Antimicrobials

• Definition: Antimicrobials are agents that selectively kill (bactericidal) or inhibit (bacteriostatic) microorganisms by exploiting targets absent or structurally distinct in human cells — peptidoglycan synthesis, the 70S ribosome, bacterial topoisomerases, and folate synthesis.
• Why it matters: Antibiotic selection is the single most common therapeutic decision in inpatient medicine, and the two errors examiners test relentlessly are (1) inadequate empiric coverage of the likely pathogen and (2) unnecessary broad-spectrum use that drives resistance, Clostridioides difficile infection, and toxicity.

Epidemiology worth recalling

• Outpatient volume: Hundreds of millions of outpatient antibiotic prescriptions are written annually in the US; the CDC estimates a large minority are unnecessary, most often for viral upper respiratory illness. CDC Core Elements of Antibiotic Stewardship are now expected in acute-care hospitals.
• Resistance burden: The CDC's Antibiotic Resistance Threats reporting lists carbapenem-resistant Enterobacterales, drug-resistant Neisseria gonorrhoeae, and C. difficile among urgent threats; MRSA and ESBL-producing gram-negatives are serious threats.
• Reported penicillin allergy: Roughly 10% of patients report a penicillin allergy, but the large majority are not truly IgE-mediated on testing (labels wane over years). Mislabeled patients receive more vancomycin, fluoroquinolones, and clindamycin, with worse outcomes and more C. difficile — hence the AAAAI/ACAAI and IDSA emphasis on allergy delabeling.
• Cross-reactivity: True cephalosporin cross-reactivity in penicillin-allergic patients is approximately 1–3%, and it is driven by shared R1 side chains, not by the beta-lactam ring itself. Cefazolin has a unique side chain and is generally tolerated.
• Who gets treated: Beta-lactams remain first-line for the majority of streptococcal, pneumococcal, and MSSA infections; vancomycin use tracks MRSA prevalence, which is highest in dialysis patients, people who inject drugs, and those with recent hospitalization or indwelling devices.

Cell wall agents

• Penicillins: The beta-lactam ring is a structural mimic of the terminal D-Ala–D-Ala of the peptidoglycan pentapeptide. It acylates the active-site serine of penicillin-binding proteins (transpeptidases), halting cross-linking; unopposed autolysin activity then lyses the cell. Killing is time-dependent (percentage of the dosing interval above MIC), which is why frequent dosing or extended infusion — not a big single dose — improves efficacy.
• Cephalosporins: Same PBP target; successive generations gain gram-negative outer-membrane penetration and beta-lactamase stability while losing some gram-positive potency. Ceftaroline is the cephalosporin with PBP2a affinity and therefore anti-MRSA activity.
• Vancomycin: Binds the D-Ala–D-Ala terminus of the precursor itself, sterically blocking transglycosylation and transpeptidation. Because the target is substrate, not enzyme, beta-lactamases are irrelevant; resistance (VanA) comes from remodeling the terminus to D-Ala–D-Lac.

Protein synthesis agents

• Macrolides: Bind the 23S rRNA of the 50S subunit at the nascent peptide exit tunnel, blocking translocation — bacteriostatic. Resistance is by *erm*-encoded ribosomal methylation (MLS-B phenotype, cross-resistance with clindamycin, detected by the D-test) or efflux.

Pharmacokinetics that change decisions

• Renal vs hepatobiliary clearance: Most penicillins and cephalosporins are renally cleared with short half-lives and need renal dose adjustment. Nafcillin, oxacillin, and ceftriaxone are hepatically/biliary cleared and do not.
• Probenecid blocks tubular secretion of penicillins, prolonging levels.
• Vancomycin is essentially not absorbed orally — IV for systemic infection, oral only for luminal C. difficile. IV vancomycin is renally cleared and dosed to a 24-hour AUC, targeting AUC/MIC 400–600 per the 2020 IDSA/ASHP/PIDS/SIDP consensus.
• Macrolide interactions: Erythromycin and clarithromycin are potent CYP3A4 inhibitors (statins, warfarin, tacrolimus); azithromycin is not, and its enormous tissue distribution gives a multi-day half-life permitting short courses.

Penicillins

• Penicillin G / penicillin VK: Still first-line for Streptococcus pyogenes pharyngitis and for syphilis. Per the CDC STI Treatment Guidelines, early syphilis (primary, secondary, early latent) is treated with a single benzathine penicillin G 2.4 million units IM dose; late latent, latent of unknown duration, and tertiary (non-neurologic) syphilis require 2.4 million units IM weekly for three doses; neurosyphilis, ocular, or otic syphilis requires IV aqueous crystalline penicillin G. Penicillin-allergic pregnant patients with syphilis require desensitization — there is no acceptable alternative.
• Amoxicillin: First-line for acute otitis media (AAP). For acute bacterial rhinosinusitis, IDSA recommends amoxicillin-clavulanate over amoxicillin alone as empiric therapy in adults and children. Amoxicillin is also used for infective endocarditis prophylaxis, 2 g orally 1 hour before dental procedures in the narrow high-risk groups defined by the ACC/AHA valvular heart disease guideline (prosthetic valve/material, prior IE, certain congenital lesions, transplant valvulopathy).
• Antistaphylococcal penicillins (nafcillin, oxacillin) or cefazolin: Preferred over vancomycin for MSSA bacteremia — beta-lactams are superior for susceptible staph (IDSA).
• Ampicillin: Covers Listeria and Enterococcus — the reason it is added empirically in meningitis at the extremes of age.
• Piperacillin-tazobactam: Anti-pseudomonal empiric coverage in hospital-acquired/ventilator-associated pneumonia and intra-abdominal sepsis (IDSA/ATS).

Cephalosporins

• Cefazolin: Standard surgical prophylaxis, given within 60 minutes of incision.
• Ceftriaxone: Backbone of empiric bacterial meningitis (with vancomycin, plus ampicillin when Listeria is a concern, and adjunctive dexamethasone before/with the first dose per IDSA); also pyelonephritis and Lyme neuroborreliosis. For gonorrhea, CDC recommends a single IM dose of ceftriaxone 500 mg (higher if ≥150 kg).
• Cefepime: Empiric febrile neutropenia (IDSA), covering Pseudomonas.

Macrolides

• Azithromycin: Atypical coverage in CAP alongside a beta-lactam (ATS/IDSA), pertussis, Mycobacterium avium complex prophylaxis/treatment, and traveler's diarrhea where fluoroquinolone resistance is prevalent.

Vancomycin

• IV: MRSA bacteremia, endocarditis, osteomyelitis, and empiric coverage when MRSA is plausible.
• Oral: C. difficile infection — the 2021 IDSA/SHEA focused update favors fidaxomicin, with oral vancomycin the recommended alternative; metronidazole is no longer preferred.

Hypersensitivity spectrum (beta-lactams)

• IgE-mediated anaphylaxis: Urticaria, bronchospasm, hypotension within minutes to an hour. Treatment is epinephrine 0.3 mg IM into the anterolateral thigh, repeated as needed — antihistamines and steroids are adjuncts, never first.
• Delayed T-cell reactions: Morbilliform rash, DRESS, SJS/TEN. The nonpruritic maculopapular rash after aminopenicillins in EBV mononucleosis is immune-mediated but not a true allergy and does not preclude future penicillins.
• Acute interstitial nephritis: Fever, rash, eosinophiluria; classically antistaphylococcal penicillins. Stop the drug.
• Coombs-positive hemolytic anemia with high-dose penicillins (hapten mechanism).

Dose- and organ-related toxicities

• Neurotoxicity/seizures: Beta-lactams antagonize GABA-A; risk rises with high doses in renal impairment — cefepime encephalopathy (nonconvulsive status, myoclonus) is the classic.
• Ceftriaxone: Biliary sludging/pseudolithiasis; avoided in neonates, particularly hyperbilirubinemic or premature infants (bilirubin displacement → kernicterus) and any neonate receiving or expected to receive calcium-containing IV solutions (risk of precipitation). It may still be used in selected neonates when neither condition applies.
• Cefotetan/cefoperazone: NMTT side chain → disulfiram-like reaction with alcohol and hypoprothrombinemia; reversal is vitamin K.

Macrolides

• QT prolongation/torsades via IKr blockade — avoid stacking with other QT-prolonging drugs; correct K and Mg.
• Motilin receptor agonism → cramping, diarrhea (exploited therapeutically in gastroparesis).
• Erythromycin in infants is associated with infantile hypertrophic pyloric stenosis; erythromycin estolate causes cholestatic hepatitis.
• CYP3A4 inhibition (erythromycin, clarithromycin) → statin myopathy, warfarin over-anticoagulation.

Vancomycin

• Vancomycin infusion reaction (red man/red neck syndrome): non-IgE mast cell degranulation from rapid infusion — slow the rate and pre-treat with an H1 blocker; do not label as allergy.
• Nephrotoxicity: Dose- and exposure-related, amplified by concurrent piperacillin-tazobactam or aminoglycosides; monitor creatinine and AUC-guided levels.
• Ototoxicity, DRESS, and linear IgA bullous dermatosis are the tested rarities.
• Any antibiotic can precipitate C. difficile colitis by disrupting colonic flora.

• Reported penicillin allergy is usually not allergy: Cross-reactivity with cephalosporins is about 1–3% and depends on shared R1 side chains, not the beta-lactam ring. The legacy "10% cross-reactivity" figure is the classic distractor. Cefazolin's distinct side chain makes it usable in most penicillin-allergic patients; a history of anaphylaxis warrants allergy evaluation or a non-beta-lactam.
• Single best next step in syphilis with penicillin allergy during pregnancy: desensitize and give penicillin. Doxycycline is contraindicated in pregnancy and does not reliably treat congenital infection, so desensitization is required (CDC STI Treatment Guidelines).
• MSSA bacteremia gets a beta-lactam, not vancomycin: nafcillin/oxacillin or cefazolin outperform vancomycin for susceptible S. aureus — a favorite stem where the culture is finalized as methicillin-susceptible and the answer is to narrow, not continue vancomycin.
• Vancomycin is monitored by 24-hour AUC, target AUC/MIC 400–600 (2020 IDSA/ASHP consensus). Trough-only targeting of 15–20 mcg/mL is the retired answer.
• Red man syndrome is a rate-related histamine release, not IgE: the correct action is slowing the infusion plus an antihistamine — not switching to linezolid and not documenting a vancomycin allergy.
• Vancomycin resistance in enterococci comes from swapping the peptidoglycan terminus to D-Ala–D-Lac; contrast with MRSA, which uses an altered PBP2a encoded by mecA. Beta-lactamase explains neither.
• Ampicillin plus mononucleosis produces a diffuse morbilliform rash that is not a penicillin allergy — do not permanently label the patient.
• Macrolide traps: erythromycin in a neonate → hypertrophic pyloric stenosis; clarithromycin plus simvastatin → rhabdomyolysis via CYP3A4 inhibition; azithromycin is the macrolide that spares CYP3A4.
• Ceftriaxone needs no renal adjustment (biliary excretion) but is avoided in neonates — especially premature or hyperbilirubinemic infants and any neonate on calcium-containing IV fluids — because of bilirubin displacement and calcium precipitation.

• Beta-lactams inhibit bacterial cell wall synthesis via penicillin-binding proteins (PBPs); bactericidal
• Aminoglycosides cause irreversible 30S ribosomal subunit inhibition; nephrotoxic and ototoxic
• Fluoroquinolones inhibit DNA gyrase/topoisomerase IV; excellent lung penetration; risk of tendinopathy and QT prolongation
• Macrolides inhibit 50S ribosomal subunit; risk of arrhythmias, GI dysmotility
• Resistance mechanisms: beta-lactamase production, altered PBPs, efflux pumps, ribosomal methylation

1. 1.Forgetting drug interactions: Macrolides/fluoroquinolones inhibit CYP3A4 (increases warfarin, statins, theophylline levels); rifampin induces multiple enzymes (reduces OCP, warfarin efficacy).

1. 1.Aminoglycosides require adequate renal function and dosing: Once-daily dosing preferred; monitor serum creatinine and trough levels—nephrotoxicity is dose-dependent and potentially reversible early, but ototoxicity is irreversible.

1. 1.Misidentifying resistance: Beta-lactamase-producing organisms need beta-lactamase inhibitors (clavulanic acid, sulbactam); MRSA requires vancomycin/linezolid, NOT standard beta-lactams.

• Community-acquired pneumonia: Beta-lactam ± macrolide (amoxicillin-clavulanate or cephalosporin); fluoroquinolone monotherapy for atypicals
• UTI: Trimethoprim-sulfamethoxazole (TMP-SMX) or nitrofurantoin; fluoroquinolone alternative
• MRSA infections: Vancomycin (IV) or linezolid (oral/IV)
• Anaerobes (aspiration, intra-abdominal): Clindamycin or metronidazole + gram-negative coverage
• Empiric sepsis: 3rd/4th-generation cephalosporin ± vancomycin ± fluoroquinolone (based on source)