Activity of Tigecycline in Combination with Colistin, Meropenem, Rifampin, or Gentamicin against KPC-Producing Enterobacteriaceae in a Murine Thigh Infection Model

Combination therapy including colistin and a carbapenem has been found to be associated with lower mortality in the treatment of bloodstream infections (BSI) due to KPC-producing Klebsiella pneumoniae when the isolates show a meropenem or imipenem MIC of Ͻ16 mg/liter. However, the optimal treatment of BSI caused by colistin-and high-level carbapenem-resistant KPC-producing K. pneumoniae is unknown. A prospective cohort study including episodes of bacteremia caused by colistin-resistant and high-level meropenem-resistant (MIC Ն 64 mg/liter) KPC-producing K. pneumoniae diagnosed from July 2012 to February 2016 was performed. The impact of combination therapy on crude 30-day mortality was analyzed by Cox regression using a propensity score as a covariate to control for indication bias and in an inverse probability of treatment weighting (IPTW) cohort. The study sample comprised 104 patients, of which 32 (30.8%) received targeted monotherapy and 72 (69.2%) received targeted combination therapy; none of them received either colistin or a carbapenem. The 30-day crude mortality rate was 30.8% (43.8% in patients treated with monotherapy and 25% in patients receiving combination therapy). In the Cox regression analysis, 30-day mortality was independently associated with septic shock at BSI onset (hazard ratio [HR], 6.03; 95% confidence interval [CI], 1.65 to 21.9; P ϭ 0.006) and admission to the critical care unit (HR, 2.87; 95% CI, 0.99 to 8.27; P ϭ 0.05). Targeted combination therapy was associated with lower mortality only in patients with septic shock (HR, 0.14; 95% CI, 0.03 to 0.67; P ϭ 0.01). These results were confirmed in the Cox regression analysis of the IPTW cohort. Combination therapy is associated with reduced mortality in patients with bacteremia due to colistin-resistant KPC-producing K. pneumoniae with high-level carbapenem resistance in patients with septic shock.

Section: Discussionmentioning

confidence: 99%

Mortality Associated with Bacteremia Due to Colistin-Resistant Klebsiella pneumoniae with High-Level Meropenem Resistance: Importance of Combination Therapy without Colistin and Carbapenems

Machuca

Gutiérrez‐Gutiérrez

Gracia-Ahufinger

et al. 2017

“…Several reports show some in vitro synergy in the killing of carbapenemase-producing K. pneumoniae between rifampin and tigecycline or colistin (119,120). However, definitive clinical data are lacking that advocate the routine use of rifampin for the treatment of infections due to carbapenemaseproducing K. pneumoniae.…”

Section: Treatment Of Infections Due To K Pneumoniae With Carbapenemmentioning

confidence: 99%

Carbapenemase-Producing Klebsiella pneumoniae, a Key Pathogen Set for Global Nosocomial Dominance

Pitout

Nordmann

Poirel

2015

683

569

The management of infections due to Klebsiella pneumoniae has been complicated by the emergence of antimicrobial resistance, especially to carbapenems. Resistance to carbapenems in K. pneumoniae involves multiple mechanisms, including the production of carbapenemases (e.g., KPC, NDM, VIM, OXA-48-like), as well as alterations in outer membrane permeability mediated by the loss of porins and the upregulation of efflux systems. The latter two mechanisms are often combined with high levels of other types of ␤-lactamases (e.g., AmpC). K. pneumoniae sequence type 258 (ST258) emerged during the early to mid-2000s as an important human pathogen and has spread extensively throughout the world. ST258 comprises two distinct lineages, namely, clades I and II, and it seems that ST258 is a hybrid clone that was created by a large recombination event between ST11 and ST442. Incompatibility group F plasmids with bla KPC have contributed significantly to the success of ST258. The optimal treatment of infections due to carbapenemase-producing K. pneumoniae remains unknown. Some newer agents show promise for treating infections due to KPC producers; however, effective options for the treatment of NDM producers remain elusive.

“…Pournaras et al also showed that MERϩTIG is not synergic in vitro (21). Previous studies of nonlethal and nonsystemic infections were discordant about the antagonistic effects of TIGϩMER in vivo (20,22) and in vitro (23). Further investigation using this combination is required, but we believe that TIGϩMER should be used with caution for treatment of infections due to KPC-producing isolates.…”

mentioning

confidence: 99%

Activity of Antimicrobial Combinations against KPC-2-Producing Klebsiella pneumoniae in a Rat Model and Time-Kill Assay

Toledo

Aranha

Arend³

et al. 2015

f This study evaluated the efficacy of tigecycline (TIG), polymyxin B (PMB), and meropenem (MER) in 80 rats challenged with Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae infection. A time-kill assay was performed with the same strain. Triple therapy and PMB؉TIG were synergistic, promoted 100% survival, and produced negative peritoneal cultures, while MER؉TIG showed lower survival and higher culture positivity than other regimens (P ‫؍‬ 0.018) and was antagonistic. In vivo and in vitro studies showed that combined regimens, except MER؉TIG, were more effective than monotherapies for this KPC-producing strain. Infections due to Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae are associated with therapeutic failure and increased mortality (1-5). It has been suggested that antibiotic combination might be a better alternative compared to monotherapy for treatment of KPC-producing isolates (4-9); however, further investigation on this therapeutic strategy is required (10, 11).In the present study, we evaluated the efficacy of regimes for a KPC-producing K. pneumoniae strain in an experimental model of systemic infection and in a time-kill assay (TKA).A KPC-producing K. pneumoniae strain, coded RM-1209, was isolated from a patient's blood and identified by Vitek 2 (bioMérieux, Craponne, France) in 2012. Antibiotic MICs were determined by agar dilution and interpreted according to CLSI and EUCAST for tigecycline (TIG) (12, 13). The strain presented MICs of Ͼ32 mg/liter, 1 mg/liter, and 0.5 mg/liter for meropenem (MER), tigecycline, and polymyxin B (PMB), respectively. Detection of the bla KPC gene was performed with BigDye v1.1 Sequencing kits (Applied Biosystems, Foster City, CA, USA), and KPC-2 was confirmed at databases queried by NCBI BLAST (6).The study was approved by the ethical committee, according to the Protocol for the Protection and Welfare of Animals (European Union). The animal model has been previously described (13). In brief, male and female immunocompetent Wistar rats weighing between 190 and 300 g were randomized into each treatment group. Absence of immunosuppression demanded administration of highly concentrated inoculums with 1.5 ϫ 10 10 CFU/ml. This solution, when diluted 1:20 presents an absorbance of 0.546 at 625 nm wavelength on spectrophotometry (corresponding to tube 50 of nephelometric scale). Seven groups of 10 rats were treated with the following regimens: MER, TIG, PMB, MERϩPMB, MERϩTIG, PMBϩTIG, or PMBϩMERϩTIG. Ten rats were untreated (control group). The sample size (80 rats) was calculated using the formula n ϭ z2PQ/d2 based on the expected proportion of deaths (50%) and 8% standard error with an 80% statistical power.Animals were injected with a 0.7-ml intraperitoneal aliquot of 1.5 ϫ 10 10 CFU/ml KPC-producing K. pneumoniae inoculum in the log growth state (14). After infection, rats received antimicrobials intraperitoneally, TIG (Tygacil) at 7 mg/kg of body weight every 12 h (15, 16), PMB (polymyxin B) at 2 mg/kg every 12 h (17, 18), or MER ...