Combination Regimens for Treatment of Carbapenem-Resistant Klebsiella pneumoniae Bloodstream Infections

Abstract

Previous studies reported decreased mortality in patients with carbapenemase-producing Klebsiella pneumoniae bloodstream infections (BSIs) treated with combination therapy but included carbapenem-susceptible and -intermediate isolates, as per revised CLSI breakpoints. Here, we assessed outcomes in patients with BSIs caused by phenotypically carbapenem-resistant K. pneumoniae (CRKP) according to the number of in vitro active agents received and whether an extended-spectrum beta-lactam (BL) antibiotic, including meropenem, or an extended-spectrum cephalosporin was administered. We retrospectively reviewed CRKP BSIs at two New York City hospitals from 2006 to 2013, where all isolates had meropenem or imipenem MICs of >4 g/ ml. Univariate and multivariable models were created to identify factors associated with mortality. Of 141 CRKP BSI episodes, 23% were treated with a single active agent (SAA), 26% were treated with an SAA plus BL, 28% were treated with multiple active agents (MAA), and 23% were treated with MAA plus BL. Ninety percent of isolates had meropenem MICs of >16 g/ml. Thirtyday mortality was 33% overall and did not significantly differ across the four treatment groups in a multivariable model (P ‫؍‬ 0.4); mortality was significantly associated with a Pitt bacteremia score of >4 (odds ratio [OR], 7.7; 95% confidence interval [CI], 3.2 to 18.1; P ‫؍‬ 0.1), and immunosuppression was protective (OR, 0.4; 95% CI, 0.2 to 1.0; P ‫؍‬ 0.04). Individual treatment characteristics were also not significantly associated with outcome, including use of SAAs versus MAA (26% versus 38%, P ‫؍‬ 0.1) or BL versus no BL (26% versus 39%, P ‫؍‬ 0.1). In summary, in patients with CRKP BSIs caused by isolates with high carbapenem MICs, the role of combination therapy remains unclear, highlighting the need for prospective studies to identify optimal treatment regimens.

Epidemiology of Klebsiella pneumoniae bloodstream infections in a teaching hospital: factors related to the carbapenem resistance and patient mortality

“…The crude 28-day mortality in KP-BSI patients was shown to be 22.8%, which increased to 33.3% in CRKP-BSI patients, similar to the rates obtained in both Chinese and foreign studies [12, 25, 29, 36–38]. Furthermore, the mortality of CRKP-BSI patients was shown to be higher than that of CSKP-BSI patients, which may be a consequence of the infection with ST11 clone, which is a dominant CRKP strain in China [28] with an increased pathogenic potential and resistance to serum killing [39, 40].…”

“…Additionally, due to the limited CRKP treatment options, inappropriate empirical therapy may contribute to their deleterious outcomes [4, 19]. According to the recent clinical observations, the treatment of CRKP infections by a combination therapy may result in the reduced mortality compared with monotherapy [11, 12], but the treatment should be further optimized.…”

“…More importantly, CRKP isolates were shown to be resistant to a variety of antibiotics, and to have the ability to hydrolyze carbapenems, leaving few effective treatment options. The use of combination therapy and appropriate empirical treatment may provide useful prognostic information in these patients [10–12]. …”

New Polymyxin B Dosing Strategies To Fortify Old Allies in the War against KPC-2-Producing Klebsiella pneumoniae

“…Polymyxin-carbapenem combination regimens have been associated with improved clinical outcomes and reduced mortality in KPC-Kp infections, providing a viable alternative to polymyxin monotherapy (8,9). However, the clinical benefit of adding a carbapenem to the polymyxin is not apparent in infections due to KPC-Kp with elevated carbapenem MICs (Ն16 mg/liter) (10). Interestingly, rifampin-containing combination regimens to combat KPC-Kp have shown promise in preclinical animal models and some in vitro studies (11)(12)(13).…”

In vitro and In vivo characterization of NOSO-502, a novel inhibitor of bacterial translation

“…NOSO-502 is active against Enterobacteriaceae , including CRE belonging to all classes of the Ambler classification and resistant to gentamicin, polymyxin B, or tigecycline. This is crucial, because these antibiotics, classically used for the treatment of such infections, are associated with high levels of resistance ranging from 9.7 to 51.3% (mean 22.6%) for colistin, 5.6 to 85.4% (mean 43.5%) for gentamicin, and 0 to 33% (mean 15.2%) for tigecycline (8, 9, 10, 11, 12, 13, 14, 15, 16, 17). Current options to address these resistance issues are not entirely satisfactory, because none of the recently approved antibiotics or those under development are effective against all CRE.…”