In Vivo Pharmacodynamic Profile of Tigecycline against Phenotypically Diverse Escherichia coli and Klebsiella pneumoniae Isolates

Abstract

Tigecycline is a glycylcycline with activity against Enterobacteriaceae, including multidrug-resistant isolates of Klebsiella pneumoniae and Escherichia coli producing extended-spectrum beta-lactamase (ESBL) and carbapenemases. Herein, we used an in vivo murine thigh model to characterize the pharmacodynamic profile of tigecycline against genotypically and phenotypically diverse K. pneumoniae and E. coli isolates. Doses of 3.125 to 300 mg/kg, divided 1 to 6 times daily, were administered subcutaneously against six (two nonresistant, one carbapenemase, and three ESBL producing) K. pneumoniae strains and five (two nonresistant and three ESBL producing) E. coli strains. The phenotypic profile (reported tigecycline MIC) for all isolates ranged from 0.125 to 2 g/ml. Mean correlation coefficients of free (f) drug exposures (percentage of the dosing interval that free drug concentration remained above the MIC [fT>MIC], the ratio of the free drug area under the concentration-time curve/MIC [fAUC/MIC], and the ratio of maximum concentration of free drug in serum/MIC) for all 11 isolates were 0.595, 0.969, and 0.897, respectively. The fAUC/MIC was the pharmacodynamic parameter that best described the efficacy of tigecycline against both E. coli and K. pneumoniae. Interestingly, reductions in the number of CFU were noted even though doses achieved an fT>MIC of 0%. With respect to fAUC/MIC in the neutropenic model, the cumulative 80% and 50% effective pharmacodynamic indexes (EI 80 and EI 50 ) for all 11 isolates were 8.4 and 4.7, respectively. An experiment in nonneutropenic mice infected with an ESBL-producing E. coli and K. pneumoniae isolate resulted in the lowest tigecycline fAUC/MIC EI 80 and EI 50 values at 1.8 and 1.0 for E. coli and 1.7 and 1.6 for K. pneumoniae. While the phenotypic profile of tigecycline appeared to drive efficacy irrespective of ESBL or carbapenemase production, the presence of a competent immune system markedly reduced this required exposure.With the recent worldwide emergence of carbapenemaseproducing Klebsiella pneumoniae and the steadily increasing prevalence of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae (11,17,24), the need for more antibiotics in the rapidly deteriorating armamentarium becomes even more important (18).Tigecycline, a glycylcycline derived from minocycline, is a novel agent displaying activity against ESBL and carbapenemase-producing K. pneumoniae and Escherichia coli (2, 4, 9). Currently, tigecycline is FDA approved for complicated intraabdominal infections (cIAI) and complicated skin-skin structure infections (15). With high susceptibilities demonstrated in surveillance studies (2) and positive clinical outcomes shown in trial data from subpopulations infected with ESBL-producing Enterobacteriaceae (6, 23), tigecycline has been increasingly utilized as a treatment option. Given these occurrences and the few available studies describing the exposure-response relationship for the treatment of gram-negative organisms (15,19,21), it seems reasonable t...

In Vitro Pharmacodynamics of Simulated Pulmonary Exposures of Tigecycline Alone and in Combination against Klebsiella pneumoniae Isolates Producing a KPC Carbapenemase

“…Clearly, the immune system plays a significant role in modeling the effects of tigecycline, as demonstrated by an in vivo murine thigh model used to characterize the pharmacodynamic profile of tigecycline. In that study, the cumulative 50% and 80% effective pharmacodynamic indices (EI 50 and EI 80 , expressed as the AUC for the free, unbound fraction of the drug [ƒAUC]/MIC) were reduced from 2.01 and 3.27, respectively, in a neutropenic model to 1.59 and 1.70, respectively, in an immunocompetent model against a K. pneumoniae isolate that produced an ESBL (32). Of note, a single KPC isolate was also evaluated in the experiment, but only with the immunocompromised model.…”

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

“…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.…”

“…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.…”

Clinical and microbiological characterization of KPC-producing Klebsiella pneumoniae infections in Brazil

“…19 In these situations, the use of combined therapy and/or higher doses of tigecycline are critical for maximal therapeutic effectiveness. 20 This would be specially useful in patients with infections due to pathogens with reduced susceptibility to polymyxin, such as those presented in the clinical cases 4 and 6.…”