Introduction

Carbapenem resistance in Klebsiella (K.) pneumoniae, mainly driven by OXA-48-like carbapenemases, has recently become widespread. Cefepime/enmetazobactam is a novel β-lactam/β-lactamase inhibitor combination with broad-spectrum activity against multidrug-resistant Enterobacterales. It has demonstrated excellent intrapulmonary penetration and hence is preferred in the treatment of hospital-acquired pneumonia.

Aim

To evaluate the in vivo efficacy of cefepime/enmetazobactam as compared to meropenem against multidrug-resistant Enterobacterales in a neutropenic murine pneumonia model infected with various clinical OXA-48-producing K. pneumoniae strains.

Method

• Cefotaxime (CTX)-M and OXA-48-producing K. pneumoniae clinical isolates (in vitro minimum inhibitory concentration, MIC values from 0.5-8 μg/mL) were used to inoculate the mice
• Antibiotics were administered at 2 h post-infection, intraperitoneally for meropenem and saline serum or subcutaneously for cefepime, alone or combined with enmetazobactam and continued for 26 h
• Mice were euthanized at 26 h post-infection for bacterial enumeration in lungs and spleen

Study Design

• Mice were randomly assigned to one of four study arms: no treatment (saline serum), meropenem alone (100 mg/kg/q2h), cefepime alone (100 mg/kg/q2h), and cefepime (100 mg/kg/q2h) plus enmetazobactam (30 mg/kg/q2h)

Endpoints

• Bacterial burden

  Results

  Efficacy

• The addition of enmetazobactam to cefepime significantly reduced the bacterial burden at 26 h in lungs (−2 log10 colony forming units/g on average) versus controls for all strains, including the K.p 246 strain harboring the highest MIC (8 μg/mL) to cefepime/enmetazobactam
• Cefepime/enmetazobactam combination showed a bacteriostatic effect using the 2-h controls as reference (bacterial reduction −0.92, −0.52, and −0.05 log10 CFU/g for K.p 549, K.p 235, and K.p 246, respectively)
• Cefepime alone or meropenem had no effect on reducing the bacterial burden in lungs after a 24-h period of in vivo treatment against OXA-48-producing Enterobacterales, even in animals infected with the most susceptible strain (MIC 0.5 μg/mL, 74% of T > MIC)
• Addition of enmetazobactam at a fixed concentration drastically reduced the MICs between 0.5 and 8 μg/mL for K. pneumoniae strains
• All bacterial strains were resistant to cefepime (MICs ranged from 16 to >256 μg/mL)
• Only K.p 549 (MIC 0.5 μg/mL) was susceptible to meropenem (MICs ranged from 0.5 to >16 μg/mL)
  

  Conclusion

• A human-mimicking regimen of cefepime and enmetazobactam combination demonstrated a significant in vivo antibacterial effect over 26-h controls, cefepime or meropenem monotherapy at 24 h post-infection in the pneumonia model induced by OXA-48-producing, cefepime-non-susceptible K. pneumoniae strains
• Cefepime/enmetazobactam may be a new alternative for lung infections due to Enterobacterales producing OXA-48

Microbiol Spectr. 2024; 12: e0234524