Acinetobacter baumannii causes pneumonias, bacteremias, and skin and soft tissue infections, primarily in the hospitalized setting. The incidence of infections caused by A. baumannii has increased dramatically over the last 30 years, while at the same time the treatment of these infections has been complicated by the emergence of antibiotic-resistant strains. Despite these trends, no vaccines or antibody-based therapies have been developed for the prevention of A. baumannii infection. In this study, an outer membrane complex vaccine consisting of multiple surface antigens from the bacterial membrane of A. baumannii was developed and tested in a murine sepsis model. Immunization elicited humoral and cellular responses that were able to reduce postinfection bacterial loads, reduce postinfection proinflammatory cytokine levels in serum, and protect mice from infection with human clinical isolates of A. baumannii. A single administration of the vaccine was able to elicit protective immunity in as few as 6 days postimmunization. In addition, vaccine antiserum was used successfully to therapeutically rescue naïve mice with established infection. These results indicate that prophylactic vaccination and antibody-based therapies based on an outer membrane complex vaccine may be viable approaches to preventing the morbidity and mortality caused by this pathogen.

Acinetobacter baumannii (American Type Culture Collection strain 19606) acquires mutations in the pmrB gene during the in vitro development of resistance to colistin. The colistin-resistant strain has lower affinity for colistin, reduced in vivo fitness (competition index, .016), and decreased virulence, both in terms of mortality (0% lethal dose, 6.9 vs 4.9 log colony-forming units) and survival in a mouse model of peritoneal sepsis. These results may explain the low incidence and dissemination of colistin resistance in A. baumannii in clinical settings.

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.

The aim of this study was to improve the understanding of the pharmacokinetic-pharmacodynamic relationships of fosfomycin against extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli strains that have different fosfomycin MICs. Our methods included the use of a hollow fiber infection model with three clinical ESBL-producing E. coli strains. Human fosfomycin pharmacokinetic profiles were simulated over 4 days. Preliminary studies conducted to determine the dose ranges, including the dose ranges that suppressed the development of drug-resistant mutants, were conducted with regimens from 12 g/day to 36 g/day. The combination of fosfomycin at 4 g every 8 h (q8h) and meropenem at 1 g/q8h was selected for further assessment. The total bacterial population and the resistant subpopulations were determined. No efficacy was observed against the Ec42444 strain (fosfomycin MIC, 64 mg/liter) at doses of 12, 24, or 36 g/day. All dosages induced at least initial bacterial killing against Ec46 (fosfomycin MIC, 1 mg/liter). High-level drug-resistant mutants appeared in this strain in response to 12, 15, and 18 g/day. In the study arms that included 24 g/day, once or in a divided dose, a complete extinction of the bacterial inoculum was observed. The combination of meropenem with fosfomycin was synergistic for bacterial killing and also suppressed all fosfomycinresistant clones of Ec2974 (fosfomycin MIC, 1 mg/liter). We conclude that fosfomycin susceptibility breakpoints (<64 mg/liter according to CLSI [for E. coli urinary tract infections only]) should be revised for the treatment of serious systemic infections. Fosfomycin can be used to treat infections caused by organisms that demonstrate lower MICs and lower bacterial densities, although relatively high daily dosages (i.e., 24 g/day) are required to prevent the emergence of bacterial resistance. The ratio of the area under the concentration-time curve for the free, unbound fraction of fosfomycin versus the MIC (fAUC/MIC) appears to be the dynamically linked index of suppression of bacterial resistance. Fosfomycin with meropenem can act synergistically against E. coli strains in preventing the emergence of fosfomycin resistance.