Antimicrobials Flashcards
Pencillin G, V
MOA: Prototype β-lactam antibiotics. D-Ala-D-Ala structural analog. Bind PBPs (transpeptidases). Block transpeptidase cross-linking of peptidoglycan cell wall. Activate autolytic enzymes.
Use: Mostly used for gram ⊕ organisms (S pneumoniae, S pyogenes, Actinomyces). Also used for gram ⊕ cocci, gram ⊕ rods, gram ⊖cocci, and spirochetes. Penicillinase sensitive.
Adverse Effects: Hypersensitivity reactions, direct Coombs ⊕ hemoltyic anemia.
Resistance: Penicillinase in bacteria (a type of β-lactamase) cleaves β-lactam ring
Penicillinase-sensitive penicillins.
Amoxicillin, ampicillin, aminopenicillins
MOA: Wider spectrum. Also combine with clavulanic acid to protect against destruction against β-lactamase.
Use: Extended spectrum penicillin - H influenzae, H pylori, E coli, Listeria monocytogenes, Proteus mirabilis, Salmonella, Shigella, enterococci.
Adverse Effects: Hypersensitivity reactions; rash; pseudomembrane colitis.
Resistance: Pencillinase in bacteria cleaves β-lactam ring
Penicillinase-resistant penicilins
Dicloxacillin, nafcillin, oxacillin
MOA: Narrow spectrum; penicillinase resistant because bulky R rings blocks access of β-lactamases to β-lactam ring
Use: S aureus (except MRSA; resistant because of altered penicillin-binding protein target site)
Adverse Effects: Hypersensitivity reactions, interstitial nephritis
What are examples of β-lactamase inhibitors? How do they work?
Clavulanic acid, sulbactam, tazobactam.
Often added to penicillin antibiotics to protect the antibiotic from destruction by β-lactamases
Cephalosporins (MOA, Adverse Effects, and Mechanism of Resistance)
MOA: β-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases. Bactericidal.
Adverse Effects: Hypersensitivity reactions, autoimmune hemolytic anemia, disulfiram-like reaction, vitamin K deficiency. Exhibit cross-reactivity with penicillins. ↑ nephrotoxicity of aminoglycosides
Resistance: Structural change in penicillin-binding proteins (transpeptidases)
What are the 1st generation cephalosporins and what are they used for?
Cefazolin, cephalexin
Use: Gram ⊕ cocci, Proteus mirabilis, E coli, Klebsiella pneumoniae. Cefazolin used before surgery to prevent S aureus wound infections
What are the 2nd generation cephalosporins and what are they used for?
Cefaclor, cefoxitin, cefuroxime
Use: Gram ⊕ cocci, H influenzae, Enterobacter aerogenes, Neisseria spp., Serratia marcescens, Proteus mirabilis, E. coli, Klebsiella pneumoniae
What are the 3rd generation cephalosporins and what are they used for?
Ceftriaxone, cefotaxime, ceftazidime
Use: Serious gram ⊖ organisms resistant to other β-lactams
Ceftriaxone: meningitis, gonorrhea, disseminated Lyme disease
Ceftazidime: Pseudomonas
What are the 4th generation cephalosporins and what are they used for?
Cefepime
Use: Gram ⊖ organisms with ↑ activity against Pseudomonas and gram ⊕ organisms
What are the 5th generation cephalosporins and what are they used for?
Ceftaroline
Use: Broad gram ⊕ and gram ⊖ organisms, including MRSA; does not cover Pseudomonas.
Carbapenems
Imipenem, meropenem, ertapenem, doripenem
MOA: Imipenem is a broad-spectrum, β-lactamase-resistant carbapenem. Always administered with cilastatin (inhibitor of renal dehyropeptidase I) to ↓ inactivation of drug in renal tubules.
Use: Gram ⊕ cocci, gram ⊖ rods, and anaerobes. Wide spectrum, but significant side effects limit use to life-threatening infections or after other drugs have failed.
Adverse Effects: GI distress, skin rash, and CNS toxicity (seizures) at high plasma levels
Monobactams (aztreonam)
MOA: Less susceptible to β-lactamases. Prevents peptidoglycan cross-linking by binding to PBP 3. Synergistic with aminoglycosides. No cross-allergenicity with penicillins.
Use: Gram ⊖ rods - no activity against gram ⊕ rods or anaerobes. For penicillin-allergic patients ad those with renal insufficiency who cannot tolerate aminoglycosides.
Adverse Effects: Usually nontoxic; occasionally GI upset
Vancomycin
MOA: Inhibits cell wall peptidogylcan formation by binding D-ala D-ala portion of cell wall precursors. Bactericidal against most bacteria (bacteriostatic against C difficile). Not susceptible to β-lactamases.
Use: Gram ⊕ bugs only - serious, multidrug-resistant organisms including MRSA, S epidermidis, sensitive Enterococcus species, and C difficile
Adverse Effects: Well tolerated in general. Nephrotoxicity, ototoxicity, thrombophlebitis, diffuse flushing.
Mechanism of Resistance: Occurs in bacteria via amino acid modification of D-ala D-ala to D-ala D-lac
Aminoglycosides
Gentamicin, neomycin, amikacin, tobramycin, streptomycin
MOA: Bactericidal; irreversible inhibition of initiation complex through binding of 30S subunit. Can cause misreading of mRNA. Also block translocation. Require O2 for uptake; therefore ineffective for anaerobes.
Use: Severe gram ⊖ rod infectons. Synergistic with β-lactam antibiotics. Neomycin for bowel surgery
Adverse Effects: Nephrotoxicity, neuromuscular blockade, ototoxicity, teratogen.
Resistance: Bacterial transferase enzymes inactivate the drug by acetylation, phosphorylation, or adenylation.
Tetracyclines
Tetracycline, doxycycline, minocycline
MOA: Bacteriostatic; bind 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, antacids, or iron-containing preparations because divalent cations inhibit drug gut absorption.
Use: Borrelia burgdorferi, M pneumoniae. Drugs’ ability to accumulate intracellularly make them effective against Rickettsia and Chlamydia. Also used to treat acne.
Adverse Effects: GI distress, discoloration of teeth and inhibition of bone growth in children, photosensitivity. Contraindicated in pregnancy.
Resistance: ↓ uptake or ↑ efflux out of bacterial cells by plasmid-encoded transport pumps
Chloramphenicol
MOA: Blocks peptidyltransferase at 50S ribosomal subunit. Bacteriostatic.
Use: Meningitis (H influenzae, N meningitidis, S pneumoniae) and Rocky Mountain spotted fever (Rickettsia rickettsii)
Adverse Effects: Anemia (dose-dependent), aplastic anemia (dose-independent), gray baby syndrome (in premature infants because they lack liver UDPGT
Resistance: Plasmid-encoded acetyltransferase inactivates the drug
Clindamycin
MOA: Blocks peptide transfer (translocation) at 50S ribosomal subunit. Bacteriostatic.
Use: Anaerobic infections (Bacteroides spp, Clostridium perfringens) in aspiration pneumonia, lung abscesses, and oral infections. Also effective against invasive group A streptococcal infection.
Adverse Effects: Pseudomembrane colitis, fever, diarrhea.
Oxazolidinones (linezolid)
MOA: Inhibit protein synthesis by binding to 50S subunit and preventing formation of the initiation complex.
Use: Gram ⊕ species including MRSA and VRE
Adverse Effects: Bone marrow suppression (especially thrombocytopenia),peripheral neuropathy, serotonin syndrome.
Resistance: Point mutation of ribosomal RNA.
Macrolides
Azithromycin, clarithromycin, erythromycin.
MOA: Inhibit protein synthesis by blocking translocation; bind to the 23S rRNA of the 50S ribosomal subunit. Bacteriostatic.
Use: Atypical pneumonias (Mycoplasma, Chlamydia, Legionella), STIs (chlamydia), gram ⊕ cocci (streptococcal infections), and B pertussis.
Adverse Effects: GI motility issues, Arrhythmia caused by prolonged QT interval, acute cholestatic hepatitis, rash, eosinophilia. Increases concentration of theophyline, oral anticoagulants. Clarithromycin and erythromycin inhibit cytochrome P-450.
Resistance: Methylation of 23S rRNA-binding site prevents binding of drug.
Sulfonamides
Sulfamethoxazole (SMX), sulfisoxazole, sulfadiazine
MOA: Inhibit dihydropteroate synthase, thus inhibiting folate synthesis. Bacteriostatic (bactericidal when combined with trimethoprim)
Use: Gram-⊕, gram ⊖, Nocardia, Chlamydia, SMX for simple UTI
Adverse Effects: Hypersensitivity reactions, hemolysis if G6PD deficient, nephrotoxicity (interstitial nephritis), photosensitivity, kernicterus in infants, displace other drugs from albumin (eg. warfarin)
Resistance: Altered enzyme (bacterial dihydropteroate synthase), ↓ uptake, or ↑ PABA synthesis
Dapsone
MOA: Similar to sulfonamides (but structurally distinct)
Use: Leprosy (lepromatous and tuberculoid), Pneumocystis jiroveii prophylaxis
Adverse Effects: Hemolysis if G6PD deficient
Trimethoprim
MOA: Inhibits bacterial dihydrofolate reductase. Bacteriostatic.
Use: Used in combination with sulfonamides, causing sequential block of folate synthesis. Combination used for UTIs, Shigella, Salmonella, Pneumocystis jirovecii pnuemonia treatment and prophylaxis, toxoplasmosis prophylaxis.
Adverse Effects: Bone marrow suppression (megaloblastic anemia, leukopenia, granulocytopenia). May alleviate with supplemental folic acid.
Fluoroquinolones
Ciprofloxacin, norfloxacin, levofloxacin, ofloxacin, moxifloxacin, gemifloxacin, enxoacin
MOA: Inhibit prokaryotic enzymes topoisomerase II (DNA gyrase) and topoisomerase IV. Bactericidal.
Contraindications: Must not be taken with antacids. Pregnant, nursing women, and children and in patients taking prednisone.
Resistance: Chromosome-encoded mutation in DNA gyrase, plasmid-mediated resistance, efflux pumps
Daptomycin
MOA: Lipopeptide that disrupts cell membrane of gram ⊕ cocci.
Use: S aureus skin infections (especially MRSA), bacteremia, endocarditis, VRE.
Adverse Effects: Myopathy, rhabdomyolysis.
Metronidazole
MOA: Forms toxic free radical metabolites in the bacterial cell that damage DNA. Bactericidal, antiprotozoal.
Use: Treats Giardia, Entamoeba, Trichomonas, Gardnerella vaginalis, Anaerobes (Bacteroides, C difficile). Used with a proton pump inhibitor and clarithromycin for “triple therapy” against H pylori.
Adverse Effects: Disulfiram-like reaction (severe flushing, tachycardia, hypotension) with alcohol; headache, metallic taste
Prophylaxis and treatment for M tuberculosis
Prophylaxis: Isoniazid
Treatment: Rifampin, Isoniazid, Pyrazinamide, Ethambutol
Prophylaxis and treatment for M avium - intracellulare
Prophylaxis: Azithromycin, rifabutin
Treatment: More drug resistant than M tuberculosis. Azithromycin or clarithromycin +/ ethambutol. Can add rifabutin or ciprofloxacin.
Treatment of M leprae
Long-term treatment with dapsone and rifampin for tuberculoid form. Add clofazimine for lepromatous form.
Rifamycins
Rifampin, rifabutin
4 Rs: RNA polymerase inhibitor, Ramps up microsomal cytochrome P-450, Red/orange body fluids, Rapid resistance if used alone.
MOA: Inhibit DNA-dependent RNA polymerase
Use: Mycobacterium tuberculosis; delay resistance to dapsone when used for leprosy. Used in meningococcal prophylaxis and chemoprophylaxis in contacts of children with Haemophilus influenza type B.
Adverse Effects: Minor hepatotoxicity and drug interactions (↑ cytochrome P-450); orange body fluids (nonhazardous side effect). Rifabutin favored over rifampin in patients with HIV infection due to less cytochrome P-450 stimulation.
Resistance: Mutations reduce drug binding to RNA polymerase. Monotherapy rapidly leads to resistance.
Isoniazid
MOA: ↓ synthesis of mycolic acids. Bacterial catalase-peroxidase (encoded by KatG) needed to convert INH to active metabolites.
Use: M tuberculosis (only agent used as solo prophylaxis, also used as monotherapy for latent TB)
Adverse Effects: Hepatotoxicity, P-450 inhibition, drug-induced SLE, vitamin B6 deficiency (peripheral neuropathy, sideroblastic anemia). Administer with vitamin B6
Resistance: Mutations leading to underexpression of KatG
Pyrazinamide
MOA: Mechanism uncertain. Pyrazinamide is a prodrug that is converted to the active compound pyrazinoic acid. Works best at acidic pH (eg in host phagolysosomes)
Use: M tuberculosis
Adverse Effects: Hyperuriemia, hepatotoxicity
Ethambutol
MOA: ↓ carbohydrate polymerization of mycobacterium cell wall by blocking arabinosyltransferase
Use: M tuberculosis
Advers Effects: Optic neuropathy (red-green color blindness)
Streptomycin
MOA: Interferes with 30S component of ribosome.
Use: M tuberculosis (2nd line)
Adverse Effects: Tinnitus, vertigo, ataxia, nephrotoxicity
Prophylaxis for patients with high risk for endocarditis and undergoing surgical or dental procedures
Amoxicillin
Prophylaxis after exposure to gonorrhea
Ceftriaxone
Prophylaxis for a history of recurrent UTIs
TMP-SMX
Prophylaxis after exposure to meningococcal infection
Ceftriaxone, ciprofloxacin, or rifampin
Prophylaxis for pregnant woman carrying group B strep
Intrapartum penicillin G or ampicillin
Prophylaxis for prevention of gonococcal conjunctivitis in newborn
Erythromycin ointment
Prophylaxis for prevention of postsurgical infection due to S aureus
Cefazolin
Prophylaxis for strep pharyngitis in child with prior rheumatic fever
Benzathine penicillin G or oral penicillin V
Prophylaxis for exposure to syphilis
Benzathine penicillin G
Treatment of MRSA
Vancomcyin, daptomycin, linezolid, tigecycline, ceftaroline
Treatment of VRE
Linezolid and streptogramins (quinupristin, dalfopristin)
Treatment of multi-drug resistant P aeruginosa, Acinetobacter baumannii
Polymyxins B and E (colistatin) (Bind to, disrupt, and interfere with permeability of cytoplasmic membrane)
Amphotericin B
MOA: Binds ergosterol; forms membrane pore that allows leakage of electrolytes
Use: Serious, systemic mycoses. Cryptococcus, Blastomyces, Coccidioides, Histoplasma, Candida, Mucro. Intrathecally for fungal meningitis Suppmement K+ and Mg2+ because of altered renal tubule permeability.
Adverse Effects: Fever/chills, hypotension, nephrotoxicity, arrhythmias, anemia IV phlebitis. Hydration ↓ nephrotoxicity. Liposomal amphotericin ↓ toxicity
Nystatin
MOA: Binds ergosterol; forms membrane pores that allow leakage of electrolytes. Topical use only as too toxic for systemic use.
Use: “Swish and swallow” for oral candidiasis; topical for diaper rash or vaginal candidiasis
Flucytosine
MOA: Inhibits DNA and RNA biosynthesis by conversion to 5-fluorouracil by cytosine deaminase
Use: Systemic fungal infections (especially meningitis caused by Cryptococcus) in combination of amphotericin B
Adverse Effects: Bone marrow suppression
Azoles
Clotrimazole, fluconazole, itraconazole, ketoconazole, miconazole, voriconazole
MOA: Inhibit fungal sterol (ergosterol) synthesis by inhibiting the cytochrome P-450 enzyme that converts lanosterol to ergosterol
Use: Local and less serious systemic mycoses.
Fluconazole: Chrnic suppression of cryptococcal meningitis in AIDS patients and candidal infection of all types
Itraconazole: Blastomyces, Coccidioides, Histoplasma
Clotrimazole & miconazole: Topical fungal infections
Adverse Effects: Testosterone synthesis inhibition (gynecomastia), liver dysfunction (inhibits cytochrome P-450).
Terbinafine
MOA: Inhibits the fungal enzyme squalene epoxidase
Use: Dermatophytoses (especially onychomycosis - fungal infection of finger or toe nails)
Adverse Effects: GI upset, headaches, hepatotoxicity, taste disturbance
Echinocandins
Anidulafungin, caspofungin, micafungin
MOA: Inhibit cell wall synthesis by inhibiting synthesis of β-glucan.
Use: Invasive aspergillosis, Candida.
Adverse Effects: GI upset, flushing (by histamine release)
Griseofulvin
MOA: Interferes with microtubule function; disrupts mitosis. Deposits in keratin-containing tissue (nails)
Use: Oral treatment of superficial infections; inhibits growth of dermatophytes (tinea, ringworm)
Adverse Effects: Teratogenic, carcinogenic, confusion, headaches, ↑ cytochrome P-450 and warfarin metabolism
Treatment of toxoplasmosis
Pyrimethamine
Treatment of Trypanosoma brucei
Suramin and melarsoprol
Treatment of T cruzi
Nifurtimox
Treatment of leishmaniasis
Sodium stibogluconate
Anti-mite/louse therapy
Permethrin (blocks Na+ channels → neurotoxicity)
Malathion (acetylcholinesterase inhibitor)
Lindane (Blocks GABA channels → neurotoxicity)
Used to treat scabies (Sarcoptes scabiei) and lice (Pediculus and Pthirus)
“Prevent Mite/Louse with PML (permethrin, malathion, lindane) because they NAG you (Na+, acetylcholinesterase, GABA)”
Chloroquine
MOA: Blocks detoxification of heme into hemozoin. Heme accumulates and is toxic to plasmodia
Use: Treatment of plasmodial species other than P falciparum.
Adverse Effects: Retinopathy; pruritis
Resistance: Membrane pump that ↓ intracellular concentration of drug
Treatment of P falciparum
Artemether/lumefantrine or atovaquone/progaunil.
For life-threatening malaria, use quinidine in US or artesunate
Antihelminthic therapy
Mebendazole (microtubule inhibitor), pyrantel pamoate, ivermectin, diethylcarbamazine, praziquantel
Oseltamivir, zanamivir
MOA: Inhibit influenza neuraminidase → ↓ release of progeny virus
Use: Treatment & prevention of influenza A & B
Acyclovir, famciclovir, valacyclovir
MOA: Guanosine analogs. Monophosphorylated by HSV/VZV thymidine kinase and not phosphorylated in uninfected cells → few adverse effects. Triphosphate formed by cellular enzymes. Preferentially inhibit viral DNA polymerase by chain termination.
Use: HSV and VZV. Weak activity against EBV. Used for HSV-induced mucocutaneous and genital lesions as well as for encephalitis. No effect on latent forms of HSV or VZV.
Valacyclovir: Prodrug of acyclovir, better oral availability
Famciclovir: Herpes zoster
Adverse Effects: Obstructive crystalline nephropathy and acute renal failure if not adequately hydrated
Resistance: Mutated viral thymidine kinase
Ganciclovir
MOA: 5’-monophosphate formed by a CMV viral kinase. Guanosine analog. Triphosphate formed by cellular kinases. Preferentially inhibits viral DNA polymerase.
Use: CMV, especially immunocompromised patients. Valganciclovir (prodrug of ganciclovir) has better oral bioavailability.
Adverse Effects: Bone marrow suppression (leukopenia, neutropenia), thromboctopenia), renal toxicity. More toxic to host enzymes than acyclovir.
Resistance: Mutated viral kinase.
Foscarnet
MOA: Viral DNA/RNA polymerase inhibitor and HIV reverse transcriptase inhibitor. Binds to pyrophosphate-binding site of enzyme. Does not require any kinase activation.
Use: CMV retinitis in immunocompromised patients when ganciclovir fails; acyclovir-resistant HSV.
Adverse Effects: Nephrotoxicity, electrolyte abnormalities (hypo- or hypercalcemia, hypo- or hyperphosphatemia, hypokalemia, hypomagnesmia) can lead to seizures.
Resistance: Mutated DNA polymerase
Cidofovir
MOA: Preferentially inhibits viral DNA polymerase. Does not require phosphorylation by viral kinase..
Use: CMV retinitis in immunocompromised patients; acyclovir-resistant HSV. Long half-life.
Adverse Effects: Nephrotoxicity (coadministered with probenecid and IV saline to ↓ toxicity)
NRTIs
Abacavir (ABC), didanosine (ddI), emtricitabine (FTC), lamivudine (3TC), stavudine (d4T), tenofovir (TDF), zidovudine (ZDV)
MOA: Competitively inhibit nucleotide binding to reverse transcriptase and terminate the DA Chain (lack a 3’ OH group). Tenofovir is a nucleotide and the others are nucleosides (need to be phosphorylated to be active)
Use: HAART; ZDV can be used for general prophylaxis and during pregnancy to ↓ risk of fetal transmission
Toxicity: Bone marrow suppression (can be reversed with G-CSF and erythropoietin), peripheral neuropathy, lactic acidosis (nucleosides), anemia (ZDV), pancreatitis (ddI).
Contraindications: Abacvir if patient has HLA-B*5701 mutation
NNRTIs
Delavirdine, Efavirenz, Nevirapine
MOA: Bind to reverse transcriptase at site different from NRTIs. Do not require phosphorylation to be active of compete with nucleotides.
Toxicity: Rash and hepatotoxicity.
Efavirenz: Vivid dreams and CNS symptoms
Delavirdine & efavirenz: Contraindicated in pregnancy
Protease inhibitors
Atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, ritonavir, saquinavir
MOA: Assembly of virions depends on HIV-1 protease (pol gene), which cleaves the polypeptide products of HIV mRNA into their functional parts. Protease inhibitors prevent maturation of new viruses.
Toxicity: Hyperglycemia, GI intolerance (nausea, diarrhea), lipodystrophy (Cushing-like syndrome).
Indinavir: Nephropthy, hematuria
Contraindications: Rifampin (decreases protease inhibitor concentration)
Integrase inhibitors
Raltegravir, elvitegravir, dolutegravir
MOA: Inhibits HIV genome integration into host cell chromosome by reversibly inhibiting HIV integrase.
Toxicity: ↑ creatine kinase
Enfurvitide
MOA: Binds gp41, inhibiting HIV viral entry
Toxicity: Skin reaction at injection sites
Maraviroc
MOA: Binds CCR-5 on surface of T cells/monocytes, inhibiting HIV interaction with gp120
Interferons (MOA & Adverse Effects)
MOA: Glycoproteins normally synthesized by virus-infected cells, exhibiting a wide range of antiviral and antitumoral properties
Adverse Effects: Flu-like symptoms, depression, neutropenia, myopathy
IFN-α (Uses)
Chronic HBV and HCV, Kaposi sarcoma, hairy cell leukemia, condyloma acuminatum, renal cell carcinoma, malignant melanoma
IFN-β (Uses)
Multiple sclerosis
IFN-γ (Uses)
Chronic granulomatous disease
Ribavirin
MOA: Inhibits synthesis of guanine nucleotides by competitively inhibiting inosine monophosphate dehydrogenase
Use: Chronic HSV; also used in RSV
Adverse Effects: Hemolytic anemia; severe teratogen
Sofosbuvir
MOA: Inhibits HCV RNA-dependent RNA polymerase acting as a chain terminator
Use: Chronic HCV in combination with ribavirin, +/- peginterferon-α
Adverse Effects: Fatigue, headache, nausea
Simpeprevir
MOA: HCV protease inhibitor; prevents viral replication
Use: Chronic HCV in combinationg with ledipasvir (NS5A inhibitor)
Adverse Effects: Photosensitivity reactions, rash
