In Vitro and In Vivo Activities of Tigecycline-Colistin Combination Therapies against Carbapenem-Resistant Enterobacteriaceae

Abstract

We assessed the activity of tigecycline (TGC) combined with colistin (COL) against carbapenem-resistant enterobacteria. Synergy occurred in vitro against the majority of isolates, with the exception of Serratia marcescens. In a simple animal model (Galleria mellonella), TGC-COL was superior (P < 0.01) in treating Escherichia coli, Klebsiella pneumoniae, and Enterobacter infections, including those with TGC-COL resistance. Clinical studies are needed to determine whether TGC-COL regimens may be a viable option. Resistance to antimicrobial agents is an ongoing problem that consistently undermines our ability to treat bacterial infections (1). The emergence of multidrug-resistant (MDR) Enterobacteriaceae producing extended-spectrum ␤-lactamases (ESBLs) has led to the increased use of carbapenems. Carbapenem resistance in Enterobacteriaceae (CRE) may be mediated by mutations affecting membrane permeability (porin loss), overexpression of intrinsic ␤-lactamases (AmpC), and/or broad-spectrum resistance-nodulation-division (RND)-type efflux pumps (2) but also via the acquisition of carbapenem-hydrolyzing enzymes, including members of the KPC, IMP, VIM, OXA-48, and NDM families (3, 4). Although CRE strains are often reported to be susceptible to polymyxins (polymyxin B, colistin) and tigecycline (TGC) (5-7), there are concerns with the use of these drugs for treatment with debate over how to safely dose colistin (COL) (8) and warnings over the efficacy of TGC in the treatment of bloodstream and other serious infections (9). Rapid emergence of resistance has also been documented with these two agents if either one is used alone in the treatment of MDR Gram-negative infections (10). Due to the lack of alternatives, clinicians are increasingly using antimicrobials in combination. The mechanism of action of COL is not entirely clear, although it has been previously shown to disrupt the integrity of the Gram-negative outer membrane (11), thereby increasing its permeability by drugs that are typically excluded (12). This may improve the activity of a number of antibiotics which would otherwise have little effect (13). This approach is validated by reports of better clinical outcomes with unorthodox therapies for an increasing range of carbapenem-resistant bacteria (14-16). In this study, we assessed the activity of TGC in combination with COL against a range of CRE both in vitro and in vivo by using standard checkerboard and time-kill assays and a simple invertebrate model (Galleria mellonella) of infection and therapeutics (17-19) (we do acknowledge that currently the G. mellonella model lacks the required validation with regard to comparability with human therapy).Enterobacteriaceae isolates used in this study (n ϭ 18) consisted of susceptible type strains and clinical isolates exhibiting resistance to ␤-lactams (including carbapenems), TGC, or COL (Table 1). MICs of TGC and COL were determined by Etest (bioMérieux, France), and mechanisms of resistance were confirmed by genetic and phenotypic tests as previously described...

In VitroActivity of Polymyxin B in Combination with Various Antibiotics against Extensively Drug-Resistant Enterobacter cloacae with Decreased Susceptibility to Polymyxin B

“…Unlike previous in vitro studies which had been conducted in KPC-producing carbapenem-resistant E. cloacae strains, our study focused on metallo-beta-lactamase (IMP and NDM)-harboring XDR E. cloacae strains, providing a fresh perspective compared to previous studies (8,32). In addition, our study investigated the activity of polymyxin B in combination with various antibiotics, which is in contrast to most previous studies, which employed colistin in combination with other antibiotics against XDR E. cloacae (8,9). Polymyxin B was employed in preference to colistin, as it has been shown to have superior clinical pharmacokinetics characteristics for infections (33).…”

“…Polymyxin B plus tigecycline also showed bactericidal effect against both E. cloacae isolates; nonetheless, the reduction in colony count was lower than that of polymyxin B plus carbapenems (32). In another study, Betts et al explored the activity of colistin plus tigecycline against CRE, including a tigecycline-resistant E. cloacae strain, by using standard checkerboard and time-kill assays and a simple invertebrate model (8). They found that colistin plus tigecycline was synergistic against the tigecycline-resistant E. cloacae strain in vitro, with significantly improved survival compared to either antibiotic when administered as a monotherapy.…”

“…Unfortunately, to date the optimal antibiotic combinations against XDR E. cloacae remain unclear. While there is an increasing number of studies exploring effective combinations against XDR E. cloacae, most studies reported effective combinations in vitro against XDR E. cloacae using time-kill studies (TKS) or checkerboard assays, and none have validated the suggested combinations in a hollow-fiber infection model (HFIM), where the bacteria are subjected to clinically relevant fluctuating concentrations (8,9).…”

In Vitro Activity of Polymyxin B plus Imipenem, Meropenem, or Tigecycline against KPC-2-Producing Enterobacteriaceae with High MICs for These Antimicrobials

“…A time-kill assay (TKA) was performed by inoculating 5 ϫ 10 TGC in carbapenem-resistant S. marcescens isolates has been demonstrated (8).This fact highlights the strain-to-strain variations in the response to antimicrobial combinations. Synergistic activity between colistin and carbapenems has been found in other studies either by checkerboard or by time-kill assay, although Acinetobacter baumannii and Pseudomonas aeruginosa have been the most common bacteria evaluated, with less in vitro data for Enterobacteriaceae (9).…”

Characterization of VIM and IMP Metallobetalactamases (MBL) in Pseudomonas aeruginosa Isolated in a Tertiary Care Hospital

“…The MBL positive strains are, at present, sensitive to polymyxin B and polymyxin E (Colistin). Colistin may be combined with tigecycline as combination therapy for better results (Betts et al, 2014;Datta and Wattal, 2010). The strains isolated from ICU showed same antibiogram profile indicating the possibility of origin from the same clone, but it needs to be confirmed by DNA sequencing.…”