Beta Lactam Antibiotics

Beta-lactam antibiotics contain a four-membered beta-lactam ring and form the largest and most widely used antibacterial class: penicillins, cephalosporins, carbapenems and monobactams, usually partnered with a beta-lactamase inhibitor where beta-lactamases limit activity. They are bactericidal against growing bacteria and have a wide therapeutic margin.

Mechanism. The drug covalently binds penicillin-binding proteins (PBPs), the transpeptidases that cross-link peptidoglycan. Cross-linking fails, autolytic enzymes are activated and the cell lyses. Activity needs active cell wall synthesis, so non-growing organisms are less affected.

Resistance. Beta-lactamases hydrolyse the ring (Ambler classes A, C and D are serine enzymes; class B metallo-enzymes hydrolyse carbapenems). Altered PBPs explain methicillin-resistant S. aureus (PBP2a) and penicillin-nonsusceptible pneumococci. Porin loss and efflux reduce access in Gram-negatives. Intrinsic gaps: Enterococcus and Listeria are resistant to cephalosporins; Mycoplasma, Chlamydia and Legionella are not reliably treated.

Pharmacokinetics. Hydrophilic, distributed in extracellular fluid, eliminated mainly unchanged by renal tubular secretion (probenecid prolongs levels). Half-lives are short (0.5 to 2 hours) except ceftriaxone (about 8 hours). Ceftriaxone has substantial biliary excretion; cloxacillin and flucloxacillin have mixed hepatic and renal clearance. CSF penetration is useful only with inflamed meninges.

• Penicillins: natural penicillins (streptococci, anaerobes, Treponema), aminopenicillins (add enterococci, Listeria, some Gram-negatives), antistaphylococcal penicillins (MSSA), antipseudomonal penicillins (Gram-negatives including Pseudomonas aeruginosa and anaerobes).
• Cephalosporins: five generations, moving from Gram-positive emphasis (first) to Gram-negative breadth (third and fourth), antipseudomonal activity (ceftazidime, cefepime) and MRSA activity (ceftaroline).
• Carbapenems: the widest spectrum, stable to most ESBL and AmpC enzymes; not active against MRSA, Enterococcus faecium or Stenotrophomonas, and inactivated by metallo-beta-lactamases and some class D enzymes.
• Monobactam: aztreonam is active against aerobic Gram-negatives only, stable to metallo-beta-lactamases, and lacks cross-reactivity with penicillins.
• Inhibitor combinations: clavulanic acid, sulbactam and tazobactam restore activity against many class A enzymes; avibactam, vaborbactam, relebactam and durlobactam extend this to some carbapenemases.

First-line use. Beta-lactams are first line for most streptococcal, MSSA, meningococcal, pneumococcal, Listeria, syphilis and Gram-negative infections. For MSSA bacteraemia and endocarditis an anti-staphylococcal beta-lactam (cloxacillin, flucloxacillin or cefazolin) is superior to vancomycin.

Optimising exposure. Efficacy relates to time with free concentration over the MIC. In critical illness, after a first dose given over 30 minutes, extended infusion (for example piperacillin-tazobactam 4.5 g over 4 hours every 8 hours, or meropenem 1 to 2 g over 3 hours every 8 hours) or continuous infusion is preferred. High-dose regimens are used for CNS infection and endocarditis.

Selection points.

• ESBL-producing bacteraemia: a carbapenem is preferred to piperacillin-tazobactam.
• Inducible AmpC organisms (Enterobacter cloacae, Klebsiella aerogenes, Citrobacter freundii): cefepime or a carbapenem rather than ceftriaxone, since third generation cephalosporins select derepressed mutants.
• Penicillin allergy: assess the history. Cross-reactivity with cephalosporins is about 2 percent overall and is driven by shared side chains (for example amoxicillin with cefalexin, cefadroxil and cefaclor; ceftazidime with aztreonam). Cross-reactivity with carbapenems is under 1 percent.

Hypersensitivity. Anaphylaxis occurs in roughly 1 to 5 in every 10,000 courses. Contraindicated after a confirmed immediate reaction or severe delayed cutaneous reaction (Stevens-Johnson syndrome, DRESS) to that class.

Neurotoxicity. Seizures and encephalopathy occur with high doses, renal impairment, CNS lesions and agents with high GABA-A antagonism: imipenem (highest), cefepime (encephalopathy, myoclonus, non-convulsive status), high-dose benzylpenicillin.

Other serious effects.

• C. difficile infection, strongest with cephalosporins, clindamycin and fluoroquinolones.
• Cholestatic hepatitis (flucloxacillin, amoxicillin-clavulanate).
• Neutropenia with courses over 2 weeks; haemolytic anaemia; platelet dysfunction with high-dose antipseudomonal penicillins.
• Interstitial nephritis; electrolyte loads (sodium, potassium with benzylpenicillin).

Interactions. Probenecid raises levels. Methotrexate clearance is reduced (toxicity). Warfarin effect may be enhanced or reduced. Carbapenems lower valproate levels by 60 to 100 percent within 24 hours, with loss of seizure control; the combination is avoided. Aminoglycosides are inactivated if mixed with beta-lactams in the same solution.

Monitoring. Renal function; full blood count and liver tests at least weekly in prolonged courses; seizure threshold in renal impairment; sodium and potassium on high-dose therapy.

Special groups. Pregnancy and breastfeeding: penicillins, cephalosporins and carbapenems are acceptable when indicated. Renal impairment: reduce dose or lengthen interval by creatinine clearance (agent-specific), with neurotoxicity the main hazard of overdose. Children: weight-based dosing; ceftriaxone needs caution in neonates. Hepatic impairment: caution with flucloxacillin and ceftriaxone (biliary clearance in combined hepatic and renal failure).