Micro - Management, Hepatitis Serology, CNS Infections and Congenital/Childhood Infections Flashcards
ABX inhibiting cell wall synthesis
BCG
Beta lactams - penicillin, cephalosporins
Carbapenems (these are also B lactams) - meropenem
Glycopeptides - vancomycin, teicoplanin
ABX inhibiting protein synthesis
TAM
Tetracyclines - tetracycline, doxycycline
Aminoglycosides - gentamycin
Macrolies - erythromycin, clarithromycin
ABX inhibiting nucleic acid synthesis
Quinolones - ciprofloxacin, ofloxacin
Other - metronidazole, trimethoprim, rifampicin
ABX inhibiting folate synthesis
Sulphonamides - trimethoprim?, septrin
Diaminopyrimidines - trimethoprim
Amoxicillin
Beta-Lactams: Penicillins (-cillin)
Cover Gram +ve mainly
Broad-spectrum, covers some Gram –ve (like Haemophilus, enterococci) –> first-line for pneumonia
broken down by β-lactamase produced by S. aureus and many Gram negative organisms
Piperacillin
Beta-Lactams: Penicillins (-cillin)
Cover Gram +ve mainly
Broad-spectrum, covers some Gram –ve (like Haemophilus) –> first-line for pneumonia. COVERS PSEUDOMONAS and other non-enteric gram -ves
broken down by β-lactamase produced by S. aureus and many Gram negative organisms
Ampicillin
Beta-Lactams: Penicillins (-cillin)
Cover Gram +ve mainly
Listeria listeria
Flucloxacillin
Beta-Lactams: Penicillins (-cillin)
Cover Gram +ve mainly
Staph aureus (skin infections)
Less active than penicillin but stable to B-lactamase produced by staph a
Benzylpenicillin
Beta-Lactams: Penicillins (-cillin)
Cover Gram +ve mainly
Group A strep (“sore throat”
Penicillis are often used with
beta-lactamase inhibitors:
Co-amoxiclav = amoxicillin + clavulanic acid
Tazocin = piperacillin + tazobactam
Protect penicillins from enzymatic breakdown and increase coverage to include S. aureus, Gram negatives and anaerobes. V useful for HAI.
What to use if someone is penicillin allergic
Just rash: use cephalosporin (5-10% cross-reactivity)
Anaphylaxis: doxycycline for pneumonia, erythromycin for impetigo
1st Generation Cephalosporins (Beta-Lactams)
(cefalexin): Gram +ve but not –ve
Cefuroxime is 2nd gen
3rd generation Cephalosporins (Beta-Lactams)
(cefotaxime, ceftriaxone, ceftazidime): Gram –ve but not +ve
Used in hospital acquired pneumonia
Cephalosporin management of pseudomonas
Ceftazidime
Cephalosporin management of meningitis
IV ceftriazone
Carbapenems - uses
For severe infections, when beta-lactams would not work
Extended-Spectrum Beta-Lactamases = resistant to beta-lactams
Carbapenemase enzymes becoming more widespread. Multi drug resistant Acinetobacter and Klebsiella species.
Meropenem
Sepsis of unknown origin, severe abdominal infections
Glycopeptides
Gram +ve only
MRSA = vancomycin (IV only)
Oral vancomycin can be used to treat serious C. difficile infection
Slowly bactericidal
Nephrotoxic – hence important to monitor drug levels to prevent accumulation
Aminoglycosides (end in –cin)
- Rapid, concentration-dependent bactericidal action
- Require specific transport mechanisms to enter cells
- Ototoxic & nephrotoxic, therefore must monitor levels
- Synergistic combination with B-lactams
- No activity vs. anaerobes
Gram -ve only
Pseudomonas = gentamycin, tobramycin
Tetracycline (end in –cycline)
- Broad-spectrum agents with activity against intracellular pathogens (e.g. chlamydiae, rickettsiae & mycoplasmas) as well as most conventional bacteria
- Bacteriostatic (stops reproduction)
- Widespread resistance limits usefulness to certain defined situations
- Do not give to children or pregnant women
- Main side-effect: Light-sensitive rash
Intracellular bacteria
Chlamydia = doxycycline
Macrolides (end in –mycin)
Bacteriostatic
Gram +ve –> substitute for penicillin if allergic (vs staph/strep).
Also active against Campylobacter sp and Legionella. Pneumophila
Atypical pneumonia = add clarithromycin to amoxicillin
Oxazolidinones (end in –zolid)
Excellent for Gram +ve (not active against most -ve)
Vancomycin-Resistant Enterococci (VRE) = linezolid
Is expensive, may cause thrombocytopoenia and should be used only with consultant Micro/ID approval. Can cause optic neuritis –> don’t tend to use over long periods (more than 4 weeks).
Nitroimidazole (end in –azole)
Anaerobic bacteria
C. Diff = metronidazole
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
Rx - herpes simplex & HSV encephalitis
HSV:
Aciclovir
2nd line = foscarnet
HSV encephalitis:
On clinical suspicion- Start empiric treatment immediately without waiting for test results
iv ACV 10mg/kg tds
If confirmed, treat for 14 - 21 days
Rx - varicella zoster
Acyclovir
Indications for Rx:
- Chickenpox in adults (risk of complication: pneumonitis)
- Zoster in adults >50 (risk of complication: post-herpetic neuralgia)
- 1o infection or reactivation in the immunocompromised
- Neonatal chickenpox
- If there is an increased risk of complications
Rx - cytomegalovirus (CMV) = immunocompromised
Ganciclovir (IV or vGCV = oral prodrug) Guanosine analogue - inhibits viral DNA synthesis.
Primary infection:
- Latency in blood monocytes and dendritic cells
- Reactivation (eg following immunosuppression)
Asymptomatic shedding in saliva, urine, semen and cervical secretions.
MAJOR pathogen in the immunocompromised (including solid organ and bone marrow transplant patients) – causes marrow suppression, retinitis, pneumonitis, hepatitis, colitis, encephalitis…
Can give:
Ganciclovir(GCV) iv. SEs: bone marrow, renal and hepatic toxicity. Contraindicated in BM suppression (neutropenia).
Valganciclovir (VGC) po
Foscarnet (FOS) iv / intravitreal - Non-competitive inhibitor of viral DNA, polymerase. Use when GCV contraindicated ie neutropenic patients (eg pre-engraftment post-BMT); GCV-resistant CMV; CMV retinitis (intravitreal implants). Nephrotixic.
Cidofovir (CDV) iv - Nucleotide (cytidine) analogue (Competitive inhibitor of viral DNA synthesis). Nephrotoxic - Require hydration + probenicid.
Also maribavir (inhibits viral kinase (UL97), effective in vitro against GCV resistant CMV), letermovir (CMV DNA terminase* inhibitor) - CMV prophylaxis in CMV+ SCT recipients. Give Ganiciclovir with IVIG for CMV pneumonitis
Rx - EBV (infectious mononucleosis, infects B cells- life-long)
Rituximab (anti-CD20) for post-transplant lymphoproliferative disease (reactivation of EBV with immunosuppression)
Rx - Influenza (A&B)
Oseltamivir (“Tamiflu”)
Neuraminidase inhibitor
Inpatients:
Indicated for all patients admitted to hospital due to influenza virus-related respiratory disease
Indicated in the community if all 3 apply (NICE guidance):
- National surveillance indicates influenza is circulating
- Patient is in a ‘risk-group’ *
- Within 48 hours of symptom onset (36 hours for zanamivir)
Peramivir - Neuraminidase inhibitor licensed in US, but also available in UK. H275Y mutation confers reduced susceptibility –> avoid use with oseltamivir resistance
Baloxavir merboxil
Rx - Respiratory Syncytial Virus (RSV) = in young kids
Treat: ribavirin (Guanosine analogue, PO)
Prevent: palivizumab
Rx - Adenovirus = after bone-marrow transplant
Cidofovir
Herd immunity threshold calculation
Herd Immunity threshold = 1 – 1/R0
R0= the average number of people that one sick person will infect. To eliminate a disease the effective R0 needs to be <1.
Herd immunity threshold = percentage of fully immune individuals required to stop the spread of disease.
Live attenuated vaccine
Stimulates all aspects of the immune system e.g. MMR, yellow fever
T cell response important in destroying infected cells.
Advantages:
Single dose often sufficient to induce long-lasting immunity
May stimulate response to multiple protective antigens
Strong immune response evoked
Local and systemic immunity produced – particularly important for infections where CMI plays an important role. Activation of all components of immune system
Disadvantages
Potential to revert to virulence
Can cause illness directly
Contraindicated in immunosuppressed patients
Interference by viruses or vaccines and passive antibody
Poor stability
Potential for contamination
Inactivated vaccine
Need adjuvant to boost immune response e.g. influenza, polio
Whole microorganism destroyed by heat, chemicals, radiation or antibiotics (e.g. Influenza, cholera, polio)
Advantages:
Stable
Constituents clearly defined
Unable to cause the infection
Disadvantages: Need several doses Local reactions commn Adjuvant needed Shorter lasting immunity
Subunit vaccine
Need adjuvant to boost immune response e.g. Hep B, HPV
Protein component of the microorganisms or synthetic virus like particles.
Lacking viral genetic material and unable to replicate.
Viral vector vaccine
Type of cloning –> grow viral proteins which induce immune response
DNA vaccine
Type of cloning –> inject genes encoding viral antigens –> host cells make the antigens (and therefore induce B and T cells)
Virus-like particles vaccine
Type of cloning –> virus which doe snot replicate (so you can give the intact virus)
Toxoid vaccine
Inactivated toxin e.g. tetanus, diptheria
Conjugate vaccine
Poorly immunogenic antigens and highly immunogenic adjuvant e.g. haemophilius influenza type B
Heterotypic vaccine
Pathogens which do not cause disease in humans e.g. BCG
Hep A Features
Faecal-oral
Acute, never chronic
“Fever, malaise, raised ALT in someone coming from India”
Hep B Features
DNA virus, same transmission modes as HIV (more likely sex than C)
Presents like Hep A, but can cause liver cancer and cirrhosis
Treatment: interferon-a and tenofovir
Hep C Features
RNA virus, same transmission modes as HIV (more likely blood than B) (“transfusion long time ago”)
80% become chronic –> 25% cirrhosis
PCR shows HCV RNA = acute; anti-HCV antibodies = chronic
Treatment: antiviral combination
Hep D Features
Need Hep B to get Hep D!
Treatment: interferon-a
Hep E Features
Like Hep A, but from Indochina, can be chronic and spread via pigs!
Treatment: ribavirin
Hep B Serology
- Surface antigen (HBsAg): current infection (Hep B vaccine is literally just surface antigen)
- “e” antigen (HBeAg): high infectivity
- Core antibody (anti-HBc): previous infection
IgM core antibody: acute
IgG core antibody: chronic
Surface antibody (anti-HBs): immune
Core and surface antibody: immune due to infection
Only surface antibody: immune due to vaccination
e antibody (anti-HBe): previous acute phase reaction, when virus replicated lots – not as important
Hep B Screening
Surface antigen = current infection
Core antibody = previous infection
If both screening tests for Hep B +ve
e antigen = infectivity
Hep B DNA = viral load
Meningitis Causes - General
Acute - bacterial
Chronic - TB, cryptococcus (immunocomp)
Aseptic - viral (most common, often preceding flu)
Acute meningitis - Neisseria meningitidis
Non-blanching rash
Acute meningitis - Streptococcus pneumoniae
Biphasic = young and old
Acute meningitis - Listeria
“Tumbling motility”
In eggs/cheese/mayo
Acute meningitis - Group B strep
Neonatal meningitis
India ink stain - CSF
India ink stain (circles are yeast)
= cryptococcus
Meningitis - Rx (adult)
Ceftriaxone - 2g IV bd
If >50y/o or immunocompromised add amoxicillin 2g IV 4 hourly (covers listeria)
Meningo-encephalitis - Rx (adult)
Acyclovir 10mg/kg IV tds (covers herpes)
Ceftriaxone 2g IV bd
If >50y/o or immunocompromised add amoxicillin 2g IV 4 hourly (covers listeria)
B lactams MOA
- 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
- Active against rapidly-dividing bacteria
- Ineffective against bacteria that lack peptidoglycan cell walls (e.g. Mycoplasma or Chlamydia)
Active against rapidly dividing bacteria. Inhibit new cell synthesis –> weak daughter cells –> osmotic lysis. Do not damage the walls of the original cells. No activity if cells aren’t dividing.
Penicillin
Gram positive organisms, Streptococci, Clostridia; broken down by an enzyme (β-lactamase) produced by S. aureus
Key Features of B lactams
Relatively non-toxic
Renally excreted (so ↓dose if renal impairment)
Short half life- most prescribed multiple times per day (need to maintain level in blood for bacterial death)
Will not cross intact blood-brain barrier (will cross inflamed meninges, good for meningitis)
Cross-allergenic (penicillins approx 10% cross-reactivity with cephalosporins or carbapenems)
Chloramphenicol
used more now due to the rise of resistance - can be used for CAP, meningitis when allergic to cephalasporins
- 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
Aminoglycosides MOA
Bind to amino-acyl site of the 30S ribosomal subunit - prevent elongation of the polypeptide chain –> cause misreading of the codons along the mRNA
Glycopeptides MOA
Stops formation of peptide cross links and glycocidic bonds –> weakened cell wall –> cells then lyse. Inhibits cell division.
Tetracylines MOA
Reversibly bind to the ribosomal 30S subunit
Prevent binding of aminoacyl-tRNA to the ribosomal acceptor site, so inhibiting protein synthesis.
Macrolides MOA
Bind to the 50s subunit of the ribosome –> interfere with translocation –> stimulate dissociation of peptidyl-tRNA
In v severe cellulitis or necrotizing fasciitis Clarthromycin prevents protein synthesis and so release of bacterial toxins.
Chloramphenicol MOA
Chloramphenicol binds to the peptidyl transferase of the 50S ribosomal subunit and inhibits the formation of peptide bonds during translation
Oxazolidinones MOA
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).
Quinolones
e.g. Ciprofloxacin, Levofloxacin, Moxifloxacin
Act on a-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) increased activity vs G +ves (pneumococcus) and intracellular bacteria, e.g. Chlamydia spp
Well absorbed following oral administration
Use for UTIs, pneumonia, atypical pneumonia & bacterial gastroenteritis.
Be wary of use in unstable pts - hypotensive, tachycardic etc.
25% e colis now resistant to them, almost all salmonella typhi resistant.
Big problems with causing c diff infection and tendonitis.
Rifamycins
e.g. rifampicin & rifabutin
Inhibitors of RNA synthesis.
Rifampicin
- 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. meningococcol 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.
Daptomycin
Cell membrane toxin
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
Cell Membrane Toxin
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. Attacks outer membrane so can allow other abxs to get in.
Sulphonamides and Diaminopyrimidines
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
Resistance Mechanisms
Inactivation
Altered Target
Reduced Accumulation
Bypass
Inactivation - B-Lactams
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.
Altered Targets: ß Lactams - MRSA
Methicillin Resistant Staphylococcus aureus (MRSA). (also fluclox resistant)
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.
Altered Targets: ß Lactams - Strep Pneumo
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.
Extended Spectrum ß Lactamases (ESBL)
Able to break down cephalosporins (cefotaxime, ceftazidime, cefuroxime) - enzymatic breakdown
Becoming more common in E. coli and Klebsiella species.
Treatment failures reported with ß Lactam/ ß Lactamase inhibitor combinations (eg. Augmentin/Tazocin).
Altered Targets: Macrolides
Adenine-N6 methyltransferase modifies 23S rRNA
Modification reduces the binding of MLS antibiotics and results in resistance
Encoded by erm (erythromycin ribosome methylation) genes.
CHOICE of the correct antimicrobial depends upon the
CHAOS
CHOICE of the correct antimicrobial depends upon the HOST characteristics ANTIMICROBIAL susceptibilities of the ORGANISM itself and also the SITE of the infection
- Ideally narrow spectrum
- Ideally bactericidal (vs static)
- Ideally choice should be based upon a bacteriological diagnosis (otherwise, “best guess” based upon likely differential diagnosis)
- Local sensitivities
- Pt characteristics
- Cost
Host factors
Age Allergy Genetics Renal function Hepatic function
Organism Factors
Sensitivity (based on agar disc diffusion methods)
(Preliminary) identification of the infecting ORGANISM
Gram stain:
CSF
Joint aspirate
Pus
Rapid antigen detection:
Immunofluorescence
PCR
When ti switch from IV to PO
i.v. to p.o. switch is recommended in hospital for most infections if the patient has stabilised after 48 hours i.v. therapy
Eagle Effect
paradoxically reduced antibacterial effect of penicillin at high doses, though recent usage generally refers to the relative lack of efficacy of beta-lactam antibacterial drugs on infections having large numbers of bacteria.
Penicillin is a bactericidal antibiotic that works by inhibiting cell wall synthesis but this synthesis only occurs when bacteria are actively replicating (or in the log phase of growth).
In cases of extremely high bacterial burden (such as with Group A Strep), bacteria may be in the stationary phase of growth.
In this instance since no bacteria are actively replicating (presumably due to nutrient restriction) penicillin has no activity.
Staph Skin Infection - Rx
Fluclox
Pen allergic - doxy
MRSA - Vanc
Pharyngitis - Rx
10 days benpen
CAP (mild) - Rx
Amoxicillin
CAP (severe) - Rx
Co-amox and clarithromycin
HAP - Rx
cephalosporin; ciprofloxacin; piperacillin/tazobactam
If MRSA colonised/risk, consider addition of Vancomycin
Second most common cause of HAI.
Associated with highest mortality (23%).
Greatest risk associated with tracheal intubation and mechanical ventilation.
Bacterial Meningitis - Rx
Ceftriaxone (+/- amoxycillin if Listeria likely)
Main pathogens:
N. Meningitidis
S. pneumoniae
+/- Listeria in the very young/elderly/immuno-compromised
Baby < 3 months : Cefotaxime PLUS Amoxicillin (to cover for listeriosis)
Note: Ceftriaxone not used in neonates as displaces bilirubin from albumin and because it can cause biliary sludging.
Neisseria meningitidis: Benzylpenicillin (high dose) or Ceftriaxone/Cefotaxime
N. Meningitidis Penicillin Resistance
- The mechanism of relative resistance to penicillin involves, at least in part, the production of altered forms of one of the penicillin-binding proteins.
- Although treatment with penicillin is still effective against these relatively resistant strains, there is evidence that low-dose treatment regimens can fail.
- Beta-Lactamase production in meningococci is extremely rare but has been reported
Community Acquired UTI -Rx
3 days trimethoprim
Hospital acquired UTI - cephalexin/augmentin
Infected urinary catheter: change under gentamicin cover.
C. diff colitis - Rx
STOP the offending antibiotic (usually a cephalosporin);
If severe, Rx with p.o. metronidazole;
If above fails, use p.o. vancomycin
If no response within 48 hours, consider the following:
- Does the patient really have a bacterial infection? (Have I collected the relevant cultures?)
- Is there a persistent focus present (e.g. an infected vascular or urinary catheter)?
- Is there a deep-seated collection (e.g. intra-abdominal) that requires drainage?
- Could the patient have bacterial endocarditis?
- Am I using the correct dose of the antimicrobial?
- Is another infection present (esp consider Candida)?
Disease Eradication - Prerequisites for Success
No animal reservoir
Antigenically stable pathogen with only one (or small number of) strains
No latent reservoir of infection and no integration of pathogen genetic material into host genome
Vaccine must induce a lasting and effective immune response
High coverage required for very contagious pathogens
UK Measles and Rubella Elimination Strategy
Achieve and sustain ≥ 95% coverage with two doses of MMR vaccine in the routine childhood programme (<5 years old)
Achieve ≥ 95% coverage with two doses of MMR vaccine in older age cohorts through opportunistic and targeted catch-up (>5 years old)
Strengthen measles and rubella surveillance through rigorous case investigation and testing ≥80% of all suspected cases with an Oral Fluid Test(OFT)
Ensure easy access to high-quality, evidence-based information for health professionals and the public.
Directly Acting Antivirals (DAAs)
Viruses encode specific proteins required for cell entry, genomic replication or transcription, assembly and release of progeny virions: Virally-encoded proteins, e.g. nucleic acid polymerases, proteases, integrase, CCR5, terminase
Small molecule inhibitors - directly-acting antivirals (DAAs) - can block production or action of the above and inhibit viral replication
Directly acting antivirals can be boosted by
exogenous immunomodulators
Examples: Interferon Rx for HBV and HCV IVIG for viral pneumonitis imiquimod for HPV steroids for HSE (?)
Complications of VZV
Chicken pox pneumonitis
Shingles- post-herpetic neuralgia
Prodrug
A prodrug is an inactive precursor of a drug, that is metabolized into the active form within the body.
Acyclovir - MOA
Guanosine analogue
Further elongation of the chain is impossible because acyclovir lacks the 3’ hydroxyl group necessary for the insertion of an additional nucleotide
Selective activity of guanosine analogues:
- Monophosphorylated by viral thymidine kinase (TK)
- Affinity for herpesvirus DNA polymerase is 10- to 30- fold higher than for cellular (host) DNA polymerase for ACV-PPP
- Selective activity means reduced drug toxicity
- VZV 10x less sensitive (than HSV) so higher doses required
BK Virus
Part of Polyomavirus family (related to JC virus)
Primary BK virus infection in childhood with minimal symptoms, but subsequent lifelong carriage in kidneys and urinary tract
Only becomes problematic in the immunocompromised:
- BMT: Haemorrhagic cystitis. Less commonly nephritis.
- Renal transplant:
BK nephritis and ureteric stenosis
Rx:
Bladder washouts
Reduce level of immunosuppression if possible
Cidofovir iv (+ probenicid) if significant morbidity
Intravesical cidofovir (5mg/kg/wk) an option if nephrotoxicity
Nephropathy - reduce level of immunosuppression, IVIG
Brincidofovir - oral prodrug of cidofovir but not licensed in UK
Hep B approved drugs
Interferon (combined antiviral and immunomodulatory effects):
INF-a
Peg-INF a2-a
Nucleoside/nucelotide analogues (direct antiviral effect): Tenofovir Telbivudine Entecavir Lamivudine
Hep C drugs
Combination of protease inhibitors, NS5A inhibitors and polymerase inhibitors (nucleoside and non-nucleoside)
Can use different DAAs spending on the HCV genotype.
glecaprevir/pibrentasvir (Maviret)
sofosbuvir/velpatasvir/voxaliprevir (Sovesi)
elbasvir/grazoprevir (Zepatier)
Mechanisms of Antiviral Resistance
Diversity - Quasispecies, mutation / recombination
Selection - Replication (eg in the presence of suboptimal drug concentrations)
Implications of of Antiviral Resistance
Treatment failure
Change to second line drugs - more toxic
Cross resistance (to prevent: Use potent drug regimens to achieve maximal suppression e.g. combo Rx/HAART, increase adherence to Rx)
Antiviral Drug Resistance Assays
Genotypic: Sequencing / resistance mutations
Example: HIV drug resistance
Phenotypic:
Cell culture
Plaque reduction assay
Routinely used for HSV drug resistance testing
HSV drug resistance (ACV)
Mutations usually in viral thymidine kinase (95%), and rarely in the viral DNA polymerase (5%)
The former mediates cross-resistance to GCV
Resistance strains selected out by drug treatment
Nearly always occurs in the context of immunosuppression – TK-deficient strains less virulent
Suspect if lesions fail to resolve despite adequate antiviral therapy
Diagnose with viral culture and phenotypic resistance test (plaque reduction assay) – time consuming and requires viable virus to be isolated
Treat ACV-resistant HSV with FOS or CDV
Virus tends to revert to wild type upon cessation of
CMV drug resistance (GCV)
CMV genetic mutations:
- In protein kinase gene (UL97) - most common
- In the DNA polymerase gene (UL54) – rare
- UL56 terminase gene (letermovir)
Most likely to occur in context of prolonged therapy in immunocompromised
Suspect if clinical or virological failure despite appropriate therapy and reduction of immune suppression
2nd line for CMV is foscarnet or cidofovir
Immunoglobulin Preparations
Prophylactic:
- palivizumab (RSV)
Post-exposure prophylaxis:
- Varicella zoster immunoglobulin - Immunocompromised / pregnant / neonates
- Hepatitis B immunoglobulin - Unvaccinated recipient exposed to hepatitis B-positive source; Non-responder to vaccine exposed to source of positive or unknown status
- Human Rabies Immunoglobulin (HRIG)
Therapeutic:
- Human normal immunoglobulin (IVIG) as adjunctive treatment for viral pneumonitis (eg CMV)
- Rituximab (anti-CD20) for EBV-driven PTLD
