Cephalosporins - Classification by Generation

1st Generation

• Excellent gram-positive coverage: Streptococci, methicillin-susceptible Staphylococci (MSSA)
• Limited gram-negative coverage: E. coli, Klebsiella pneumoniae, Proteus mirabilis (the "EKP" triad)
• No activity against: MRSA, Pseudomonas aeruginosa, Enterobacter, Serratia, Acinetobacter, Bacteroides fragilis

• Cefazolin is the drug of choice for surgical prophylaxis
• Skin/soft tissue infections, cellulitis, streptococcal/staphylococcal infections
• Cefazolin effective in MSSA bacteremia; does NOT penetrate the CNS - cannot treat meningitis
• Oral cephalexin for UTIs and mild soft tissue infections

2nd Generation

• Retain reasonable gram-positive activity (but less than 1st gen)
• Extended gram-negative coverage: H. influenzae, Moraxella catarrhalis, Klebsiella (including 1st-gen-resistant strains)
• Cefuroxime and Cefaclor: active against H. influenzae but NOT Serratia or B. fragilis
• Cefoxitin and Cefotetan (cephamycins): active against B. fragilis and some Serratia - useful for anaerobic coverage
• Still NO activity against enterococci or P. aeruginosa

• Sinusitis, otitis media, lower respiratory tract infections (beta-lactamase-producing H. influenzae)
• Cefoxitin/Cefotetan: mixed anaerobic infections - peritonitis, diverticulitis, pelvic inflammatory disease
• Community-acquired pneumonia (cefuroxime)
• Note: Cefuroxime crosses the blood-brain barrier but is LESS effective than ceftriaxone for meningitis - should not be used for meningitis

3rd Generation

• Markedly expanded gram-negative coverage: Citrobacter, Serratia marcescens, Providencia, Haemophilus, Neisseria
• Ceftazidime: the ONLY 3rd-gen agent with useful activity against P. aeruginosa
• Penetrate the blood-brain barrier (CSF penetration) - usable for meningitis
• Effective against beta-lactamase-producing strains of Haemophilus and Neisseria
• Reduced gram-positive potency compared to 1st gen
• Hydrolyzed by AmpC beta-lactamase - NOT reliably active against Enterobacter (avoid even if in vitro susceptible - emergence of resistance is rapid)
• ESBL-producing organisms are NOT susceptible

• Meningitis (ceftriaxone or cefotaxime are drugs of choice for pneumococcal, meningococcal, H. influenzae, gram-negative rod meningitis)
• Ceftriaxone: drug of choice for gonococcal infections (IM)
• Empiric therapy for sepsis (immunocompetent and immunocompromised)
• Ceftriaxone and cefotaxime most active against penicillin-non-susceptible Streptococcus pneumoniae - add vancomycin if MIC >1 mcg/mL

• Ceftriaxone has a long half-life (7-8 hours) - can be dosed once daily (1 g/day for most infections; 2 g for meningitis/endocarditis); biliary excretion - NO renal dose adjustment needed
• Others have half-lives of 1-7 hours, every 6-8 hour dosing; renally excreted - require dose adjustment

4th Generation

• Broader than 3rd gen: retains excellent gram-negative coverage AND improved gram-positive coverage
• Active against: P. aeruginosa, Enterobacterales (including Enterobacter - more resistant to AmpC hydrolysis), MSSA, Streptococcus pneumoniae, Haemophilus and Neisseria
• Excellent CNS penetration
• Still hydrolyzed by extended-spectrum beta-lactamases (ESBL) - not active against ESBL producers
• No activity against MRSA, anaerobes

• Febrile neutropenia
• Hospital-acquired pneumonia, bacteremia
• Infections due to Enterobacter (preferred over 3rd gen due to greater beta-lactamase stability)
• Treatment of Pseudomonas infections (check local antibiogram)

5th Generation (Anti-MRSA Cephalosporins)

• Ceftaroline is the ONLY beta-lactam in the USA with activity against MRSA. It binds to the altered PBP2a of MRSA and also PBPs of penicillin-resistant Streptococcus pneumoniae. Gram-negative activity similar to 3rd-gen ceftriaxone. Gaps: no activity against P. aeruginosa, ESBL-producers, or Acinetobacter baumannii
• Ceftolozane/tazobactam: Enhanced anti-Pseudomonal activity (including many MDR P. aeruginosa)

• Ceftaroline: complicated skin and soft tissue infections (cSSTI) and community-acquired pneumonia (CAP)
• Limitation: twice-daily dosing limits outpatient use of ceftaroline

Siderophore Cephalosporin (Novel Class)

• Active against aerobic gram-negative organisms, including multidrug-resistant (MDR) strains
• Unique mechanism: acts as an iron chelator (siderophore) - binds extracellular ferric iron and is actively transported into the bacterial cell via iron uptake channels (active transport, not just passive porin diffusion)
• Stable against virtually ALL beta-lactamases: KPC, OXA-type, metallo-beta-lactamases (MBL)
• Active against drug-resistant Enterobacterales, P. aeruginosa, Acinetobacter baumannii
• NO activity against gram-positive or anaerobic organisms

• Complicated UTIs / pyelonephritis
• Hospital-acquired and ventilator-associated pneumonia
• Reserved for cases with limited or no alternative options (FDA black-box warning: increased mortality seen in one clinical trial of carbapenem-resistant gram-negative infections)

Summary Comparison Table