All beta-lactams contain a beta-lactam ring. They bind penicillin-binding proteins (PBPs) — the enzymes that cross-link peptidoglycan in the bacterial cell wall. Without cross-links the wall weakens and the growing bacterium bursts. Beta-lactams are bactericidal and time-dependent: killing depends on how long the free drug level stays above the MIC, so doses must be given on time.

Resistance

• Beta-lactamases (penicillinases, ESBLs, carbapenemases) break the ring
• Altered PBPs — MRSA carries PBP2a, so it resists nearly all beta-lactams except the anti-MRSA cephalosporins (ceftaroline, ceftobiprole)
• Reduced entry through porins in gram-negative bacteria

Beta-lactamase inhibitors (clavulanate, sulbactam, tazobactam, avibactam, vaborbactam) protect the partner drug from many beta-lactamases.

Penicillins

Cephalosporins — broader gram-negative activity with each generation

Carbapenems — meropenem (prototype), imipenem–cilastatin, ertapenem (no Pseudomonas activity; once daily): broadest spectrum; reserved for ESBL-producing and other resistant organisms and severe polymicrobial infections.

Monobactam — aztreonam: gram-negative only (including Pseudomonas); useful in severe penicillin allergy.

Hypersensitivity is the most important adverse effect of every beta-lactam:

• Immediate (IgE): urticaria, angioedema, bronchospasm, anaphylaxis — usually within an hour
• Delayed benign rash (maculopapular) — common with aminopenicillins, especially during infectious mononucleosis (not a true allergy in most cases)
• Severe delayed reactions: SJS/TEN, DRESS, serum sickness-like reaction (cefaclor), interstitial nephritis, hemolytic anemia

Other effects

• GI: nausea, diarrhea, C. difficile infection (especially cephalosporins, amoxicillin–clavulanate, broad-spectrum drugs)
• Neurotoxicity/seizures with high doses in kidney failure — especially penicillin G, cefepime (encephalopathy, nonconvulsive status), and imipenem
• Electrolytes: hypokalemia (nafcillin, piperacillin); sodium load with some IV formulations; hyperkalemia with very high doses of penicillin G potassium
• Hepatotoxicity: amoxicillin–clavulanate (cholestatic, may appear after stopping), oxacillin
• Hematologic: neutropenia and thrombocytopenia with prolonged high-dose therapy; positive Coombs test
• Ceftriaxone: biliary sludge/pseudolithiasis; displaces bilirubin; precipitates with calcium
• Cefotetan: hypoprothrombinemia and bleeding; disulfiram-like reaction with alcohol
• Local: phlebitis; nafcillin extravasation injury; pain at IM sites
• Jarisch–Herxheimer reaction after treating syphilis: fever, chills, headache, myalgia within 24 hours — not an allergy; treat with antipyretics
• Rare with benzathine/procaine penicillin: procaine reaction (anxiety, hallucinations) and inadvertent IV or intra-arterial injection → cardiac arrest, limb ischemia

Allergy assessment (2022 US drug allergy practice parameter)

• History of anaphylaxis or severe immediate reaction to penicillin → avoid penicillins; a cephalosporin with a dissimilar side chain (e.g., cefazolin) can be given without testing when needed; carbapenems and aztreonam can be used
• Non-anaphylactic penicillin reaction (e.g., hives, rash) → cephalosporins can be given without prior testing
• Low-risk histories (remote rash, family history only, GI symptoms) → candidates for direct oral amoxicillin challenge or skin testing to remove the label
• SJS/TEN, DRESS, or other severe delayed reactions → avoid the beta-lactam involved and discuss the whole class with an allergist
• Aztreonam shares a side chain with ceftazidime (and cefiderocol) — caution in ceftazidime allergy

Kidney impairment: most beta-lactams need dose or interval adjustment by creatinine clearance (exceptions: ceftriaxone, nafcillin, oxacillin).

Specific cautions

• Ceftriaxone in neonates: contraindicated in hyperbilirubinemic neonates (kernicterus risk) and must not be given with IV calcium-containing solutions in neonates up to 28 days (fatal precipitates)
• Benzathine penicillin: IM only; never IV
• Mononucleosis → avoid ampicillin/amoxicillin (rash)
• Pregnancy: penicillins and cephalosporins are generally safe; penicillin is the only recommended treatment of syphilis in pregnancy (desensitize if allergic)

Interactions

• Probenecid raises penicillin and cephalosporin levels (sometimes used deliberately)
• Carbapenems lower valproic acid levels within hours → breakthrough seizures; use another antibiotic or antiseizure drug
• Aminoglycosides: do not mix in the same IV bag or line with penicillins (inactivation); give separately
• Warfarin: INR may rise
• Allopurinol with ampicillin/amoxicillin → more rash
• Methotrexate levels rise with penicillins
• Oral penicillins may slightly reduce the effectiveness of hormonal contraceptives in theory; current US guidance does not require backup for most antibiotics other than rifamycins

1. Ask about allergy before every first dose — record the drug, reaction, and timing; verify the allergy band
2. Collect ordered cultures before the first dose without significantly delaying therapy in sepsis
3. Anaphylaxis readiness: observe during and after the first dose (and for at least 15–30 minutes after IM benzathine penicillin in outpatient settings); have epinephrine and airway equipment ready
4. Administration
   • Benzathine penicillin G: deep IM into the gluteal muscle in adults (the midlateral thigh in infants and young children, per the label); the US label directs aspirating before injecting to avoid a vessel, then injecting slowly and steadily; never IV; the suspension is thick — use the prefilled syringe and follow the product sheet for imported products
   • IV beta-lactams: correct dilution and infusion time; extended infusions of piperacillin–tazobactam or meropenem when ordered
   • Give on schedule — time-dependent killing
   • Ceftriaxone IM: may be reconstituted with lidocaine per product labeling (never give that preparation IV)
   • Nafcillin: monitor the IV site closely (vesicant)
5. Monitor: creatinine and urine output; CBC and liver tests with prolonged courses; potassium (nafcillin, piperacillin, high-dose penicillin G potassium); neurologic status with cefepime or imipenem in kidney impairment; INR with warfarin
6. Watch for superinfection: new diarrhea (C. difficile testing and contact precautions), oral thrush, vaginal yeast infection
7. Syphilis treatment: warn about Jarisch–Herxheimer reaction; ensure partner notification and follow-up titers

• Take oral penicillins at evenly spaced times; penicillin V and dicloxacillin on an empty stomach (1 hour before or 2 hours after meals); amoxicillin and amoxicillin–clavulanate can be taken with food (reduces stomach upset)
• Finish the prescribed course; do not share or save antibiotics
• Refrigerate reconstituted oral suspensions as labeled; shake well; discard after the labeled time; use an oral syringe for accurate dosing in children
• Stop and seek emergency care for hives, swelling of the lips or throat, wheezing, or fainting
• Report watery or bloody diarrhea (even weeks later), yellowing skin, dark urine, or a blistering rash
• Avoid alcohol with cefotetan during and for 72 hours after (disulfiram-like reaction)
• If you have a penicillin allergy label from childhood or a mild reaction, ask about allergy testing — most people can safely take penicillin after evaluation
• After benzathine penicillin: fever and aches within 24 hours of syphilis treatment are expected; keep every rheumatic fever prophylaxis injection on schedule

There is no specific antidote for beta-lactam toxicity.

• Beta-lactams inhibit cell-wall synthesis (PBPs); bactericidal, time-dependent — give on time
• Always ask about allergy before the first dose; anaphylaxis → epinephrine IM
• True penicillin allergy is uncommon; cephalosporin cross-reactivity is low and side-chain based; cefazolin is usable even after penicillin anaphylaxis
• Benzathine penicillin G: deep IM only, never IV; syphilis 2.4 million units once (early) or weekly × 3 (late latent/unknown duration); rheumatic fever prophylaxis every 3–4 weeks
• Ceftriaxone: not with IV calcium in neonates; not in hyperbilirubinemic neonates; biliary sludge
• Cefazolin = surgical prophylaxis; ceftaroline covers MRSA
• Carbapenems lower valproate levels; imipenem and cefepime → seizures in kidney failure
• Do not mix aminoglycosides with penicillins in the same line
• Amoxicillin + mononucleosis → rash; amoxicillin–clavulanate → diarrhea, liver injury
• Adjust doses for kidney function (not ceftriaxone or nafcillin)