Synergistic effects of colistin-based combinations against colistin and carbapenem-resistant Klebsiella pneumoniae isolated from nosocomial bloodstream infections

The emergence of colistin and carbapenem-resistant Klebsiella pneumoniae (CRCR-KP) poses a critical challenge in treating bloodstream infections. As resistance reduces colistin's efficacy, alternative strategies are urgently needed. Combination therapy may offer improved outcomes, but its effectiveness remains uncertain. This study evaluated in vitro interactions between colistin and 12 commonly used antibiotics against CRCR-KP isolates from nosocomial bloodstream infections. A retrospective analysis identified 25 CRCR-KP isolates (10.8%) among 270 K. pneumoniae bloodstream infections, with 18 isolates included in synergy testing. Checkerboard assays were used to assess colistin-based interactions, quantified using the Fractional Inhibitory Concentration Index (FICI), Loewe Additivity, and Bliss Independence models. Demographic and clinical data were collected, including ward distribution, comorbidities, prior antibiotic exposure, and patient outcomes. The median patient age was 65 years (range: 2-94), and the mortality rate was 77.8% (14/18), underscoring the severity of these infections. Patients were primarily admitted to the ICU (22.2%), emergency department (33.3%), and hematology unit (22.2%), with frequent invasive procedures (94.4%) and hospital stays ranging from 4 to 60 days. 66% of isolates were classified as extensively drug-resistant (XDR). Disk diffusion and MIC testing revealed high resistance across most antibiotic classes, though tigecycline (44.4%), amikacin (50%), and minocycline (34%) demonstrated partial efficacy. Synergy detection rates varied by model, FICI (75%), Loewe (50%), and Bliss (41.6%), highlighting the importance of using multiple analytical approaches. Clindamycin, chloramphenicol, erythromycin, and minocycline exhibited strong synergy with colistin at lower concentrations, suggesting a promising combination strategy for managing CRCR-KP bloodstream infections. Minocycline appears particularly viable due to its achievable serum concentrations and moderate Gram-negative coverage. Further pharmacokinetic, pharmacodynamic, and clinical research is essential to validate these findings and guide the development of effective treatment regimens.