Efficacy and safety of colistin-doxycycline combination therapy in multi-drug resistance Gram-negative infections: a double-blind randomized controlled trial

Abstract

Background & objectives: Multidrug-resistant (MDR) Klebsiella pneumoniae poses a critical treatment challenge. Colistin remains a last-resort antibiotic but is limited by nephrotoxicity and resistance. Though clinical data are limited, Doxycycline has demonstrated in vitro synergy with colistin. Colistin-meropenem is frequently used as a comparator regimen, despite mixed evidence on its synergistic activity. This study evaluates the efficacy, microbiological response, and safety of colistin-doxycycline versus colistin-meropenem in MDR Gram-negative infections.

Methods: A double-blind, randomized controlled trial was conducted at a teaching hospital. Adult patients with culture-confirmed MDR Klebsiella pneumoniae infections were randomized to receive colistin-doxycycline or colistin-meropenem. The primary outcome was clinical cure, defined as resolution of infection signs without therapy escalation and in-hospital mortality. Secondary outcomes included microbiological eradication, acute kidney injury (AKI), and treatment-related adverse events. Patients were followed throughout hospitalization and for 14 days post-treatment.

Results: A total of 46 patients were enrolled, with 23 patients in each group. Clinical cure rates were significantly higher in the colistin-doxycycline group (87.0% vs. 46.7%, p = 0.012), and mortality was lower (69.6% vs. 86.7%, p = 0.017). Microbiological eradication was also superior (p = 0.016), and nephrotoxicity incidence was numerically lower (19.1% vs. 33.3%, p = 0.092). Faster resolution of inflammation (p < 0.05) and reduced need for mechanical ventilation (60.9% vs. 33.3%, p = 0.028) were observed in the colistin-doxycycline group.

Conclusions: Colistin-doxycycline showed superior efficacy to colistin-meropenem in MDR Klebsiella pneumoniae infections, with higher cure rates, better bacterial eradication, and a favorable safety trend. These results support its potential as a possible alternative option in managing MDR Gram-negative infections, though confirmation in larger multicenter trials is needed.

Keywords: Antibiotic synergy; Colistin; Doxycycline; Gram-negative infections; Multidrug-resistant bacteria.