Second Generation Cephalosporins

Second generation cephalosporins keep the Gram-positive activity of the first generation and add activity against Haemophilus influenzae, Moraxella catarrhalis and some Enterobacterales. The group divides into two parts: true cephalosporins (cefuroxime, cefaclor, cefprozil) and the cephamycins (cefoxitin, cefotetan), which add anaerobic cover including Bacteroides fragilis. Cefamandole is obsolete.

Mechanism. PBP binding with time-dependent bactericidal action. Cefuroxime is stable to many TEM-1 beta-lactamases of H. influenzae. Cephamycins carry a 7-alpha-methoxy group that confers stability to many ESBLs in vitro, but this does not make them reliable treatment for ESBL bacteraemia.

Pharmacokinetics. Cefuroxime axetil is a prodrug with about 50 percent oral bioavailability that improves with food. Cefaclor and cefprozil are well absorbed. Cefuroxime, cefoxitin and cefotetan are eliminated by the kidney (half-lives about 1 hour for cefuroxime and cefoxitin, 3 to 4 hours for cefotetan). Cefuroxime reaches CSF but is no longer used for meningitis because of poorer outcomes than third generation agents.

Gaps. Enterococci, MRSA, Listeria, atypicals, Pseudomonas and ESBL producers.

• Cefuroxime: the most used agent; intravenous and oral axetil forms.
• Cefaclor and cefprozil: oral only, for respiratory and skin infection. Cefaclor is associated with serum-sickness-like reaction in children.
• Cefoxitin: intravenous cephamycin for mixed pelvic, abdominal and diabetic foot infection and surgical prophylaxis. B. fragilis resistance is increasing.
• Cefotetan: longer half-life, twice-daily dosing, but carries a methylthiotetrazole side chain that causes hypoprothrombinaemia and a disulfiram-like reaction.

Adult regimens (normal renal function).

• Cefuroxime 750 mg to 1.5 g IV every 8 hours; oral axetil 250 to 500 mg every 12 hours with food. Maximum IV 6 g daily.
• Community pneumonia of moderate severity: cefuroxime 1.5 g IV every 8 hours, usually with a macrolide for atypical cover; step down to oral 500 mg every 12 hours.
• Early Lyme disease: cefuroxime axetil 500 mg orally every 12 hours for 14 to 21 days.
• Cefoxitin 1 to 2 g IV every 6 to 8 hours (maximum 12 g daily). Pelvic inflammatory disease (hospital regimen): cefoxitin 2 g IV every 6 hours with doxycycline 100 mg every 12 hours.
• Cefotetan 1 to 2 g IV every 12 hours.
• Surgical prophylaxis: cefuroxime 1.5 g IV with metronidazole 500 mg for colorectal surgery, or cefoxitin 1 to 2 g IV, within 60 minutes before incision.
• Cefaclor 250 to 500 mg orally every 8 hours; cefprozil 250 to 500 mg every 12 hours.
• Children: cefuroxime 50 to 100 mg/kg daily IV in three divided doses (maximum 6 g daily); oral axetil 15 mg/kg every 12 hours (maximum 500 mg each dose).

Selection. Useful for respiratory infection where H. influenzae is likely and for surgical prophylaxis requiring anaerobic cover. Third generation agents have largely replaced the class for serious Gram-negative and CNS infection.

Contraindications. Severe hypersensitivity to a cephalosporin. Cefotetan is avoided with alcohol and in patients on warfarin unless INR is monitored.

Serious effects. Anaphylaxis; serum-sickness-like reaction (cefaclor); C. difficile infection; hypoprothrombinaemia and bleeding (cefotetan, particularly in malnourished or older patients; treat with vitamin K); immune haemolytic anaemia (cefotetan); disulfiram-like reaction with alcohol; seizures in renal failure; interstitial nephritis.

Interactions. Warfarin (potentiated by cefotetan), probenecid, aminoglycosides (additive nephrotoxicity), antacids and H2 blockers (reduce cefuroxime axetil absorption).

Monitoring. Renal function; INR with cefotetan and warfarin; full blood count in courses over 14 days.

Special groups.

• Pregnancy and breastfeeding: acceptable.
• Renal impairment: cefuroxime 750 mg every 12 hours at creatinine clearance 10 to 20 mL/min and 750 mg every 24 hours under 10 mL/min; cefoxitin interval extended to every 12 to 24 hours under 30 mL/min; cefotetan halved or interval doubled at clearance under 30 mL/min.
• Older adults: higher risk of cefotetan-related bleeding.