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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.

BackgroundOptimal 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.MethodsThirty-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.ResultsThe median (IQR) of meropenem AUC0–24 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 ConclusionsAn 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 registrationThe trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT-no.2016-002796-10). Registered on 27 December 2016.

Objectives To assess the pharmacokinetics of formed colistin in plasma and the safety of two different high doses of colistimethate sodium administered via nebulization in critically ill surgical patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP). Patients and methods Formed colistin plasma concentrations were measured in critically ill surgical patients with pneumonia treated with two different doses of nebulized colistimethate sodium (3 MIU/8 h versus 5 MIU/8 h). Adverse events possibly related to nebulized colistimethate sodium were recorded. Results Twenty-seven patients (15 in the 3 MIU/8 h group and 12 in the 5 MIU/8 h group) were included. Colistin plasma concentrations were unquantifiable ( Conclusions In this limited observational case series of critically ill patients with HAP or VAP treated with high doses of nebulized colistimethate sodium, systemic exposure was minimal and the treatment was well tolerated.

During neuroendoscopic procedures, pressure inside the neuroendoscope (PIN) monitored through the irrigation channel correlates with the occurrence of postoperative complications. Our aim was to analyze the reliability of PIN measurement as a surrogate for intracranial pressure (ICP) by comparing PIN with simultaneously epidural ICP measurement as the standard.Seventeen consecutive patients undergoing neuroendoscopy were studied prospectively. Type and length of procedure and PIN and epidural ICP values during neuroendoscopy were recorded. Lin's concordance coefficient and Bland-Altman analysis of agreement were used to assess correspondence between the 2 systems.A consistent relation between PIN and epidural ICP waveforms was observed during neuroendoscopic navigation. A strong Pearson correlation between PIN and epidural ICP data were found in 15 patients. Epidural ICP values were systematically higher than PIN values in 15 patients. Lin concordance coefficients showed moderate global agreement between the 2 methods, at 0.58 (95% confidence interval, 0.577-0.592). In 6 cases (35.2%) concordance was good according to this analysis, in 7 cases (41.2%) agreement was moderate/fair, and in 4 cases (23.5%) agreement was poor. The Bland-Altman analysis of patient data showed good agreement between the PIN and epidural ICP measurements for most patients, although discrepancies were greater at higher ICP values for 11 patients. Bland-Altman analysis of the complete dataset, after the normalization of individual's measurements, showed good overall agreement.PIN measurement seems useful for evaluating ICP changes related to neuroendoscopic procedures and seems to be more consistent than epidural ICP at high pressures.