Penicillin
- Penicillin G (IV and IM form)- Penicillin V (oral) Mechanism: D-Ala-D-Ala structural analog- Bind penicillin-binding proteins (transpeptidases)- Block transpeptidase cross-linking of peptidoglycan in cell wall.- Activate autolytic enzymes. Clinical use:- Mostly for gram ⊕ organisms (S pneumoniae, S pyogenes, Actinomyces)- Gram ⊝ cocci (mainly Neisseria meningitides) and spirochetes (Treponema pallidum) Adverse effects: - Hypersensitivity reactions- Jarisch-Herxheimer reaction in treatment of syphilis- Direct Coombs ⊕ hemolytic anemia- Drug-induced interstitial nephritis Resistance: β-lactamase cleaves the β-lactam ring. Mutations in penicillin-binding proteins.
Penicillinase-sensitive penicillins
Amoxicillin, ampicillin; aminopenicillins Mechanism: same as penicillin, wider spectrum.- Combine with clavulanic acid to protect against β-lactamase.- Amoxicillin has greater oral bioavailability than ampicillin. Clinical use: Extended-spectrum penicillin - H influenzae, H pylori, E coli, Listeria monocytogenes, Proteus mirabilis, Salmonella, Shigella, enterococci Adverse effects:- Hypersensitivity reactions- Rash- Pseudomembranous colitis
Penicillinase-resistant penicillins
Dicloxacillin, nafcillin, oxacillin Mechanism: Same as penicillin. Narrow spectrum; penicillinase resistant because bulky R group blocks access of β-lactamase to β-lactam ring. Clinical use: S. aureus (except MRSA) Adverse effects:- Hypersensitivity reactions- Interstitial nephritis Resistance: MRSA has altered penicillin-binding protein target site.
β-lactamase inhibitors
Often added to penicillin antibiotics to protect from destruction by β-lactamase (penicillase). CAST- Clavulanic acid- Avibactam- Sulbactam- Tazobactam
Cephalosporins (generations I-V)
Mechanism: β-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases. Bactericidal.Organisms typically not covered by cephalosporins are LAME (Listeria, atypicals, MRSA, Enterococci) 1st generation (cefazoline, cephalexin): - gram ⊕ cocci- Proteus mirabillis, E coli, Klebsiella pneumoniae- Cefazoline used prior to surgery to prevent S aureus wound infections. 2nd generation (cefaclor, cefoxitin, cefuroxime): [2nd graders wear fake fox fur]- gram ⊕ cocci- H influenzae, Neisseria, Serratia, Proteus mirabillis, E coli, Klebsiella pneumoniae 3rd generation (ceftriaxone, cefotaxime, cefpodoxime, ceftazidime):- Serious gram ⊝ infections- Can cross blood-brain barrier (good against meningitis)- Ceftriaxone – meningitis, gonorrhea, disseminated Lyme disease- Ceftazidime – Pseudomonas 4th generation (cefepime):- gram ⊝ organisms with ↑ activity against Pseudomonas and gram ⊕ organisms 5th generation (ceftaroline):- Broad gram ⊕ and gram ⊝ coverage; unlike 1-4th generation cephalosporines, ceftaroline covers MRSA, Listeria, Enterococcus faecalis- No coverage for Pseudomonas Adverse effects: Hypersensitivity reactions, autoimmune hemolytic anemia, disulfiram-like reaction, vitamin K deficiency, ↑ nephrotoxicity of aminoglycosides, low rate of cross-reactivity in penicillin-allergic patients
Carbapenems
Imipenem, meropenem, doripenem, ertapenem Mechanism: broad-spectrum, β-lactamase-resistant carbapenem.- Always administered with cilastatin (inhibitor of renal dehydropeptidase I) to ↓ inactivation of drug in renal tubules Clinical use: Gram ⊕ cocci, gram ⊝ rods, and anaerobes- Wide spectrum and significant side effects limit use to life-threatening infections or after other drugs have failed. Side effects: CNS toxicity (seizures), GI distress, and skin rash at high plasma levels.- Meropenem has a ↓ risk of seizures and is stable to dehydropeptidase I
Vancomycin
Inhibits cell wall peptidoglycan formation by binding to D-ala-D-ala portion of cell wall precursors.- Bactericidal against most bacteria (bacteriostatic against C difficile).- Not susceptible to β-lactamases. Clinical use: Gram ⊕ bugs only – serious, multidrug-resistant organisms including MRSA, S epidermidis, sensitive Enterococcus species, and Clostridium difficile (oral dose for pseudomembranous colitis) Adverse effects: - Nephrotoxicity- Ototoxicity- Thrombophlebitis- Diffuse flushing – Red man syndrome (Diffuse flushing of the skin, hypotension, and dyspnea due to the rapid release of histamine following nonspecific mast cell degranulation; Red man syndrome can be prevented by slowing the rate of infusion and possibly pretreating with antihistamines.)- DRESS syndrome Resistance: Occurs via amino acid modification (D-Ala-D-Ala to D-Ala-D-Lac)
Aminoglycosides
Gentamicin, Neomycin, Amikacin, Streptomycin, Tobramycin(Not daptomycin; interferes with membrane integrity.) Mechanism: Bactericidal- Irreversible inhibition of initiation complex through binding of the 30S subunit- Can cause misreading of mRNA- Block translocation- Require O2 for uptake; therefore ineffective against anaerobes Clinical use: Severe gram ⊝ rod infections. Synergistic with β-lactam antibiotics.- Neomycin for bowel surgery. Adverse effects: Teratogen, nephrotoxic, ototoxic (especially when used with loop diuretics), neuromuscular blockade. Mechanism of resistance: Bacterial transferase enzymes inactivate the drug by acetylation, phosphorylation, or adenylation.
Tetracyclines
Tetracycline, doxycycline, minocycline Mechanism: Bacteriostatic- Bind to 30S and prevent attachment of aminoacyl-tRNA- Limited CNS penetration.- Doxycycline is fecally eliminated and can be used in patients with renal failure.- Do not take with milk (Ca2+), antacids (Ca2+ or Mg2+), or iron-containing preparations because divalent cations inhibit drugs' absorption in the gut. Clinical use: Borrelia burgdorferi, M pneumoniae. Drugs' ability to accumulate intracellulary makes them effective against Rickettsia and Chlamydia. Also used to treat acne. Doxycycline effective against MRSA. Adverse effects: GI distress, discoloration of teeth, inhibition of bone growth in children, photosensitivity. Contraindicated in pregnancy. Mechanism of resistance: ↓ Uptake or ↑ efflux out of bacterial cells by plasmid-encoded transport pumps.
Chloramphenicol
Mechanism: Blocks peptidyltransferase at 50S ribosomal subunit. Bacteriostatic. Clinical use: Meningitis (H influenzae, N meningitidis, S pneumonia) and Rocky Mountain spotted fever (Rickettsia rickettsii).- Limited use due to toxicities but often still used in developing countries because of low cost. Adverse effects: Anemia (dose dependent), aplastic anemia (dose independent), gray baby syndrome (in premature infants because they lack liver UDP-glucuronosyltransferase). Mechanism of resistance: Plasmid-encoded acetyltransferase inactivates the drug.
Clindamycin
Mechanism: Blocks peptide transfer (translocation) at 50S subunit. Bacteriostatic. Clinical use: Anaerobic infections (eg Bacteriodes spp, Clostridium perfringes) in aspiration pneumonia, lung abscesses, and oral infections. Also effective against invasive group A streptococcal infection. Bacterial vaginosis (Gardnerella) instead of metronidazole. - Treats anaerobic infections above the diaphragm vs metronidazole (anaerobic infections below the diaphragm). Adverse effects: Pseudomembranous colitis (C difficile overgrowth), fever, diarrhea.
Oxazolidinones
Linezolid Mechanism: Inhibit protein synthesis by binding to 50S subunit preventing formation of initiation complex. Clinical use: Gram ⊕ species including MRSA and VRE Adverse effects: Bone marrow suppression (especially thrombocytopenia), peripheral neuropathy, serotonin syndrome. Mechanism of resistance: Point mutation of ribosomal RNA.
Macrolides
Erythromycin, azithromycin, clarithromycin Mechanism: Block translocation by binding to the 23S rRNA of the 50S ribosomal subunit. Bacteriostatic. Clinical use: Atypical pneumonias (Mycoplasma, Chlamydia, Legionella), STIs (Chlamydia), gram ⊕ cocci (streptococcal infections in patients allergic to penicillin), and B pertussis. Adverse effects: GI motility issues, arrhythmia caused by prolonged QT interval, acute cholestatic hepatitis, rash, eosinophilia. Increases serum concentration of theophylline, oral anticoagulants. Clarithromycin and erythromycin inhibit cytochrome P-450. Mechanism of resistance: Methylation of 23S rRNA-binding site prevents binding of drug.
Sulfonamides
Sulfamethoxazole (SMX), sulfisoxazole, sulfadiazine Mechanism: Inhibit dihydropteroate synthase, thus inhibiting folate synthesis. Bactericidal when combined with trimethoprim. Clinical use: Gram ⊕, gram ⊝, Nocardia. TMP-SMX for simple UTI. Adverse effects: Hypersensitivity reactions, hemolysis if G6PD deficient, nephrotoxicity (tubulointerstitial nephritis), photosensitivity, Stevens-Johnson syndrome, kernicterus in infants, displace other drugs from albumin (eg warfarin). Mechanism of resistance: Altered enzyme (bacterial dihydropteroate synthase), ↓ uptake, or ↑ PABA synthesis.
Dapsone
Mechanism: Similar to sulfonamides (inhibits dihydropteroate synthase), but structurally distinct agent. Clinical use: Leprosy (lepromatous and tuberculoid), Pneumocystis jirovecii prophylaxis. Adverse effect: Hemolysis if G6PD deficient, methemoglobinemia.
Trimethoprim
Mechanism: Inhibits bacterial dihydrofolate reductase (vs SMX, inhibits dihydrofolate synthase). Bacteriostatic. Clinical use: Used in combination with sulfonamides (trimethoprim-sulfamethoxazole [TMP-SMX]), causing block of folate synthesis. Combination used for UTIs, Shigella, Salmonella, Pneumocystis jirovecii pneumonia treatment and prophylaxis, toxoplasmosis prophylaxis. Adverse effects: Megaloblastic anemia, leukopenia, granulocytopenia, which may be avoided with coadministration of folinic acid.
Fluoroquinolone
Ciprofloxacin, Enoxacin, Norfloxacin, OfloxacinRespiratory fluoroquinolones – Levofloxacin, Gemifloxacin, Moxifloxacin Mechanism: Inhibit DNA gyrase (topoisomerase II) and topoisomerase IV. Bactericidal. Must not be taken with antacids. Clinical use: Gram ⊝ rods of urinary and GI tracts (including Pseudomonas), some gram ⊕ organisms, otitis externa. Adverse effects: GI upset, superinfections, skin rashes, headache, dizziness. Less commonly, can cause leg cramps and myalgias. Some may prolong QT interval.- Contraindicated in pregnant women, nursing mothers, children <18 years old due to possible damage to cartilage. - May cause tendonitis or tendon rupture in people >60 years and in patients taking prednisone.- Ciprofloxacin inhibits cytochrome P-450. Mechanism of resistance: Chromosome-encoded mutation in DNA gyrase, plasmid-mediated resistance, efflux pumps.
Daptomycin
Mechanism: Lipopeptide that disrupts cell membrane of gram ⊕ cocci by creating transmembrane channels. Clinical use: S aureus skin infections (especially MRSA), VRE, bacteremia, endocarditis. - Not used for pneumonia (avidly binds to and is inactivated by surfactant). Adverse effects: Myopathy, rhabdomyolysis.
Metronidazole
Mechanism: Forms toxic free radical metabolites in the bacterial cell that damage DNA. Bactericidal, antiprotozoal. Clinical use: Giardia, Entamoeba, Trichomonas, Gardnerella vaginalis, anaerobes (Bacteroides, C difficile). Can be used in place of amoxicillin in H pylori "triple therapy" in case of penicillin allergy.Treats anaerobic infection below the diaphragm vs clindamycin (above the diaphragm). Adverse effects: Disulfram-effect (severe flushing, tachycardia, hypotension) with alcohol; headache, metallic taste.
Antimycobacterial drugs
M. tuberculosis: Rifampicin, Isoniazid, Pyrazinamide, Ethambutol M. avium: Azithromycin or clarithromycin + ethambutol- Can add rifabutin or ciprofloxacin M. leprae: Long-term treatment with dapsone and rifampin for tuberculoid form. Add clofazimine for lepromatous form.
Rifamycins
Rifampin, rifabutin Mechanism: Inhibit DNA-dependent RNA polymerase Clinical use:- Mycobacterium tuberculosis- Delay resistance to dapsone when used for leprosy. - Meningococcal prophylaxis and chemoprophylaxis in contacts of children with Haemophilus influenzae type b. Adverse effects: Minor hepatotoxicity and drug interactions (↑ cytochrome P-450); orange body fluids. Rifabutin favored over rifampin in patients with HIV infection due to less cytochrome P-450 stimulation. Mechanism of resistance: Mutations reduce drug binding to RNA polymerase. Monotherapy rapidly leads to resistance.
Isoniazid
Mechanism: ↓ synthesis of mycolic acids. Bacterial catalase-peroxidase (encoded by KatG) needed to convert INH to active metabolite. Clinical use: Mycobacterium tuberculosis. The only agent used as solo prophylaxis against TB.- Also used as monotherapy for latent TB.- Different INH half-lives in fast vs slow acetylators. Adverse effects: Hepatotoxicity, P-450 inhibition, drug-induced SLE, anion gap metabolic acidosis, vitamin B6 deficiency (peripheral neuropathy, sideroblastic anemia). Administer with pyridoxine (B6). Mechanism of resistance: Mutations leading to underexpression of KatG.
Pyrazinamide
Mechanism: Uncertain. Pyrazinamide is a prodrug that is converted to active compound pyrazinoic acid. Works best at acidic pH (eg, in host phagolysosomes). Clinical use: Mycobacterium tuberculosis Adverse effects: Hyperuricemia, hepatotoxicity.
Ethambutol
↓ carbohydrate polymerization of mycobacterium cell wall by blocking arabinosyltransferase. Clinical use: Mycobacterium tuberculosis Adverse effects: Optic neuropathy (red-green color blindness).
Streptomycin
Mechanism: Interferes with 30S component of ribosome Clinical use: Mycobacterium tuberculosis (2nd line) Adverse effects: Tinnitus, vertigo, ataxia, nephrotoxicity
Antimicrobial prophylaxis
High risk for endocarditis and surgical/dental procedures – Amoxicillin Exposure to gonorrhea – Ceftriaxone History of recurrent UTIs – TMP-SMX Prevention of gonococcal conjunctivitis in newborn – Erythromycin ointment on eyes Exposure to meningococcal infection – Ceftriaxone, ciprofloxacin, rifampin Pregnant woman carrying group B strep – Intrapartum penicillin G Prevention of gonococcal conjunctivitis in newborn – Erythromycin ointment on eyes Prevention of postsurgical infection due to S. aureus – Cefazolin (1st generation) Prophylaxis of strep pharyngitis in child with rheumatic fever – Benzathine penicillin G or oral penicillin V Exposure to syphilis – Benzathine penicillin G
Amphotericin B
Mechanism: Binds ergosterol (unique to fungi); forms membrane pores, allowing leakage of electrolytes. Clinical use: Serious, systemic mycosis. 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. Adverse effects: Fever/chills ("shake and bake"), hypotension, nephrotoxicity, arrhythmias, anemia, IV phlebitis. Hydration ↓ nephrotoxicity. Liposomal amphotericin ↓ toxicity.- Adverse effects are explained by the ability to bind cholesterol to a degree
Nystatin
Mechanism: Same as amphotericin B (binds ergosterol and forms membrane pores). - Topical use only as too toxic for systemic use. Clinical use: - "Swish and swallow" for oral candidiasis (thrush)- Topical for diaper rash or vaginal candidiasis
Flucytosine
Mechanism: Inhibits DNA and RNA biosythesis by conversion to 5-fluorouracil by cytosine deaminase. Clinical use: Systemic fungal infections (especially meningitis caused by Cryptococcus) in combination with amphotericin B. Adverse effects: Bone marrow suppression.
Azoles
Clotrimazole, fluconazole, isavuconazole, itraconazole, ketoconazole, miconazole, voriconazole Mechanism: Inhibit fungal sterol (ergosterol) synthesis by inhibiting the cytochrome P-450 enzyme that converts lanosterol to ergosterol (14α-demethylase). Clinical use: Local and less serious systemic mycoses. - Fluconazole for chronic suppression of cryptococcal meningitis in AIDS patients and candidal infections of all types. - Itraconazole for Blastomyces, Coccidioides, Histoplasma. - Clotrimazole and miconazole for topical fungal infections. - Voriconazole for Aspergillus and some Candida. - Isavuconazole for serious Aspergillus and Mucor infections. Adverse effects: Testosterone synthesis inhibition (gynecomastia, especially with ketoconazole), liver dysfunction (inhibits cytochrome P-450).
Terbinafine
Mechanism: Inhibits the fungal enzyme squalene epoxidase. Clinical use: Dermatophytoses (especially onychomycosis – fungal infection of finger or toe nails) Adverse effects: GI upset, headaches, hepatotoxicity, taste disturbance.
Chloroquine
Mechanism: Blocks detoxification of heme into hemozoin. Heme accumulates and is toxic to plasmodia. Clinical use: Treatment of plasmodial species other than P falciparum (frequency of resistance in P falciparum is too high). - Resistance due to membrane pump that ↓ intracellular concentration of drug. - Treat P falciparum with arthemethur/lumefantrine or atovaquone/proguanil. - For life-threatening malaria, use quinidine in US (quinine elsewhere) or artesunate. Adverse effects: Retinopathy; pruritus (especially in dark-skinned individuals).
Oseltamivir, zanamivir
Mechanism: Inhibit influenza neuraminidase → ↓ release of progeny virus. Clinical use: Treatment and prevention of both influenza A and B. - Beginning therapy within 48 hours of symptom onset may shorten duration of illness.
Acyclovir, valacyclovir, famciclovir
Mechanism: Guanosine analogs. Monophosphorylated by HSV/VZV thymidine kinase and not phosphorylated in uninfected cells. Triphosphate formed by cellular enzymes. Preferentially inhibit viral DNA polymerase by chain termination. Clinical use: HSV and VZV. Weak activity against EBV. No activity against CMV. - Used for HSV-induced mucocutaneous and genital lesions as well as for encephalitis.- Prophylaxis in immunocompromised patients. - No effect on latent forms of HSV and VZV. - Valacyclovir, a prodrug of acyclovir, has better oral bioavailability.- For herpes zoster, use famciclovir. Adverse effects: Obstructive crystalline nephropathy and acute renal failure if not adequately hydrated. Mechanism of resistance: Mutated viral thymidine kinase.
Ganciclovir
Mechanism: Guanosine analog. 5'-monophosphate formed by a CMV viral kinase. Triphosphate formed by cellular kinases. Preferentially inhibits viral DNA polymerase. Clinical use: CMV, especially in immunocompromised patients. - Valganciclovir, a prodrug of ganciclovir, has better oral bioavailability. Adverse effects: Bone marrow suppression (leukopenia, neutropenia, thrombocytopenia), renal toxicity. More toxic to host than acyclovir. Mechanism of resistance: Mutated viral kinase.
Foscarnet
Mechanism: Viral DNA/RNA polymerase inhibitor and HIV reverse transcriptase inhibitor. Binds to pyrophosphate-binding site of enzyme. Does not require any kinase activation. Clinical use: CMV retinitis in immunocompromised patients when ganciclovir fails; acyclovir-resistant HSV. Adverse effects: Nephrotoxicity, electrolyte abnormalities (hypo- or hypercalcemia, hypo- or hyperphosphatemia, hypokalemia, hypomagnesemia) can lead to seizures. Mechanism of resistance: Mutated DNA polymerase.
NNRTIs
Delavirdine, Nevirapine, Efavirenz Bind to reverse transcriptase at site different from NRTIs.- Do not require phosphorylation to be active or compete with nucleotides. Adverse effects:- Rash and hepatotoxicity are common to all NNRTIs- Vivid dreams and CNS symptoms (efavirenz)- Delavirdine and efavirenz are contraindicated in pregnancy
NRTIs
Abacavir (ABC), Didanosine (ddI), Emtricidabine (FTC), Lamivudine (3TC), Stavudine (d4T), Zidovudine (ZVD, formerly AZT), Tenofovir (TDF) - Competitively inhibit nucleotide binding to reverse transcriptase and terminate the DNA chain (lack a 3'-OH group).- Tenofovir is a nucleotide.- All needed to be phosphorylated to be active.- Zidovudine can be used for general prophylaxis and during pregnancy to ↓ risk of fetal transmission. Adverse effects: - Bone marrow suppression → neutropenia, anemia- Peripheral neuropathy- Lactic acidosis - Didanosine/stavudine: pancreatitis- Abacavir contraindicated if patient has HLA-B*5701 mutation due to ↑ risk of hypersensitivity.- HIV-associated lipodystrophy
Protease inhibitors
Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinavir, Ritonavir, Saquinavir- All protease inhibitors end in -navir. 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.- Ritonavir can "boost" other drug concentrations by inhibiting cytochrome P-450. Adverse effects: Hyperglycemia, GI intolerance, lipodystrophy (Cushing-like syndrome). - Indinavir: Urolithiasis, hematuria, thrombocytopenia.- Rifampin (potent CYP/UGT inducer) reduces protease inhibitor concentrations; use rifabutin instead.
Hepatitis C therapy
Chronic HCV infection is treated with different combinations of the following drugs; none is approved as monotherapy. Ribavarin also used to treat RSV (palivizumab preferred in children). Ledipasvir: Viral phosphoprotein (NS5A) inhibitor; NS5A plays important role in replication. Ribavirin: Inhibits synthesis of guanine nucleotides by competitively inhibiting inosine monophosphate dehydrogenase.- Adverse effects: Hemolytic anemia, severe teratogen Sofosbuvir: Inhibits HCV RNA-dependent RNA polymerase (NS5B) acting as a chain terminator- Adverse effects: Fatigue, headache, nausea Simeprevir: HCV protease (NS3/4A); prevents viral replication.- Adverse effects: Photosensitivity reactions, rash
Monobactams
Aztreonam Mechanism: Same as penicillin/cephalosporins. Prevents peptidoglycan cross-linking by binding to penicillin-binding protein 3.- Resistant to β-lactamases- Synergistic with aminoglycosides- No cross-allergenicity with penicillins Uses:- Gram ⊝ rods only – no activity against gram ⊕ rods or anaerobes.- For penicillin-allergic patients and those with renal insufficiency who cannot tolerate aminoglycosides. Adverse effects: Usually nontoxic; occasional GI upset.
Antimicrobials to avoid in pregnancy
- Aminoglycosides (Ototoxicity)- Fluoroquinolones (Cartilage damage)- Sulfonamides (Kernicterus)- Tetracyclines (Discolored teeth, inhibition of bone growth)- Clarithromycin (Embryotoxic)- Ribavarin (Teratogenic)- Griseofulvin (Teratogenic)- Chloramphenicol (Gray baby syndrome)
