Intrapulmonary concentrations of meropenem administered by continuous infusion in critically ill patients with nosocomial pneumonia: a randomized pharmacokinetic trial
Adela Benítez-Cano,
Sonia Luque,
Luisa Sorlí,
Jesús Carazo,
Isabel Ramos,
Nuria Campillo,
Víctor Curull,
Albert Sánchez-Font,
Carles Vilaplana,
Juan P. Horcajada,
Ramón Adalia,
Silvia Bermejo,
Enric Samsó,
William Hope,
Santiago Grau
Affiliations
Adela Benítez-Cano
Department of Anaesthesiology and Surgical Intensive Care, Hospital del Mar, Parc de Salut Mar
Sonia Luque
Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
Luisa Sorlí
Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
Jesús Carazo
Department of Anaesthesiology and Surgical Intensive Care, Hospital del Mar, Parc de Salut Mar
Isabel Ramos
Department of Anaesthesiology and Surgical Intensive Care, Hospital del Mar, Parc de Salut Mar
Nuria Campillo
Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
Víctor Curull
Universitat de Barcelona
Albert Sánchez-Font
Universitat de Barcelona
Carles Vilaplana
Laboratory Department, Laboratori de Referència de Catalunya
Juan P. Horcajada
Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
Ramón Adalia
Department of Anaesthesiology and Surgical Intensive Care, Hospital del Mar, Parc de Salut Mar
Silvia Bermejo
Department of Anaesthesiology and Surgical Intensive Care, Hospital del Mar, Parc de Salut Mar
Enric Samsó
Department of Anaesthesiology and Surgical Intensive Care, Hospital del Mar, Parc de Salut Mar
William Hope
Department of Molecular and Clinical Pharmacology, Antimicrobial Pharmacodynamics and Therapeutics, University of Liverpool and Royal Liverpool Broadgreen University Hospital Trust
Santiago Grau
Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
Abstract Background Optimal antimicrobial drug exposure in the lung is required for successful treatment outcomes for nosocomial pneumonia. Little is known about the intrapulmonary pharmacokinetics (PK) of meropenem when administered by continuous infusion (CI). The aim of this study was to evaluate the PK of two dosages of meropenem (3 g vs 6 g/day by CI) in the plasma and epithelial lining fluid (ELF) in critically ill patients with nosocomial pneumonia. Methods Thirty-one patients (81% male, median (IQR) age 72 (22) years) were enrolled in a prospective, randomized, clinical trial. Sixteen patients received 1 g/8 h and 15 2 g/8 h by CI (8 h infusion). Plasma and ELF meropenem concentrations were modeled using a population methodology, and Monte Carlo simulations were performed to estimate the probability of attaining (PTA) a free ELF concentration of 50% of time above MIC (50% fT>MIC), which results in logarithmic killing and the suppression of resistance in experimental models of pneumonia. Results The median (IQR) of meropenem AUC0–24 h in the plasma and ELF was 287.6 (190.2) and 84.1 (78.8) mg h/L in the 1 g/8 h group vs 448.1 (231.8) and 163.0 (201.8) mg h/L in the 2 g/8 h group, respectively. The penetration ratio was approximately 30% and was comparable between the dosage groups. In the Monte Carlo simulations, only the highest approved dose of meropenem of 2 g/8 h by CI allowed to achieve an optimal PTA for all isolates with a MIC < 4 mg/L. Conclusions An increase in the dose of meropenem administered by CI achieved a higher exposure in the plasma and ELF. The use of the highest licensed dose of 6 g/day may be necessary to achieve an optimal coverage in ELF for all susceptible isolates (MIC ≤ 2 mg/L) in patients with conserved renal function. An alternative therapy should be considered when the presence of microorganisms with a MIC greater than 2 mg/L is suspected. Trial registration The trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT-no. 2016-002796-10). Registered on 27 December 2016.
