Antimicrobial resistance among Acinetobacter baumannii is increasing worldwide, often necessitating combination therapy. The clinical utility of using minocycline with polymyxin B is not well established. In this study, we investigated the activity of minocycline and polymyxin B against 1 laboratory isolate and 3 clinical isolates of A. baumannii. Minocycline susceptibility testing was performed with and without an efflux pump inhibitor, phenylalanine-arginine ␤-naphthylamide (PA␤N). The intracellular minocycline concentration was determined with and without polymyxin B (0.5 g/ml). Time-kill studies were performed over 24 h using approximately 10 6 CFU/ml of each strain with clinically relevant minocycline concentrations (2 g/ml and 8 g/ml), with and without polymyxin B (0.5 g/ml). The in vivo efficacy of the combination was assessed in a neutropenic murine pneumonia model. Infected animals were administered minocycline (50 mg/kg), polymyxin B (10 mg/kg), or both to achieve clinically equivalent exposures in humans. A reduction in the minocycline MIC (>4؋) was observed in the presence of PA␤N. The intracellular concentration and in vitro bactericidal effect of minocycline were both enhanced by polymyxin B. With 2 minocyclinesusceptible strains, the bacterial burden in lung tissue at 24 h was considerably reduced by the combination compared to monotherapy with minocycline or polymyxin B. In addition, the combination prolonged survival of animals infected with a minocycline-susceptible strain. Polymyxin B increased the intracellular concentration of minocycline in bacterial cells and enhanced the bactericidal activity of minocycline, presumably due to efflux pump disruption. The clinical utility of this combination should be further investigated.A cinetobacter baumannii is a common nosocomial pathogen globally which has been implicated as an etiologic agent in ventilator-associated pneumonia, skin and skin structure infections (traumatic battlefield and other wounds), urinary tract infections, meningitis, and bacteremia (1). Over the past decades, infections due to increasingly resistant strains of Acinetobacter have emerged (2, 3). This is particularly alarming because there are very limited therapeutic options for these infections (4, 5). Multidrug-resistant strains of A. baumannii have been reported to adversely affect patient outcomes. Studies have found significantly higher rates of hospital mortality in patients infected with multidrug-resistant strains than in patients with susceptible strains (6, 7).Current treatment strategies for multidrug-resistant A. baumannii include combination therapy with tigecycline, minocycline, carbapenems, polymyxins, and even daptomycin (8-11). However, the rationale of using certain agents together in a combination is not well established. In this study, the combination of minocycline and polymyxin B was studied based on a mechanistically plausible approach. Resistance to the tetracycline class in A. baumannii is commonly mediated through the upregulation of efflux pumps loca...

Receipt of COMBO therapy did not decrease the rate of clinical failure but was associated with expedited bacteremia clearance. Early adjuvant β-lactam therapy deserves continued evaluation and clinical consideration.

e Pseudomonas aeruginosa bacteremia is associated with high hospital mortality. Empirical combination therapy is commonly used to increase the likelihood of appropriate therapy, but the benefits of employing >1 active agent have yet to be established. The purpose of this study was to compare outcomes of patients receiving appropriate empirical combination versus monotherapy for P. aeruginosa bacteremia. This was a retrospective, multicenter, cohort study of hospitalized adult patients with P. aeruginosa bacteremia from 2002 to 2011. The primary endpoint (30-day mortality) was assessed using multivariate logistic regression, adjusting for underlying confounding variables. Secondary endpoints of hospital mortality and time to mortality were assessed by Fisher's exact test and the Cox proportional hazards model, respectively. A total of 384 patients were analyzed. Thirtyday mortality was higher for patients receiving inappropriate therapy than for those receiving appropriate empirical therapy (43.8% versus 21.5%; P ‫؍‬ 0.03). However, there were no statistical differences in 30-day mortality following appropriate empirical combination versus monotherapy after adjusting for baseline APACHE II scores and lengths of hospital stay prior to the onset of bacteremia (P ‫؍‬ 0.55). Observed hospital mortality was 36.6% for patients administered combination therapy, compared with 28.7% for monotherapy patients (P ‫؍‬ 0.17). After adjusting for baseline APACHE II scores, the relationship between time to mortality and combination therapy was not statistically significant (P ‫؍‬ 0.59). Overall, no significant differences were observed for 30-day mortality, hospital mortality, and time to mortality between combination and monotherapy for P. aeruginosa bacteremia. Empirical combination therapy did not appear to offer an additional benefit, as long as the isolate was susceptible to at least one antimicrobial agent.

Safe and effective therapies are urgently needed to treat polymyxinresistant KPC-producing Klebsiella pneumoniae infections and suppress the emergence of resistance. We investigated the pharmacodynamics of polymyxin B, rifampin, and meropenem alone and as polymyxin B-based double and triple combinations against KPC-producing K. pneumoniae isolates. The rates and extents of killing with polymyxin B (1 to 128 mg/liter), rifampin (2 to 16 mg/liter), and meropenem (10 to 120 mg/liter) were evaluated against polymyxin B-susceptible (PB s ) and polymyxin B-resistant (PB r ) clinical isolates using 48-h static time-kill studies. Additionally, humanized triple-drug regimens of polymyxin B (concentration at steady state [C ss ] values of 0.5, 1, and 2 mg/liter), 600 mg rifampin every 12 or 8 h, and 1 or 2 g meropenem every 8 h dosed as an extended 3-h infusion were simulated over 48 h by using a one-compartment in vitro dynamic infection model. Serial bacterial counts were performed to quantify the pharmacodynamic effect. Population analysis profiles (PAPs) were used to assess the emergence of polymyxin B resistance. Monotherapy was ineffective against both isolates. Polymyxin B with rifampin demonstrated early bactericidal activity against the PB s isolate, followed by regrowth by 48 h. Bactericidal activity was sustained at all polymyxin B concentrations of Ն2 mg/liter in combination with meropenem. No two-drug combinations were effective against the PB r isolate, but all simulated triple-drug regimens showed early bactericidal activity against both strains by 8 h that was sustained over 48 h. PAPs did not reveal the emergence of resistant subpopulations. The triple-drug combination of polymyxin B, rifampin, and meropenem may be a viable consideration for the treatment of PB r KPC-producing K. pneumoniae infections. Further investigation is warranted to optimize triple-combination therapy.