In vivo efficacy of enmetazobactam combined with cefepime in a murine pneumonia model induced by OXA-48-producing Klebsiella pneumoniae

Abstract

Cefepime/enmetazobactam is a new β-lactam/β-lactamase inhibitor combination with broad-spectrum activity against multidrug-resistant Enterobacterales, including OXA-48-producing isolates. Furthermore, cefepime and enmetazobactam have demonstrated similar and excellent intrapulmonary penetration, supporting the use of this new antibiotic combination in the treatment of hospital-acquired pneumonia. This study evaluated the in vivo efficacy of cefepime/enmetazobactam in a murine neutropenic pneumonia model infected with various OXA-48-producing K. pneumoniae strains. Mice were subcutaneously administered with cefepime (100 mg/kg/q2h), alone or combined with enmetazobactam (30 mg/kg/q2h), or intraperitoneally with meropenem (100 mg/kg/q2h) at 2 h post-infection. Mice were euthanized at 26 h post-infection for bacterial enumeration in lungs and spleen. A robust growth was achieved in untreated control mice. Cefepime alone or meropenem had no effect on reducing the bacterial burden in lungs after a 24-h period of treatment. The addition of enmetazobactam to cefepime resulted in a 2-log₁₀ CFU/g bioburden reduction in lungs compared to 26-h controls for all strains, including the strain harboring the highest MIC (= 8 µg/mL) to cefepime/enmetazobactam. When changes of bacterial burden were assessed relative to 2-h controls, bacterial stasis was observed. These data highlight the limited in vivo activity of meropenem against OXA-48-producing Enterobacterales despite in vitro susceptibility. Conversely, cefepime/enmetazobactam with a human-mimicking regimen demonstrated a significant antibacterial effect in the pneumonia model induced by three OXA-48-producing K. pneumoniae strains, compared with cefepime or meropenem at 24 h post-infection. Therefore, cefepime/enmetazobactam may be a new alternative for lung infections due to Enterobacterales producing OXA-48.

Importance: Third-generation cephalosporin-resistant Klebsiella pneumoniae with extended-spectrum β-lactamases as principal resistance determinants are classified as critical priority pathogens. Their increasing occurrence has led clinicians to widely use carbapenems. Accordingly, carbapenem resistance in Klebsiella pneumoniae has spread in recent decades across several countries, and OXA-48-like carbapenemases are one of the main determinants of carbapenem resistance in Enterobacterales. Cefepime/enmetazobactam is a novel β-lactam/β-lactamase inhibitor combination that demonstrated excellent intrapulmonary penetration, supporting its use in the treatment of pneumonia. This study examined the efficacy of enmetazobactam, in combination with cefepime, compared to carbapenems for OXA-48-producing Klebsiella pneumoniae in a 24-h murine neutropenic pneumonia model. The combination showed a bacteriostatic effect using the 2-h controls as reference. Compared to 24-h controls, and to cefepime or meropenem monotherapies, the co-administration of enmetazobactam with cefepime demonstrated a pronounced in vivo bactericidal activity against cefepime-non-susceptible K. pneumoniae isolates with cefepime/enmetazobactam MICs up to 8 µg/mL in this model.

Keywords: OXA-48; cefepime; enmetazobactam; pharmacodynamics; pharmacokinetics; pneumonia model.

Fig 1

Plasma PK profile for cefepime and enmetazobactam; both drugs were administered separately subcutaneously (s.c.) at 0 h, with sampling over a 4-h period. A destructive design was used, with groups of mice at each time point being serially sacrificed. Data are means ± standard deviations from three mice.

Fig 2

Therapeutic effects on bacterial load in lung (expressed as mean ± standard deviation of log₁₀ of colony-forming units per gram of lung) after intranasal infection: comparison among three different Klebsiella pneumoniae strains producing OXA-48 and CTX-M1 or CTX-M15 (A: K.p 549; B: K.p 235; C: K.p 246). Quantitative variables were compared using an analysis of variance and a post hoc analysis using Bonferroni’s test. P < 0.05 was considered significant: *P < 0.05, **P < 0.01, ***P < 0.001, **** P < 0.0001. CTRL, control.