Effect of pharmacokinetic/pharmacodynamic ratio on tigecycline clinical response and toxicity in critically ill patients with multidrug-resistant Gram-negative infections

Abstract

Introduction: The information about the pharmacokinetics and optimal dose of tigecycline in critically ill patients with severe underlying diseases is limited and controversial. In this study, we evaluate the pharmacokinetic parameters of tigecycline in critically ill patients with multidrug-resistant Gram-negative infection and explore the association between the pharmacokinetic/pharmacodynamic ratio and treatment response. Methods: A prospective study was designed including critically ill patients treated with tigecycline for multidrug-resistant Gram-negative infections. Blood samples were collected at day 3–5 of treatment, and pharmacokinetics parameters were evaluated using NONMEM® software. Relationship between area under the free concentration–time curve and minimum inhibitory concentration ratio (fAUC/MIC) and treatment failure was evaluated. Association between tigecycline fAUC and hepatobiliary toxicity was also investigated. Results: Twenty-five critically ill patients were included in the study. In the pharmacokinetic model, weight and total bilirubin level were found to be significant predictors of tigecycline clearance. Fifteen (60.0%) patients achieved an fAUC/MIC ratio >4.5, seven (28.0%) an fAUC/MIC > 6.96 and only three (12.0%) an fAUC/MIC > 17.9. No differences in fAUC/MIC ratio were obtained between those patients with and without clinical failure (5.28 (IC95%: 2.57–7.94) vs 8.71 (3.57–13.84)). fAUC values were higher in those patients who suffered hepatobiliary disorders (7.63 (3.93–11.34) vs 17.63 (7.85–26.28) mg/L/h). Conclusion: An important percentage of critically ill patients with multidrug-resistant Gram-negative infection treated with tigecycline do not achieve an appropriate pharmacokinetic/pharmacodynamic value. Tigecycline fAUC seems to be associated with hepatobiliary disorders in this study population. The effect of fAUC/MIC ratio on clinical response remains unclear.

Risk Factors for Tigecycline‐Associated Hepatotoxicity in Patients in the Intensive Care Units of 2 Tertiary Hospitals: A Retrospective Study

“…Fan et al 16 reported that the hepatotoxicity of tigecycline was observed in 28.9% (11/38) of patients in the ICU. 16 In the study reported by Ruiz et al 15 elevated bilirubin and liver enzymes were observed in 20% of patients treated with tigecycline, and only elevated bilirubin was observed in 12% of patients. 15 In the present study, the incidence of tigecycline-associated hepatotoxicity was 33.8%.…”

“…16 In the study reported by Ruiz et al 15 elevated bilirubin and liver enzymes were observed in 20% of patients treated with tigecycline, and only elevated bilirubin was observed in 12% of patients. 15 In the present study, the incidence of tigecycline-associated hepatotoxicity was 33.8%. Our result was consistent with the result from Fan et al 16 Evaluating hepatotoxicity in critically ill patients treated with tigecycline is challenging due to various factors (such as underlying diseases, the severity of infection, and the use of other potentially hepatotoxic drugs).…”

“…Ruiz et al 15 reported that tigecycline-associated hepatotoxicity was related to a high tigecycline dose and a free concentration-time curve and minimum inhibitory concentration ratio >17.9 in the univariate analysis, whereas no significant results were obtained in the multivariate analysis. 15 Another study by Chen and Shi reported that a high dose of tigecycline was not a risk factor for hepatotoxicity. 14 In our study, age, sex, underlying diseases, the main sites of infection, the pathogens of infection, APACHE II scores and SOFA scores at the initiation of tigecycline treatment, combination therapy, the loading dose and maintenance dose of tigecycline, and the LFT results at baseline were not different between the hepatotoxicity group and nonhepatotoxicity group.…”

Carbapenem-Resistant Klebsiella pneumoniae in Southwest China: Molecular Characteristics and Risk Factors Caused by KPC and NDM Producers

“…However, the treatment was hardly successful because of the low blood concentrations when tigecycline was used in monotherapy. 30 Adverse events, such as hypofibrinogenemia, also resulted in treatment termination associated with tigecycline therapy. 31 In addition, nephrotoxicity and unclear dosing also limited the widespread clinical usage of polymyxin B.…”

Clinical management of cUTI, cIAI, and HABP/VABP attributable to carbapenem-resistant Gram-negative infections in Spain

“…However, a large proportion of critically ill patients with multidrug-resistant GN infection are treated with tigecycline and do not achieve an appropriate pharmacokinetic and pharmacodynamic value. Even, tigecycline seems to be associated with hepatobiliary disorders in the critically ill population [19]. Fosfomycin has a very unique mechanism of action against Gram-positive and GN bacteria.…”