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Background: In recent years, numerous dosing studies have been conducted to optimize therapeutic antibiotic exposures in patients with serious infections. These studies have led to the inclusion of dose optimization recommendations in international clinical practice guidelines. The last international survey describing dosing, administration and monitoring of commonly prescribed antibiotics for critically ill patients was published in 2015 (ADMIN-ICU 2015). This study aimed to describe the evolution of practice since this time. Methods: A cross-sectional international survey distributed through professional societies and networks was used to obtain information on practices used in the dosing, administration and monitoring of vancomycin, piperacillin/tazobactam, meropenem and aminoglycosides. Results: A total of 538 respondents (71% physicians and 29% pharmacists) from 409 hospitals in 45 countries completed the survey. Vancomycin was mostly administered as an intermittent infusion, and loading doses were used by 74% of respondents with 25mg/kg and 20mg/kg the most favoured doses for intermittent and continuous infusions, respectively. Piperacillin/tazobactam and meropenem were most frequently administered as an extended infusion (42% and 51%, respectively). Therapeutic drug monitoring was undertaken by 90%, 82%, 43%, and 39% of respondents for vancomycin, aminoglycosides, piperacillin/tazobactam, and meropenem, respectively, and was more frequently performed in high-income countries. Respondents rarely used dosing software to guide therapy in clinical practice and was most frequently used with vancomycin (11%). Conclusions: We observed numerous changes in practice since the ADMIN-ICU 2015 survey was conducted. Beta-lactams are more commonly administered as extended infusions, and therapeutic drug monitoring use has increased, which align with emerging evidence.

Objectives Critical illness reduces β-lactam pharmacokinetic/pharmacodynamic (PK/PD) attainment. We sought to quantify PK/PD attainment in patients with hospital-acquired pneumonia. Methods Meropenem plasma PK data (n = 70 patients) were modelled, PK/PD attainment rates were calculated for empirical and definitive targets, and between-patient variability was quantified [as a coefficient of variation (CV%)]. Results Attainment of 100% T>4×MIC was variable for both empirical (CV% = 92) and directed (CV% = 33%) treatment. Conclusions Individualization is required to achieve suggested PK/PD targets in critically ill patients.

Additional file 1. Supplementary Material, Description of data: Table S1. Definition of infusion types and duration; Table S2. Online survey questions; Table S3. Exclusions; Table S4. Respondents as per Region and Economy; Table S5. Results according to Region and Economy; Table S6. TDM utilization and beta-lactam prolonged infusion administration according to hospital type.

Additional file 2. Survey instrument.

Additional file 3. Semi-structured interview guide.

Antimicrobial Recommendations for TRUSP Prophylaxis. This supplementary document describes the protocol for selection of prophylactic antimicrobial agents. (DOCX 16Â kb)

Pre-biopsy Questionnaire. This supplementary document details the data obtained from participants prior to biopsy to collect demographic information and to evaluate risk factors for infection. (DOCX 13Â kb)

Post-biopsy Phone Questionnaire. This supplementary document lists the questions asked of participants via phone following biopsy to assess for infectious complications and adverse drug reactions. (DOCX 71Â kb)

Surveillance for Ciprofloxacin Resistant Enterobacteriaceae using MacConkey Agar with 1Â Îźg/ml Ciprofloxacin. This supplementary document describes the protocol used for rectal swab culture in this study. (DOCX 16Â kb)

Background Vancomycin induces exposure-related acute kidney injury [AKI]; yet the toxicodynamic (TD) driver for toxicity (area under the curve [AUC], vs. maximum concentration [CMAX] vs. trough concentrations [CMIN]) remains unclear. Recent vancomycin guidelines now recommend monitoring AUC over troughs. Here we employed our translational rat model with intensive dose fractionation and sensitive FDA qualified urinary biomarkers to better understand TD relationship. Methods Male Sprague-Dawley rats received intravenous (IV) vancomycin via an internal jugular vein catheter. Total daily doses of 300 and 400 mg/kg/day were administered as a single, twice, thrice and four times a day injection over 24 hours. Controls received IV saline. Plasma sampling was conducted via a second dedicated jugular catheter, with up to 8 samples in 24 hours. Twenty-four-hour urine was collected during this time and assayed for kidney injury molecule 1 (KIM-1) and other urinary biomarkers using the MILLIPLEX MAP Rat Kidney Panel. Vancomycin in plasma was quantified via LC-MS/MS. PK analyses were conducted using Pmetrics for R. PK exposures during the first 24 hours (i.e., AUC0-24hours, CMAX0-24hours) were calculated from Bayesian posteriors. Pharmacokinetic-toxicodynamic (PK-TD) relationships were assessed with the best fit mathematic model (e.g., exposure-response curve fitting in GraphPad v.7). Results Sixty-four vancomycin treated and control rats contributed to PK-TD data. An exposure-response (via 4-parameter Hill) model was identified for AUC0-24hoursvs KIM-1 (R2 = 0.62, Figure 1a). Convergence was not obtained for exposure-response models for CMAX0-24hours and CMIN, which was also verified visually (Figure 1b and c). Despite the intensive fractionation, AUC0-24hoursand CMAX0-24hours were highly correlated (P < 0.001, rho = 0.89) and this correlation was consistent across KIM-1 values (Figure 2). Conclusion Vancomycin-induced kidney injury was driven by AUC0-24 hours and not CMIN. Continuous infusion studies are needed to understand if changing the infusion profile can improve safety; however, these studies suggest that isometric AUCs may result in similar toxicity. When using intermittent infusion schemes, clinicians should focus on AUC to prevent AKI. Disclosures All authors: No reported disclosures.

Vancomycin (VAN) has been associated with acute kidney injury (AKI) since it has been put into clinical use in the 1950's. Early reports of AKI were likely linked to the impurities of the VAN preparation. With the advent of the more purified forms of VAN, the incidence of AKI related to VAN were limited to acute interstitial nephritis (AIN) or as a potentiating agent to other nephrotoxins such as Aminoglycosides. VAN as the sole etiologic factor for nephrotoxic acute tubular necrosis (ATN) has not been described. Here, we report a case of biopsy-proven ATN resulting from VAN.