Fifth Generation Cephalosporins

Fifth generation cephalosporins are the anti-MRSA cephalosporins: ceftaroline (given as ceftaroline fosamil) and ceftobiprole (given as ceftobiprole medocaril). They are the only beta-lactams with reliable activity against MRSA, vancomycin-intermediate S. aureus and penicillin-resistant pneumococci, together with broad cover of common Gram-negatives. Cefiderocol and ceftolozane-tazobactam are sometimes grouped with them as novel cephalosporins and are described here because they serve resistant Gram-negative infection.

Mechanism. Ceftaroline and ceftobiprole bind PBP2a of MRSA with high affinity, which explains the anti-MRSA effect, and bind PBP2x of pneumococci. Cefiderocol is a siderophore cephalosporin that chelates iron and enters Gram-negatives through iron transport channels, bypassing porin loss. Ceftolozane is stable to Pseudomonas AmpC and efflux; tazobactam covers many ESBLs.

Pharmacokinetics. All are intravenous, renally eliminated, with half-lives of 2 to 3 hours. Ceftaroline fosamil converts rapidly to active ceftaroline.

Gaps. Ceftaroline and ceftobiprole do not reliably cover Pseudomonas (ceftobiprole has partial activity), ESBL producers, Enterococcus faecium or anaerobes. Ceftolozane-tazobactam lacks carbapenemase activity. Cefiderocol has no Gram-positive or anaerobic role.

• Ceftaroline: licensed for acute skin and soft tissue infection and community-acquired pneumonia; widely used off-label for MRSA bacteraemia and endocarditis (usually salvage or in combination).
• Ceftobiprole: licensed in several regions for hospital-acquired pneumonia (excluding ventilator-associated) and community-acquired pneumonia, and more recently for S. aureus bacteraemia and skin infection; licensing varies by region.
• Ceftolozane-tazobactam: activity against multidrug-resistant Pseudomonas aeruginosa and many ESBL producers.
• Cefiderocol: active against carbapenem-resistant Enterobacterales (including metallo-beta-lactamase producers), Pseudomonas and Acinetobacter.

Adult regimens (normal renal function).

• Ceftaroline fosamil 600 mg IV every 12 hours over 1 hour; for S. aureus with higher MIC (2 to 4 mg/L) or severe infection, 600 mg every 8 hours over 2 hours. Duration: skin infection 5 to 14 days, pneumonia 5 to 7 days.
• Ceftobiprole 500 mg IV every 8 hours over 2 hours (extended 4-hour infusion for hospital-acquired pneumonia in some regimens).
• Ceftolozane-tazobactam 1.5 g (1 g/0.5 g) IV every 8 hours over 1 hour for complicated urinary and intra-abdominal infection (with metronidazole for the latter); 3 g (2 g/1 g) every 8 hours for hospital-acquired and ventilator-associated pneumonia.
• Cefiderocol 2 g IV every 8 hours over 3 hours (creatinine clearance 60 to 119 mL/min); reduced when clearance is under 60 mL/min and increased to 2 g every 6 hours in augmented renal clearance (120 mL/min or more).

Selection. Ceftaroline or ceftobiprole when a beta-lactam is wanted for MRSA, for example in pneumonia with MRSA risk or persistent bacteraemia (often with daptomycin or vancomycin). Ceftolozane-tazobactam and cefiderocol are reserve agents chosen by susceptibility results and specialist advice. Cefiderocol showed a higher all-cause mortality signal in one study of carbapenem-resistant infections, driven by Acinetobacter, so it is not used as sole therapy for Acinetobacter when alternatives exist.

Contraindications. Hypersensitivity to cephalosporins.

Serious and common effects. Diarrhoea and nausea; rash; positive Coombs test (ceftaroline) with rare haemolysis; C. difficile infection; neutropenia in prolonged courses; seizures in renal impairment; raised transaminases; hypokalaemia (cefiderocol).

Interactions. Few. Cefiderocol and ceftolozane-tazobactam have no major CYP interactions.

Monitoring. Renal function and dose adjustment; full blood count at least weekly for courses over 2 weeks; direct Coombs test if haemolysis is suspected.

Special groups.

• Renal impairment: ceftaroline 400 mg every 12 hours at creatinine clearance 30 to 50 mL/min, 300 mg every 12 hours at 15 to 29 mL/min, 200 mg every 12 hours under 15 mL/min.
• Pregnancy and breastfeeding: limited data; use only when no alternative exists.
• Children: ceftaroline and ceftobiprole are licensed for paediatric use in some regions with weight-based dosing; cefiderocol and ceftolozane-tazobactam have limited paediatric data.
• Region: availability and cost severely limit use in East Africa; MRSA prevalence is variable and local data should direct empirical vancomycin versus a beta-lactam.