Chapter 35  ·  Module 2  ·  Antibacterial Agents
Cephalosporins & Beta-Lactamase Inhibitor Combinations
Generation spectrum, inhibitor classes, and clinical selection at a glance
Abbreviations: PBP = penicillin-binding protein  ·  MSSA = methicillin-susceptible Staphylococcus aureus  ·  MRSA = methicillin-resistant Staphylococcus aureus  ·  ESBL = extended-spectrum beta-lactamase  ·  KPC = Klebsiella pneumoniae carbapenemase  ·  NDM = New Delhi metallo-beta-lactamase  ·  CAP = community-acquired pneumonia  ·  CSF = cerebrospinal fluid
Cephalosporin Generations — Spectrum and Clinical Use
Generation Key Agents Gram-Positive Gram-Negative Primary Use
1st Cefazolin, Cephalexin Excellent (MSSA, strep) E. coli, Proteus, Klebsiella (non-ESBL) Surgical prophylaxis; MSSA infections; skin and soft tissue
2nd Cefuroxime; Cefoxitin (cephamycin) Good + H. influenzae, M. catarrhalis; cephamycins add anaerobes Respiratory infections; intra-abdominal (cefoxitin)
3rd Ceftriaxone, Cefotaxime, Ceftazidime Moderate Broad Enterobacteriaceae; ceftazidime adds Pseudomonas Meningitis; CAP; gram-negative bacteremia
4th Cefepime Good (comparable to 1st) Pseudomonas; AmpC-stable; ESBL-susceptible Febrile neutropenia; nosocomial infections
5th Ceftaroline MRSA + MSSA + strep Enterobacteriaceae (no Pseudomonas) Skin and soft tissue; CAP; MRSA (off-label bacteremia)
Beta-Lactamase Inhibitors
Classical Inhibitors
Clavulanate / Sulbactam / Tazobactam
  • Irreversible — suicide inhibitors of Class A serine beta-lactamases
  • No activity vs. Class B metallo-beta-lactamases or Class C AmpC
  • Amoxicillin-clavulanate: oral; H. influenzae, Moraxella, E. coli
  • Piperacillin-tazobactam: broad IV coverage including Pseudomonas
  • Sulbactam: intrinsic activity vs. Acinetobacter baumannii
  • Inoculum effect: unreliable for ESBL bacteremia
Novel Inhibitors (diazabicyclooctane)
Avibactam / Relebactam / Vaborbactam
  • Reversible — regenerated after enzyme inactivation
  • Cover Class A (ESBL, KPC), Class C (AmpC), some Class D
  • No activity vs. Class B metallo-beta-lactamases (NDM, VIM)
  • Ceftazidime-avibactam: KPC-producing carbapenem-resistant organisms
  • Imipenem-relebactam, meropenem-vaborbactam: similar KPC coverage
  • Confirm KPC vs. NDM genotype before use
Key Clinical Rules

Cross-reactivity between penicillins and cephalosporins is side-chain based, not ring based. True cross-reactivity is approximately 1–2%. Cefazolin has the lowest risk and is safe for surgical prophylaxis in most penicillin-allergic patients.

Ceftriaxone: no renal dose adjustment needed (40% biliary elimination). Cefepime: dose-adjust in renal impairment; watch for neurotoxicity (non-convulsive status epilepticus, myoclonus).

Novel inhibitor combinations cover KPC but not NDM. Genotypic resistance testing guides selection.