobacter
Acinetobacter, aeromonas
Proteus (but not Proteus mirabilis)
Pseudomonas
Providencia
Morganella
What pattern of resistance is ampC associated with?
AmpC is an Ambler Class C chromosomally encoded, inducible beta lactamase
Induced by cell wall breakdown products
When expressed in large amounts, ampC conveys resistance to 1st - 3rd gen cephalosporins, augmentin DF, tazocin, penicillins
Susceptible to carbapenems, aminoglycosides (gentamicin), cefepime, bactrim, ciprofloxacin
What induces expression of ampC?
Which organisms have highly inducible ampC?
Exposure to antibiotics - > cell wall breakdown products
Ampicillin & cephazolin are strong inducers of ampC -> therefore ESCAPPM organisms should always be considered resistant
Organisms with highly inducible ampC -> Klebsiella aerogenes, Enterobacter, Citrobacter -20% chance of treatment failure with ‘susceptible’ antibiotics
Providencia & morganella are less likely to have ampC induced
What are the treatment options for ESCAPPM?
Carbapenems 1st line
Cefepime
Ceftazidime-avibactam
Tazocin - weak inducer of ampC
What are the risk factors for colonisation with carbapenemase producing enterobacterales?
What are the classes of beta-lactamases?
What is the gene encoding colistin resistance?
Colistin resistance identified in 2015
Found in livestock & waterways
Plasmid mediated
Encoded by MCR-1 = mobilised colistin resistance 1
What is avibactam? What is it’s mechanism of action? What organisms is it effective against?
- very potent, novel, second generation beta lactamase inhibitor
- binds to beta-lactamase enzyme via reversible cyclisation (rather than suicide inhibitio) - it is released / regenerated to continue to inhibit other molecules
- can inhibit class A (e.g. KPC, ESBL), class C (ampC), class D (OXA-48), BUT no activity against metallo-beta-lactamases
**for KPC ceftazidime-avibactam is the best
What are the available therapies for carbapenemase producing organisms?
- usually combination therapy - monotherapy associated with high mortality 40%
- combination therapy includes colistin backbone PLUS other agent
- colistin = polymyxin E
- tigecycline - inhibits ribosome 30s subunit, bacteriostatic, poor tissue penetration
- amikacin - aminoglycoside - inhibits 30s
- fosfomycin - oral, efficacy in cystitis but otherwise data is lacking
- dual carbapenem therapy may be effective for KPC
- Ceftazidime - avibactam for class A, class C & class D carbapenemases (but NOT against class B)
What are the different groups of carbapenemases?
- Class A - Klebsiella pneumonia carbapenemase
- Class B:
New delhi metallo-beta-lactamase
Imipenem resistant Pseudomonas
Verona integron encoded metallo-beta-lactamase - Class D
Oxacillinases - OXA-48 or OXA-181
What are the main side effects of colistic / polymyxin E?
Neurotoxicity & nephrotoxicity (nephrotoxicity is more common)
Neurotoxicity includes opthalmoplegia, paraesthesias, dysphagia, vertigo, respiratory apnoea
What is the mechanism of action of polymyxins?
Act against the outer cell membrane of gram negative bacteria - specifically targets phospholipids & lipopolysaccharides. Bind to negatively charged lipopolysaccharides disrupting cell membrane integrity
Leading to cell death
Which organisms are resistant to carbapenems?
Ertapenem has no activity against Pseudomonas
Carbapenems generally not effective against VRE, MRSA, E.faecium, chlamydia, mycoplasma, strenotrophomonas maltophilia
What do the gag, pol & env genes encode?
- Env gene encodes surface proteins - gp120 for surface attachment, gp41 for membrane fusion
- Pol gene encode enzymes - reverse transcriptase, integrase, protease
- Gag gene encodes structural proteins - capsid, matrix, core & nucleocapsid
How does HIV enter cells? Which cells does HIV infect?
-Early infection - gp120-gp41 on HIV binds to CCR5 on CD4+ T cells (Europeans with CCR5 mutation - CCR5 delta 32 homozygote - are immune to HIV infection can bind bc do not present CCR5 on cell surface)
-Late infection - mutant HIV can later bind to CD4+ CXCR4
(an aggressive HIV strain can bind both CCR5 & CXCR4)
M-tropic HIV - early in infection => SELECTIVELY infects dendritic cells
Expresses RANTEs ligand (chemokine 5 ligand) which binds to CCR5
Low ability to induce fusion
Moderate pathogenicity
T-tropic HIV - later in infection, expresses SDF-1 ligand (AKA chemokine 12 ligand), high ability to induce fusion, high pathogenicity
Describe the HIV virus lifecycle
-M-tropic HIV selectively infects dendritic cells (via RANTES ligand & CCR5; and gp120/gp41 -> CCR5)
-dendritic cells travel to lymph nodes & infect CD4+ T cells (INTEGRATION can only occur in resting & terminally differentiated cells)
-reverse transcription - NO check points - many mutants formed.
- only 0.1% of infected T cells are active and produce HIV
- 99% infected cells act as a reservoir for HIV
- when CD4 T cells are activated -> produce NFkappaB -> binds to U3 region of 5’LTR region of HIV DNA => causes upregulation of HIV transcription
- Release of immature virions containing GagPol polyprotein -> GagPol polyprotein cleaves & activates proteins
- Resting memory CD4 T cells harbour latent virus
How does acute / primary HIV infection present?
= primary infection / seroconversion illness
-occurs** 3-4 weeks **post transmission
-caused by **CD8+ cytotoxic T cells **
because CD4+ T cells are being killed in large numbers by cytotoxic T cells - via binding to MHC1 containing HIV peptisdes
Specifically also massive loss of CD4 T cells in the GALT - gut epithelial cell apoptosis & break down of tight junctions
Associated with high viral load -> eventual CD4 exhaustion leading to decline in HIV replication rate
**People with HLA-5701 have better immune response to HIV & slower progression to AIDS because this HLA binds strongly to an important core peptide involved in HIV replication **
Called seroconversion illness because people become Ab positive at this time-point
-Lasts 1-4 weeks
-Variable severity - may not recall having any illness or hospitalisation ; often assumed to be the or grandular fever
Presents with fever, lymphadenopathy, respiratory Sx, rash, headache, retro-orbital pain
Skin features
- seborrheic dermatitis, oral hairy leukoplakia, kaposi sarcoma (deep brown-red papules & plaques), disseminated candiasis, psoriasis, Herpes Zoster, large perianal HSV ulceratyion
At what point do HIV antibodies become detectable?
At 3-4 weeks post infection
At the time of the primary seroconversion illness
Incubation period - fever in returned traveller
Malaria prophylaxis
CSF characteristics in meningitis
Characteristic features of common causes of bacterial meningitis
Causes of eosinophilic meningitis
> 5% eosinophils in CSF is uncommon & suggestive of
- parasitic infection
- fungal infection - although primarily mononuclear cells with 6-20% eosinophils
- neoplastic process
- inflammatory process
eosinophilic meningitis usually presents with prolonged Sx suggestive of chronic meningitis
Have evidence of cerebral involvement as well
Fungal causes of eosinophilic meningitis - Candida, coccidioides immitis
3 most important parasitic infections that cause eosinophilic meningitis
- Angiostrongylus cantonesis (rat lung worm disease) - most common parasitic cause, SE Asia - Malaysia & Thailand, acquired by eating raw or undercooked snails or slugs or crab & shrimp which have eaten them
Supportive Rx
Anti-helmintic Rx no evidence
Usuallyself-limiting & recover completely - Gnathostomiasis - endemic in SE Asia, parts of China & Japan, migratory cutaneous swellings is a common presenting feature
- Baylisascariasis - found in raccoons
Duration of therapy in IE
At what point should a faecal transplant be considered in Clostridium difficile infections?
Usually after adequate antimicrobial treatment for 3 infections, including index infection and 2 recurrences -> who then present with their 3rd recurrence or 4th infection
However, some favour FMT at the 2nd recurrence
What are some mechanisms by which HIV evades the immune system?
- high error rate in reverse transcription producing sequence variation
- loss of effector CD4 T cells to fight infection
- Latency in resting CD4 T cells
- Infection of privileged sites
What are the AIDS-defining illnesses?
- PJP pneumonia
- CMV retinitis
- Toxoplasma encephalitis
- Kaposi sarcoma - HHV-8 - brown lesions on skin & mucosal surfaces
- Candidiasis - throat, oesophagus, bronchus or lungs (but not mouth)
- Cachexia & wasting
- Illnesses associated with herpes virus re-activation - CMV retinitis, EBV-associated hairy leukoplakia on tongue, EBV associated CNS lymphoma
- HIV-associated dementia
- Disseminated mycobacterium avium complex / TB
- Chronic cryptosporidiosis / microsporidiosis
What are the renal manifestations of HIV?
CKD in HIV may be due to HAART or HIV infection
Most commonly focal sclerosing GN - presents with nephrotic range proteinuria and renal impairment
What is DILS and how does it present?
DILS = diffuse infiltrative lymphocytosis syndrome
-rare, seen in HIV infected patientsm, usually in untreated infection, but can also manifest independent of CD4 T cell count
-due to CD8 T cell lymphocytosis and CD8 T cell infiltration into multiple organs
-clinical presentation - Sjogren-like disease with sicca signs (dry eyes, dry mouth), bilateral parotiditis, lymphadenopathy, extraglandular involvement
-Rx is ART, sometimes steroids
What are the diagnostic tests for HIV?
- ELISA testing - very sensitive. Detects the presence of HIV Abs in patient’s serum.
- Western blot - very specific. No longer done.
What is the expected change to CD4 count and HIV viral load after commencing anti-retroviral therapy?
- Increase in CD4 count of 50-150 in 1st year
- then slower increase of 50-100 per year until steady state is reached - most patients will plateau after 4 yrs.
Factors associated with reduced CD4 recovery
- Older age, male sex, lower pre-ART CD4 count, certain co-infections e.g. HCV, longer time from initiation of ART to viral suppression
ART leads to a near-normal lifespan, especially when ART started early with a high baseline CD4 count
Viral load should fall quickly to undetectable levels
Rising viral load suggests non-adherence, resistance or both
Main objective of ART by baseline CD4 cell count
What are the risk factors for IRIS after commencing ART in HIV?
- Low baseline CD4 count - usually only if baseline CD4 count <100 (exception is TB infection - IRIS can still occur if baseline CD4 count >200)
- High baseline viral load
- Early ART therapy
- TB infection - risk of IRIS 40%
- Rapid improvement after commencing ART
When should ART be started?
- Start within 2 weeks of HIV diagnosis
Only 2 reasons to delay - TB infection, cryptococcal meningitis
TB and CD4 <50 - start in 2 weeks of starting TB treatment
TB and CD4 count >50 - start in 8 weeks; consider prophylactic steroids if CD4 count <100 and starting ART within 30 days of TB treatment
TB meninigitis - wait 8 weeks regardless of CD4 count
Cryptococcal meningitis - wait 2 weeks after starting Rx
PJP do not need to wait - would be giving everyone steroids regardless
PML - only Rx for PML is ART - but can trigger life-threatening IRIS
CNS toxo - IRIS with toxo not well described
When should pharmacokinetic boosters be used with antiretroviral therapy?
-Use with protease inhibitors AND elvitegravir (Genvoya)
-PK boosters are ritonavir and cobicistat - both inhibit CYP450
CYP450 metabolises majority of the ART drugs - main mechanism of drug interactions
*Cobicistat can make serum Cr elevated due to effect on Cr secretion - but does not reduce renal function
What ART regimen should be used in patients with HIV plus HBV co-infection?
Use a regimen containing tenofivir (alafenamide OR disoproxil fumarate) & emtricitabine
e.g. Biktarvy or Genvoya
If tenofovir or emtricitabine therapy is stopped abruptly - can have acute exacerbation of hepatitis B
(Lamivudine can also treat Hep B; however not routinely used for the management of co-infection -> however if abruptly stopped can lead to acute exacerbation of Hep B)
regi
What are the typical 1st line ART regimens?
What are the adverse effects associated with abacavir (a nucleoside reverse transcriptase inhibitor) used to treat HIV?
-Presence of HLA-B5701 allele associated with a hypersensitivity reaction which can be fatal
-possible association with IHD (hypersensitivity due to HLA-B5701 and CD8+T cells)
-Abacavir with HLA-B5701 also associated with DRESS
What are the adverse effects associated with integrase inhibitors?
Can elevate creatinine concentration due to effects on Cr secretion, but do not reduce renal function
Dolutegravir (in Tivicay / Triumeq) - associated with anxiety, depression, neural tube defects
Raltegravir (in Isentress) - associated with myopathy & rhabdo (but low risk - monitor CK)
Elvitegravir needs to be given with cobicistat
*low barrier for resistance for raltegravir, but higher comparatively for dolutegravir & elvitegravir
Neutral effect on lipids - advantage over protease inhibitors & NNRTIs
What are the differences in the adverse effect profile of tenofovir alafenamide vs tenofovir disoproxil fumarate?
Nucleoside / non-nucleoside reverse transcriptase inhibitors bind to viral reverse transcriptase at the deoxynucleotide binding site -> inhibit DNA synthesis
Low barrier to resistance
Cause **mitochondrial toxicity **
- TDF = older prodrug of tenofovir
-TAF & TDF both associated with nephroxicity via damage to proximal tubule (proteinuria, ATN, glycosuria) - but TDF > TAF
Check renal function & urine protein every 6 months - reduction in bone density - TDF > TAF
TAF - more drug interactions with rifamycins & anticonvulsants, more hyperlipidaemia than TDF.
Zidovudine (AZT) is used to prevent HIV transmission in pregnancy. What are the side effects?
- Nail dyspigmentation
- GI side defects
- Lipodystrophy
- Increased truncal obesity
- Metabolic toxicity
What is the side effect profile of non-nucleoside reverse transcriptase inhibitors?
‘virenz’, ‘virapine’, ‘virine’
Do not bind to the deoxynucleotide binding site of viral reverse transcriptase -> lead to altered enzyme conformation -> impaired DNA synthesis
**Severe cutaneous adverse reactions **
Hyperlipidaemia
- Associated with a risk of SJS and TEN
- Nevirapine with HLA B3505 associated with SJS
- Nevirapine hypersensitivity reactions include fatal hepatitis / hepatic necrosis (higher risk if higher baseline CD4 count)
Efavirenz - CNS toxicity in 1st few weeks (sedation, insomnia, vivid dreams, suicidality), rash (can continue Rx), deranged LFTs, hyperlipidaemia, 1st trimester - neural tube defects, facial clefts, anopthalmia
Rilpiverine - QTc prolongation (2nd gen NNRTI) - used as part of 3-drug regimen
Delaverdine - rash, headache
Which classes of anti-retroviral therapy are more commonly associated with resistance?
Protease inhibitors - high barrier to resistance
Integrase inhibitors - some e.g. Dolutegravir have a higher barrier to resistance
Nucleoside & non-nucleoside reverse transcriptase inhibitors - low barrier to resistance (e.g. K103N mutation)
What are the adverse effects associated with protease inhibitors?
‘navir’ - inhibit cleavage of Gag-Pol polyproteins
Require PK boosting - drug interactions due to inhibition of CYP3A4 / CYP450
Class AEs include GI symptoms, CV risk / metabolic side effects including dyslipidaemia, impaired glucose tolerance, lipodystrophy
Atazanavir (ATV) - elevated bili; non-adherent will have low bili; lower risk of CVD complications
What forms of anti-retroviral therapy are associated with mitochondrial toxicity?
- major adverse effect of nucleoside reverse transcriptase inhibitors
- occurs because NRTIs also bind to human DNA polymerases e.g. mitrochondrial DNA polymerase gamma -> deplete mitochondrial DNA
- highest risk NRTIs are stavudine & didanosine (not really used much now)
- lamivudine, emtricitabine, abacavir, tenofovir - uncommonly associated with mitochondrial toxicity
Presents with myopathy, lactic acidosis, neuropathy, lipoatrophy, pancreatitis
Cutaneous manifestations of ART toxicity
Lipodystrophy - atrophy in face, limbs, buttocks; incr. in central obesity, buffalo hump
Nevirapine - SJS with HLA B3505
Abacavir - DRESS with HLA B5701
Zidovudine - nail dyspigmentation
Bactrim related reactions
Which classes of antiretroviral therapy are effective against both HIV1 & HIV2?
NRTIs, protease inhibitors, integrase inhibitors are effective against both
NNRTIs only effective against HIV1
Lamivudine & emtricitabine are two nucleoside reverse transcriptase inhibitors used for the treatment of HIV. What are the side effects associated with these drugs?
Lamivudine - pancreatitis (rare)
Emtricitabine - skin pigmentation (rare)
NRTIs are associated with risk of mitochondrial toxicity
What is the risk of perinatal transmission with and without ART in a HIV-positive mother?
- no drug - risk of transmission 25%
- IV AZT (zidovudine) alone at delivery -8%
- if on ART with VL <50 - risk of transmission <0.09%
What are the recommendations for ART in pregnancy with HIV positive mother?
Start ART as soon as possible REGARDLESS of CD4 count
ART does NOT increase the risk of birth defects
Can give ALL HIV drugs in pregnancy
Use standard 3 x drug regimen (no role for 2 drug regimens)
If VL >1000 or unknown at the time of delivery - recommend
How effective is PrEP? What are the indications/ contraindications, and recommended regimen?
Pre-exposure prophylaxis - 90-99% effective in at risk population if taken consistently
Who should have PrEP?
- MSM, condomless anal intercourse
- Sex workers
- recent rectal STI
- Must not have HBV or CrCl < 90
- documented HIV negative within 1 week of commencement
Regimen - emtricitabine + tenofovir once daily (TRUVADA)
Cabetogravir (integrase inhibitor) in the pipeline, half life 8w eeks
Who should get PEP / when & what drugs?
- PEP has to be within 72 hrs - 28 day course - success rate 100% if given within 24 hours, 50% people will develop infections if given in 72 hrs.
- CD4 T cell HIV reservoir can occur within 24 hours of exposure
2 drug regimen - tenofovir plus emtricitabine OR lamivudine
3 drug regimen - typically 2 NRTIs (pick from above) PLUS integrase inhibitor (dolutegravir or raltevgravir) OR protease inhibitor / rilpivirine
Risk of transmission highest in receptive anal intercourse with ejaculation (1:70 from HIV + source); 1:440 for needlestick injury, <1:1000 for mucous membrane & non-intact skin exposure
Risk of source having HIV
10% MSM
0.5% IVDU
30% MDM & IVDU
<0.003% heterosexuals
If undetectable viral load = untransmittable = do NOT require PEP
Non-occupational exposure
- HIV source with detectable or unknown viral load - 3 drug regimen (SEX all kinds but oral; sharing needles; contact with MM or non-intact skin)
Occupational exposure
HIV pos with undetectable viral load - consider 2 drug regimen
If detectable or unknown viral load - 3 drug regimen
Most common
1. Opportunistic infection in HIV
2. Respiratory infection in HIV
3. Opportunistic respiratory infection in HIV
4. Most common CNS infection in HIV
- Oesophageal candidiasis
- Streptococcus CAP
- PJP
- Toxoplasma encephalitis
How CD4 count relate to which opportunistic infections are more likely to occur?
Respiratory infections in HIV
What infectious disease prophylaxis should a patient with HIV receive?
- CD4 count <200 - Bactrim for PJP prophylaxis & toxo prophylaxis
- CD4 count <100 - fluconazole for fungal / cryptococcal prophylaxis
- CD4 count <50 - azithromycin 1g weekly for MAC prophylaxis
Summary of PJP in HIV
-PJP caused by Pneumocytis jirovecii (unicellular fungus)
- most common opportunistic respiratory infection in AIDs
- airborne transmission
- usually if CD4 <200 & not on ART.
- Start Bactrim prophylaxis when CD4 <200 - thrice weekly vs daily are equally effective
- subacute progressive exertional dyspnoea is the presentation in 91%
- CXR - fine reticular nodular changes with apical & basal sparing
- HRCT - ground glass changes, predominantly apical
- PJP commonly found in healthy lungs - positive PCR does not always indicate infection
- Sputum PJP PCR - low sensitive 50-90%; 99% specific
- bronchial washings - diagnostic yield > 90%
- Serum beta D glucan - elevated levels of 1,3, beta D glucan suggestive of invasive fungal infection (PJP or Aspergillus)
- LDH usually elevated
Bactrim is 1st line Rx - fungus cannot produce its own folate. Does not have ergosterol in its cell wall - therefore cannot use azoles, polyene antifungals or echinocandins
Patients with HIV 100x more likely to get SJS from Bactrim
Steroids if hypoxia, PAO2 <70, improve mortality
Expect clinical improvement in 4-8 days after starting Rx
Best prognostic indicator for survival is level of oxygenation at time of diagnosis
Alternatives to Bactrim - atovaquone, dapsone, pentamidine
After 21 day course of Rx - continue at prophylactic dose till undetectable viral load and CD4 count >200 for at least 3 months
Do not need to delay ART - just start steroids
HIV-associated CNS lesions with mass effect
Toxoplasma encephalitis
Primary CNS lymphoma
Tuberculoma
HIV-associated CNS lesions without mass effect
Progressive multifocal leukoencephalopathy
HIV encephalopathy
CMV encephalitis
CNS lesions in HIV by CD4 count
CD4 >500 - same as immunocompetent hosts - benign & malignant brain tumours
CD4 200-500 - HIV associated cognitive & motor disorders
CD4 <200
- CNS mass lesions most common - primary CNS lymphoma
Opportunistic infections - toxo, PML, CMV
HIV encephalopathy (HAND)
Leading DDx for CNS lesion in HIV positive patient with advanced immunosuppression - toxo, primary CNS lymphoma, PML
Summary of toxoplasma gondii infections in HIV patients
- most common CNS infection who are not on ART; usually when CD4 <100
- toxoplasma gondii = intracellular parasite
- asymptomatic in immunocompetent - > latent infection which can last lifelong
- transmission through ingestion of infectious oocytes in cat litter, soil, contaminated feline faeces, undercooked meat from infected animal
- parasite remains latent in brain, eyes, myocardium & skeletal muscle
- Bactrim prophylaxis for PJP is also effective for toxo
- presentation - headache, fever, confusion, focal neurology, seizures
MRI - multiple ring enhancing lesions with surrounding oedema + mass effect (single lesions can rarely occur with TE BUT usually solitary large >4cm lesions more suspicious for primary CNS lymphoma)
Lesions in posterior fossa more likely TE / infection rather than CNS lymphoma. CNS lymphoma more commonly in corpus callosum, periventricular or periependymal areas
CSF toxo PCR positive
Management - sulfadiazine + pyrimethamine + leucovorin for 2 weeks (then ART 2 weeks later)
Can also use clinda instead of sulfadiazine
Can consider a 2 week trial of rx in someone with multiple ring enhancing lesions
should see clinical & radiological improvement in 2 weeks
What virus is associated with CNS lymphoma in HIV patients?
EBV
Check for EBV DNA in CSF
Summary of cryptococcal meningitis in HIV
-risk increases when CD4 count <100 - start fluconazole
-presents with subacute / chronic headache, fever, mild confusion / behavioural changes, meningism occurs late
-diagnosis on LP - raised opening pressure, lymphocytosis, low glucose, high protein, **India ink stain positive, cryptococcal antigen positive **
Management
- therapeutic LP for ICH
- high dose amphotericin + flucytosine for 2 weeks (flucytosine has survival benefit)
- followed by high dose fluconazole 800mg daily for 8 weeks
- secondary prophylaxis till CD4 count >100 and suppressed viral load for 3 months
IRIS can occur
- fevers, seizures, new CN palsies, new MRI lesions - KEY Is that all cultures negative
- other signs can include LNadenopathy, dry cough
Mx - NSAIDs, pred
CMV infections in HIV
CMV encephalitis / retinitis - AIDS defining illness in advanced immunosuppression
MRI - diffuse micronodular encephalitis
CMV retinitis is not an indication for Rx unless organ disease
Immediate sight-threatening lesion - ARV, IV ganciclovir, intravitreal ganciclovir
Small peripheral lesion - ARV, oral valganciclovir
Summary of PML in HIV
=progressive multifocal leukoencephalopathy
- caused by reactivation of JC virus (polyoma virus)
- asymptomatic primary infection in childhood - remains latent in kidneys and lymphoid organs
- can reactivate when CD4 <200 -> attacks myelin
- Presentation - rapidly progressive neurological deficits including hemiparesis, visual field defects, ataxia, aphasia, cog impairment
- **MRI - **- white matter lesions, multifocal demyelination, NOT contrast enhancing, no mass effect, in periventricular & subcortical white matter
- CSF JC virus PCR positive - but negative PCR does not exclude diagnosis
What are the features of HIV encephalopathy?
Memory & psychomotor speed impairment
Depressive Sx
Movement disorders
Multiple hyperintense T2 weighted images
Non-enhancing
Usually symmetrical and less well-demarcated compared to PML
How does MAC present in HIV positive patients?
- Disseminated MAC is an AIDS defining illness - associated with advanced immunosuppression CD4 count <50
- presents with systemic Sx - MAC does not present with isolated pulmonary infection in immunosuppressed patients
- Management - ethambutol, clarithromycin +/- rifamycin
How does TB present in HIV positive patients?
Co-infection is common - risk of acquiring TB is 9-16x higher if you have HIV
Presents with atypical infection if CD4 <200
- typical upper lobe cavitation only seen in 20-30% patients (more common if CD4 count >200)
Can instead present atypically with intrathoracic adenopathy, lower lobe opacities, pleural effusions
How does melioidosis present in HIV?
-Melioidosis is caused by Burkholderia Pseudomallei - gram negative intracellular organism
Widely distributed in water & soil - hyperendemic regions in North Australia associated with seasonable peaks / wet season. Majority of cases from SE Asia
-Transmission vai percutaneous innoculation tosoil or contaminated H20
Most infections are subclinical
Most comon clinical presentation is pneumonia
CXR shows discrete, patchy, lobar or multilobar consolidation, necrotising lesions, effusions. - can lead to fibrotic changes mimicking TB in chronic meliodosis
Mx - meropenem or ceftazidime
How does IRIS present?
Organisms associated with ART include MAC, TB, CMV, cryptococcus, HHV-8, HSV, HBV
What are the types of IRIS & when do they present?
IRIS = immune reconstitution inflammatory syndrome
- paradoxical IRIS - previously well-treated infection flares post ART
- Unmasking IRIS - previously unrecognised infection becomes apparent after ART
Typically occurs within 6 weeks of starting ART
IRIS may develop faster with integrase inhibitors
How should IRIS be managed?
Continue ART
Treat underlying infection
Give steroids for severe symptoms
What ART drugs are associated with increased CV risk?
- Abacavir (NRTI) - possible association with increased risk of MI
- Protease inhibitors - have shown to increase CV risk, associated with dyslipidaemia, insulin resistance and lipodystrophy
Lopinavir / ritonavir and indinavir - no longer used
Atazanavir & darunavir - more commonly used PIs and less CV risk
*However, discontinuation of ART is associated with an even higher risk of CV events
What are the drug interactions between ART and statins?
Protease inhibitors inhibit CYP3A4 - can result in reduced metabolism of statins & severe rhabdo
-Simvastatin is contraindicated with protease inhibitors
Pravastatin does not interact with PIs
Atorvastatin & rosuvastatin only partially metabolised bY CYP3A4 and can be used at reduced dose
Why do patients with HIV have increased CV risk?
-CVD is an important cause of death in HIV patients (incidence of AIDS related death now decreasing since the advent of ART)
HIV causes chronic inflammatory state that damages coronary endothelium
Traditional CV RFs - smoking, HTN
ART related effects
HIV decreases HDL, increases LDL and trigs irrespective of HAART
HIV positive men - 6 x increased risk of CVD, 2 x increased in women
What antibodies is anti-voltage gated K channel encephalitis associated with?
Anti-LG-1 and Anti-Caspr2 Abs
What antibodies are associated with paraneoplastic limbic encephalitis?
Mostly T cell mediated
- Anti-Hu - SCLC
- Anti-Ma-2 - testicular Ca
How is HSV encephalitis diagnosed?
- CSF HSV PCR - HSV PCR is 96% specific
- CSF shows lymphocyte predominance - but can have neutrophilia in early HSV encephalitis, or enterovirus & mumps encephalitis
Mildly elevated protein
Normal glucose - MRI - asymmetrical temporal inflammation
Paraneoplastic encephalitis - limb inflammation
EBV, CMV, enteroviruses - changes in cerebellum - EEG- high amplitude slow waves over temproal regions; can aid diagnosis, sensitive but NOT specific
Key facts about anti-NMDA receptor encephalitis
Antibody-mediated autoimmune encephalitis
- Abs against NMDA receptor - NMDA important for thought & memory
- Strong association with ovarian teratoma in young women
- also associated with HSV
- Initial symptoms often hallucinations & delusions (may be mistaken for psychiatric illness)
- Seizures, dysautonomia, memory loss & movement disorders develop 1-2 weeks later
- Anti-NMDA-R Abs in plasma or CSF - CSF much more sensitive
- MX - immunosuppression, IVIG, plasma exchange
Key facts about ADEM
ADEM = acute disseminated encephalomyelitis
- type of autoimmune encephalitis - inflammatory demyelinating encephalopathy
- often mimics MS
- most common in children
- USUALLY PRECEDED BY INFECTION - strong association with measles infection ro vaccination
- anti-MOG Ab in serum = anti-myelin oligodendrocyte glycoprotein
- MRI - diffuse white matter lesions, perivascular inflammation & demyelination
- EEG - diffuse slowing
- Rx - methylpred
AHLE - acute haemorrhagic leuco-encephalopathy
- severe & rapidly progressive ADEM
- with necrotising vasculitis
What infections are stereotypically associated with specific animal exposure?
Rat - leptospirosis
Cat - bartonella
Birds - chlamydia psittaci
Animal bites - rabies
Ticks - Rickettsia
What are the causes of bacterial meningitis in people >60 yrs and <60 yrs.?
Most common cause in all age groups is Strep pneumoniae
2nd most common cause in <60 yrs - Neisseria meningitidis
2nd most common cause in > 60 yrs - Listeria monocytogenes
Other common causes - Haemophilus influenzae, Strep agalactiae
What is the most common cause of aseptic meningitis?
Enteroviruses - coxsackievirus, echovirus etc.
What is the most common cause of recurrent meningitis?
Recurrent (Mollaret’s) meningitis - form of benign recurrent lymphocytic meningitis
- defined as 3 or more episodes of fever with meningism - that spontaneously resolves within 2-5 days
- most common cause is HSV-2
While most HSV encephalitis is HSV1, HSV meningitis is usually HSV2
85% have genital lesions at the time
What organisms cause healthcare-associated meningitis? What is the appropriate empiric therapy for healthcare-associated meningitis?
Healthcare-associated meningitis - occurs soon after cranial or spinal surgery or cranial trauma; OR any time point after insertion of a ventricular shunt
Causative organism
- MC gram neg bacteria including Pseudomonas 33%
- Staph (aureus & coagulase neg) - 18%
- Strep pneumoniae, L.monocytogenes & Neisseria meningitidis - only 8% combined
Empiric therapy - anti-pseudomonal beta lactam PLUS vancomycin
What proportion of Strep pneumoniae is penicillin or cephalosporin resistant?
- Approx. 10% of Strep pneumoniae is penicillin resistant due to the PBP2x protein
if MIC <0.125 = susceptible - 2% of Strep pneumoniae has intermediate susceptibility or is resistant to 3rd gen cephalosporins e.g. ceftriaxone
If MIC <1 - susceptible
MIC 1-2 - intermediate susceptibility
MIC >4 - resistant
What proportion of Neisseria meningitidis is resistant to penicillins or cephalosporins?
6-13% resistant to penicillin
90% intermediate susceptibility to penicillin
0% resistant to ceftriaxone
In patients receiving empiric therapy for acute meningitis, which patients should also receive empiric cover for Listeria monocytogenes?
Extremes of age
> 50 yrs.
ESRF, cirrhosis, diabetes, alcoholism, steroids or other immunosuppressive agents, malignancy, HIV/AIDS, organ transplantation, pregnant, children
IV benpen 2.4g Q4H or Bactrim IV 960mg q6h
For which patients should we add IV vancomycin to the empiric therapy for acute meningitis?
For patients at risk of ceftriaxone-resistant pneumococcal meningitis
- because 2% of Strep pneumoniae is resistant or has intermediate susceptibility to ceftriaxone
Patients who should receive vancomycin in addition to ceftriaxone:
-gram positive diplococci on gram stain
-CSF pneumococcal antigen positive -> BETTER than gram stain & culture for pneumococcus - >95% specific, >85% sensitive
-otitis media, sinusitis
-recent beta-lactam treatment
What is the empiric therapy for acute meningitis?
What is the role for steroids in the management of acute meningitis?
- Dexamethasone reduces neurological morbidity & mortality (ESP CN VIII / prevents hearing loss) in patients with pneumococcal meningitis
- MUST give BEFORE antibiotics
- reduces the inflammatory response from antibiotic mediated bacteriolysis
-Reduces CNS inflammation & oedema
Continue IV dex 10mg QID for 4 days in pneumococcal meningitis
If diagnosed as Neisseria meningitidis meningitis - cease dex as no benefit
Directed therapy for acute bacterial meningitis
What is the empiric therapy for infective endocarditis?
Ceftriaxone, benzylpenicillin, flucloxacillin
If MRSA suspected or in patients with fulminant endocarditis, replace benpen with vanc
In IVDU or hospital acquired - empiric Rx is vanc plus gent
Empiric therapy for prosthetic valve or pacemaker lead IE - fluclox, vanc, gent
What are the common causes of infective endocarditis?
- Staph aureus is the most common cause of native & prosthetic valve endocarditis. More aggressive - associated with higher rates of embolisation & stroke, prolonged bacteraemia & higher mortality - 31%
- Virdians Streptococci - 17%
- Enterococcus -11%
- Coagulase neg staph (including staph lugdenesis) - 11%
- Staph bovis / gallolyticus - 7%
- Non-HACEK GNs
- HACEK - haemophilus parainfluenzae, aggregatibacter, cardiobacterium, eikenella, kingella
- Fungi
Prosthetic valve IE within 12 months of valve replacement - CoNS including Staph Lugdenesis is an important cause. CoNS often methicillin resistant
After 2 months - causes same as for native ie
In IVDU - R) sided IE is due to Staph aureus
L) sided IE - pseudomonas, candida, bacillus
Directed therapy for Streptococcal, enterococcal and HACEK IE
- HACEK IE - IV ceftriaxone for 4-6 weeks
- Enterococcal IE (vast majority is E.faecalis) - use gent for synergy. Benpen or amoxicillin / ampicillin PLUS gent. if high level aminoglycoside resistance or gent contrainidcated - use ceftriaxone alongside ampicillin
- Streptococcal IE - use benpen if penicillin MIC <2 PLUS gent
If MIC >2 - vanc plus gent
What organisms cause necrotising SSTI?
- Type 1 = polymicrobial; type 2 = monomicrobial
What is the empiric & directed therapy for necrotising fasciitis?
What is the role of clindamycin?
Empiric therapy WITHOUT water exposure - IV taz or mero + IV vanc + IV clinda or lincomycin
Empiric therapy WITH water exposure is different bc risk of Aeromonas infection which often produces carbapenemases
IV mero plus IV clinda or lincomycin plus IV vanc plus IV cipro
IV clinda is a helpful adjunct in patients with necrotising SSTI who have sepsis or shock - reduces production of toxins by GAS (M protein). No benefit in patients with sepsis or shock
Directed therapies:
GAS - IV benpen plus clinda plus IVIG
Role of IVIG controversial
Clostridium - benpen plus clinda
Community acquired MRSA - IV vanc PLUS clinda
When should tetanus vaccination & immunoglobulin given in patients with traumatic wounds?
Give tetanus vaccine if >5 yrs. since last or 3rd dose of tetanus toxoid vaccine
If 5-10 yrs since last tetanus vaccine but only minor clean wound - nil need for vax
Tetanus immunoglobulin indicated if significant wound AND not fully vaccinated (i.e. has not received 3 days OR history unknown)
What clinical features are suggestive of osteomyelitis in a patient with with a diabetic foot ulcer?
- bone to probe
- visible bone
- ESR > 70
- > ulcer duration > 2 weeks
- ulcer size > 2cm2
- presence of a “sausage” toe with erythema & non-pitting oedema that obliterates the normal contour of the digit
Definitive diagnosis - isolation of bacteria from a bone biopsy
What microorganisms cause diabetic foot ulcers?
Acute infection - in patients who have not recently had antibiotics - staph aureus or streptococci
Chronic diabetic foot infections - often polymicrobial, combination of gram positive & negative aerobic & anaerobic infections
Superficial diabetic foot infections (cellulitis, infected ulcer) - often caused by aerobic gram positive cocci - Staph aureus, CoNS, strep pyogenes, strep agalacticae
Deep chronically infected ulcers - often polymicrobial
- gram positive aerobic cocci - Staph aureus, Strep pyogenes, Strep agalacticae, CoNS
- enterococci
- enterobactericae
- Pseudomonas - often colonises but not necessarily the primary pathogenic organism
- Anaerobes
MRSA - particularly in patients with previous MRSA infection or colonisation; previous Abx use, recent hospitalisation or living in care facility
What is the empiric therapy for diabetic foot ulcers?
- Mild infection - no evidence of OM, SA
- dicloxacillin or fluclox to cover OR cephalexin to cover Staph aureus & beta haemolytic strep
- if concerned re MRSA - add clinda, bactrim, linezolid OR cephalexin + bactrim or doxy
- if no response within 1 week - broaden cover to include MRSA, anarobes & aerobic GNRs with bactrim + Aug DF OR moxifloxacin OR clinda plus cipro
- duration 1-2 weeks - Moderate / deep infection - cover Staph aureus, beta haemolytic Strep, aerobic GNRs, anaerobes
IV Augmentin OR IV cephazolin plus metronidazole
2-4 weeks if no OM
6 weeks if OM - Severe / limb-threatening infection
Signs of shock, bacteraemia, systemic toxicity, marked necrosis or gangrene, ulceration of deep tissue, severe cellulitis, **presence of OM or septic arthritis **
- tazocin OR
- meropenem OR
- Metro & ceft OR ceftazidime OR cipro
if penicillin allergy - clinda plus cipro
Add vanc, linezolid, daptomycin for MRSA cover
What microorganisms cause cellulitis?
Most commonly - staph aureus, beta haemolytic strep (strep pyogenes, strep dysagalacticae)
Gram negative rods - cirrhosis, abdominal wall or groin cellulitis, immunosuppressed, chronic leg ulceration
Vibrio vulmiticus - blistering cellulitis caused by eating oysters
Pasteurella - dog / cat bites
Are PO and IV antibiotics equally effective for cellulitis?
Yes
Indications for IV therapy
- evidence of sepsis
- comorbidities that increase risk of treatment failure - obesity, chronic venous insufficiency, peripheral vascular disease, heart failure, multiple previous episodes of cellulitis
- failure of PO Abx
Scabies - key facts
Caused by mite Sarcoptes scabei
Can live outside host for 24-36 hrs
Transmission requires prolonged direct skin contact
Key Sx is itch - often worse at night
Incubation period for primary infection 4-6 weeks
Small erythematous papules, burrows - thin red or brown lines
Clinical diagnosis usually
Often do not need skin biopsy
Can do skin scrapings
1st line Rx - topical permethrin
2nd line - oral ivermectin
Gonoccal septic arthritis summary
- caused by gram neg diplococci - Neisseria gonorrhoea
- in younger <40 yrs sexually active patients
- occurs due to haematogenous / bacteraemic spread of STI
- Urethritis / local genitourinary infection precedes disseminated infection
- can present as purulent septic arthritis (monoarticular OR oligoarticular) - typically involving distal joints - ankles, wrists, knees
OR
presents as arthritis -dermatitis syndrome - migratory polyarthralgia without purulent arthritis, dermatitis - painless pustular or vesicopustular lesions - 2-10 on distal extremities AND tenosynovitis
- definitive Dx via detection of N.gonorrhoea in blood, synovisual fluid, tissue, skin lesion (NON-mucosal sites) with NAAT testing or culture
- mean synovial leukocyte count approx 50,000
- cultures positive in 50% purulent arthritis, less in those with arthritis - dermatitis syndrome
Rx - IV ceftriaxone 1g daily for 1-2 days then consider de-escalation
Which groups are more likely to have gram negative causes of septic arthritis?
IVDU
Extremes of age
Immunosuppression
Trauma
What are the causes of native and prosthetic joint septic arthritis?
- Native septic arthritis
- staph aureus - presents typically, but can be polyarticular, may be less painful if taking PO Abx in community
- Low virulence organisms e.g. N. gonorrhoea may have less pain - may be missed - Periprosthetic joint infection
- eary infection <3 months - staph aureus vs staph epidermidis
- late infection
If caused by low virulence organisms e.g. Staph epidermidis - may be asymptomatic & found incidentally on imaging for chronic mild pain
High virulence organisms - staph aureus; present typically
How is a definitive diagnosis of septic arthritis made?
Empiric & directed therapy for septic arthritis
What is the gold standard for osteomyelitis diagnosis?
Bone biopsy - surgical sampling
- inflamm markers not always up - in low grade infections, compromised hosts or early infection
- prone to bone test
- imaging - XR changes can take 6/52 to develop, MRI changes can take up to 1 week - MRI may exclude epidural abscess but will not show discitis / osteomyelitis very early on
- surgical sampling is gold standard
WCC <50,000 - 5% infected
50,000-100,000 - 33% infected
>100,000 50% infected
presence of sinus tract confirms infection
Empiric & targeted antibiotic therapy for osteomyelitis
What are the adverse effects associated with Linezolid?
Myelosuppression - reversible, particularly anaemia & thrombocytopenia. Associated with duration of therapy
Serotonin syndrome
Taste change
LFT derangement
Inhibition of mitochondrial protein synthesis can result in optic neuropathy & peripheral neuropathy which may be irreversible; anaemia & lactic acidosis
What is the mechanism of action of Linezolid?
Inhibition of protein synthesis
Binds to 50S ribosomal unit - prevents formation of functional 70S ribosomal complex
What antibiotics are associated with Clostridium difficile infections?
Commonly associated Abx:
- Fluoroquinolones - use of broad-spectrum quinolones e.g. moxifloxacin is associated with hypervirulent strains e.g. PCR ribotype 027 and 078)
-Clindamycin (Lincosamides)
-broad spectrum penicillins & combinations
-2nd, 3rd, 4th generation cephalosporins
-carbapenemes
Rarely associated:
- Aminoglycosides
- Tetracyclines
- Tigecycline
- metro
- vanc
- chloramphenicol
-nitrofurantoin
Risk factors for C.difficile infection
Risk factors for recurrent C. difficile infection
Risk factors for complications of CDI - toxic megacolon, perforation, colectomy, admission to ICU or death
RFs for CDI infection
- Abx use is most important risk factors
-advanced age - VERY important
-hospitalisation
- severe comorbid illness
- cancer chemotherapy
- PPI
RFs for recurrent CDI
- age > 65 yrs.
-severe underlying medical disorders
-need for ongoing Abx therapy during treatment for CDI
- renal impairment
- lack of Ab respsonse to CD toxins - especially toxin B
RFs for complications from CDI
-older age
-abnormal blood tests - elevated WCC, low albumin, elevated urea, elevated CRP, abnormal vital signs
** PPI use also associated with increased risk of CDI
Management of CDI
First episode mild-mod CDI
-metro 400mg PO TDS for 10 days OR vanc 125mg PO QID for 10 days - metro preferred for stewardship although equally effective
Severe CDI
Any of the following features - leucocytosis, high fever, severe abdominal pain, organ dysfunction, elevation Cr, elevated lactate
PO vanc 125mg QID for 10 days
IV vanc -> inadequate colonic penetration
Evidence to suggest that fidaxomicin is associated with lower rates of recurrence compared to vanc but insufficient data for severe disease
IF shock / hypotension, ileus or megacolon
Add IV metro 500mg TDS to vanc for 10 days
Consider intracolonic vanc - especially if ileus
Early surgical referral as poor outcomes after organ dysfunction established
Recent data show lower mortality in patients with severe CDI treated with FMT
Role of bezlotoxumab - monoclonal Ab against CD toxin B not yet defined - NEJM trial 2017 showed lower rate of recurrence compared to placebo
First recurrence or refractory disease
Recurrence = within 2 months of last infection after resolution of first episode.
Refractory = no improvement after 3-4 days therapy
PO vanc 125mg QID for 10 days
Fidaxomicin 200mg PO BD for 10 days
IV vanc cannot be used due to inadequate penetration into lumen
Second or subsequent recurrence or ongoing refractory disease
- FMT is the preferred therapy for 2nd recurrence or ongoing refractory disease
FMT via nasoduodenal tube is superior to vancomycin in patients with recurrent CDI
If FMT not available - vanc or fidaxomicin as above
**NOTE CDT stool tests can remain positive for >1 month post effective therapy - repeat testing only indicated for symptomatic patients
What are the indications for surgery in infective endocarditis?
Surgery: removal of vegetation and repair/replacement of valve
Only if:
# Heart failure due to valvular dysfunction or perforation
- Refractory pulmonary oedema or cardiac shock due to aortic valve or mitral valve dysfunction, obstruction, fistula or shunt
- Severe Aortic or mitral regurgitation or dysfunction with poorly compensated haemodynamic function
Uncontrolled endocardial infection
- Fungal pathogen
- Multi-drug resistant pathogen - MRSA, VRE
- Paravalvular extension with abscess, fistula or heart block
- Persistently positive blood cultures for 6-7 days despite adequate antibiotics - persistent bacteraemia
- Partially dehisced prosthetic valve
Prevention of systemic embolization
Vegetation >10mm when accompanied by >1 embolic event while receiving therapy
What are appropriate oral options for the treatment of MRSA skin & soft issue infections?
Preferred agents:
Bactrim 1-2 DS tabs BD
Clindamycin 450mg TDS
Doxycyline 100mg BD
Minocycline - 200mg once, then 100mg daily
For empiric therapy Bactrim & Clindamycin would be preferred as also effective against GAS - doxy is not
Alternative agents:
Linezolid 600mg BD
Tedizolid
Delafloxacin
Omadacycline
What are appropriate intravenous options for the treatment of MRSA?
Antibiotics of choice:
Vancomycin 15-20mg/kg/dose every 8-12 hours
Daptomycin 4-6mg once daily
Alternate agents
- with PO or IV dosing
Linezolid
Tedizolid
Delafloxacin
Omadacycline
- short acting with IV dosing
Ceftaroline - 5th gen cephalosporin
Telavancin - synthetic derivative of vancomycin; lipoglycopeptide Abx - long acting with IV dosing
Dalbavancin & Oritavancin - synthetic vancomycin derivatives - lipoglycopeptide Abx
What is the mechanism of action of daptomycin and what microorganisms does it treat?
-Bactericidal lipopeptide antibiotic - distinct mechanism of action to vancomycin
-binds to cell membrane -> causes formation of oligomeric complexes -> creates pores & channels that disrupt thebacterial cell membrane
Daptomycin is non-inferior to Vancomycin for staph aureus bacteraemia
May be more effective than vancomycin if vancomycin MIC > 1-2 microg/ml
Should not be used for MRSA pneumonia as is inactivated by surfactant
Only effective for gram positive organisms
Cannot penetrate the outer membrane of gram negative bacteria effectively
Also effective against VRE
Daptomycin susceptibility testing must be conducted before using as therapy as MIC can be influenced by prior exposure to vancomycin
Adverse effects
Myopathy - weekly CK level
Peripheral neuropathy
Eosinophilic pneumonia
Which underlying cardiac lesions require Abx prophylaxis when underdoing dental procedures?
Prophylaxis
As per eTG, antibiotic prophylaxis is only indicated in certain conditions
- Mechanical valve/prosthetic material
- Previous IE
- Uncorrected congenital defects → cyanotic
- Rheumatic heart disease
and certain settings
- Dental
- Dermatological if infected
- Gastrointestinal if active infection
- Respiratory/ENT for tonsils/adenoids or biopsy of the respiratory mucosa
- Genitourinary if active infection
What is the significance of the C. difficile PCR ribotype 027?
C.difficile normally produces toxin A (enterotoxin) and toxin B (cytotoxin)
- toxin A increases endothelial permability & apoptosis leading to diarrhoea
- toxin B is 10x more potent than toxin A and is a major virulence factor for C.difficile
Hypervirulent PCR ribotype 027 - associated with severe outbreaks
Produces toxin A & B in increased amounts
But also produces a binary toxin - which is not produced by C.difficile normally
Also characterised by fluoroquinolone resistance
Associated with more severe disease including toxic megacolon, ICU admission, death etc.
Increased rates of recurrence and lower rates of cure
What is the most sensitive and earliest test that can be used for HIV infection?
HIV RNA viral load - can be detected 9-11 days after exposure - most sensitive & earliest test for acute HIV infection (can detect HIV prior to seroconversion)
HIV antibody test - most commonly used for screening - however, can take weeks- months to become positive
p24 antigen can detect HIV prior to antibody tests - however, HIV RNA becomes detectable prior to p24 antigen. p24 antigen can also decrease & become undetectable after seroconversion
What is the strongest predictor of HIV disease progression at all stages of HIV infection?
HIV viral load - predicts progression to AIDS and mortality
HIV viral load is a stronger predictor than CD4 count
CD38 expression on CD8 cytotoxic T cells is also associated with disease progression
What mutation is associated with resistance to HIV infection?
CCR5 delta 32 homozygous mutation inhibits HIV entry into cells due to reduced CCR5 expression on macrophages & T cells -> people with this mutation are strongly resistant to acquiring HIV
CCR5 delta 32 heterozygosity is associated with slower progression to AIDS
What vaccines are required post splenectomy?
- Influenza vaccine - take twice in the year post splenectomy
- PCV13 (conjugated pneumococcal vaccine) - single dose. After 12 months - 2 x doses of PPV23 five years apart. MUST not take the PPV23 vaccine before the PCV13 vaccine due to risk of vaccine hyperresponsiveness
Either 2 weeks before splenectomy or 1 week post - MenACWY x 2 doses eight weeks apart (conjugated vaccine)
Men B vaccine
-> Bexsero - 2x doses 8 weeks apart + 1 x booster 5 years later
-> Trumenba - 3 x doses + booster 5 years later - Haemophilus influenza B at least once in lifetime
Why does asplenism / hyposplenism increase the risk of infection with encapsulated organisms?
Spleen mediated the IgM response against encapsulated bacteria
Without IgM response - CLASSICAL COMPLEMENT pathway is NOT activated - polysaccharide encapsulated bacteria are not opsonised or phagcytosed
What does this blood film show?
Howell-Jolly bodies seen in hyposplenism / asplenia
- basophilic bodies that contain nuclear remnants that are normally removed by the spleen
What are the risk factors for overwhelming post splenectomy infection?
Extremes of age - > 50 yrs OR <5 yrs.
Splenectomy due to haematologic conditions - e.g. beta thalassaemia, sickle cell, Hodgkin’s lymphoma, ITP, spherocytosis ; associated with higher risk of OPSI than traumatic spleen removal
risk of OPSI is highest in first 1-3 years post splenectomy
-50% of OPSI occurs in the first 3 yrs. post splenectomy
What is the recommended duration of antibiotic therapy in Staph aureus bacteraemia?
2 weeks IV minimum
4-6 weeks IV if complicated infection
Complicated infection =
1. a positive blood culture result 48 hours after starting appropriate antibiotics
2. fever 72 hours after starting appropriate antibiotics
3. abnormal valvular morphology or evidence of valvular lesions, regurgitation or endocarditis on transthoracic echocardiogram (TTE) or transoesophageal echocardiogram (TOE)
4. no identifiable source of infection or an identifiable source of infection that has not been addressed
5. evidence of metastatic infection (eg vertebral osteomyelitis, endocarditis)
6. intravascular prosthetic material (eg pacemaker, prosthetic cardiac valve, prosthetic arteriovenous graft).
What is the 1st line antifungal therapy for each of the following conditions;
1) Aspergillosis
2) Mucutaneous / oral / oesophageal candidiasis
3) invasive candidiasis
4) Cryptococcal meningitis
5) Histoplasmosis
6) Zygomycosis
1) Aspergillosis - voriconazole
2) Oral / oesophageal candidiasis - fluconazole.
3) Invasive candidiasis - echinocandins
4) Cryptoccal meningitis - amphotericin B + flucytosine. Consolidation with fluconazole
5) Histoplasmosis - amphotericin B
6) Zygomycosis - amphotericin B
Spectrum of anti-fungal activity
Mechanism of action of antifungal therapy:
1) Azoles
2) Polyenes
3) Echinocandins
1) Azoles - inhibit 14 alpha demethylase (a cytochrome p450 enzyme) which converts lanosterol to **ergosterol ** -> disrupts **cell membrane integrity ** -> **inhibition of fungal growth ** (i.e. generally fungistatic)
2) Polyenes - bind to ergosterol in cell membrane -> pore formation -> generally fungicidal
3) Echinocandins - disrupts fungal cell wall. Inhibits beta 1,3, D-glucan synthase which cross-links beta glucans which are polysaccharide polymers that form the fungal cell wall. Generally fungicidal (fungicidal to Candida, fungistatic to Aspergillus)
What are the indications for echinocandin use?
Invasive candidiasis
Invasive aspergillosis
Candida parapsilosis is resistant to caspofungin
**Fungicidal to candida
Fungistatic to Aspergillus **
What are the adverse effects of echinocandins?
- mild side effects from histamine release - flushing, GI side effects, rash
-
Hepatotoxic - caspofungin
Caspofungin metabolised by liver - hydrolysis and N-acetylation & undergoes spontaneous degeration THEREFORE dose adjust in hepatic failure. Anidulafungin is degraded slowly by chemical hydrolysis - does NOT rely on hepatic or renal excretion. - cannot use in pregnancy
Only available IV - poor CNS & renal penetration
Potential drug interactions
- anti-retroviral agents
- rifampicin
- phenytoin, carbamazepine
- cyclosporin, tacrolimus
What are the drug interactions associated with azole antifungals?
Azoles are **CYP3A4 inhibitors **
Therefore, can increase levels of:
- Warfarin
- Statins
- Citalopram, escitalopram
- tacrolimus, sirolimus, everolimus
- fentanyl, methadone, oxycodone
- erythromycin
- many tyrosine kinase inhibitors
- phenytoin
What are the adverse effects associated with azole antifungals?
- Hepatotoxicity
30% patients develop LFT derangement with voriconazole - Drug interactions due to CYP3A4 inhibition
- Inhibition of androgen synthesis -> gynaecomastia, infertility
- Voriconazole - visual disturbance, photosensitivity
Cutaneous fungal infections
Indications for specific azole drugs
- Voriconazole - Aspergillosis, Scedosporium. Needs tDM.
- Isavuconazole - broadest spectrum of action; safe in ESRF / CLD. Does not require TDM. PO & IV options. Indications - candida, aspergillus, **zygomycosis **
- Posaconazole - can be used as prophylaxis in patients at very high risk of fungal infections (e.g. AML, allogeneic HSCT etc.). Broader spectrum against candida & moulds. Needs TDM
- Fluconazole
- acute or recurrent mucucutaneous candidiasis
- vulvovaginal candidiasis where topical therapy has failed
- Candidaemia due to susceptibel strains
- not effective against Candida Krusei - complete resistance
- dose dependent efficacy against Candida glabrata
- Tinea corporis, cruris or pedis resistant to topical therapy
- cryptococcus consolidatiion therapy
- coccidioidomycosis
- histoplasmosis
Adverse effects & indications of polyene antifungals
Polyenes - broadest spectrum antifungal; good CNS & wide tissue penetration
Amphotericin B - good for cryptococcal meningitis, resistant bacteraemia
Adverse effects
- nephrotoxicity
- infusion related side effects - fevers, hypotension, rigours, bronchospasm, arthralgias / myalgias, tachycardia, vomiting
Liposomal amphotericin - slightly less AEs - HOWEVER, still use echinocandins in preference - echinocandins are non-inferior for invasive candidaemia
What are the options for antifungal prophylaxis in immunocompromised patients?
Fluconazole - against invasive and mucosal candidiasis
Posaconazole - against candidiasis, aspergillus and moulds; indications -AML, graft vs host disease
Types of immunosuppressants & associated infections
Bactrim is used for PJP prophylaxis. What other infections does Bactrim protect against?
- Toxoplasma gondii
- Nocardia
- Listeria
A patient with Strongyloides hyperinfection syndrome should be tested for which other infection?
HTLV-1 - risk factor for strongyloides hyperinfection
Prevalence of HTLV1 is high amongst indigenous people in Central & Northern Australia
What is the most common route of transmission of HTLV-1 infection?
Primarily vertical transmission
but can also have sexual transmission
Summary of Strongyloides infection
- parasitic / helminthic; caused by Strongyloides stercoralis
- SE Asia, sub-saharan Africa, Northern Australia, Latin America / Carribean
- chronic asymptomatic infection can last decades
- main mode of transmission - skin contact with contaminated soil
- flaviform larvae penetrate skin -> travel to alveoli via blood / lymphatics -> proliferate in alveoli -> ascend endobronchial tree -> swallowed -> mature into adult worms and burrow in duodenum & jejunum
Risk factors for severe Strongyloides infection - defects in cell mediated immunity (HIV, malignancy, ETOH, malnutrition, hypogamma, congenital immunodeficiency)
Clinical presentation
- acute inflammation, petechiae, itch at site where larvae penetrate skin
- evanescent pink tracts as larvae migrate (larva currens)
- urticaria around waist in chronic infection
- dry cough, dyspnoea, wheeze, haemoptysis. Rarely recurrent fever & pneumonitis. Chronic strongyloides can develop asthma that paradoxically worsens wth steroids.
- Duodenitis - leading to upper abdo pain. Chronic enterocolitis & malabsorption from high intestinal worm burden
Risk factors for hyperinfection - corticosteroids, TNF inhibitors
Disseminated disease - kidneys, brain, liver, meninges
Migrating larvae can carry enteric bacteria into blood stream -> sepsis, pneumonia, endocarditis (strep bovis), meningitis
transient eosinophilia seen in majority of chronic infection (not in hyperacute phase)
Stool MCS - higher yield in disseminated / hyperinfection
Serology with ELISA has low specificity
Treatment is 2 x doses of Ivermectin in immunocompetent or 4 x doses in immunosuppressed
Daily ivermectin in hyperinfection
Follow up with repeat serology at 3-6 months
