First Generation Cephalosporins

First generation cephalosporins (cefazolin, cefalexin, cefadroxil; cefalotin and cefapirin are obsolete) are narrow-spectrum agents with strong activity against MSSA and streptococci and moderate activity against community-acquired E. coli, Klebsiella pneumoniae and Proteus mirabilis. They are the workhorse for surgical prophylaxis and skin and soft tissue infection.

Mechanism. PBP inhibition with time-dependent killing. They resist staphylococcal penicillinase but not ESBL or AmpC.

Pharmacokinetics. Cefazolin is parenteral only, highly protein-bound (about 80 percent) with half-life about 2 hours and renal elimination. Cefalexin and cefadroxil are well absorbed orally (over 90 percent); cefadroxil has a longer half-life (about 1.5 hours) allowing twice-daily dosing. None penetrate CSF in useful concentrations.

Gaps. Enterococci, MRSA, Listeria, atypicals, Bacteroides, Pseudomonas, H. influenzae (variable) and ESBL producers.

• Cefazolin: the preferred intravenous first generation agent, used for prophylaxis, MSSA bacteraemia, endocarditis, bone and joint infection and pyelonephritis with susceptible organisms. It has a unique R1 side chain, so it rarely cross-reacts with penicillins and other cephalosporins.
• Cefalexin: oral agent for skin infection, cystitis, bone step-down and streptococcal pharyngitis.
• Cefadroxil: oral, twice daily, similar uses.

Adult regimens (normal renal function).

• MSSA bacteraemia, endocarditis, bone and joint infection: cefazolin 2 g IV every 8 hours. Duration depends on the indication (at least 14 days uncomplicated bacteraemia; 4 to 6 weeks complicated).
• Cellulitis and skin infection: cefalexin 500 mg orally every 6 hours for 5 days; severe: 1 g every 8 hours.
• Uncomplicated cystitis where susceptible: cefalexin 500 mg orally every 12 hours for 5 days.
• Surgical prophylaxis: cefazolin 2 g IV (3 g if weight 120 kg or more) within 60 minutes before incision; repeat after 4 hours or if blood loss exceeds 1,500 mL; stop within 24 hours of the procedure.
• Cefadroxil 500 mg to 1 g orally every 12 hours.
• Children: cefazolin 25 to 50 mg/kg IV every 8 hours (maximum 2 g each dose); cefalexin 25 to 50 mg/kg daily in two to four divided doses.

Selection. Cefazolin is preferred over antistaphylococcal penicillins for MSSA when hepatic, renal or phlebitis risks are a concern. A large inoculum can reduce cefazolin activity through staphylococcal type A beta-lactamase (inoculum effect), and clinical significance is debated; high-burden CNS or endovascular infection is the main concern. Not suitable for MRSA, meningitis or enterococcal infection.

Contraindications. Prior severe hypersensitivity to a cephalosporin. Cefazolin is acceptable in most penicillin allergy because of its unique side chain, unless the reaction was severe cutaneous; cefalexin and cefadroxil share a side chain with amoxicillin and ampicillin and are avoided in confirmed IgE-mediated allergy to those drugs.

Serious effects. Anaphylaxis; delayed rash; C. difficile infection; interstitial nephritis; seizures in renal failure at high doses; positive Coombs test with rare haemolysis; transient transaminase rise.

Interactions. Probenecid, warfarin (rare INR rise), aminoglycosides (additive nephrotoxicity).

Monitoring. Renal function in prolonged courses; full blood count and liver tests weekly in courses over 14 days.

Special groups.

• Pregnancy and breastfeeding: acceptable. Cefazolin is a common agent for prophylaxis at caesarean section.
• Renal impairment: cefazolin full dose for clearance 55 mL/min or more; creatinine clearance 35 to 54 mL/min, full dose at intervals of 8 hours or longer; 11 to 34 mL/min, half dose every 12 hours; 10 mL/min or less, half dose every 18 to 24 hours. Cefalexin: extend the interval to 8 to 12 hours when clearance is under 30 mL/min and to 12 to 24 hours when under 10 mL/min. Dialysis patients are dosed after dialysis.
• Obesity: higher prophylactic dose (3 g at 120 kg or more).
• Older adults: adjust for renal function.