4.2 Non-Beta-Lactam Antibacterials

Macrolides

Macrolides — azithromycin, clarithromycin, erythromycin — bind the 50S ribosomal subunit, blocking translocation and protein synthesis; they are generally bacteriostatic. Their clinical value is coverage of atypical pathogens (Legionella, Mycoplasma pneumoniae, Chlamydophila) plus respiratory streptococci, making azithromycin a partner to ceftriaxone in community-acquired pneumonia. Azithromycin's very long half-life allows once-daily 3–5 day courses; clarithromycin is a component of Helicobacter pylori eradication regimens.

Exam-critical cautions: clarithromycin and erythromycin are potent CYP3A4 inhibitors — co-prescription with simvastatin can precipitate rhabdomyolysis, and levels of many substrates (some calcium-channel blockers, DOACs) rise. All macrolides prolong the QT interval and should be used cautiously with other QT-prolonging drugs or in congenital long-QT. Erythromycin also causes dose-related gastrointestinal motility stimulation (nausea, cramping).

Fluoroquinolones

Fluoroquinolones — ciprofloxacin, levofloxacin, moxifloxacin — inhibit bacterial DNA gyrase (topoisomerase II) and topoisomerase IV, and are bactericidal with concentration-dependent killing. Ciprofloxacin is the most active against Pseudomonas and is used for complicated UTIs and gastroenteritis; levofloxacin and moxifloxacin are "respiratory" fluoroquinolones with reliable Streptococcus pneumoniae cover. Moxifloxacin adds anaerobic activity but is not used for UTIs because urinary excretion is poor, and it carries the greatest QT prolongation of the class.

Safety profile the DHA exam loves: tendinopathy and Achilles tendon rupture (risk increases over age 60, with corticosteroid use, and after organ transplantation); avoidance in pregnancy and children because of cartilage toxicity in juvenile animal studies; QT prolongation; dysglycemia; CNS effects including confusion and rare seizures; photosensitivity; and an association with aortic aneurysm/dissection in at-risk patients. Chelation is a classic dispensing question: divalent and trivalent cations — calcium, iron, magnesium, zinc, antacids, sucralfate, dairy — bind fluoroquinolones and block absorption, so administration should be separated (typically take the antibiotic 2 hours before or 4–6 hours after the cation).

Tetracyclines

Doxycycline (and the older tetracyclines) binds the 30S ribosomal subunit, is bacteriostatic, and covers atypicals, rickettsiae, chlamydia, Borrelia (Lyme disease), acne, and malaria prophylaxis. Key counseling points: photosensitivity (advise sun protection), pill esophagitis (take with a full glass of water and remain upright for at least 30 minutes), and chelation by the same cations as fluoroquinolones. Tetracyclines are contraindicated in pregnancy and in children under 8 years because they chelate calcium in developing teeth and bone, causing permanent discoloration. Doxycycline is the exception that does not need renal dose adjustment.

Aminoglycosides

Gentamicin (with tobramycin and amikacin) binds the 30S subunit, causes misreading of mRNA, and is bactericidal with concentration-dependent killing and a post-antibiotic effect — the pharmacodynamic rationale for extended-interval (once-daily) dosing, which maximizes the peak-to-MIC ratio while reducing toxicity. Spectrum is aerobic gram-negative bacilli; gentamicin is also used at low, synergistic doses with a beta-lactam for gram-positive endocarditis. Aminoglycosides are not absorbed orally and are eliminated renally, so therapeutic drug monitoring is mandatory: peak and trough levels (or a random level on the nomogram) with once-daily dosing. Toxicity is the exam focus: nephrotoxicity (usually reversible acute tubular necrosis) and ototoxicity (vestibular and cochlear, potentially irreversible), worsened by loop diuretics, vancomycin, and prolonged courses.

Vancomycin

Vancomycin is a glycopeptide that binds the D-Ala-D-Ala terminus of peptidoglycan precursors, blocking cell-wall synthesis. It covers gram-positives only, including MRSA, and is given intravenously for serious infections; oral vancomycin is not absorbed and is used purely for Clostridioides difficile colitis. Monitoring has moved to AUC/MIC-guided dosing with a target ratio of 400–600 (assuming a MIC of 1 mg/L); where trough-based monitoring is still used, troughs of 15–20 mg/L are targeted for serious MRSA infections such as bacteremia, endocarditis, and pneumonia. Toxicities: nephrotoxicity (additive with aminoglycosides and piperacillin-tazobactam), ototoxicity at high levels, and the red-man (vancomycin infusion) reaction — flushing and pruritus of the face, neck, and torso from histamine release when infused too quickly. It is not an allergy: slow the infusion over at least 60–120 minutes and premedicate with an antihistamine if needed.

Folate Antagonists, Nitrofurantoin, and the Anaerobe Agents

Trimethoprim-sulfamethoxazole (co-trimoxazole) sequentially blocks folate synthesis — sulfamethoxazole inhibits dihydropteroate synthase and trimethoprim inhibits dihydrofolate reductase — giving bactericidal synergy against urinary pathogens, Pneumocystis jirovecii pneumonia (treatment and prophylaxis), and MRSA skin infections. High-yield problems: trimethoprim inhibits CYP2C9, raising S-warfarin levels and spiking the INR; it blocks renal sodium channels (ENaC) like a potassium-sparing diuretic, causing hyperkalemia — dangerous with ACE inhibitors, ARBs, and spironolactone — and raises serum creatinine by inhibiting tubular secretion without truly reducing GFR. Additional risks: sulfa allergy including Stevens-Johnson syndrome, bone-marrow suppression, and folate antagonism — avoid in the first trimester of pregnancy (neural tube defect risk) and near term (kernicterus risk).

Nitrofurantoin is concentrated in urine and used only for uncomplicated lower UTI (cystitis) — never pyelonephritis or systemic infection because therapeutic serum and tissue levels are not achieved. Efficacy falls as renal function declines; current guidance restricts use to creatinine clearance of at least 30 mL/min. Watch for pulmonary toxicity (acute pneumonitis; chronic fibrosis with long-term prophylaxis), peripheral neuropathy, hemolysis in G6PD deficiency, and harmless brown urine discoloration. Proteus and Pseudomonas are intrinsically resistant.

Metronidazole is activated under anaerobic conditions to free radicals that damage DNA; it covers anaerobes (intra-abdominal and pelvic infection, bacterial vaginosis) and protozoa (Giardia, Trichomonas, Entamoeba). Its defining interaction is the disulfiram-like reaction with alcohol — flushing, vomiting, and tachycardia — so patients must avoid alcohol during therapy and for at least 48–72 hours after. It also inhibits CYP2C9 and can raise warfarin effect; metallic taste is common.

Clindamycin (50S inhibitor) covers gram-positives and anaerobes and is used in severe skin infections, aspiration pneumonia, and toxin-mediated streptococcal disease; its label warning is the highest association with C. difficile diarrhea of any commonly used antibiotic. Linezolid, an oxazolidinone for MRSA and vancomycin-resistant enterococci, is a reversible monoamine oxidase inhibitor — combining it with SSRIs or other serotonergic drugs risks serotonin syndrome, and courses beyond two weeks cause reversible thrombocytopenia and myelosuppression. Fosfomycin inhibits MurA (an early cell-wall enzyme) and is given as a single 3 g sachet for uncomplicated cystitis, retaining activity against many ESBL-producing E. coli.

High-Yield Summary: Non-Beta-Lactam Antibacterials

The table consolidates the mechanism and the single most-tested toxicity or interaction for each class — the pairings the DHA exam repeatedly rewards. Use it as a last-week revision grid: cover the right-hand column and recall the toxicity before checking it.