Risk Factors for Treatment Failure of Polymyxin B Monotherapy for Carbapenem-Resistant Klebsiella pneumoniae Infections

Abstract

I nfections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) have been associated with poor outcomes. An overall mortality rate of 48% is reported for patients with CRKP, compared to 26% for those with carbapenem-susceptible K. pneumoniae infections (1). CRKP isolates confer resistance through the production of K. pneumoniae carbapenemases (KPCs), which are able to hydrolyze all currently available ␤-lactams, including carbapenems (2). Due to additional mechanisms of resistance commonly found in KPC-producing isolates, they often demonstrate resistance to other antimicrobial classes, including fluoroquinolones and aminoglycosides (2, 3). This limits therapeutic choices, as polymyxins (polymyxin B or colistin) and tigecycline may be the only antibiotics that retain in vitro and in vivo microbiological activity.CRKP infections are often treated with combination therapy (4, 5); however, the choice of agents is both limited and challenging. Combination therapy with aminoglycosides, if susceptibility is preserved, carries an increased risk of nephrotoxicity. Due to a high volume of distribution, low blood levels, and high MIC, tigecycline is a "last resort" option, particularly for bloodstream infections. High MICs of carbapenems preclude achieving therapeutic levels even with pharmacodynamically optimized dosing strategies. Although in vitro synergy against CRKP has been observed when polymyxin B is used in combination with rifampin, cefepime, aminoglycosides, carbapenems, or tigecycline, testing methods are nonstandardized, and therefore the clinical effect of synergy remains unclear (3,(6)(7)(8). Limited data have demonstrated survival benefits of combination therapy using polymyxin B or colistin with carbapenems and/or tigecycline for patients with CRKP bacteremia (4, 5). Given the frequently encountered challenges of combination therapy, we aimed to describe the outcomes for patients with CRKP infections treated with polymyxin B monotherapy and to identify risk factors for treatment failure. MATERIALS AND METHODSStudy design. This was a retrospective study in a tertiary care academic medical center in New York City. The study population included adult patients (aged Ն18 years) with CRKP infections who received polymyxin B monotherapy for Ն72 h. Only the first treatment course was included.Microbiology. Cases were identified from a microbiology lab report of CRKP isolates from 1 January 2007 to 15 August 2011 and by review of medical records. The Vitek-2 system (bioMérieux) used by our microbiology laboratory has built-in analysis software (version R05.01) that enables it to identify resistance phenotypes. Isolates were included if the ertapenem/imipenem MIC was reported as resistant by Vitek-2. For tigecycline and polymyxin B, susceptibility was defined as an MIC of Յ2 mg/liter by Etest, according to Food and Drug Administration (FDA) breakpoints for Enterobacteriaceae and Clinical and Laboratory Standards Institute (CLSI) breakpoints for Acinetobacter baumannii, respectively. Data collection. Patient...

Infection with Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae in cancer patients

“…A study of 40 patients receiving monotherapy with polymyxin B for KPC-Kp infection identified renal failure as the only risk factor for treatment failure. Renal failure, in isolation, has also been reported to be a mortality risk factor in other studies of cancer patients with bacterial infections, as well as in studies of KPC-Kp infections in other populations [30,[43][44][45].…”

Antimicrobial Activity and Toxicity of the Major Lipopeptide Components of Polymyxin B and Colistin: Last-Line Antibiotics against Multidrug-Resistant Gram-Negative Bacteria

“…2,15–18,29,30 Furthermore, suboptimal dosing may promote the emergence of polymyxin resistance. 29–32 In the present study, we first examined the in vitro apoptotic effect of the major lipopeptide components of polymyxin B and colistin on human kidney proximal tubular cells (HK-2). 33 The HK-2 cells were chosen in this study, as pharmacokinetic studies have demonstrated that polymyxin B and colistin are significantly reabsorbed by renal tubular cells after filtration by glomeruli.…”

Is combination therapy for carbapenem-resistantKlebsiella pneumoniaethe new standard of care?

“…Moreover, combination therapy was an independent predictor of survival and patients with advanced age were more likely to have received monotherapy. In contrast, another retrospective study that examined polymyxin B monotherapy for CR-KP infections found a treatment success rate of 73%, including 82% for bacteremia [10]. However, it is concerning that 3 out of 40 patients treated with polymyxin B developed breakthrough infections from polymyxin-resistant organisms while on therapy.…”

“…However, it is concerning that 3 out of 40 patients treated with polymyxin B developed breakthrough infections from polymyxin-resistant organisms while on therapy. Because these studies [7][8][9][10] were retrospective, the results may have been influenced by confounding factors like comorbidities, severity of sepsis and timing of the initiation of antibiotics. In a recent report, Demiraslan et al [11] compared colistin or tigecycline monotherapy to colistin plus tigecycline in a murine model of CR-KP sepsis.…”