USMLE Antimirobials

  1. Antimicrobials - mechanisms of action
    • 1) block cell wall synthesis by inhibition of peptidoglycan cross-linking( e.g. penicillin, ampicillin, ticarcillin, piperacillin, imipenem, aztreonam, cephalosporins)
    • 2) Block peptidoglycan synthesis (e.g. bacitracin, vancomycin)
    • 3) Disrupt bacterial cell membranes (e.g. polymixins)
    • 4) Block nucleotide synthesis (e.g. sulfonamides, trimethoprim)
    • 5) Block DNA topoisomerases (e.g. fluoroquinolones)
    • 6) Block mRNA synthesis (e.g. Rifampin)
    • 7) Block protein synthesis at 50S subunit (e.g. chloramphenical, macrolides, clindamycin, streptogramins (quinupristin, dalfoprristin), linezolid)
    • 8) Block protein synthesis at 30S ribosomal subunit( e.g. Aminoglycosides, tetracyclines)
  2. Bacteriostatis vs bactericidal antibiotics
    • Bacteriostatis - Erythromycin, Clindamycin, Sulfamethoxazole, Trimethoprim, Tetracyclines, Chloramphenicol
    • Bactericidal - Vancomycin, Fluoroquinolones, penicillin, aminoglycosides, cephalosporins, metronidazole
  3. Penicillin
    • Pen G (IV form), Pen V (oral) - prototype beta-lactam Abx
    • 1) Binds penicillin-binding protein
    • 2) Blocks transpeptidase cross-linking of cell wall
    • 3) activate autolytic enzymes
    • Use - bactericidal for gram+ cocci, gram + rods and gram neg cocci and spirochetes. Not penicillinase resistant
    • Toxicity - Hypersensitivity reactions, hemolytic anemia
  4. Methicillin, nafcillin, dicloxacillin( penicillinase resistant penicillins)
    • Mech: Same as penicillin. Narrow spectrum; penicillinase resistant b/c of bulkier R group
    • Use: S. aureus 9except MRSA)
    • Toxicity - hypersensitivity reactions; methicillin - interstitial nephritis
  5. Ampicillin, amoxicillin (aminopenicilins)
    • Same an penicillin. Wider spectrum; penicillinase sensitive. Also combine with clavulanic acid (penicillinase inhibitor) to enhance spectrum. Amox has greater oral bioavialbility than ampicillin
    • Use - extended spectrum penicillins - certain gram + bacteria and gram neg rods (H influenzae, E. coli, listeria, Proteus, Salmonella, enterococci)
    • Toxicity - hypersensitivity reactions; ampicillin rash, pseudomembranous colitis
  6. Ticarcillin, carbenicillin, piperacillin (antipseudomonas)
    • Mech - same as penicillin, extended spectrum
    • Use - Pseudomonas and gram-neg rods. Susceptible to penicillinase, use with clavulanic acid
    • Toxicity - hypersensitivity reactions
  7. Cephalosporins: general
    • Beta-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases. Bactericidal
    • Toxicity - hypersensitivity reactions. Cross-hypersensitivity with penicillins occur in 5-10% of pts..Increaes nephrotoxocity of aminoglycosides; disulfiram-like reaction with ethanol
  8. Cephalosporins: 1st generation
    Cefazolin, cephalexin - gram positive cocci, proteus mirabilis, E. coli, Klebsiella pneumoniae
  9. Cephalosporins: 2nd generation
    Cefoxitin, cefaclor, cefuroxime - gram + cocci, H. influenzae, Enterobacter aerogenes, Neisseria, Proteus mirabilis, E. Coli, Kelbsiella pneumoniae, Serratia marcenscens
  10. Cephalosporins: 3rd generation
    Ceftriaxone, cefotaxime, ceftazidime) - serious gram neg infections resistant to other beta-lactams. Meningitis (most penetrate blood-brain barrier)..Examples: ceftazidime for pseudomonas ceftriaxone for gonorrhea
  11. Cephalosporins: 4th generation
    Cefepime - increased activity against pseudomonas and gram-Positive organisms
  12. Aztreonam
    • Monobactam resistant to beta-lactamases. Inhibits cell wall synthesis (binds to PBP3, synergistic with aminoglycosides. No cross-allergenicity with penicillins
    • Use - gram neg rods - klebsiella, pseudomonas, serratia. No activity against gram + or anaerobes. For penicillin-allergic pts and those with renal insufficiency who cannot tolerate aminoglycosides
    • Toxicity - Usually non toxic; occasional GI upset. No cross-sensitivity with penicillins or cephalosporins
  13. Imipenem/cilastin, meropenem
    • Mech - broad-spectrum btea-lactamase resistant carbapenum. Always administered with cilastin (inhibitor of renal dihydropeptidase I) to decrease inactivation in renal tubules
    • Use - gram + cocci, gram neg rods and anaerobes. Drug of choice for enterobacter.
    • Significant side effects: life threatening infectioun, lowers sz threshold. Morepenemhas reduced risk of sz and is stable to dihydropeptidase
    • Toxicity - GI distress, skin rash and CNS toxicity and high plasma levels
  14. Vancomycin
    • Inhibits cell wall mucopeptide formation by binding D-ala D-ala to D-ala D-lac.
    • Use - for serious gram + multidrug resistant organisms including S. aureus and C. difficile
    • Toxicity - Nephrotoxicity, Ototoxicity, red-man syndrome
  15. Protein synthesis inhibotrs
    • 30S (AT)
    • - Aminoglycosides (streptomycin, gentamicin, tobramycin amikacin)
    • 50S inhibitors: chloramphenicol, erythromycin, lincomycin, linezolid
  16. Aminoglycosides
    • - gent, neomycin, amikacin, tobramycin
    • Mech - bacterial cidal, inhibit formaiton of initiation complex and cause misreading of mRNA. Require O2 for uptake, therefore ineffective against aerobes
    • use - severe gram-neg rod infections
    • Toxicity (especially if used with cephlosporins
    • Use - severe gram-negative rod infections.
  17. Tetracyclines
    • Tetracycline, doxycycline, demeclocycline, minocycline
    • Demeclocycline - ADH antagonist; acts as a diuretic in SIADH
    • Mech - bacteristati; bind to 30S and prevent aminoacyl-tRNA; limited CNS penetration. Doxy is fecally eliminated and can be used in pts with renal failure. Must NOT take with milk, antacids or iron-containing preparations b/c divalent cations inhibit absorption in gut
    • Use - Vibrio cholerae, acne, chlamydia, ureaplasma urealyticum, Mycoplasma pneumoniae, Tularemia, H. pylori, Borrelia burgdorferi, Rickettsia
    • Toxicity - GI distress, discolouration of teeth and inhibiition of bone growth in children, photosensitivity. Contraindicated in pregnancy
  18. Macrolides
    • Erythromycin, azithromycin, clarithromycin
    • Mech - inhibit protein synthesis by blocking translocation: bind to 23S rRNA of the 50S ribosomal subunit. Bacteriostatic
    • Use - URI, pneumonias, STDs - gram + cocci (streptococcal infections in pts allergic to penicillin), mycoplasma, legionella, chlamydia, neisseria
    • Toxicity - prolonged QT interval (especially erythromycin), GI discomfort (most common cause of noncompliance), acute cholestatic hepatitis, eosinophilia, skin rashes. Increases serum concentration of theophyllines, oral anticoagulants
  19. Chloramphenicol
    • Mech - Inhibit 50S peptidyltransferase activity - bacteriostatic.
    • Use - Meningitis (H. Influenzae, N meningitidis, streptococcus pneumoniae). Conservative use owing to toxicities.
    • Toxicities - Anemia (dose dependant), aplastic anemia (dose independent), gray baby syndrome (in premature infants b/c they lack liver UDP-glucuronyl transferase
  20. Clindamycin
    • Mech - blocks peptide bond formation at 50S ribosomal subunit. Bacteriostati
    • Clinical use - Treat anaerobic infections (e.g. bacteroides fragilis, Clostridium perifringens)
    • Toxicity - pseudomembranous colitis (C. Difficile overgrowth), fever diarrhea
  21. Sulfonamides
    • Sulfamethoxazole, sulfisoxazole, sulfadiazine
    • Mech - PABA antimetaboites inhibits dihydropteroat sythetase. Bacteristatic
    • Use - Gram-positive, gram -neg, Nocardia, chlamydia. Triple sulfas or SMX for simple UTI
    • Toxicity - hypersensitivity reactions, hemolysis if G6PD deficient, nephrotoxicity (tubulointerstitial nephritis), photosensitivity, kernicterus in infants, displace other drugs from albumin
  22. Trimethoprim
    • Mech - inhibits bacterial dihydrofolate reductase - bacteriostatic
    • Use incombination with sulfonamides, causing sequential block of folate synthesis. Combination used for recurernt UTIs, shigella, salmonella, pneumocystis jiroveci pneumonia
    • Toxicity - megaloblastic anemia, leukopenia, granulocytopenia
  23. Sulfa drug allergies
    pts who do not tolerate sulfa drugs should not be given sulfonamides or other sulfa drugs, such as sulfasalazine, sulfonylureas, thiazide diuretics, acetazolamide or furosemide
  24. Amphotericin B
    • Mech - binds ergosterol (unique to fungi); forms membrane pores that allo leakage of electrolytes
    • Use - wide spectrum of systemic mycosses: cryptococcus, blastomyces, coccidioides, aspergillus, histoplasma, candida, mucor (systemic mycoses). Intrathecally for fungal meningitis - does not cross blood-brain
    • Toxicity - fever/chills, hypotension, nephrotoxicity, arrhythmias, anemia, IV phlebitis
  25. Nystatin
    • Mechanism - binds to ergosterol, disrupting fungal membranes. Too toxic for systemic use
    • Use - Swish and swallow for oral candidiases; topical for diaper rash or vag cnadidiasis
  26. Azoles
    • fluconazole, ketoconazole, clotrimazole, miconazole, itraconazole, voriconazole
    • Mech - inhibit fungal sterol (ergosterol) synthesis
    • Use - systemic mycoses. Fluconazole for cryptococcal meningitis in AIDS pts (b/c it can cross blood-brain barrier) and candidal infection of all types (yeast). Keto for blastomyces, coccidioides, Histo, candida, ,hypercotrisolism. Clotrimazole and miconazole for topical fungal infections
    • Toxicity - hormone synthesis inhibition (gynecomastia), liver dysfunction (inhibits cytochrom p-450), fever chills
  27. Flucytosine
    • Mech - inhibits DNA synthesis by conversion to 5-fluorouracil
    • Use - used in systemic fungal infections (candida, cryptococcus) in combination with Ampho-B
  28. Caspofungin
    • Mech - inhibits cell wall synthesis by inhibiting synthesis of beta-glucan
    • Use - invasive aspergillosis
    • Toxicity - GI upset, flushing
  29. Terbinafine
    • Mech - Inhibits the fungal enzyme squalene epoxidase.
    • Clinical use - Used to treat dermatophytoses (esp onychomycosis)
  30. Griseofulvin
    • Mech - interferes with microtubule function; disrupts mitosis. Deposits in keratin-containing tissues (nails)
    • Use- oral treatment of superficial infections; inhibits growth of dermatophytes (tinea, ringworm)
    • Toxicity - teratogenic, carcinogenic, confusion, headaches, increased p-450 warfarin metabolism
  31. Key action points in antiviral chemotherapy
    • 1) Viral adsorption and penetration into cell (blocked by gamma-globulins...non-specific)
    • 2) Uncoating of virus (blocked by amantadine)
    • 3) Nucleic acid synthesis (blocked by purine and pyrimidine analogs and reverse transcriptase inhibitors)
    • 4) Repackaging and assembly of new virions (blocked by rifampin)
    • 5) Viral release (blocked by neuraminidase inhibitors
  32. Amantadine
    • Mech - blocks viral penetration/uncoating (M2 protein); may buffer pH of endosome. Also causes the release of dopamine from intact nerve terminals
    • Use - prophylaxis and treatment for influenza A. Parkinson's disease
    • Toxicity - Ataxia, dizziness, slurred speech
    • mechanism of resistant - mutated M2 protein. 90% of all influenza A stains are resistant to amantadine so not used.
    • *Rimantidine is a derivative with fewer CNS side effects - does not cross blood-brain barrier
  33. Zanamivir, oseltamivir
    • Mech - Inhibit influenza neuraminidase, decreasing release of progeny virus
    • Use - both influenza A and B
  34. Ribavirin
    • Mech - Inhibits synthesis of guanine nucleotides by competitively inhibiting IMP dehydrogenase
    • Use - RSV, chronic hepatitis C
    • Toxicity - Hemolytic anemia - severe teratogen
  35. Acyclovir
    • Mech - Monophosphorylated by HSV/VZV thymidine kinase. Guanosine analog. Triphosphate formed by cellular enzymes. Preferntially inhibits viral DNA polymerase by chain termination
    • Use - HSV, VZV, EBV. Used for HSV-induced mucocutaneous and genital lesions as well as a related agent, famciclovir. No effect on latent forms of HSV and VZV.
    • Toxicity - well tolerated
    • mech of resistant - lack of thymidine kinase
  36. Ganciclovir
    • Mech - 5'-monophosphate formed by a CMV viral kinase or HSV/VZV thymidine kinase. Guanosine analog. Triphosphate formed by cellular kinases. Preferentially inhibits viral DNA polymerase
    • Use - CMV, especially in immunocompromised patients
    • Toxicity - leukopenia, neutropenia, thrombocytopenia, renal toxicity. More toxic to host enzymes than acyclovir.
    • Mech of resistant - Mutated CMV DNA polymerase or lack of viral kinase
  37. Foscarnet
    • MEch - viral DNA polymerase inhibitor that binds to the pyrophosphate-binding site of the enzyme. Does not require activation by viral kinase
    • Clinical use - CMV retininitis in immunocompromised patients when ganciclovir fails; acyclovir-resistant HSV
    • Toxicity - nephrotoxicity
    • Mech of resistance - mutated DNA polymerase
  38. HIV therapy: Protease inhibitors
    • Saquinavir, ritonavir, indinavir, nelfinavir, amprenavir
    • Mech - Inhibit maturation of new virus by blocking protease in progeny virions
    • Tox - GI intolerance (nausea, diarrhea), hyperglycemia, lipodystrophy, thrombocytopenia (indinavir)
  39. HIV therapy: Reverse transcriptase inhibitors
    • Nucleosides - Zidovudine (ZDV, formally AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir
    • Non - nucleosides - Nevirapine, Efavirenz, Delavirdine
    • Mechanism - preferentially inhibit reverse transcriptase of HIV; prevent incorporation of DNA copy of viral genome into host DNA
    • Toxicity - bone marrow suppression (neutropenia, anemia), peripheral neuropathy, lactic acidosis (nucleosides), rash (non-nucleosides), megaloblastic anemia (ZDV)
    • Clinical use - highly active antiretroviral therapy. generally combination of protease inhibitors and reverse transcriptase inhibitors.
  40. HIV therapy: Fusion inhibitors
    • Enfubirtide
    • Bind viral gp41 subunit; inhibit conformational change required for fusion with CD4 cells. Therefore block entry and subsequent replication
    • Toxicity - hypersensitivity reactions, reactions at subcutaneous injection site, inc risk of bacterial pneumonia
    • Clinical use - in pts with persistent viral replication in spite of antiretroviral therapy...used in combination with other drugs.
  41. Interferons
    • Mech - Glycoproteins from human leukocytes that block various stages of viral RNA and DNA synthesis. Induce ribonuclease that degrades viral mRNA
    • Use - IFN-apha - chronic hepatitis B and C, Kaposi's sarcoma. IFN-beta-MS. IFN-gamma-NADPH oxidase deficiency
    • Toxicity - neutropenia
  42. Antibiotics to avoid in pregnancy
    • SAFE Moms Take Really Good Care
    • Sulfonamides, Aminoglycosides, fluoroquinolones, erythromycin (and clarithromycin), Metronidazole, Tetracyclines - discoloured teeth , Ribavirin (teratogenic), chloramphenicol
Card Set
USMLE Antimirobials
USMLE Antimicrobials