The relationship between drug exposure and treatment effect of antibiotics has been studied since the 1980s. Indeed, PK/PD is considered superior to empirical dose response clinical trials for the selection of a dosing regimen for pivotal clinical efficacy trials. In addition, PK/PD analyses and PoP PK modeling is now integrated into both antibiotic drug approval and breakpoint determination. However, recent comprehensive analyses of phase 3 clinical data have failed to demonstrate a relationship between PK/PD and clinical or microbiological outcomes, including mortality.
Through an integrated review of published data, both preclinical and clinical, an effort will be made to explain why there is a disconnect between the PK/PD parameters of antibiotics and their validation in the clinical trial setting, including both randomized clinical trials and retrospective cohort analyses.
The Topic Editors welcome submissions related but not limited to the following areas:
1. PK/PD principles derived from in vitro and in vivo preclinical studies. Focus is on antibiotics of any antibiotic class used to treat gram-negative bacillary infections. It is expected that much of the information will be for beta-lactam antibiotics. Data to include in vitro static (AST, time-kill) and dynamic (chemostat, hollow fiber) models and in vivo animal infection models (dose fractionation and humanized drug exposure.
2. PK/PD analyses from clinical studies human subjects and patients. Individual papers could review single drugs or drug classes that provide evidence of PK correlations with clinical and microbiologic outcomes. Both positive or negative (or inconclusive) outcomes should be included.
3. Assessment of published data where PK/PD principles did not work as expected and understanding possible reasons for the lack of correlation between PK/PD parameters and clinical outcomes in clinical studies. Could include sensitivity of MIC determination to the lack of subtherapeutic drug exposure.
4. Implications of the lack of validation of PK/PD principles in clinical studies. Are PK/PD principles wrong or are studies involving patients too complex? Are clinical and microbiological endpoints including mortality insensitive (or inadequately insensitive) to treatment effect? If PK/PD parameters are not valid in a clinical setting, what role is there for therapeutic drug monitoring (TDM)?
5. Assess the validity of MIC determination and its critical importance in PK/PD analyses.
6. Assess the validity of clinical breakpoints, how they are determined and their validity in predicting outcomes. Discuss the clinical implications of not updating breakpoints as the changes based on new dosing regimens and PK/PD data.
7. Assessment of individualized dosing regimens especially in serious ill ICU patients, i.e. the benefit or lack for therapeutic drug monitoring (TDM). Also assess evidence that augmented renal clearance (ARC) impacts clinical outcomes.
8. Is the immune system really only “background noise” or are there other problems by neglecting it in in-vitro PK/PD models or by using neutropenic mice?
The relationship between drug exposure and treatment effect of antibiotics has been studied since the 1980s. Indeed, PK/PD is considered superior to empirical dose response clinical trials for the selection of a dosing regimen for pivotal clinical efficacy trials. In addition, PK/PD analyses and PoP PK modeling is now integrated into both antibiotic drug approval and breakpoint determination. However, recent comprehensive analyses of phase 3 clinical data have failed to demonstrate a relationship between PK/PD and clinical or microbiological outcomes, including mortality.
Through an integrated review of published data, both preclinical and clinical, an effort will be made to explain why there is a disconnect between the PK/PD parameters of antibiotics and their validation in the clinical trial setting, including both randomized clinical trials and retrospective cohort analyses.
The Topic Editors welcome submissions related but not limited to the following areas:
1. PK/PD principles derived from in vitro and in vivo preclinical studies. Focus is on antibiotics of any antibiotic class used to treat gram-negative bacillary infections. It is expected that much of the information will be for beta-lactam antibiotics. Data to include in vitro static (AST, time-kill) and dynamic (chemostat, hollow fiber) models and in vivo animal infection models (dose fractionation and humanized drug exposure.
2. PK/PD analyses from clinical studies human subjects and patients. Individual papers could review single drugs or drug classes that provide evidence of PK correlations with clinical and microbiologic outcomes. Both positive or negative (or inconclusive) outcomes should be included.
3. Assessment of published data where PK/PD principles did not work as expected and understanding possible reasons for the lack of correlation between PK/PD parameters and clinical outcomes in clinical studies. Could include sensitivity of MIC determination to the lack of subtherapeutic drug exposure.
4. Implications of the lack of validation of PK/PD principles in clinical studies. Are PK/PD principles wrong or are studies involving patients too complex? Are clinical and microbiological endpoints including mortality insensitive (or inadequately insensitive) to treatment effect? If PK/PD parameters are not valid in a clinical setting, what role is there for therapeutic drug monitoring (TDM)?
5. Assess the validity of MIC determination and its critical importance in PK/PD analyses.
6. Assess the validity of clinical breakpoints, how they are determined and their validity in predicting outcomes. Discuss the clinical implications of not updating breakpoints as the changes based on new dosing regimens and PK/PD data.
7. Assessment of individualized dosing regimens especially in serious ill ICU patients, i.e. the benefit or lack for therapeutic drug monitoring (TDM). Also assess evidence that augmented renal clearance (ARC) impacts clinical outcomes.
8. Is the immune system really only “background noise” or are there other problems by neglecting it in in-vitro PK/PD models or by using neutropenic mice?