Exposure-Response Analyses of Tigecycline Efficacy in Patients with Complicated Intra-Abdominal Infections

Abstract

Exposure-response analyses were performed to test the microbiological and clinical efficacies of tigecycline in complicated intra-abdominal infections where Escherichia coli and Bacteroides fragilis are the predominant pathogens. Data from evaluable patients enrolled in three clinical trials were pooled. Patients received intravenous tigecycline (100-mg loading dose followed by 50 mg every 12 h or 50-mg loading dose followed by 25 mg every 12 h). At the test-of-cure visit, microbiological and clinical responses were evaluated. Patients were prospectively classified into cohorts based on infection with a baseline pathogen(s): E. coli only (cohort 1), other mono-or polymicrobial Enterobacteriaceae (cohort 2), at least one Enterobacteriaceae pathogen plus an anaerobe(s) (cohort 3), at least one Enterobacteriaceae pathogen plus a gram-positive pathogen(s) (cohort 4), and all other pathogens (cohort 5). The cohorts were prospectively combined to increase sample size. Logistic regression was used to evaluate ratio of steady-state 24-hour area under the concentration-time curve (AUC) to MIC as a response predictor, and classification-and-regression-tree (CART) analyses were utilized to determine AUC/MIC breakpoints. Analysis began with cohorts 1, 2, and 3 pooled, which included 71 patients, with 106 pathogens. The small sample size precluded evaluation of cohorts 1 (34 patients, 35 E. coli pathogens) and 2 (16 patients, 24 Enterobacteriaceae). CART analyses identified a significant AUC/MIC breakpoint of 6.96 for microbiological and clinical responses (P values of 0.0004 and 0.399, respectively). The continuous AUC/ MIC ratio was also borderline predictive of microbiological response (P ‫؍‬ 0.0568). Cohort 4 (21 patients, 50 pathogens) was evaluated separately; however, an exposure-response relationship was not detected; cohort 5 (31 patients, 60 pathogens) was not evaluated. The prospective approach of creating homogenous populations of pathogens was critical for identifying exposure-response relationships in complicated intra-abdominal infections.Evaluating exposure-response relationships by use of clinical trial data is an essential component of optimizing antimicrobial treatment, yet it is often quite challenging. A single dosing regimen is often used, thus limiting the range of observed drug exposure, and it is difficult to collect on an individual-patient basis the three integral pieces of information required to perform such analyses: pharmacokinetic (PK), clinical, and microbiological outcome data. The value of such analyses, however, has become increasingly important in quantifying drug efficacy and in contributing to the establishment of appropriate in vitro MIC susceptibility breakpoints by regulatory and clinical agencies (e.g., the Clinical and Laboratory Standards Institute [CLSI] and the European Committee on Antimicrobial Susceptibility Testing [EUCAST]) (5). Utilizing results from PKpharmacodynamic (PK-PD) analyses may allow a better understanding of the causes of variability in responses among subgroup...

Randomized Phase 2 Trial To Evaluate the Clinical Efficacy of Two High-Dosage Tigecycline Regimens versus Imipenem-Cilastatin for Treatment of Hospital-Acquired Pneumonia

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

“…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 to uncover the pharmacodynamics of tigecycline.Herein, we described the pharmacodynamic profile of tigecycline and the magnitude of its efficacy against a diverse group of E. coli and K. pneumoniae isolates in the mouse thigh model. …”

Pharmacokinetics-Pharmacodynamics of Tigecycline in Patients with Community-Acquired Pneumonia

“…During the course of its development, tigecycline has been the subject of several pharmacokinetic-pharmacodynamic (PK-PD) analyses, using data from animal infection models as well as data from clinical trials of patients suffering from complicated skin and skin structure infections or those with complicated intra-abdominal infections (3,4,8). These analyses have characterized the magnitude of the ratio of the area under the concentration-time curve at 24 h to the MIC of the pathogen (AUC 0-24 :MIC), the PK-PD measure most predictive of outcome, which is associated with efficacy.…”