Efficacy of Rifampin and Its Combinations with Imipenem, Sulbactam, and Colistin in Experimental Models of Infection Caused by Imipenem-Resistant Acinetobacter baumannii

Abstract

There are currently no defined optimal therapies available for multidrug-resistant (MDR) Acinetobacter baumannii infections. We evaluated the efficacy of rifampin, imipenem, sulbactam, colistin, and their combinations against MDR A. baumannii in experimental pneumonia and meningitis models. The bactericidal in vitro activities of rifampin, imipenem, sulbactam, colistin, and their combinations were tested using time-kill curves. Murine pneumonia and rabbit meningitis models were evaluated using the A. Acinetobacter baumannii is an important nosocomial pathogen worldwide (5, 35), with pneumonia, bacteremia, and surgical site and urinary tract infections being the most important infections caused by this organism (16). A Spanish study showed A. baumannii as the cause of nearly 9% of cases of ventilator-associated pneumonia (VAP) (2), with a crude mortality of 40% to 70% (14). A. baumannii may also cause meningitis and ventriculitis, especially in patients undergoing neurosurgical procedures or with head trauma (17), with mortality rates between 20% and 27% (5).The well-known ability of A. baumannii to acquire resistance to almost all groups of available antibiotics leads to serious problems in the management of infections caused by multidrug-resistant (MDR) A. baumannii infections (5, 16). In these cases, carbapenems have been considered the treatment of choice. However, increasing numbers of carbapenem-resistant A. baumanii isolates have been reported worldwide (1, 28), prompting the search for other therapeutic options.Sulbactam has been used successfully in cases of meningitis and pneumonia caused by A. baumannii (17,21,39). Colistin has good in vitro activity (37) but has shown contradictory results in clinical practice (12) and experimental models (23). Rifampin has demonstrated in vitro and in vivo bactericidal activities against MDR A. baumannii in an experimental pneumonia model (23), but rifampin-resistant mutants appear shortly after treatment initiation with rifampin alone (23, 27). The combination of rifampin plus imipenem has been evaluated in clinical infections caused by highly imipenem-resistant A. baumannii strains, with inconclusive results (33). Two clinical studies have shown efficacy rates of 76% to 100% for colistin plus rifampin in VAP, bacteremia, and meningitis (4, 25). The aims of this study were to evaluate the efficacies of rifampin and its combinations with imipenem, sulbactam, and colistin in experimental pneumonia and meningitis models caused by MDR A. baumannii strains.

Investigation of Colistin Heteroresistance and Some Factors Affecting Heteroresistance in Carbapenem-Resistant A. baumannii Strains

“…In accordance with this, several studies and case reports confirmed the inhibitory effect of Col+Rif combination [25] . In a study performed in 2005, Timurkaynak et al [26] showed that the combination of colistin and rifampicin was synergistic against multidrug-resistant A. baumannii isolates.…”

Innate Immune Responses to Systemic Acinetobacter baumannii Infection in Mice: Neutrophils, but Not Interleukin-17, Mediate Host Resistance

“…However, antibiograms performed on these strains showed a rough correlation between virulence and degree of antibiotic resistance, a relationship that has not previously been investigated. The tendency for A. baumannii strains to exhibit a high level of antibiotic resistance is well established in the literature (1,2,6,7,18,20,22,27,28,33,39,49,59). Resistance is due both to chromosomally encoded resistance genes and to ones found on plasmids and transposons (12).…”

<i>In Vitro</i> Activity of Colistin and Vancomycin or Azithromycin Combinations on Extensively Drug Resistant <i>Acinetobacter baumannii</i> Clinical Isolates

“…Another problem with colistin especially with multidrug resistant isolates is heteroresistance that has been observed in vitro and has also developed during therapy [4] [5], raising issues about colistin being used alone as a monotherapy which may lack sufficient killing activity and aid in selection of resistant subpopulation [6].…”