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 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.

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 (<0.1 mg/L) in eight (53.3%) patients in the 3 MIU/8 h group and in seven patients (58.3%) in the 5 MIU/8 h group. Median (IQR) quantifiable colistin plasma concentrations before nebulization and at 1, 4 and 8 h were 0.17 (0.12–0.33), 0.20 (0.11–0.24), 0.17 (0.12–0.23) and 0.17 (0.11–0.32) mg/L, respectively, in the 3 MIU/8 h group and 0.20 (0.11–0.35), 0.24 (0.12–0.44), 0.24 (0.10–0.49) and 0.23 (0.11–0.44) mg/L, respectively, in the 5 MIU/8 h group, with no differences between the two groups at any time. Renal impairment during nebulized treatment was observed in three patients in each group, but was unlikely to be related to colistimethate sodium treatment. Nebulized colistimethate sodium therapy was well tolerated and no bronchospasms or neurotoxicity events were observed. 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.

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.

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Objectives: To describe a process change and evaluate compliance with use of preventive analgesia and deep venous thromboembolic (DVT) prophylaxis in an ESRP pathway following implementation of order set. Methods: The ESRP at MD Anderson was initiated in the Department of Gynaecologic Oncology in November 2014. We used the following medications for preventive analgesia; pregabalin (neuropathic pain), celecoxib (non-steroidal anti-inflammatory), and tramadol (mu-opioid receptor, synthetic opioid). An order set was developed to include these medications in all patients undergoing gynaecologic surgery provided there were no contraindications. All patients were also written in the order set to receive subcutaneous heparin 5,000 units administered subcutaneously on arrival to the holding area. Medications were administered upon arrival in the preoperative holding area by the nursing staff. Training on the new order set was provided prior to ESRP rollout in November 2014 to members of the gynaecologic oncology team as well as to the nurses in the preoperative holding area. To improve adherence to the process change, a repeat training was performed for the clinic staff 6 weeks after implementation. Attending anaesthesiologist for the case had final say on the medications to be administered to the patients. Statistical analyses with Wilcoxon ranksum, Fisher's exact, and unpaired t test were used for comparisons. Results: All 272 patients on our ESRP pathway had order set completion at the time of arrival to the surgical holding area for preventive analgesia and DVT prophylaxis. The rate of administration of each of the pre-medications found in the order set were as follows: heparin 262 (96.3%), celecoxib 251 (92.3%), pregabalin 254 (93.4%), and tramadol 257 (94.5%), respectively. The reasons for failure to achieve full compliance in these were: contraindications or allergic reactions. Conclusion: Development of a specific order set in ESRP gynaecologic surgery programme demonstrated excellent compliance with order completion. However, as with any new process change, audits of process flow can identify areas for improvement. Disclosure of interest: None declared.