Fosfomycin-based combinations against carbapenemase-producing Klebsiella pneumoniae bloodstream infections: Correlating in vitro synergy with clinical outcomes

Abstract

Background

Carbapenemase-producing Klebsiella pneumoniae (CP-Kp) poses a significant global health threat due to its limited treatment options and increasing resistance. Fosfomycin (FOF) has regained interest, particularly in combination therapies. This study aimed to evaluate the in vitro synergy of FOF with meropenem (MEM) and polymyxin in CP-Kp bloodstream infections (BSI) and to investigate clinical outcomes.

Methods

Fifty-two patients with CP-Kp BSI who received FOF-based combination therapy (FOF-C) for ≥72 h were evaluated retrospectively for clinical outcomes. Minimum inhibitor concentrations (MICs) were determined on stored isolates: FOF by agar dilution (AD) and broth microdilution, MEM and COL by broth microdilution. In vitro synergy testing of FOF with MEM and COL was performed using the checkerboard method. Data were analysed using logistic regression.

Results

Among 50 isolates, the FOF AD MIC_50/90 were 64/>128 µg/mL. Positive in vitro interactions (synergistic or additive) were observed in 43.5% of isolates for both FOF + MEM and FOF + COL, with no antagonism. The clinical and microbiological response rates were 61.5% and 80.5%, 14- and 30-d mortality rates were 21.2% and 40.4%, respectively. Patients receiving at least one agent with in vitro positive interaction had higher clinical response, but the difference wasn’t significant (73.7% vs. 52.2% P = 0.153). In multivariable analysis, increased FOF AD MIC and Pitt bacteraemia score were associated with clinical nonresponse, while higher COL MIC and Pitt bacteraemia score predicted 30-d mortality.

Conclusions

FOF AD MIC value may have potential as a predictive marker for FOF-C treatment response in CP-Kp BSI and could aid in guiding combination therapy decisions. Larger, prospective studies using standardized synergy testing methods are needed.