Penetration of Meropenem into Epithelial Lining Fluid of Patients with Ventilator-Associated Pneumonia

Abstract

Antibiotic penetration to the infection site is critical for obtaining a good clinical outcome in patients with ventilator-associated pneumonia (VAP). Surprisingly few studies have quantified the penetration of ␤-lactam agents into the lung, as measured by the ratio of area under the concentration-time curve (AUC) in epithelial lining fluid (ELF) to AUC in plasma (AUC ELF /AUC plasma ratio). These have typically involved noninfected patients. This study examines the penetration and pharmacodynamics of meropenem in the ELF among patients with VAP. Meropenem plasma and ELF concentration-time data were obtained from patients in a multicenter clinical trial. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model with zero-order infusion and first-order elimination and transfer (big nonparametric adaptive grid [BigNPAG]). A Monte Carlo simulation was performed to estimate the range of ELF/ plasma penetration ratios one would expect to observe in patients with VAP, as measured by the AUC ELF / AUC plasma ratio. The range of AUC ELF /AUC plasma penetration ratios predicted by the Monte Carlo simulation was large. The 10th percentile of lung penetration was 3.7%, while the 90th percentile of penetration was 178%. The variability of ELF penetration is such that if relatively high ELF exposure targets are required to attain multilog kill or resistance suppression for bacteria like Pseudomonas aeruginosa, then even receiving the largest licensed dose of meropenem with an optimal prolonged infusion may not result in target attainment for a substantial fraction of the population.Ventilator-associated pneumonia (VAP) remains a frequent cause of morbidity and mortality among intensive care unit patients despite advances in antimicrobial therapy, better supportive care modalities, and the use of a wide range of preventive measures (1, 26). Prompt delivery of empirical therapy for patients likely to have VAP is of paramount importance, since delays in appropriate antibiotic therapy have been associated with deleterious outcomes (1,18,19,24,25). An important consideration when selecting empirical therapy for VAP is the agent's ability to adequately penetrate the infected site and achieve sufficient concentrations for the desired endpoint. For extracellular respiratory tract pathogens, the determination of drug concentration in epithelial lining fluid (ELF) currently provides the best estimate for ascertaining the degree of antibiotic exposure for these organisms in patients with 12,[15][16][17]21,25,27,28).While it is well established that the efficacy of an antibiotic regimen largely depends on its penetration in the infection site, relatively few studies have focused on the penetration of antibiotics into the ELF (3-8, 12, 15-17, 21, 23, 25, 27, 28). Of those available, most have been among patients treated with fluoroquinolones and macrolides (12,15,16,23,27,28). A surprisingly small body of data is available for the penetration of ␤-lactam agents into the ELF. In the older li...

Population Pharmacokinetics and Monte Carlo Dosing Simulations of Meropenem during the Early Phase of Severe Sepsis and Septic Shock in Critically Ill Patients in Intensive Care Units

“…The exposure targets developed in the murine model to ascertain how well a dose of 2 g of meropenem administered as a 3-h infusion could achieve those targets were simulated. The target attainment of this dosage regimen in achieving a 2-log 10 (CFU/g) cell kill was Ͻ80% at a MIC of 2 g/ml, while values for a 3-log 10 (CFU/g) cell kill and resistance suppression were Ͻ90% at a MIC of 0.25 g/ml and Ͻ75% at a MIC of 1 g/ml (25,26). These findings indicate that PD targets may not be achieved even when the largest licensed dose of meropenem, administered as a prolonged infusion, is prescribed for critically ill patients being treated for VAP, because of the variability of penetration and the high exposure targets for meropenem in ELF in the lungs for this patient population.…”

“…The determination of drug concentrations in the ELF for extracellular respiratory tract pathogens provided the best estimate of antibiotic exposure in this patient population (24). A previous study of meropenem PK in plasma and ELF among seriously ill patients with VAP found the mean plasma CL of meropenem to be variable, due to differing physiological conditions across the patient population, leading to variability in the penetration of this agent into the ELF, with the 10th-to-90th-percentile range of penetration being 3.67% to 177.90%, and inadequate drug exposure at the primary infection site for some patients (25). A study in a murine pneumonia model with P. aeruginosa to determine the penetration of meropenem into the ELF of mice also demonstrated different levels of penetration (26).…”

Use of pharmacodynamic principles to inform β‐lactam dosing: “S” does not always mean success

“…However, the median ELF/plasma penetration ratio for meropenem among patients with ventilator-associated pneumonia (VAP) is only 25%. 37 The only way to achieve a favorable fT > MIC PD profile at the site of infection with meropenem is to administer higher doses over prolonged periods of time ( Figure 4). In light of the meropenem ELF data, data available on concentrations at the site of infection, particularly difficult-to-penetrate sites, such as ELF and cerebrospinal fluid, should be considered before designing dosing scheme for implementation into clinical practice.…”

Bacterial sepsis

“…These recommendations are derived from animal experiments; clinical investigations underscore the fact that in sepsis patients, an fT>MIC of 100% elicits a more effective anti-infective effect, and is thus relevant for outcome [190,[201][202][203]. Especially on the basis of striving to achieve adequate tissue concentrations even in deep-lying compartments (pneumonia; bone infections; infections of the central nervous system, CNS)-frequently in the context of disturbed microcirculation in sepsis patients [204][205][206] and also wishing to avoid development of resistance [207,208]-many experts recommend aiming for a concentration of β-lactam antibiotics in the primary compartment (serum/plasma) that exceeds the MIC by 4-times (up to 6-times) for 60-100% of the dosing interval [209]. In addition to individual dosing of antibiotics, the current DGI guideline [124] names therapeutic drug monitoring (TDM) as a possibility for treatment management and reduction of undesirable side effects of antibiotics.…”