Dose-dependent Synergistic Interactions of Colistin with Rifampicin, Meropenem and Tigecycline against Carbapenem-resistant Klebsiella pneumoniae Biofilms [Pharmacology]

Carbapenem-resistant Klebsiella pneumoniae (CR-Kp) can cause biofilm-related bloodstream infections associated with significant morbidity and mortality worldwide. We investigated the bactericidal activities of colistin (CST), rifampicin (RIF), meropenem (MEM), gentamicin (GEN) and tigecycline (TGC) alone and that of CST in combination with RIF, MEM, GEN or TGC against CR-Kp mature biofilms. Twenty CR-Kp blood isolates were derived from equal number of bloodstream infections in adult patients. Biofilm formation was assessed by staining with 0.4% crystal violet and measuring optical density spectrophotometrically at 545 nm. Biofilm damage was measured as % reduction of metabolic activity by XTT assay. MIC50 for biofilms was determined as the minimum concentration that caused ≥50% bacterial damage compared to that for untreated controls. Antibacterial drug interactions were analyzed by the Bliss independence model. Four of the twenty CR-Kp isolates were biofilm producers. Biofilm MIC50's of CST, RIF, MEM, GEN and TGC for these isolates were 64, 8, >256, 128 and 8 mg/L, respectively. Synergistic interactions were observed at 32-64 mg/L of CST combined with 0.25-4 mg/L of RIF, at 32 mg/L of CST combined with 0.007-0.25 mg/L of MEM, and at 16-32 mg/L of CST combined with 16-64 mg/L of TGC. The synergy was highest for CST+RIF, with %E±SE 49.87±9.22 compared to 29.52±4.97 for CST+MEM (p<0.001) and 32.44±6.49 for CST+TGC (p<0.001). Indifferent results were exhibited by CST+GEN. None of the combinations exhibited antagonism. These drug interactive findings, especially that of CST with RIF, may be of importance in the treatment of biofilm-related CR-Kp infections.

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