Clinical Pharmacokinetics of Meropenem and Biapenem in Bile and Dosing Considerations for Biliary Tract Infections Based on Site-Specific Pharmacodynamic Target Attainment

Abstract

The present study investigated the pharmacokinetics of meropenem and biapenem in bile and estimated their pharmacodynamic target attainment at the site. Meropenem (0.5 g) or biapenem (0.3 g) was administered to surgery patients (n ‫؍‬ 8 for each drug). Venous blood samples and hepatobiliary tract bile samples were obtained at the end of infusion (0.5 h) and for up to 5 h thereafter. Drug concentrations in plasma and bile were analyzed pharmacokinetically and used for a Monte Carlo simulation to predict the probability of attaining the pharmacodynamic target (40% of the time above the MIC). Both drugs penetrated similarly into bile, with mean bile/plasma ratios of 0.24 to 0.25 (maximum drug concentration) and 0.30 to 0.38 (area under the drug concentration-time curve). The usual regimens of meropenem (0.5 g every 8 h [q8h]) and biapenem (0.3 g q8h) (0.5-h infusions) achieved similar target attainment probabilities in bile (>90%) against Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae isolates. However, against Pseudomonas aeruginosa isolates, meropenem at 1 g q8h and biapenem at 0.6 g q8h were required for values of 80.7% and 71.9%, respectively. The biliary pharmacodynamic-based breakpoint (the highest MIC at which the target attainment probability in bile was >90%) was 1 mg/liter for 0.5 g q8h and 2 mg/liter for 1 g q8h for meropenem and 0.5 mg/liter for 0.3 g q8h and 1 mg/liter for 0.6 g q8h for biapenem. These results help to define the clinical pharmacokinetics of the two carbapenems in bile while also helping to rationalize and optimize the dosing regimens for biliary tract infections based on site-specific pharmacodynamic target attainment.

Is Meropenem as a Monotherapy Truly Incompetent for Meropenem-Nonsusceptible Bacterial Strains? A Pharmacokinetic/Pharmacodynamic Modeling With Monte Carlo Simulation

“…However, to the best of our knowledge, penetration of meropenem in infected tissues to achieve the exposure targets has not been studied often, and drug concentrations in extracellular compartments are difficult to determine; thus, correlations between the PK/PD index in the tissue and antimicrobial effects are less well-understood (Nightingale and Mur, 2007). Therefore, serum PK parameters based on the plasma drug concentrations are most commonly used as surrogates for establishing and estimating the PK/PD indices in some studies (Kuti et al, 2003; Ikawa et al, 2011), and so it is with the present study.…”

“…Generally, 40–50% of f T > MIC for meropenem based on the serum concentration is usually used for predicting clinical and microbiological outcomes and for optimizing dosage regimens in most current meropenem PK/PD studies (Burgess et al, 2007; Watanabe et al, 2007; Ikawa et al, 2011; Kondo et al, 2014). However, given the profiles of meropenem tissue penetration described previously, we consider that (i) this exposure target in plasma may be underestimated when 40–50% of f T > MIC for meropenem is required in infected tissues; and (ii) it is reasonably speculated that a meropenem drug concentration of 1–2 × MIC in plasma for most types of infection but 5 × MIC in plasma for pulmonary, bronchial and pleural infection is sufficient to achieve the pathogen MIC without considering the influence of inflammation on meropenem tissue penetration.…”

Antimicrobial Stewardship Program: Reducing Antibiotic’s Spectrum of Activity Is not the Solution to Limit the Emergence of Multidrug-Resistant Bacteria

“…The functions of the microbiota are multiple including the fermentation of food, synthesis of vitamins and amino acids, regulation of the inflammatory/immune system, modulation of gastrointestinal hormone release, regulation of brain behavior, and finally, resistance to colonization by exogenous bacteria. There are many direct and indirect mechanisms involved in resistance to colonization [ 34 , 38 , 43 , 44 , 47 , 48 ] including bacteriocins, mucus, antimicrobial peptides, nutrient competition, type VI secretion system, and bile acid metabolism ( Figure 1 ). Most of these mechanisms are related to the anaerobic flora.…”

“…The authors suggested that the observed lack of impact could be explained by the known low biliary elimination of imipenem-cilastatin. Indeed, among carbapenems, there are significant differences in terms of biliary elimination [ 43 , 44 ]. Thus, it has become evident that the idea of biliary elimination alone is insufficient to explain the ecological impact of an antibiotic.…”

Biapenem: Clinical and Microbiological Characteristics and the Place of The New Carbapenem In The Treatment of Severe Infections In The Hospital. Clinical Pharmacologists' Point of View

“…Эффективность биапенема изучена в многочисленных несравнительных и сравнительных исследованиях при инфекциях нижних дыхательных путей, включая нозокомиальную и внебольничную пневмонии [54][55][56][57][58], осложнённых инфекциях мочевыводящих путей [54,56,57,59], абдоминальных инфекциях [60], холецистите и холангите [61]. Антибиотиками сравнения были имипенем [54,[58][59][60] и меропенем [56,57,61]. Во всех сравнительных исследованиях показана равная АНТИБИОТИКИ И ХИМИОТЕРАПИЯ, 2022, 67; 5-6 клиническая и микробиологическая эффективность в сравнении с другими карбапенемами.…”