Micro FA p.187 - 204 Antimicrobials Flashcards
(224 cards)
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MoA of Penicillin
A
D-Ala-D-Ala structural analog
Bind penicillin-binding proteins (transpeptidases)
Block transpeptidase cross-linking of peptidoglycan in cell wall.
6
Q
Clinical use of penicillins
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gram ⊕ organisms (S pneumoniae, S pyogenes, Actinomyces).
Also used for gram ⊝ cocci (mainly N meningitidis) and spirochetes (mainly T pallidum).
(Bactericidal for gram ⊕ cocci, gram ⊕ rods, gram ⊝ cocci, and spirochetes. )
7
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Adverse effects of penicillins
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Hypersensitivity reactions, direct Coombs ⊕ hemolytic anemia, drug-induced interstitial nephritis
8
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How do bact form resistence to penicillin?
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β-lactamase cleaves the β-lactam ring. Mutations in PBPs.
9
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Penicillinase sensitive penicillins ex.
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Amoxicillin, ampicillin; aminopenicillins
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MoA of Penicillinase sensitive penicillins, what do you combine it with
A
Same as penicillin. Wider spectrum; penicillinase sensitive. Also combine with clavulanic acid to protect against destruction by β-lactamase.
11
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Amoxicillin has greater ____ ________than ampicillin.
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AmOxicillin has greater Oral bioavailability than ampicillin.
12
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Clinical use of penicillinase sensitive penicillins
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Extended-spectrum penicillin—H influenzae, H pylori, E coli, Listeria monocytogenes, Proteus mirabilis, Salmonella, Shigella, enterococci.
Coverage: ampicillin/amoxicillin HHELPSS kill enterococci.
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SE/ Penicillinase sensitive penicillins
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Hypersensitivity reactions, rash, pseudomembranous colitis
14
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How does bact form resistence vs amoxicillin (et al)
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Penicillinase (a type of β-lactamase) cleaves β-lactam ring.
15
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Ex of penicillinase resistant penicillins
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Dicloxacillin, nafcillin, oxacillin.
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MoA of penicillinase resistant penicillins
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Same as penicillin. Narrow spectrum; penicillinase resistant because bulky R group blocks access of β-lactamase to β-lactam ring.
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Clinical use of penicillinase resistant penicillins
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S aureus (except MRSA).
“Use naf (nafcillin) for staph.”
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SE/ of Dicloxacillin, Nafcillin, etc
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Hypersensitivity reactions, interstitial nephritis.
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Mech of resistance of penicillinase resistant penicillins
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MRSA has altered penicillin-binding protein target site
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Ex of antipseudomonal penicillins
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Piperacillin, ticarcillin.
21
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Clinical use of piperacillin
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Pseudomonas spp. & G- rods
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MoA of Cephalosporins
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β-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases. Bactericidal.
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Organisms typically not covered by 1st–4th generation cephalosporins are
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4.
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Organisms typically not covered by 1st–4th generation cephalosporins are LAME: Listeria, Atypicals (Chlamydia, Mycoplasma), MRSA, and Enterococci.
24
Q
1st gen cephalosporins used for?
ex/ of Rx
A
1st generation (cefazolin, cephalexin)—gram ⊕ cocci, Proteus mirabilis, E coli, Klebsiella pneumoniae.
1st generation—⊕ PEcK
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\_\_\_\_\_\_\_ used prior to surgery to prevent S aureus wound infections.
Cefazolin used prior to surgery to prevent S aureus wound infections.
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Clinical use of 2nd gen cephalosporins
ex/ of Rx?
2nd generation (ce**fac**lor, ce**fox**itin, ce**fur**oxime, ce**fote**tan)—gram ⊕ cocci, **H** influenzae, **E**nterobacter aerogenes, **N**eisseria spp., **S**erratia marcescens, **P**roteus mirabilis, **E** **c**oli, **K**lebsiella pneumoniae.
2nd graders wear **fake fox fur** to **tea** parties. 2nd generation—**HENS PEcK**.
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Ex of 3rd gen cephalosporins?
ceftriaxone, cefotaxime, cefpodoxime, ceftazidim
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Which gen of cephalosporins can cross brain barrier
3rd gen
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Which cephalosporin is used for meningitis, gonorrhea, and disseminated Lyme disease?
Ceftriaxone
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Which cephalosporin is used for Pseudomonas?
Ceftazidime—Pseudomonas
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4th gen cephalosporins used for? ex?
—gram ⊝ organisms, with activity against Pseudomonas and gram ⊕ organisms.
ex/ cefepime
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unlike 1st–4th generation cephalosporins, ceftaroline covers \_\_\_\_, and ______ \_\_\_\_\_\_\_\_
and does not cover \_\_\_\_\_\_\_\_\_\_\_.
unlike 1st–4th generation cephalosporins, ceftaroline covers _MRSA_, and _Enterococcus faecalis_—does not cover _Pseudomonas_.
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SE/ Cephalosporins
Hypersensitivity reactions, autoimmune hemolytic anemia, **disulfiram-like reaction**, vitamin K deficiency.
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Cephalosporins increase what toxicity of aminoglycosides?
Inc nephrotoxicity of aminoglycosides.
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Ex of β-lactamase inhibitors
Clavulanic acid, Avibactam, Sulbactam, Tazobactam
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List antibiotic/B lactamase (-)'r combos (4)
amoxicillin-clavulanate, ceftazidime-avibactam, ampicillin-sulbactam, piperacillin-tazobactam)
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List Carbapenems
Doripenem, Imipenem, Meropenem, Ertapenem (DIME antibiotics are given when there is a 10/10 [life-threatening] infection).
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Imipenem is always administered with? MoA of that rx?
Imipenem always administered with cilastatin (inhibitor of renal dehydropeptidase I) to dec inactivation of drug in renal tubules.
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Clinical use of carbapenems
Gram ⊕ cocci, gram ⊝ rods, and anaerobes.
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Meropenem has a dec risk of _______ and is stable to \_\_\_\_\_\_\_\_\_\_\_.
Meropenem has a dec risk of seizures and is stable to dehydropeptidase I.
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SE// of Carbapenems
GI distress, rash, and CNS toxicity (seizures) at high plasma levels.
**Carb**apenems **C**ause a bad **rash**
C- CNS
**CARB**a-penems - GI
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Mech of resistance of carbapenems?
Inactivated by carbapenemases produced by, eg, K pneumoniae, E coli, E aerogenes.
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Which antibiotic is synergistic with aminoglycosides?
Aztreonam
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MoA of monobactams?
Less susceptible to β-lactamases. Prevents peptidoglycan cross-linking by binding to penicillinbinding protein 3.
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What are monobactam used for clinically?
Gram ⊝ rods only—no activity against gram ⊕ rods or anaerobes.
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MoA of Vancomycin?
Inhibits cell wall peptidoglycan formation by binding D-Ala-D-Ala portion of cell wall precursors. Bactericidal against most bacteria
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Clinical use of Vancomycin?
Gram ⊕ bugs only - for serious, multidrug-resistant organisms, including MRSA, S epidermidis, sensitive Enterococcus species, and Clostridium difficile (oral dose for pseudomembranous colitis).
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SE/ of Vancomycin
Well tolerated in general—but NOT trouble free. Nephrotoxicity, Ototoxicity, Thrombophlebitis, diffuse flushing—red man syndrome A (largely preventable by pretreatment with antihistamines and slow infusion rate), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).
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Mech of resistance against Vanco?
Occurs in bacteria (eg, Enterococcus) via amino acid modification of D-Ala-D-Ala to D-Ala-D-Lac. “If you Lack a D-Ala (dollar), you can’t ride the van (vancomycin).”
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All protein synthesis inhibitors are bacteriostatic, except ______ (bactericidal) and \_\_\_\_\_\_(variable).
All are bacteriostatic, except _aminoglycosides_ (bactericidal) and _linezolid_ (variable).
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Give ex of aminoglycosides?
Gentamicin, Neomycin, Amikacin, Tobramycin, Streptomycin
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MoA of Aminoglycosides?
* Bactericidal; irreversible inhibition of initiation complex through binding of the 30S subunit.
* Can cause misreading of mRNA.
* Also block translocation.
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Aminoglycosides require ___ for uptake; therefore ineffective against \_\_\_\_\_.
Aminoglycosides require _O2_ for uptake; therefore ineffective against _anaerobes._
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Clinical use of aminoglycosides
Severe gram ⊝ rod infections. Synergistic with β-lactam antibiotics
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What aminoglycoside is used for bowel surgery?
Neomycin
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SE of Aminoglycosides
Nephrotoxicity, Neuromuscular blockade (absolute contraindication with myasthenia gravis), Ototoxicity (especially with loop diuretics), Teratogenicity.
also dec Mg2+ in the body
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Ex of tetracyclines
Tetracycline, doxycycline, minocycline
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MoA of tetracyclins?
Bacteriostatic; bind to 30S and prevent attachment of aminoacyl-tRNA
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Doxycycline is _____ eliminated and can be used in patients with ____ \_\_\_\_\_\_\_.
Doxycycline is fecally eliminated and can be used in patients with renal failure.
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Can't take tetracyclins with what?
Do not take tetracyclines with milk (Ca2+), antacids (eg, Ca2+ or Mg2+), or iron-containing preparations because divalent cations inhibit drugs’ absorption in the gut.
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Clinical use of tetracyclins?
Borrelia burgdorferi, M pneumoniae. Drugs’ ability to accumulate intracellularly makes them very effective against Rickettsia and Chlamydia.
Doxycycline effective against community-acquired MRSA.
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SE/ of Tetracyclins
GI distress, discoloration of teeth and inhibition of bone growth in children, photosensitivity. Contraindicated in pregnancy.
Tetracyclin - severe nephrotox
TEETHracyclins
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Mech of resistance of tetracyclins
Dec uptake or inc efflux out of bacterial cells by plasmid-encoded transport pumps.
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MoA of Tigecyclin
Tetracycline derivative. Binds to 30S, inhibiting protein synthesis. Generally bacteriostatic.
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Clinical use of Glycylcyclines?
Broad-spectrum anaerobic, gram ⊝, and gram ⊕ coverage.
Multidrug-resistant organisms (MRSA, VRE) or infections requiring deep tissue penetration.
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MoA of Chloramphenicol
Blocks peptidyltransferase at 50S ribosomal subunit. Bacteriostatic
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Clinical use of chloramphenicol?
Meningitis (Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae) and rickettsial diseases (eg, Rocky Mountain spotted fever [Rickettsia rickettsii]).
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SE of Chloramphenicol
Anemia (dose dependent), aplastic anemia (dose independent), grey baby syndrome
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Why does admin of chloramphenicol in premature infants lead to grey baby syndrome?
because they lack liver UDP-glucuronosyltransferase
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Mech of resistance vs chloramphenicol
Plasmid-encoded acetyltransferase inactivates the drug
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Clindamycin MoA
Blocks peptide transfer (translocation) at 50S ribosomal subunit. Bacteriostatic
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Clinical use of clindamycin?
Anaerobic infections (eg, Bacteroides spp., Clostridium perfringens) in aspiration pneumonia, lung abscesses, and oral infections. Also effective against invasive group A streptococcal infection.
Treats anaerobic infections **above** the diaphragm, and Metronidazole **below** diaphragm
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\_\_\_\_\_\_\_ treats anaerobic infections above the diaphragm vs ________ anaerobic infections below diaphragm.
Clindamycin treats anaerobic infections above the diaphragm vs metronidazole (anaerobic infections below diaphragm).
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SE/ of Clindamycin
Pseudomembranous colitis (C difficile overgrowth), fever, diarrhea
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MoA of Linezolid.
Inhibit protein synthesis by binding to 50S subunit and preventing formation of the initiation complex.
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Use of Linezolid?
Gram ⊕ species including MRSA and VRE
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SE/ of Linezolid
**BO**ne marrow suppression (especially thrombocytopenia), peripheral **NE**uropathy, **S**erotonin syndrome (due to partial MAO inhibition).
Linezolid is bad for BONES
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Mech of resistance of Linezolid
point mutation of ribosomal DNA
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Macrolide MoA
Inhibit protein synthesis by blocking translocation (“macroslides”); bind to the 23S rRNA of the 50S ribosomal subunit. Bacteriostatic.
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Clinical use of Macrolides
Atypical pneumonias (Mycoplasma, Chlamydia, Legionella), STIs (Chlamydia), gram ⊕ cocci (streptococcal infections in patients allergic to penicillin), and B pertussis.
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SE of Macrolides
MACRO: Gastrointestinal Motility issues, Arrhythmia caused by prolonged QT interval, acute Cholestatic hepatitis, Rash, eOsinophilia
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Macrolides Inc serum conc of ___________ & ____ \_\_\_\_\_\_\_\_\_\_\_\_\_
Theophylline & oral anticoagulants
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Which macrolides (-) Cyt p450?
Clarithromycin Erythromycin
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Mech of resistance vs macrolides
Methylation of 23S rRNA-binding site prevents binding of drug.
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MoA of Polymyxins
Cation polypeptides that bind to phospholipids on cell membrane of gram ⊝ bacteria. Disrupt cell membrane integrity --\> leakage of cellular components--\> cell death
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Clinical use of Polymyxins
Salvage therapy for multidrug-resistant gram ⊝ bacteria (eg, P aeruginosa, E coli, K pneumoniae)
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Polymyxins tox
Nephrotoxicity, neurotoxicity (eg, slurred speech, weakness, paresthesias), respiratory failure.
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Ex of Sulfonamides?
Sulfamethoxazole (SMX), sulfisoxazole, sulfadiazine.
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MoA of Sulfonamides
Inhibit dihydropteroate synthase, thus inhibiting folate synthesis.
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Are Sulfonamides bacteriostatic or cidal?
Bacteriostatic (bactericidal when combined with trimethoprim).
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Use of Sulfonamides
Gram ⊕, gram ⊝, Nocardia. TMP-SMX for simple UTI.
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SE of Sulfonamides
Hypersensitivity reactions, hemolysis if G6PD deficient, **nephrotoxicity (tubulointerstitial nephritis), photosensitivity**, Stevens-Johnson syndrome, kernicterus in infants, **displace other drugs from albumin (eg, warfarin)**
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Mech of resistance of Sulfonamides
Altered enzyme (bacterial dihydropteroate synthase), dec uptake, or inc PABA synthesis
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Clinical use of Dapsone
Leprosy (lepromatous and tuberculoid), Pneumocystis jirovecii prophylaxis, or treatment when used in combination with TMP.
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SE/ of Dapsone
Hemolysis if G6PD deficient, methemoglobinemia, agranulocytosis.
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SE of Trimethoprim
Hyperkalemia (high doses), megaloblastic anemia, leukopenia, granulocytopenia, which may be avoided with coadministration of leucovorin (folinic acid).
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Mech of Trimethoprim
Inhibits bacterial dihydrofolate reductase. Bacteriostatic
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Use of Trimethoprim?
Used in combination with sulfonamides (trimethoprim-sulfamethoxazole [TMPSMX]), causing sequential block of folate synthesis.
Combination used for UTIs, Shigella, Salmonella, Pneumocystis jirovecii pneumonia treatment and prophylaxis, toxoplasmosis prophylaxis.
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Ex of Flouroquinolones
Ciprofloxacin, enoxacin, norfloxacin, ofloxacin; respiratory fluoroquinolones—gemifloxacin, levofloxacin, moxifloxacin
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Mech of Flouroquinolones
Inhibit prokaryotic enzymes topoisomerase II (DNA gyrase) and topoisomerase IV. Bactericidal. Must not be taken with antacids.
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Clinical use of Flouroquinolones
Gram ⊝ rods of urinary and GI tracts (including Pseudomonas), some gram ⊕ organisms, otitis externa
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SE/ of Flouroquinolones
GI upset, superinfections, skin rashes, headache, dizziness. Less commonly, can cause leg cramps and myalgias
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Flouroquinolones contraindicated in?
Contraindicated in pregnant women, nursing mothers, and children \< 18 years old due to possible damage to cartilage. Some may prolong QT interval.
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SE/ of Flouroquinolones in ppl \>60 yrs and in pt taking prednisone
May cause tendonitis or tendon rupture in people \> 60 years old and in patients taking prednisone.
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Mech of resistance of flouroquinolones
Chromosome-encoded mutation in DNA gyrase, plasmid-mediated resistance, efflux pumps.
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Daptomycin MoA
Lipopeptide that disrupts cell membranes of gram ⊕ cocci by creating transmembrane channels
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Clinical use of Daptomycin
S aureus skin infections (especially MRSA), bacteremia, endocarditis, VRE.
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Why can't Daptomycin be used in pneumonia?
Not used for pneumonia (avidly binds to and is inactivated by surfactant).
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SE/ of Daptomycin
Myopathy, rhabdomyolysis.
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MoA of Metronidazole?
Forms toxic free radical metabolites in the bacterial cell that damage DNA. Bactericidal, antiprotozoal.
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Clinical use of Metronidazole?
Treats **G**iardia, **E**ntamoeba, **T**richomonas, **G**ardnerella vaginalis, **A**naerobes (Bacteroides, C difficile). - Can be used in place of amoxicillin in H **p**ylori “triple therapy” in case of penicillin allergy.
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SE/ of Metronidazole
Disulfiram-like reaction (severe flushing, tachycardia, hypotension) with alcohol; headache, metallic taste.
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Rifamycins
Inhibit DNA-dependent RNA polymerase.
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Clinical use of Rifamycins
Mycobacterium tuberculosis; delay resistance to dapsone when used for leprosy. Used for meningococcal prophylaxis and chemoprophylaxis in contacts of children with H influenzae type b.
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SE/ of Rifamycins
Minor hepatotoxicity and drug interactions (cytochrome P-450); orange body fluids (nonhazardous side effect).
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In patients with HIV, which rifamycin do we use?
Rifabutin favored over rifampin in patients with HIV infection due to less cytochrome P-450 stimulation.
Rifampin ramps up cytochrome P-450, but rifabutin does not.
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What is the mech of resistance of Rifamycins?
Mutations reduce drug binding to RNA polymerase. Monotherapy rapidly leads to resistance.
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Rifampin’s 4 R’s:
* RNA polymerase inhibitor
* Ramps up microsomal cytochrome P-450
* Red/orange body fluids
* Rapid resistance if used alone
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MoA of Isoniazid
dec synthesis of mycolic acids.
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\_\_\_\_\_ ____________ (encoded by \_\_\_\_\_) needed to convert INH to active metabolite
_Bacterial catalaseperoxidase_ (encoded by _KatG_) needed to convert INH to active metabolite
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Only agent used as solo prophylaxis vs TB
Isoniazid
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Monotherapy for latent TB
Isoniazid
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SE of Isoniazid
Hepatotoxicity, P-450 inhibition, drug-induced SLE, anion gap metabolic acidosis, seizures (in high doses, refractory to benzodiazepines).
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What vitamin do we co-administer with Isoniazid?
Give vitamin B6 bc it can lead to vitamin B6 deficiency (peripheral neuropathy, sideroblastic anemia),
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MoA of Pyrazinamide
Pyrazinamide is a prodrug that is converted to the active compound pyrazinoic acid. Works best at acidic pH (eg, in host phagolysosomes).
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SE/ of Pyrazinamide & what disease?
Used for TB; hyperuricemia, hepatoxicity
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MoA of Ethambutol
dec carbohydrate polymerization of mycobacterium cell wall by blocking arabinosyltransferase.
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Ethambutol SE/
Optic neuropathy (red-green color blindness, may be reversible). Pronounce “eyethambutol.
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Streptomycin MoA and use
Interferes with 30S component of ribosome.
2nd line Tx for TB
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Streptomycin Tox
tinnitus, vertigo, ataxia, nephrotox
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Prophylaxis - Exposure to meningococcal infection
Ceftriaxone, ciprofloxacin, or rifampin
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High risk for endocarditis and undergoing surgical or dental procedures prophylaxis
Amoxicillin
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History of recurrent UTIs - prophylaxis
TMP-SMX
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Malaria prophylaxis for travelers
Atovaquone-proguanil, mefloquine, doxycycline, primaquine, or chloroquine (for areas with sensitive species)
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Pregnant woman carrying group B strep
intrapartum penicillin G/ ampicillin
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Prevention of gonococcal conjunctivitis in newborn
Erythromycin ointment on eyes
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Prevention of postsurgical infection due to S aureus
Cefazolin
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Prophylaxis of strep pharyngitis in child with prior rheumatic fever
Benzathine penicillin G or oral penicillin V
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MRSA Tx
vancomycin, daptomycin, linezolid, tigecycline, ceftaroline, doxycycline.
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VRE Tx
linezolid, tigecycline, and streptogramins (quinupristin, dalfopristin).
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Multidrug-resistant P aeruginosa, multidrug-resistant Acinetobacter baumannii
polymyxins B and E (colistin).
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MoA of Amphotericin B
Binds ergosterol (unique to fungi); forms membrane pores that allow leakage of electrolytes.
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Use of Amphotericin
Serious, systemic mycoses. Cryptococcus (amphotericin B with/without flucytosine for cryptococcal meningitis), Blastomyces, Coccidioides, Histoplasma, Candida, Mucor. Intrathecally for fungal meningitis. Supplement K+ and Mg2+ because of altered renal tubule permeability.
150
Tox of Amphotericin B, how to reduce it?
Fever/chills (“shake and bake”), hypotension, nephrotoxicity, arrhythmias, anemia, IV phlebitis (“amphoterrible”).
Hydration dec nephrotoxicity.
Liposomal amphotericin dec toxicity.
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Use of Nystatin
“Swish and swallow” for oral candidiasis (thrush); topical for diaper rash or vaginal candidiasis.
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Inhibits DNA and RNA biosynthesis by conversion to 5-fluorouracil by cytosine deaminase
Flucytosine
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SE/ of Flucytosine
Bone marrow suppression.
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Inhibit fungal sterol (ergosterol) synthesis by inhibiting the cytochrome P-450 enzyme that converts lanosterol to ergosterol. ex/
Azoles - Clotrimazole, fluconazole, isavuconazole, itraconazole, ketoconazole, miconazole, voriconazole.
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Tx for chronic suppression of cryptococcal meningitis in AIDS patients and candidal infections of all types
Fluconazole
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Blastomyces, Coccidioides, Histoplasma, Sporothrix schenckii - Which azole can be used for them?
Itraconazole
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Which azoles for Topical fungal infections
Clotrimazole and miconazole
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Voriconazole used for?
for Aspergillus and some Candida
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Isavuconazole for ?
Serious Aspergillus/ Mucor
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SE/ of azoles
Testosterone synthesis inhibition (gynecomastia, especially with ketoconazole), liver dysfunction (inhibits cytochrome P-450).
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Inhibits the fungal enzyme squalene epoxidase.
Terbinafin
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Clinical use of Terbinafine
Dermatophytoses
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SE of Terbinafine
GI upset, headaches, hepatotoxicity, taste disturbance.
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Inhibit cell wall synthesis by inhibiting synthesis of β-glucan.
ex?
Echinocandins
Anidulafungin, caspofungin, micafungin
165
The flushing that is a SE of Echinocandins is caused by ?
Histamine release
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Interferes with microtubule function; disrupts mitosis. Deposits in keratin-containing tissues (eg, nails).
Griseofulvin
167
SE of Griseofulvin
Teratogenic, carcinogenic, confusion, headaches, disulfiram-like reaction, Inc cytochrome P-450 and warfarin metabolism.
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Rx for (toxoplasmosis),
(Trypanosoma brucei), (T cruzi),
(leishmaniasis).
Pyrimethamine (toxoplasmosis), suramin and melarsoprol (Trypanosoma brucei), nifurtimox (T cruzi), sodium stibogluconate (leishmaniasis).
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Permethrin
Permethrin (inhibits Na+ channel deactivation --\> neuronal membrane depolarization),
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Malathion MoA
malathion (acetylcholinesterase inhibitor),
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Lindane - MoA and used for?
lindane (blocks GABA channels neurotoxicity). Used to treat scabies (Sarcoptes scabiei) and lice (Pediculus and Pthirus).
PML (Pesty Mites and Lice) with PML (Permethrin, Malathion, Lindane), because they NAG you (Na, AChE, GABA blockade).
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What rx? Blocks detoxification of heme into hemozoin. Heme accumulates and is toxic to _____ species
Chloroquine;
Plasmodia
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Which species of Plasmodium can one not use Chloroquine for?
P falciparum (frequency of resistance in P falciparum is too high).
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Resistance to chloroquine - mech?
Resistance due to membrane pump that dec intracellular concentration of drug. Treat P falciparum with artemether/lumefantrine or atovaquone/proguanil
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Chloroquine Tox
Retinopathy; pruritus
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Helminth Tx
Pyrantel pamoate, Ivermectin, Mebendazole, Praziquantel, Diethylcarbamazine.
Helminths get PIMP’D.
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MoA of Mebendazole & Praziquantel?
Mebendazole (microtubule inhibitor), Praziquantel (inc Ca2+ permeability, inc vacuolization),
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Inhibit influenza neuraminidase --\> dec release of progeny virus.
Oseltamivir, zanamivir
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Use of Oseltamivir, zanamivir
Treatment and prevention of both influenza A and B. Beginning therapy within 48 hours of symptom onset may shorten duration of illness
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inhibit viral DNA polymerase by chain termination
Acyclovir, famciclovir, valacyclovir
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How is Acyclovir (etc) activated? why does it not affect uninfected cells?
Guanosine analogs. Monophosphorylated by HSV/VZV thymidine kinase and not phosphorylated in uninfected cells --\> few adverse effects. Triphosphate formed by cellular enzymes
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Use of Acyclovir, Famciclovir, etc
HSV and VZV. Weak activity against EBV. No activity against CMV. Used for HSVinduced mucocutaneous and genital lesions as well as for encephalitis
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Tx for herpes zoster?
Famciclovir
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Which guanosine analog has best oral availability?
Valacyclovir, a prodrug of acyclovir, has better oral bioavailability.
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SE of Acyclovir
Obstructive crystalline nephropathy and acute kidney injury if not adequately hydrated.
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Mech of resistance of Acyclovir
mutated viral thymidine kinase
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Ganciclovir MoA
5′-monophosphate formed by a CMV viral kinase. Guanosine analog. Triphosphate formed by cellular kinases. Preferentially inhibits viral DNA polymerase.
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Use of Ganciclovir?
CMV, esp in immunocompromised
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prodrug of Ganciclovir? advantage?
Valganciclovir, a prodrug of ganciclovir, has better oral bioavailability.
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SE of Ganciclovir?
Bone marrow suppression (leukopenia, neutropenia, thrombocytopenia), renal toxicity. More toxic to host enzymes than acyclovir.
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Viral DNA/RNA polymerase inhibitor and HIV reverse transcriptase inhibitor.
Foscarnet
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How does Foscarnet bind/activate?
Binds to pyrophosphate-binding site of enzyme. Does not require any kinase activation.
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Use of Foscarnet?
CMV retinitis in immunocompromised patients when ganciclovir fails; acyclovir-resistant HSV
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Tox of Foscarnet?
Nephrotoxicity, electrolyte abnormalities (hypo- or hypercalcemia, hypo- or hyperphosphatemia, hypokalemia, hypomagnesemia) can lead to seizures.
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Preferentially inhibits viral DNA polymerase
Cidofovir
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Use of Cidofovir?
CMV retinitis in immunocompromised patients; acyclovir-resistant HSV. Long half-life.
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SE of Cidofovir?
Nephrotoxicity
200
How to avoid nephrotox of Cidofovir?
(coadminister with probenecid and IV saline to dec toxicity).
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Mech of NRTIs
Competitively inhibit nucleotide binding to reverse transcriptase and terminate the DNA chain (lack a 3′ OH group)
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Which NRTI is a nucleotide? what's the advantage?
Tenofovir is a nucleoTide; the others are nucleosides. All need to be phosphorylated to be active
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What drug is used to decrease fetal transmission?
ZDV can be used for general prophylaxis and during pregnancy to dec risk of fetal transmission
204
Abacavir contraindicated when?
Abacavir contraindicated if patient has HLA-B\*5701 mutation due to inc risk of hypersensitivity.
205
Which NRTI is assoc with pancreatitis?
Didanosine
206
How do you treat the SE of NRTIs?
Bone marrow suppression (can be reversed with granulocyte colony-stimulating factor [G-CSF] and erythropoietin)
207
Which Rx bind to reverse transcriptase at site different from NRTIs. Do not require phosphorylation to be active or compete with nucleotides.
Delavirdine Efavirenz Nevirapine
208
SE/ of NNRTIs?
Rash and hepatotox
209
What do protease inhibitors do?
Assembly of virions depends on HIV-1 protease (pol gene), which cleaves the polypeptide products of HIV mRNA into their functional parts. Thus, protease inhibitors prevent maturation of new viruses.
210
Which protease inhibitor inhibits cyt p450?
Ritonavir can “boost” other drug concentrations by inhibiting cytochrome P-450.
211
Tox of Protease inhibitors in gen?
Hyperglycemia, GI intolerance (nausea, diarrhea), lipodystrophy (Cushing-like syndrome).
212
Tox of Indinavir?
Nephropathy, hematuria, thrombocytopenia
213
Inhibits HIV genome integration into host cell chromosome by reversibly inhibiting HIV integrase - ex?
Dolutegravir Elvitegravir Raltegravir
214
What lab parameter is inc by integrase (-)'rs?
Inc CK
215
What does Enfurviritide bind to? What does that accomplish?
Binds gp41, inhibiting viral entry.
216
What Binds CCR-5 on surface of T cells/monocytes, inhibiting interaction with gp120?
Maraviroc
217
Inhibits NS5A, a viral phosphoprotein that plays a key role in RNA replication, unknown exact mechanism?
Ledipasvir & Ombitasvir
(-) NS**5A** = -**as**vir
218
Tox of Ledipasvir Ombitasvir?
headache diarrhea
219
Inhibits NS5B, an RNA-dependent RNA polymerase acting as a chain terminator. Prevents viral RNA replication.
NS5**B** - **B**uvirs
Sofosbuvir
Dasabuvir
220
Inhibits NS3/4A, a viral protease, preventing viral replication.
Grazoprevir
Simeprevir
221
Tox of Grazoprevir, Simeprevir
Grazoprevir: Photosensitivity reactions, rash. Simeprevir: Headache, fatigue
222
What enzyme is inhibited by Ribavirin?
IMP DH
223
Tox of Ribavirin?
Hemolytic anemia, severe teratogen
224
