What is the treatment for infections caused by gram-negative bacteria using cephamycins (e.g. cefoxitin, cefotetan)?

Cephamycins for Gram-Negative Bacterial Infections

Primary Recommendation

Cephamycins (cefoxitin, cefotetan) should NOT be used for infections caused by third-generation cephalosporin-resistant Enterobacterales (3GCephRE), and their use should be limited to specific susceptible infections where they remain active in vitro. 1

Evidence-Based Guidance

When NOT to Use Cephamycins

The 2022 ESCMID guidelines explicitly recommend against using cephamycins for 3GCephRE infections (conditional recommendation against use, very low certainty of evidence). 1 This represents the most current high-quality guideline evidence and should guide clinical decision-making for resistant gram-negative infections.

Appropriate Clinical Uses for Cephamycins

Cephamycins remain indicated for susceptible infections in the following scenarios:

Intra-Abdominal Infections

• Cefoxitin and cefotetan are FDA-approved for intra-abdominal infections including peritonitis and intra-abdominal abscess caused by susceptible organisms (E. coli, Klebsiella species, Bacteroides species including B. fragilis, Clostridium species). 2, 3
• For mild-to-moderately severe community-acquired intra-abdominal infections, cefoxitin can be used as single-agent empiric therapy when local susceptibility patterns support its use. 1
• Clinical trials demonstrate 95-98% response rates for community-acquired intra-abdominal infections when organisms remain susceptible. 4

Gynecological Infections

• Cefoxitin is specifically indicated for pelvic inflammatory disease (PID) as part of the regimen: cefoxitin 2g IM plus probenecid 1g orally, followed by doxycycline 100mg orally twice daily for 10-14 days. 1, 2
• Both cefoxitin and cefotetan are effective for endometritis, pelvic cellulitis, and PID caused by susceptible organisms including E. coli, N. gonorrhoeae, Bacteroides species, and anaerobes. 2, 3
• Critical caveat: Cephamycins have NO activity against Chlamydia trachomatis; appropriate anti-chlamydial coverage (doxycycline) must always be added for PID treatment. 2, 3

Other Susceptible Infections

• Lower respiratory tract infections (pneumonia, lung abscess) caused by susceptible S. pneumoniae, S. aureus, E. coli, Klebsiella, H. influenzae, and Bacteroides species. 2
• Urinary tract infections caused by susceptible E. coli, Klebsiella, Proteus species, and Providencia. 2, 3
• Skin and soft tissue infections caused by susceptible staphylococci, streptococci, E. coli, and anaerobes. 2, 3

Dosing Considerations

Cefotetan offers a practical advantage with twice-daily dosing (1-2g every 12 hours) compared to cefoxitin's four-times-daily requirement (1-2g every 6 hours). 5, 4, 6 This represents a significant cost-saving and compliance advantage when both agents are equally effective. 4, 6

Critical Limitations

Resistance Concerns

• Cephamycins should be avoided in settings with high ESBL-producing Enterobacteriaceae prevalence unless susceptibility is confirmed. 1
• They have limited activity against Pseudomonas aeruginosa and should not be used for pseudomonal infections. 5
• No activity against MRSA or enterococci (e.g., Enterococcus faecalis). 2

Comparative Activity

• Cephamycins are less active against Bacteroides fragilis than clindamycin or metronidazole, though clinical differences may not be significant in mixed infections. 7
• For severe infections or those with resistant organisms, carbapenems (meropenem, imipenem) remain the preferred agents. 1

Antibiotic Stewardship Considerations

The extended use of cephalosporins, including cephamycins, should be discouraged due to selective pressure leading to ESBL-producing Enterobacteriaceae and MRSA emergence. 1 Their use should be:

• Limited to pathogen-directed therapy when susceptibility is confirmed 1
• Avoided for empiric treatment in areas with high resistance rates 1
• Reserved for situations where narrower-spectrum alternatives are inappropriate 1

Surgical Prophylaxis

Cefoxitin and cefotetan are indicated for surgical prophylaxis in uncontaminated gastrointestinal surgery, vaginal hysterectomy, abdominal hysterectomy, and cesarean section. 2, 3 However, the 2024 WHO guidelines suggest cefazolin, cefuroxime, or ceftriaxone may be more appropriate first-line options for most surgical prophylaxis scenarios. 1