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 AUC_0–24 hin 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.

Background: Pathophysiological changes such as extreme body weights in critically ill patients with severe infections may alter the pharmacokinetics (PK) of antimicrobials, leading to treatment failure or toxicity. There are almost no PK data on meropenem in critically ill patients with low body weight (LwBW) and therefore information is lacking on the most appropriate dosing regimens, especially when administered by extended infusion. Objectives: To assess if the current administered doses of meropenem could lead to supratherapeutic concentrations in LwBW patients and to identify the factors independently associated with overexposure. Methods: A matched case-control 1:1 study of surgical critically ill patients treated with meropenem administered by extended or continuous infusion and undergoing therapeutic drug monitoring was conducted. Cases (patients with LwBW (body mass index (BMI) < 18.5 kg/m²)) were matched with normal body weight controls (NBW) (patients with BMI ≥ 18.5 kg/m² and ≤30 kg/m²)) by age, gender, baseline renal function and severity status (APACHE II score). A 100% fT > MIC was considered an optimal pharmacokinetic/pharmacodynamic (PK/PD) target and 100% fT > 10 × MIC as supratherapeutic exposure. Results: Thirty-six patients (18 cases and 18 controls) were included (median (range) age, 57.5 (26–75) years; 20 (55.6% male)). Meropenem was administered by 6 h (extended) or 8 h (continuous) infusion at a median (range) daily dose of 5 (1–6) g/day. Similar median meropenem trough plasma concentrations (Cmin,ss), measured pre-dose on day three to four of treatment) were observed in the two groups (19.9 (22.2) mg/L vs 22.4 (25.8) mg/L, p > 0.999). No differences in the proportion of patients with an optimal or a supratherapeutic PKPD target between cases and controls were observed. A baseline estimated glomerular filtration rate (eGFR) < 90 mL/min was the only factor independently associated with a supratherapeutic PK/PD target. Conclusions: LwBW seems not to be a risk factor for achieving a supratherapeutic PK/PD target in critically ill patients receiving meropenem at standard doses by extended or continuous infusion.

Ceftaroline is a novel cephalosporin active against MDR Gram-positive (GP) bacteria. For β-lactam antibiotics, such as ceftaroline, prolonged infusions and therapeutic drug monitoring (TDM) are used for dosage optimization based on their pharmacokinetics/pharmacodynamics (PK/PD). To describe our experience with TDM and PK/PD target attainment of ceftaroline administered by intermittent and prolonged infusion in a cohort of patients with MDR-GP bacterial infections. Patients treated with ceftaroline administered by continuous (24 h), extended (3 h/6 h) and intermittent infusion (1 h) and undergoing TDM of plasma concentrations were included. A 100%fT_>4×MIC was the pre-specified PK/PD target and 100%fT_>10×MIC was considered overexposure. Dose recommendations were made based on TDM results and each patient’s clinical condition. Twelve patients [83.3% male, median age of 73 (38–83) years] were included. Nine patients (75%) achieved 100%fT_>4×MIC, all under prolonged infusions. In one patient, the 100%fT was >10×MIC but no toxicity was observed. Based on TDM results, initial doses were recommended to be maintained in eight patients, decreased in three and increased in one. The administration of ceftaroline by prolonged infusion together with TDM may be a useful strategy for achieving the desired PK/PD target in these patients. However, more studies evaluating the relationship between PK/PD attainment and clinical outcomes are needed.

Ceftolozane/tazobactam (TOL/TAZ) and ceftazidime-avibactam (CAZ/AVI) are increasingly used to treat pneumonia caused by multidrug-resistant Gram-negative b

Respiratory infections are frequent and life-threatening complications of surgery. This study aimed to evaluate the clinical, microbiological and treatment characteristics of severe postoperative pneumonia (POP) and tracheobronchitis (POT) in a large series of patients. This single-center, prospective observational cohort study included patients with POP or POT requiring intensive care unit admission in the past 10 years. We recorded demographic, clinical, microbiological and therapeutic data. A total of 207 patients were included, and 152 (73%) were men. The mean (SD) age was 70 (13) years and the mean (SD) ARISCAT score was 46 (19). Ventilator-associated pneumonia was reported in 21 patients (10%), hospital-acquired pneumonia was reported in 132 (64%) and tracheobronchitis was reported in 54 (26%). The mean (SD) number of days from surgery to POP/POT diagnosis was 6 (4). The mean (SD) SOFA score was 5 (3). Respiratory microbiological sampling was performed in 201 patients (97%). A total of 177 organisms were cultured in 130 (63%) patients, with a high proportion of Gram-negative and multi-drug resistant (MDR) bacteria (20%). The most common empirical antibiotic therapy was a triple-drug regimen covering MDR Gram-negative bacteria and MRSA. In conclusion, surgical patients are a high-risk population with a high proportion of early onset severe POP/POT and nosocomial bacteria isolation.