Pharmacological and patient-specific response determinants in patients with hospital-acquired pneumonia treated with tigecycline

Abstract

Pharmacokinetic and clinical data from tigecycline-treated patients with hospital-acquired pneumonia (HAP) who were enrolled in a phase 3 clinical trial were integrated in order to evaluate pharmacokinetic-pharmacodynamic (PK-PD) relationships for efficacy. Univariable and multivariable analyses were conducted to identify factors associated with clinical and microbiological responses, based on data from 61 evaluable HAP patients who received tigecycline intravenously as a 100-mg loading dose followed by 50 mg every 12 h for a minimum of 7 days and for whom there were adequate clinical, pharmacokinetic, and response data. The final multivariable logistic regression model for clinical response contained albumin and the ratio of the free-drug area under the concentration-time curve from 0 to 24 h (fAUC(0-24)) to the MIC (fAUC(0-24):MIC ratio). The odds of clinical success were 13.0 times higher for every 1-g/dl increase in albumin (P < 0.001) and 8.42 times higher for patients with fAUC(0-24):MIC ratios of ≥0.9 compared to patients with fAUC(0-24):MIC ratios of <0.9 (P = 0.008). Average model-estimated probabilities of clinical success for the albumin/fAUC(0-24):MIC ratio combinations of <2.6/<0.9, <2.6/≥0.9, ≥2.6/<0.9, and ≥2.6/≥0.9 were 0.21, 0.57, 0.64, and 0.93, respectively. For microbiological response, the final model contained albumin and ventilator-associated pneumonia (VAP) status. The odds of microbiological success were 21.0 times higher for every 1-g/dl increase in albumin (P < 0.001) and 8.59 times higher for patients without VAP compared to those with VAP (P = 0.003). Among the remaining variables evaluated, the MIC had the greatest statistical significance, an observation which was not surprising given the differences in MIC distributions between VAP and non-VAP patients (MIC(50)and MIC(90) values of 0.5 and 0.25 mg/liter versus 16 and 1 mg/liter for VAP versus non-VAP patients, respectively; P = 0.006). These findings demonstrated the impact of pharmacological and patient-specific factors on the clinical and microbiological responses.

Fig 1

Estimated relationships between the probabilities of clinical (A) or microbiological (B) success and tigecycline fAUC_0–24:MIC ratio, based on univariable logistic regression models (P = 0.023 and 0.031, respectively). The solid lines represent the estimated logistic regression functions, while the dashed-dotted lines represent the upper and lower 95% pointwise confidence bounds. The histogram represents the distribution of observed fAUC_0–24:MIC ratio values. The solid boxes on the estimated logistic regression functions represent the thresholds for fAUC_0–24:MIC ratios of 0.9 and 0.35 for the probabilities of clinical and microbiological success, respectively, which were derived based on classification trees.

Fig 2

Tigecycline MIC distribution stratified by VAP and non-VAP status (adapted with from reference with permission of the publisher).

Fig 3

Estimated relationships between the probability of clinical success and albumin concentration related to fAUC_0–24:MIC ratio, evaluated as a two-group categorical variable (A) or between the probability of microbiological success and VAP status (B).