β-Lactam Antibiotics

Structure, mechanism and pharmacology

The shared ring. Every β-lactam carries a four-membered β-lactam ring. Penicillins fuse it to a five-membered thiazolidine ring, cephalosporins to a six-membered dihydrothiazine ring, and carbapenems to a five-membered ring with carbon in place of sulfur; the monobactam aztreonam has the β-lactam ring alone. Side chains, not the core, set spectrum, β-lactamase stability and most allergic cross-reactivity.

Mechanism. Penicillin-binding proteins (PBPs) are the transpeptidases that cross-link the peptide side chains of peptidoglycan. The β-lactam mimics the D-Ala-D-Ala terminus and irreversibly acylates the PBP active site. Without cross-links the wall weakens, autolysins keep cutting, and the cell lyses. The effect is bactericidal but requires actively growing bacteria. Other cell-wall drugs act at earlier steps: fosfomycin inhibits MurA, bacitracin blocks recycling of the bactoprenol lipid carrier, and vancomycin binds D-Ala-D-Ala to stop transglycosylation.

Time-dependent killing. Efficacy tracks the fraction of the dosing interval during which free drug stays above the MIC, not the peak level. Hence frequent dosing, extended or continuous infusions, and long-acting depots such as benzathine penicillin. Most β-lactams are renally cleared and need dose reduction in kidney failure; nafcillin (hepatic) and ceftriaxone (biliary plus renal) are the main exceptions. Probenecid blocks tubular secretion of penicillin and raises its levels.

Penicillins

Natural penicillins. Penicillin G is given IV or IM; penicillin V is acid-stable for oral use. Their niche is streptococci, N. meningitidis, Treponema pallidum, Actinomyces and C. perfringens. Benzathine penicillin G is a slow-release IM depot: a single dose treats early syphilis, and injections every 3–4 weeks prevent rheumatic fever recurrences. Penicillin is the only recommended syphilis therapy in pregnancy, so an allergic pregnant woman is desensitized.

Antistaphylococcal penicillins. Nafcillin, oxacillin and dicloxacillin carry bulky side chains that keep staphylococcal penicillinase away from the ring. They are first-line for MSSA, with cefazolin as the equivalent alternative, but fail against MRSA, whose mecA-encoded PBP2a binds them poorly, and against gram-negatives. Acute interstitial nephritis is their classic toxicity; methicillin, the original member, is no longer used clinically.

Aminopenicillins. An amino group on the side chain helps ampicillin and amoxicillin pass gram-negative porins; amoxicillin is better absorbed orally. Ampicillin is the drug of choice for Listeria and susceptible Enterococcus faecalis; amoxicillin anchors otitis media and sinusitis therapy, H. pylori regimens and dental endocarditis prophylaxis. Given during EBV mononucleosis they commonly cause a pruritic morbilliform rash that does not signify lasting IgE allergy.

Piperacillin-tazobactam. Piperacillin adds Pseudomonas but is β-lactamase-labile, so it is always paired with tazobactam. The combination covers streptococci, MSSA, most gram-negatives including Pseudomonas, and anaerobes, making it a workhorse for hospital-acquired pneumonia, intra-abdominal sepsis and febrile neutropenia.

β-Lactamase inhibitors. Clavulanate, sulbactam and tazobactam are β-lactam–like suicide substrates that permanently inactivate many β-lactamases, restoring the partner drug against producers such as H. influenzae, M. catarrhalis, B. fragilis and MSSA. Amoxicillin-clavulanate (oral) treats bite wounds, sinusitis and otitis; ampicillin-sulbactam and piperacillin-tazobactam are IV. Sulbactam also has intrinsic activity against Acinetobacter. Avibactam, a non-β-lactam inhibitor paired with ceftazidime, blocks KPC carbapenemases but not metallo-β-lactamases such as NDM. No inhibitor rescues activity against MRSA, because its resistance is an altered target, not an enzyme.

Cephalosporins

First and second generations. Cefazolin kills skin flora well, which makes it the standard surgical-site prophylaxis, and it treats MSSA bacteremia; it does not reach the CSF. Among second-generation drugs, cefuroxime is used for respiratory infections, while the cephamycins cefoxitin and cefotetan carry a 7-methoxy group that resists many β-lactamases and adds anaerobic coverage, so they serve for colorectal surgery prophylaxis and, with doxycycline, inpatient pelvic inflammatory disease.

Ceftriaxone. Its long half-life allows once-daily IV or IM dosing for most infections (twice daily for meningitis), and it crosses inflamed meninges and is the backbone of empiric bacterial meningitis therapy (with vancomycin for resistant pneumococci). A single 500 mg IM dose treats gonorrhea; it also treats Lyme carditis and meningitis, typhoid, pneumonia and pyelonephritis. Partial biliary excretion lets calcium–ceftriaxone precipitate as biliary sludge (pseudolithiasis). In neonates it displaces bilirubin from albumin, raising the risk of kernicterus, so it is avoided in jaundiced or premature newborns.

Do not give ceftriaxone with calcium-containing IV fluids to neonates: ceftriaxone–calcium precipitates in the lungs and kidneys have been fatal.

Antipseudomonal cephalosporins. Ceftazidime has weak gram-positive activity; cefepime adds MSSA and streptococci and resists AmpC β-lactamases. Both treat febrile neutropenia and hospital-acquired pneumonia. Cefepime accumulates when its dose is not reduced in renal failure, causing encephalopathy, myoclonus and nonconvulsive seizures that resolve after stopping the drug or dialysis.

Ceftaroline and the gaps. Ceftaroline binds PBP2a, the low-affinity PBP encoded by mecA, making it the classic anti-MRSA β-lactam (the newer ceftobiprole shares this property); its gram-negative spectrum resembles ceftriaxone's without Pseudomonas. Otherwise MRSA calls for vancomycin, daptomycin or linezolid. No cephalosporin covers Listeria, enterococci or atypicals (Mycoplasma, Chlamydia, Legionella), so ampicillin is added to empiric meningitis therapy in neonates, adults over 50 and the immunocompromised, and a macrolide or doxycycline covers atypical pneumonia.

Carbapenems and aztreonam

Carbapenems. Imipenem, meropenem and ertapenem have the broadest β-lactam spectrum: most gram-positives, gram-negatives and anaerobes. They are stable to ESBLs and AmpC enzymes, making them the drugs of choice for serious ESBL infections, where piperacillin-tazobactam is not a reliable substitute. Ertapenem is given once daily but misses Pseudomonas and Acinetobacter. Gaps include MRSA, E. faecium, atypicals and Stenotrophomonas maltophilia, which carries its own metallo-β-lactamase and is treated with TMP-SMX. Carbapenemases such as KPC and NDM are the main cause of carbapenem-resistant Enterobacterales.

Imipenem-cilastatin. Renal dehydropeptidase I on the proximal tubule brush border hydrolyzes imipenem. Cilastatin inhibits this enzyme, prolonging imipenem's half-life; it has no antibacterial activity of its own. Imipenem has the highest seizure risk of the class, so meropenem is preferred for CNS infection.

All carbapenems drop valproate levels sharply within about a day, causing breakthrough seizures; raising the valproate dose does not overcome the interaction, so change the antibiotic or the antiseizure drug.

Aztreonam. This monobactam binds PBP3 of aerobic gram-negative rods, including Pseudomonas, and has no gram-positive or anaerobic activity; it is synergistic with aminoglycosides and is inhaled for Pseudomonas in cystic fibrosis. It does not cross-react with penicillins, so it can be used after penicillin anaphylaxis, but it shares an identical side chain with ceftazidime and is avoided in ceftazidime allergy.

Adverse effects and allergy

Immediate reactions. True IgE-mediated (type I) reactions begin within minutes to an hour: urticaria, angioedema, bronchospasm, anaphylaxis. Most allergy labels are wrong, and delabeling through skin testing or graded oral challenge widens safe choices.

Side-chain logic. Cross-reactivity follows similar R1 side chains rather than the shared ring: amoxicillin with cefadroxil, ampicillin with cephalexin, aztreonam with ceftazidime. A cephalosporin with a dissimilar side chain is rarely a problem.

Jarisch-Herxheimer reaction. Within hours of the first dose for a spirochetal infection (syphilis, especially secondary; Lyme disease; leptospirosis; relapsing fever), dying organisms release lipoproteins and other antigens that trigger a surge of host pyrogenic cytokines. Fever, chills, myalgia, headache, a flare of the rash and occasionally hypotension follow and settle within about 24 hours. It is not an allergy: continue treatment and give antipyretics. In pregnancy it can trigger contractions, but that should not delay therapy.