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Beta-lactams remain a critical member of our antibiotic armamentarium and are among the most commonly prescribed antibiotic classes in the inpatient setting. For these agents, the percentage of time that the free concentration remains above the minimum inhibitory concentration (% f T > MIC) of the pathogen has been shown to be the best predictor of antibacterial killing effects. However, debate remains about the quantity of f T > MIC exposure needed for successful clinical response. While pre-clinical animal based studies, such as the neutropenic thigh infection model, have been widely used to support dosing regimen selection for clinical development and susceptibility breakpoint evaluation, pharmacodynamic based studies in human patients are used validate exposures needed in the clinic and for guidance during therapeutic drug monitoring (TDM). For the majority of studied beta-lactams, pre-clinical animal studies routinely demonstrated the f T > MIC should exceed approximately 40–70% f T > MIC to achieve 1 log reductions in colony forming units. In contrast, clinical studies tend to suggest higher exposures may be needed, but tremendous variability exists study to study. Herein, we will review and critique pre-clinical versus human-based pharmacodynamic studies aimed at determining beta-lactam exposure thresholds, so as to determine which targets may be best suited for optimal dosage selection, TDM, and for susceptibility breakpoint determination. Based on our review of murine and clinical literature on beta-lactam pharmacodynamic thresholds, murine based targets specific to each antibiotic are most useful during dosage regimen development and susceptibility breakpoint assessment, while a range of exposures between 50 and 100% f T > MIC are reasonable to define the beta-lactam TDM therapeutic window for most infections.

Infections in critically ill patients are associated with persistently poor clinical outcomes. These patients have severely altered and variable antibiotic pharmacokinetics and are infected by less susceptible pathogens. Antibiotic dosing that does not account for these features is likely to result in suboptimum outcomes. In this Review, we explore the challenges related to patients and pathogens that contribute to inadequate antibiotic dosing and discuss how to implement a process for individualised antibiotic therapy that increases the accuracy of dosing and optimises care for critically ill patients. To improve antibiotic dosing, any physiological changes in patients that could alter antibiotic concentrations should first be established; such changes include altered fluid status, changes in serum albumin concentrations and renal and hepatic function, and microvascular failure. Second, antibiotic susceptibility of pathogens should be confirmed with microbiological techniques. Data for bacterial susceptibility could then be combined with measured data for antibiotic concentrations (when available) in clinical dosing software, which uses pharmacokinetic/pharmacodynamic derived models from critically ill patients to predict accurately the dosing needs for individual patients. Individualisation of dosing could optimise antibiotic exposure and maximise effectiveness.

Obesity can cause physiological changes resulting in antibiotic pharmacokinetic alterations and suboptimal drug exposures. This systematic review aimed to summarise the available evidence on this topic and provide guidance for dose adjustment of antibiotics in adult (age ≥18 years) patients with obesity (BMI >30 kg/m2). We searched PubMed, Embase, and CENTRAL databases to find relevant studies published between database inception and Dec 30, 2023. We initially identified 6113 studies, which became 4654 studies after duplicate removal, and 128 studies were included in the final review. β-lactam antibiotics were most commonly studied (57 studies), followed by the group of glycopeptides, lipoglycopeptides, and oxazolidinones (45 studies). The certainty of evidence was low or very low for all antibiotics and a meta-analysis was not possible due to the heterogeneity of study populations and methods. Obesity modestly alters the pharmacokinetics of β-lactam antibiotics, but evidence does not support routine dose adjustments. For aminoglycosides and glycopeptides, the impact of obesity on pharmacokinetics is evident and weight-based dosing is recommended. Data are sparse for other antibiotic classes and research needs are described. In the absence of robust pharmacokinetic data, therapeutic drug monitoring can be used to guide individualised dosing.

Meropenem and vaborbactam is an intravenous beta-lactam/beta-lactamase inhibitor combination antibiotic active against multidrug resistant gram-negative bacteria. It may be a suitable treatment for inpatient and outpatient management of infections, and the intravenous admixture stability is therefore important for optimal utilization. The purpose of this study was to determine the stability of meropenem and vaborbactam in polyvinyl chloride (PVC) infusion bags and elastomeric pumps at room and refrigerated temperatures. Meropenem and vaborbactam vials were reconstituted according to manufacturer instructions and diluted in PVC infusion bags to final concentrations of 4, 8, and 16 mg/mL and in elastomeric pumps to 11.4 mg/mL (n = 5 replicates per concentration and per temperature). PVC bags and elastomeric pumps were stored at room temperature (~24 °C) or in the refrigerator (~4 °C) and sampled over 12 and 144 h, respectively. Stability was defined as the duration that meropenem and vaborbactam concentrations remained ≥90% of the original concentrations. All room temperature replicates across the tested concentrations retained meropenem and vaborbactam stability over 12 h and displayed concentration-dependent degradation. Refrigerated studies resulted in meropenem and vaborbactam stability at all tested concentrations up to 120 h. Meropenem and vaborbactam in PVC bags (4, 8, and 16 mg/mL) and elastomeric pumps (11.4 mg/mL) were stable for 12 h at room temperature and 120 h when refrigerated. These stability data allow for enhanced flexibility in the preparation, storage, wastage, and administration of meropenem and vaborbactam in the hospital and outpatient setting.

Purpose To develop a meropenem population pharmacokinetic model in critically ill patients with particular focus on optimizing dosing regimens based on renal function. Methods Population pharmacokinetic analysis was performed with creatinine clearance (CrCl) and adjusted body weight to predict parameter estimates. Initial modeling was performed on 21 patients (55 samples). Validation was conducted with 12 samples from 5 randomly selected patients excluded from the original model. A 5,000-patient Monte Carlo simulation was used to ascertain optimal dosing regimens for three CrCl ranges. Results Mean ± SD age, APACHE, and CrCl were 59.2 ± 16.8 years, 13.6 ± 7, and 78.3 ± 33.7 mL/min. Meropenem doses ranged from 0.5 g every 8 h (q8h)–2 g q8h as 0.5–3 h infusions. Median estimates for volume of the central compartment, K 12 , and K 21 were 0.24 L/kg, 0.49 h −1 , and 0.65 h −1 , respectively. K 10 was described by the equation: K 10  = 0.3922 + 0.0025 × CrCl. Model bias and precision were −1.9 and 8.1 mg/L. R 2 , bias, and precision for the validation were 93%, 1.1, and 2.6 mg/L. At minimum inhibitory concentrations (MICs) up to 8 mg/L, the probability of achieving 40% f T > MIC was 96, 90, and 61% for 3 h infusions of 2 g q8h, 1 g q8h, and 1 g q12h in patients with CrCl ≥50, 30–49, and 10–29, respectively. Target attainment was 75, 65, and 44% for these same dosing regimens as 0.5 h infusions. Conclusions This pharmacokinetic model is capable of accurately estimating meropenem concentrations in critically ill patients over a range of CrCl values. Compared with 0.5 h infusions, regimens employing prolonged infusions improved target attainment across all CrCl ranges.

Objectives Cystic fibrosis (CF) acute pulmonary exacerbations are often caused by Pseudomonas aeruginosa , including multi-drug resistant strains. Optimal antibiotic therapy is required to return lung function and should be guided by in vitro susceptibility results. There are sparse data describing ETEST performance for CF isolates using contemporary isolates, methods and interpretation, as well as novel antibiotics, such as ceftazidime–avibactam and ceftolozane–tazobactam. Methods Pseudomonas aeruginosa (n = 105) isolated during pulmonary exacerbation from patients with CF were acquired from 3 US hospitals. Minimum inhibitory concentrations (MICs) were assessed by reference broth microdilution (BMD) and ETEST for aztreonam, cefepime, ceftazidime, ceftazidime–avibactam, ceftolozane–tazobactam, ciprofloxacin, levofloxacin, meropenem, piperacillin–tazobactam, and tobramycin. Broth microdilution was conducted in concordance with the Clinical and Laboratory Standards Institute M100. ETEST methodology reflected package insert recommendations. Performance of ETEST strips was evaluated using the Food and Drug Administration (FDA) and Susceptibility Testing Manufacturers Association (STMA) guidance. Results Of the 105 P. aeruginosa included, 46% had a mucoid phenotype. ETEST MICs typically read 0–1 dilution higher than BMD for all drugs. Categorical agreement and essential agreement ranged from 64 to 93% and 63 to 86%, respectively. The majority of observed errors were minor. A single very major error occurred with ceftazidime (4.2%). For ceftazidime–vibactam, 2 very major errors were observed and both were within essential agreement. Major errors occurred for aztreonam (3.3%), cefepime (9.4%), ceftazidime–avibactam (5.3%, adjusted 2.1%), ceftolozane–tazobactam (1%), meropenem (3.3%), piperacillin–tazobactam (2.9%), and tobramycin (1.5%). Conclusions ETEST methods performed conservatively for most antibiotics against this challenging collection of P. aeruginosa from patients with CF.

Eravacycline is a broad-spectrum, intravenous fluorocycline antibiotic approved for the treatment of complicated intra-abdominal infections in adults. A 60-minute infusion is recommended for each infused dose. Compatibility data that may allow convenient Y-site administration of eravacycline with other parenteral medications are unavailable. We aimed to determine the physical compatibility of eravacycline with other intravenous medications by simulated Y-site administration. Eravacycline was reconstituted according to published prescribing information and diluted with 0.9% sodium chloride to a concentration of 0.6 mg/mL. Simulated Y-site administration was performed by mixing 5 mL of eravacycline with an equal volume of 51 other intravenous medications, including crystalloid and carbohydrate hydration fluids and 20 antimicrobials. Secondary medications were assessed at the upper range of concentrations considered standard for intravenous infusion. Mixtures underwent visual inspection and turbidity measurement immediately on mixture and at 3 subsequent time points (30, 60, and 120 minutes after admixture), and pH was measured at 60 minutes for comparison with the baseline value of the secondary medication. Eravacycline was physically compatible with 41 parenteral drugs (80%) by simulated Y-site administration. Incompatibility was observed with albumin, amiodarone hydrochloride, ceftaroline fosamil, colistimethate sodium, furosemide, meropenem, meropenem/vaborbactam, micafungin sodium, propofol, and sodium bicarbonate. Eravacycline for injection was physically compatible with most parenteral medications assessed. Pharmacists and nurses should be knowledgeable of the observed incompatibilities with eravacycline to prevent the unintentional mixing of incompatible intravenous medications.

Inappropriate antibiotic use and associated consequences, including pathogen resistance and Clostridioides difficile infection, continue to serve as significant threats in the United States, with increasing incidence in the community setting. While much attention has been granted towards antimicrobial stewardship in acute care settings, the transition to the outpatient setting represents a significant yet overlooked area to target optimized antimicrobial utilization. In this article, we highlight notable areas for improved practices and present an interventional approach to stewardship tactics with a framework of disease, drug, dose, and duration. In doing so, we review current evidence regarding stewardship strategies at transitional settings, including diagnostic guidance, technological clinical support, and behavioral and educational approaches for both providers and patients.

Meropenem/vaborbactam is a novel intravenous antibiotic combining the carbapenem, meropenem, with a novel β-lactamase inhibitor, vaborbactam. Meropenem/vaborbactam is administered as a 3-hour infusion given every 8 hours, thereby potentially restricting an intravenous line for 9 h/d. Intravenous medications may be given concurrently via Y-site when compatibility data are available. Herein, physical compatibility was determined for the identification which medications can be coadministered with meropenem/vaborbactam via Y-site. Y-site administration was simulated in vitro by admixing 5 mL of meropenem 8 mg/mL and vaborbactam 8 mg/mL with an equal volume of 88 other diluted intravenous medications, including 34 antimicrobials. All other medications were diluted with 0.9% sodium chloride to the upper range of concentrations considered standard for intravenous infusion. Visual inspection, turbidity measurement, and pH measurement were performed prior to admixture, directly after admixture, and at time points up to 3 hours after admixture. Of the 88 medications tested, meropenem/vaborbactam was compatible with 73 (83%), including many antibiotics such as aminoglycosides (amikacin, gentamicin, and tobramycin), colistin, fosfomycin, linezolid, tedizolid, tigecycline, and vancomycin. Physical incompatibility was observed with albumin, amiodarone, anidulafungin, calcium chloride, caspofungin, ceftaroline, ciprofloxacin, daptomycin, diphenhydramine, dobutamine, isavuconazole, midazolam, nicardipine, ondansetron, and phenytoin. The majority of intravenous medications tested were found to be physically compatible with meropenem/vaborbactam. These data will help pharmacists and nurses to improve line access in patients receiving meropenem/vaborbactam.

In the Phase III Study of Plazomicin Compared With Colistin in Patients With Infection Due to Carbapenem-Resistant Enterobacteriaceae (CARE), plazomicin was studied for the treatment of critically ill patients with infections caused by carbapenem-resistant Enterobacterales. Initial plazomicin dosing was guided by creatinine clearance (CrCl) and subsequent doses adjusted by therapeutic drug monitoring to achieve AUC0–24 exposures within a target range (210–315 mg∙h/L). We applied the Hartford nomogram to evaluate whether this clinical tool could reduce plazomicin troughs levels and increase the proportion of patients within the target AUC range. Thirty-seven patients enrolled in cohorts 1 or 2 of CARE were eligible for analyses. Observed 10-hour concentrations after the initial dose were plotted on the Hartford nomogram to determine an eligible dosing interval group (q24h, q36h or q48h). On the basis of baseline CrCl, a 15- or 10-mg/kg dose was simulated with the nomogram-recommended dosing interval. The proportion of patients in each dosing interval group with a trough ≥3 mg/L (trough threshold associated with serum creatinine increases ≥0.5 mg/dL in product label) was quantified. Simulated interval-normalized AUC0–24 was compared with the target AUC range. Among the 28 patients with a CrCl ≥60 mL/min, the nomogram recommended every-24-hour dosing in 61% and an extended-interval (q36h or q48h) in 39% of patients. For patients with a CrCl ≥30–59 mL/min (n = 9), the nomogram recommended every-24-hour dosing and an extended-interval in 22% and 78% of patients, respectively. Among both renal function cohorts, exposure simulation with the nomogram significantly reduced the proportion of patients with trough concentrations ≥3 mg/L (CrCl ≥60 mL/min cohort: 91% vs 9%, P < 0.001; CrCl ≥30–59 mL/min cohort, 100% vs 0%, P < 0.001). Relative to the observed mean (SD) AUC0–24 of 309 mg∙h/mL (96 mg∙h/mL), simulation of extended intervals resulted in a mean interval-normalized AUC0–24 of 210 mg∙h/mL (40 mg∙h/mL) in all patients eligible for an extended interval, resulting in a similar proportion (49% vs 54%) of patients within the target AUC0–24 range after the first dose. Application of the Hartford nomogram successfully reduced the likelihood of elevated plazomicin trough concentrations while improving AUC exposures in these patients with carbapenem-resistant Enterobacterales infections.