In vitro activity and post-antibiotic effects of colistin in combination with other antimicrobials against colistin-resistant KPC-producing Klebsiella pneumoniae bloodstream isolates

142

103

Colistin is one of the antibiotics of last resort for the treatment of carbapenem-resistant Klebsiella pneumoniae infection. This study showed that capsular type K64 (50%) and ST11 (53.9%) are the prevalent capsular and sequence types in the colistin-resistant strains in Taiwan. The interruption of transcripts (38.5%) and amino acid mutation (15.4%) in mgrB are the major mechanisms contributing to colistin resistance. In addition, novel single amino acid changes in MgrB (Stop48Tyr) and PhoQ (Leu26Pro) were observed to contribute to colistin resistance. Klebsiella pneumoniae is an important human pathogen that causes several hospital-acquired and community-acquired diseases (1, 2). Although carbapenem is generally used to treat infections caused by extended-spectrum ␤-lactamase (ESBL)-carrying K. pneumoniae (3), K. pneumoniae strains carrying carbapenemases or ESBL strains combined with the loss of porins can result in carbapenem-resistant K. pneumoniae (CRKP) (4-6). To eradicate CRKP, colistin and tigecycline are typically used to treat patients (7). Unfortunately, resistance to colistin and tigecycline has also been reported, with a 17% resistance rate of CRKP to colistin in Taiwan (8). A surveillance study also revealed that 43% of carbapenemase-producing K. pneumoniae isolates were resistant to colistin in Italy (9).Colistin, also called polymyxin E, is a cationic antimicrobial peptide that targets bacterial lipopolysaccharide (LPS), causing cell membrane leakage (10). Previous studies have demonstrated that the modification of lipid A with 4-amino-4-deoxy-L-arabinose (Ara4N) and phosphoethanolamine neutralizes the negative charge and reduces susceptibility to colistin in Enterobacteriaceae (11)(12)(13)(14)(15). Modification of Ara4N is achieved by the pmrHFIJKLM operon (13), and the two-component systems PhoPQ and PmrAB with connector PmrD are involved in the regulation of the pmrHFIJKLM operon (16,17). Moreover, MgrB is a negative regulator that influences PhoQ-PhoP phosphorylation (18)(19)(20). In this study, we analyzed capsular type and multilocus sequence type (MLST) distribution of colistin-resistant K. pneumoniae in Taiwan and attempted to define the mechanisms of resistance to colistin.Colistin-resistant K. pneumoniae strains were retrospectively collected from patients in the Taipei Veterans General Hospital (VGH) from February to August 2013. All 26 strains were clinical isolates and were isolated from different patients. Among the 26 clinical isolates, the Col14 and Col40 strains were CRKP, and only the Col14 strain harbored the carbapenemase KPC. Colistin was used to treat infections in 16 of the 26 patients prior to the isolation of strains, and the other patients did not receive colistin in the VGH (Table 1). However, we could not trace the colistin usage of these patients in other hospitals. Previous studies also showed that some colistin-resistant strains are isolated from healthy individuals (21). Resistance to colistin in strains that were not exposed to colistin might be due to spontaneous...

supporting

confidence: 72%

mentioning

confidence: 99%

Colistin Resistance Mechanisms in Klebsiella pneumoniae Strains from Taiwan

Cheng

Lin

Pan

et al. 2015

142

103

“…This is consistent with previous in vitro studies that indicated synergy between polymyxins and rifampin against KPC-producing K. pneumoniae (21)(22)(23)(24). However, beyond 24 h, our analyses revealed that clinically achievable free-drug concentrations were unable to provide a sustained reduction in the bacterial burden.…”

Section: Discussionsupporting

confidence: 90%

“…KPC enzyme expression, a common mechanism of resistance among carbapenemresistant Enterobacteriaceae, has further compounded the antibiotic resistance crisis, resulting in the increased use of polymyxins (22,23). Recently, increasing numbers of reports of polymyxin resistance in strains that were previously susceptible have clinicians worried, as they could potentially be faced with the challenge of having virtually no therapeutic alternatives (25).…”

Section: Discussionmentioning

confidence: 99%

Polymyxin B in Combination with Rifampin and Meropenem against Polymyxin B-Resistant KPC-Producing Klebsiella pneumoniae

Diep

Jacobs

Sharma

et al. 2017

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.

“…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). However, optimized combination regimens involving polymyxins, carbapenems, and rifampin have yet to be fully elucidated.…”

mentioning

confidence: 99%

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

Bulman

Satlin

Chen

et al. 2017

Pharmacodynamics of a polymyxin B, meropenem, and rifampin triple combination were examined against Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) ST258. In time-kill experiments against three KPC-Kp isolates, triple combination generated 8.14, 8.19, and 8.29 log 10 CFU/ml reductions within 24 h. In the hollow-fiber infection model, the triple combination caused maximal killing of 5.16 log 10 CFU/ml at 78 h and the time required for regrowth was more than doubled versus the 2-drug combinations. Remarkably, combinations with a high single-dose polymyxin B burst plus rifampin preserved KPC-Kp polymyxin susceptibility (MIC 240 h ϭ 0.5 mg/liter) versus the same combination with traditionally dosed polymyxin B, where resistance was amplified (MIC 240 h ϭ 32 mg/liter).