Population pharmacokinetics of ampicillin and sulbactam in patients with community-acquired pneumonia: evaluation of the impact of renal impairment

Abstract

AIMSThe aims of this study were to develop a population pharmacokinetic (PK) model of ampicillin and sulbactam, to identify patient characteristics influencing the PK, and to explore the relationship between dose regimen and degree of renal impairment with exposure and time above minimum inhibitory concentration (MIC). METHODSThis analysis was performed on PK data for ampicillin and sulbactam and MIC data from a clinical trial in Japanese patients with community acquired pneumonia. Simulations were performed to investigate the effects of different dosing intervals on exposure and time above MIC in various degrees of renal impairment. RESULTSThe plasma concentrations from 47 patients were adequately described by a two compartment model with simultaneous fit of ampicillin and sulbactam PK data, where creatinine clearance on clearance and body weight on volume in the peripheral compartment were identified as covariates for both drugs. Creatinine clearance contributed to reducing inter-individual variability of clearance by 16%. Mean clearance (inter-individual variability) for ampicillin and sulbactam was estimated to be 10.7 l h −1 (14.8%) and 10.4 l h −1 (15.2%), respectively. The time above MIC for each pathogen was generally > 50% of the treatment period. Simulations for exposure and time above MIC supported currently recommended dose adjustments. CONCLUSIONSThis study provided a PK model for ampicillin and sulbactam, the time above MICs for identified pathogens and associated simulation results. These findings provide useful information and augment evidence for the established dosage regimens in patients with various degrees of renal impairment.

Population Pharmacokinetics and Pharmacodynamics Modeling To Optimize Dosage Regimens of Sulbactam in Critically Ill Patients with Severe Sepsis Caused by Acinetobacter baumannii

“…Increased renal clearance resulting from increased cardiac output during the initial hyperdynamic state of severe sepsis and, on the other hand, decreased renal clearance with end-organ dysfunction can be observed with severe sepsis and septic shock (12,17,18). Our population PK studies of sulbactam were performed during the steady state on the 4th day of sulbactam administration, and the two-compartment model was the best model for describing the concentration-time profile of sulbactam, which was consistent with the results of previous population PK studies (11,19,20). The central V (V c ) and peripheral V (V p ) of sulbactam were 14.56 and 9.55 liters, respectively, which are greater than the values obtained from previous studies in patients with impaired renal function (11) and healthy volunteers (21).…”

Efficacy and safety of intravenous sulbactam/ampicillin 3 g 4 times daily in Japanese adults with moderate to severe community-acquired pneumonia: A multicenter, open-label, uncontrolled study

“…Percentage of time above the MIC (%T > MIC) was calculated from the estimated plasma ampicillin concentration-time data and MIC values for the identified pathogens in each subject [5]. The %T > MIC achieved 50% or higher (the target percentage) of MIC values (0.06e16 mg/l) for all identified pathogens.…”

“…This was our motivation for conducting this first phase 3 study of the SBT/ABPC 3 g QID regimen in Japanese adults to confirm its therapeutic efficacy and safety for treating moderate to severe CAP. Population PK and PK-PD analyses were also conducted to clarify the relationship between drug dosage, efficacy, and PK-PD characteristics [5]. In Japan, SBT/ABPC 3 g QID regimen was approved in 2012 for the treatment of severe pneumonia, lung abscess, and peritonitis based on the results from this study.…”

β-Lactams Enhance Daptomycin Activity against Vancomycin-Resistant Enterococcus faecalis and Enterococcus faecium in In Vitro Pharmacokinetic/Pharmacodynamic Models

“…Fresh medium (MHB) was continuously supplied and removed from the compartment along with the drug via a peristaltic pump (Masterflex; Cole-Parmer Instrument Company, Chicago, IL) at an appropriate rate to simulate the average human clearance and half-lives (t 1/2 ) of the antimicrobials. The antimicrobial regimens evaluated were simulations of 10 mg/kg DAP every 24 h (q24h) (targeted maximum free-drug concentration in serum [fC max ], 11.3 g/ ml; t 1/2 , 8 h; protein binding, 92%; area under the concentration-time curve for the free, unbound fraction of a drug over 24 h [fAUC 0 -24 ], 114.8 g · h/ml), 600 mg CPT every 8 h (fC max , 17.04 g/ml; t 1/2 , 2.66 h; protein binding, 20%), 1 g ERT every 24 h (fC max , 15.5 g/ml; t 1/2 , 4 h; protein binding, 90%), 2 g AMP every 4 h (fC max ,70 g/ml; t 1/2 , 1.9 h; protein binding, 20%), 10 mg/kg DAP q24h plus 600 mg CPT q8h, 10 mg/kg DAP q24h plus 1 g ERT q24h, and 10 mg/kg DAP q24h plus 2 g AMP q4h (29)(30)(31)(32)(33)(34). The models were performed in duplicate to ensure reproducibility.…”