Tigecycline Displays In Vivo Bactericidal Activity against Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae after 72-Hour Exposure Period

Abstract

Progressively enhanced activity of a humanized tigecycline (TGC) regimen was noted over 3 days against an extended-spectrum-␤-lactamase (ESBL)-producing Escherichia coli isolate and an ESBL-producing Klebsiella pneumoniae isolate. Bacterial density reduction approximated 3 log 10 approaching bactericidal activity at 72 h. This level of activity has not been previously noted for compounds such as tetracyclines, normally considered bacteriostatic antimicrobials. Extended regimen studies in vivo may aid in better delineation of antimicrobial effects, producing improved correlation with clinical outcomes. Historically, in vitro and in vivo pharmacodynamic (PD) assessments have been conducted over 24 h. While these studies have been noted to correlate with clinical outcomes for rapidly bactericidal agents (i.e., fluoroquinolones or aminoglycosides), these PD endpoints appear more poorly correlated for agents such as the tetracyclines and related derivatives which have slower killing profiles in vitro. The tetracyclines and the class-related extended-spectrum agents, such as tigecycline (TGC), have demonstrated bacteriostatic activity in in vitro studies against a variety of bacterial strains (1). In a recent study using the endpoint of reduction in numbers of CFU after 24 h of TGC exposure against several Escherichia coli and Klebsiella pneumoniae isolates, we noted antibacterial activity in both immunocompromised and immunocompetent mice (2). The majority of doses were bacteriostatic at best. The maximum reduction in numbers of CFU was 2 log 10 over this 24-h exposure period; however, these effects were noted only when exposures were well above that typically seen in humans. In addition, it was also noted that the in vivo exposures required to produce substantial reductions in numbers of CFU in the immunocompromised murine model were well in excess of that recognized to produce good clinical and microbiologic outcomes in patients (2). While the immunocompromised model appeared to have exposures discordant to that observed in humans, the immunocompetent model required exposures similar to that observed in patients. Therefore, in the current study, we sought to determine the magnitude of bacterial kill over an extended treatment period of 72 h using an exposure in immunocompetent animals that would mimic the regimen of a 100-mg loading dose with subsequent 50-mg doses every 12 h (q12h) of TGC in humans.Two extended-spectrum-␤-lactamase (ESBL)-producing clinical strains, one E. coli (E. coli strain 363; TGC MIC, 0.125 g/ml) and one K. pneumoniae (K. pneumoniae strain 404; TGC MIC, 0.25 g/ml), provided by Tetraphase Pharmaceuticals, Inc. IN). These studies were approved by and followed the guidelines of the Institutional Animal Care and Use Committee at our facility. Bacterial colonies of a fresh subculture of each isolate were suspended in sterile 0.9% sodium chloride to produce a suspension of approximately 10 8 CFU/ml. Final inoculum concentrations were confirmed by plating serial dilutions of inocula on Trypticase ...

Antibacterial Efficacy of Eravacycline In Vivo against Gram-Positive and Gram-Negative Organisms

“…Humanized doses of tigecycline (Wyeth Pharmaceuticals, Inc., Dallas, TX; lot AJP512), linezolid (Pfizer Inc., Groton, CT; lot 1210600015), vancomycin (Hospira, Inc., Lake Forest, IL; lot 511048E03), and meropenem (Fresenius Kabi USA, LLC, Lake Zurich, IL; lot 0004D45) were prepared to produce exposures consistent with previously published data for each agent (11)(12)(13)(14).…”

“…However, with respect to their efficacy over a course of treatment, these slowly occurring bactericidal effects result in substantial reductions in bacterial density. For instance, recent in vivo murine models with typically defined bacteriostatic agents, such as linezolid and tigecycline, achieved Ն3-log reductions in bacterial burden over a 72-h treatment period against Staphylococcus aureus and Enterobacteriaceae, respectively (11,12).…”

In Vitro Discordance with In Vivo Activity: Humanized Exposures of Ceftazidime-Avibactam, Aztreonam, and Tigecycline Alone and in Combination against New Delhi Metallo-β-Lactamase-Producing Klebsiella pneumoniae in a Murine Lung Infection Model

“…These tigecycline doses were based on a previous murine thigh model regimen that demonstrated in vivo efficacy against extended-spectrum-␤-lactamase-producing Escherichia coli and K. pneumoniae. Furthermore, tigecycline demonstrated efficacy in a murine pneumonia model against Staphylococcus aureus, thereby eliminating an inadequate pharmacokinetic model or animal model selection as the cause of tigecycline failure (6,15). The humanized dose of CZA monotherapy resulted in extensive in vivo killing, and as a result, synergy was not observed with combinations.…”

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

“…A combination was considered to be synergistic when resulting in a higher reduction of CFU yielded from treated mice than with each of the drugs alone; antagonism was considered when monotherapy caused a higher log CFU reduction than the combination (26). CFU reductions of Ͼ3 ⌬log were considered to indicate bactericidal levels of activity (10).…”

“…Susceptibility data suggest that the treatment of infections caused by KPC producers commonly requires the use of tigecycline, colistin, gentamicin, or meropenem as a last-resort drug (2,5,7). Regarding the therapeutic activity of tigecycline combinations against infections caused by Enterobacteriacae, data are scarce in the literature, which is derived mainly from in vitro studies on carbapenem-susceptible isolates and to a lesser degree from in vivo studies and human case reports (8)(9)(10). In particular, tigecycline combinations tested in vitro produced primarily an indifferent response (8).…”