Antibiotics: Resistance, Mechanisms, Classes, Uses and Adverse Effects

Bactericidal vs bacteriostatic

Bactericidal kills (only growing bacteria); bacteriostatic only halts growth

Why are tetracycline + penicillin antagonistic?

Bacteriostatic tetracycline stops the growth that bactericidal penicillin needs

Why prefer narrow-spectrum antibiotics?

Hit few microbes, less resistance, spare normal flora (fewer superinfections)

Superinfection

New infection during treatment when normal flora is killed (C. diff, thrush, vaginal candidiasis)

Synergism example

Trimethoprim + sulfamethoxazole (1+1 much greater than 2)

Acquired vs innate resistance

Acquired = gene species didn't have (plasmids, big clinical problem); innate = chromosomal trait of whole species

Resistome

All antibiotic resistance genes that exist, known or unknown

Persisters

Dormant bacteria with shut-down metabolism; antibiotics need active processes so they survive; cause chronic infection

Resistance mechanisms (list)

Beta-lactamases, target mutations, porin loss, efflux pumps, plasmids

Penicillin MOA

Beta-lactam ring binds PBPs, blocks transpeptidase cross-linking, activates autolysins; bactericidal

Penicillin resistance mechanism

Bacteria make beta-lactamase (penicillinase)

Penicillinase-resistant penicillins (NOD)

Nafcillin, Oxacillin, Dicloxacillin; target Staph aureus

Aminopenicillins

Ampicillin (IV) and amoxicillin (oral); wider gram-negative coverage

Antipseudomonal penicillins

Piperacillin and ticarcillin

Augmentin = ?

Amoxicillin + clavulanic acid (beta-lactamase inhibitor)

Unasyn = ?

Ampicillin + sulbactam

Zosyn = ?

Piperacillin + tazobactam

Most common penicillin side effect

Allergic reaction; also GI upset and superinfection

Cross-allergy penicillin to cephalosporin

About 1%; cephalosporin may be used for mild allergy

Penicillin alternatives in allergy

Vancomycin, erythromycin, clindamycin

Probenecid + penicillin

Raises penicillin levels

Tetracycline + penicillin / oral contraceptive + penicillin

Tetracycline decreases penicillin effect; penicillin may decrease contraceptive efficacy

Cephalosporin trend as generation increases

More gram-negative coverage and more beta-lactamase resistance

1st gen cephalosporins

Cefazolin (IV, surgical prophylaxis), cephalexin (PO); poor CSF penetration

2nd gen cephalosporins

Cefuroxime, cefoxitin, cefotetan; poor CSF penetration

3rd gen cephalosporins

Ceftriaxone, cefotaxime, ceftazidime, cefdinir, cefixime; reach CSF; gram-negative meningitis

Which cephalosporin covers Pseudomonas?

Ceftazidime (3rd gen); cefepime (4th gen) also very broad

4th gen cephalosporin

Cefepime; very broad, meningitis, febrile neutropenia; poor vs MRSA and anaerobes

5th gen cephalosporin

Ceftaroline; covers MRSA but NOT Pseudomonas

Which cephalosporins reach CSF?

3rd, 4th, 5th generation (not 1st or 2nd)

Cephalosporins that cause bleeding and alcohol intolerance

Cefotetan (2nd) and ceftriaxone (3rd)

Ceftriaxone special warnings

Precipitates with calcium (neonates); eliminated by liver (others by kidney)

Carbapenems (list)

Imipenem, meropenem, ertapenem, doripenem

Carbapenems: what they do NOT cover

MRSA

Imipenem is given with?

Cilastatin (dipeptidase inhibitor prevents kidney breakdown)

Carbapenem seizure risk

Seizures, especially with valproate

Vancomycin spectrum

Narrow, gram-positive: MRSA, Staph epidermidis, enterococci, C. diff

Vancomycin adverse effects

Vancomycin flushing syndrome (infuse slowly), ototoxicity (may be permanent), nephrotoxicity

C. diff drugs most likely to cause it

Clindamycin, 2nd/3rd gen cephalosporins, fluoroquinolones

C. diff treatment

Stop offending antibiotic; switch to vancomycin or metronidazole

Tetracycline drugs

Tetracycline, demeclocycline, doxycycline, minocycline

Tetracycline drug of choice for

Rickettsiae (RMSF), Mycoplasma, Chlamydia, Lyme, syphilis, cholera, anthrax

Tetracycline adverse effects

Teeth staining/bone growth problems, photosensitivity, GI upset, hepatotoxicity

Tetracycline absorption problem

Calcium, antacids, dairy chelate it; doxy/mino taken WITH food for GI upset

Macrolides (list)

Erythromycin, clarithromycin, azithromycin, dirithromycin

Erythromycin big adverse effects

GI upset (most), QT prolongation/sudden cardiac death, cholestatic jaundice (estolate)

Macrolides for dental prophylaxis

Clarithromycin and azithromycin (not erythromycin or dirithromycin)

Clindamycin (lincosamide) uses

Anaerobes (Bacteroides), lung abscess, aspiration pneumonia, bone infections

Clindamycin special risk

High-risk cause of C. diff; gut effect up to 2 weeks

Aminoglycosides (list)

Gentamicin, tobramycin, amikacin, neomycin, streptomycin

Aminoglycoside adverse effects

Ototoxicity, nephrotoxicity, neuromuscular blockade, neuropathy

Streptomycin also treats?

Mycobacterium tuberculosis

Sulfonamide MOA

Block folic acid synthesis; bacteriostatic

Sulfonamide key adverse effects

Crystalluria (drink lots of water); allergy/rash, skin reactions

Fluoroquinolone MOA

Inhibit DNA gyrase

Fluoroquinolone adverse effects

Tendon rupture (Achilles), cartilage damage, QT prolongation, hypoglycemia; avoid in pregnancy

Metronidazole spectrum

Anaerobes only (Bacteroides, Fusobacterium, C. diff); also trichomonas, ameba, giardia

Metronidazole adverse effects

Metallic taste, GI cramping, dark/reddish-brown urine, neuropathy

Active TB induction phase

2 months, 4 drugs: isoniazid, rifampin, pyrazinamide, ethambutol

Active TB continuation phase

4 months, isoniazid + rifampin

Why DOT for TB?

Directly observed therapy improves adherence; nonadherence is most common cause of resistance

Latent TB regimens

INH daily x 9 months OR INH + rifapentine weekly x 3 months

MDR-TB

Resistant to isoniazid AND rifampin

XDR-TB

Resistant to INH, rifampin, all fluoroquinolones, and at least one injectable second-line agent

Second-line TB drugs

Fluoroquinolones, injectables (kanamycin, amikacin, capreomycin, streptomycin), PAS, ethionamide, cycloserine

TB + HIV drug problem

Rifampin induces CYP450 and lowers protease inhibitor/NNRTI levels

Rifamycin preferred in HIV

Rifabutin (watch uveitis)

RIPE

Rifampin, Isoniazid, Pyrazinamide, Ethambutol

Isoniazid adverse effects

Hepatotoxicity and peripheral neuropathy (B6 deficiency)

Isoniazid neuropathy fix

Pyridoxine (vitamin B6); higher risk with alcoholism and diabetes

Isoniazid + phenytoin

INH inhibits CYP450 so phenytoin rises; decrease phenytoin dose (watch ataxia)

Rifampin patient teaching

Orange body fluids; empty stomach; induces CYP450 (affects contraceptives, warfarin, HIV drugs)

Rifampin most common adverse effect

Hepatitis

Pyrazinamide adverse effects

Hepatotoxicity and non-gouty polyarthralgias (joint pain)

Ethambutol adverse effect

Dose-related optic neuritis (stop drug; clears); bacteriostatic

Bedaquiline

First new TB drug in 40+ years; for resistant TB; Black Box: QT prolongation and hepatotoxicity

Bedaquiline advantage in HIV

Does not speed metabolism of other drugs

Terbinafine MOA

Inhibits squalene epoxidase, blocking ergosterol synthesis

Terbinafine uses

Tinea pedis/cruris/corporis (topical); oral for tinea capitis and onychomycosis

Terbinafine adverse effects

Headache, taste change, rash, hepatotoxicity, SJS, neutropenia, visual disturbances

Polyene MOA (ampho B, nystatin)

Bind ergosterol, form channels, cell leaks cations

Amphotericin B use

Deep, severe systemic mycoses (invasive candidiasis, aspergillosis, cryptococcal meningitis)

Amphotericin B infusion reactions

Fever, chills, rigors, nausea, headache; premedicate with acetaminophen + diphenhydramine

Amphotericin B toxicity

Renal damage in ALL patients (dose related), hypokalemia, bone marrow suppression

Nystatin use

Superficial candidiasis; topical drug of choice for oral thrush

Azole MOA

Inhibit enzyme for fungal ergosterol synthesis; also inhibit CYP450 (main drug interaction problem)

Fluconazole uses

Cryptococcal meningitis, candidiasis, blastomycosis, histoplasmosis; HIV mucosal prophylaxis

Fluconazole adverse effects

GI upset, alopecia, QT/cardiotoxicity, hepatotoxicity; teratogenic at high dose in 1st trimester

Ketoconazole absorption

Needs acidic stomach; antacids and H2 blockers decrease absorption

Ketoconazole toxicity

Severe hepatotoxicity; inhibits testosterone/estradiol (gynecomastia, menstrual irregularity)

Tolnaftate

Topical thiocarbamate for superficial skin/nail infection; ineffective vs yeast

Clotrimazole / Miconazole

Topical azoles; clotrimazole also intraoral; miconazole 2% cream for cutaneous/vaginal Candida

Log kill hypothesis

Each chemo cycle kills a constant FRACTION of tumor cells, not a fixed number

Why combination chemo?

Different mechanisms and non-overlapping toxicities; cancer must be sensitive to each drug

Tissues hit hardest by chemo

Fast-dividing: bone marrow, hair follicles, GI tract, gonads, wounds, fetus

Common chemo toxicities

Myelosuppression, alopecia, mucositis, N/V, diarrhea, impaired healing, teratogenicity

Neutropenia supportive drugs

Pegfilgrastim, sargramostim

Chemo anemia / thrombocytopenia drugs

Darbepoetin alfa (anemia); oprelvekin (thrombocytopenia)

Alkylating agent MOA

Covalently bind DNA (cross-linking); cell cycle non-specific

Cyclophosphamide / ifosfamide

Nitrogen mustard prodrugs activated by liver CYP450; toxic metabolite acrolein