In silico Evaluation of a Vancomycin Dosing Guideline Among Adults with Serious Infections.

BACKGROUND: This study aimed to compare the achievement of pharmacokinetic-pharmacodynamic (PK-PD) exposure targets for vancomycin using a newly developed dosing guideline with product-information-based dosing in the treatment of adult patients with serious infections. METHODS: In silico product-information- and guideline-based dosing simulations for vancomycin were performed across a range of doses and patient characteristics, including body weight, age, and renal function at 36-48 and 96 hours, using a pharmacokinetic model derived from a seriously ill patient population. The median simulated concentration and area under the 24-hour concentration-time curve (AUC 0-24 ) were used to measure predefined therapeutic, subtherapeutic, and toxicity PK-PD targets. RESULTS: Ninety-six dosing simulations were performed. The pooled median trough concentration target with guideline-based dosing at 36 and 96 hours was achieved in 27.1% (13/48) and 8.3% (7/48) of simulations, respectively. The pooled median AUC 0-24 /minimum inhibitory concentration ratio with guideline-based dosing at 48 and 96 hours was attained in 39.6% (19/48) and 27.1% (13/48) of simulations, respectively. Guideline-based dosing simulations yielded improved trough target attainment compared with product-information-based dosing at 36 hours and significantly less subtherapeutic drug exposure. The toxicity threshold was exceeded in 52.1% (25/48) and 0% (0/48) for guideline- and product-information-information-based dosing, respectively ( P < 0.001). CONCLUSIONS: A Critical care vancomycin dosing guideline appeared slightly more effective than standard dosing, as per product information, in achieving PK-PD exposure associated with an increased likelihood of effectiveness. In addition, this guideline significantly reduced the risk of subtherapeutic exposure. The risk of exceeding toxicity thresholds, however, was greater with the guideline, and further investigation is suggested to improve dosing accuracy and sensitivity.

Pharmacokinetic and pharmacodynamic considerations for antifungal therapy optimisation in the treatment of intra-abdominal candidiasis.

Intra-abdominal candidiasis (IAC) is one of the most common of invasive candidiasis observed in critically ill patients. It is associated with high mortality, with up to 50% of deaths attributable to delays in source control and/or the introduction of antifungal therapy. Currently, there is no comprehensive guidance on optimising antifungal dosing in the treatment of IAC among the critically ill. However, this form of abdominal sepsis presents specific pharmacokinetic (PK) alterations and pharmacodynamic (PD) challenges that risk suboptimal antifungal exposure at the site of infection in critically ill patients. This review aims to describe the peculiarities of IAC from both PK and PD perspectives, advocating an individualized approach to antifungal dosing. Additionally, all current PK/PD studies relating to IAC are reviewed in terms of strength and limitations, so that core elements for the basis of future research can be provided.

International survey of antibiotic dosing and monitoring in adult intensive care units.

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 25 mg/kg and 20 mg/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.

Plasma and Cerebrospinal Fluid Population Pharmacokinetics of Meropenem in Neurocritical Care Patients: a Prospective Two-Center Study.

Morbidity and mortality related to ventriculitis in neurocritical care patients remain high. Antibiotic dose optimization may improve therapeutic outcomes. In this study, a population pharmacokinetic model of meropenem in infected critically ill patients was developed. We applied the final model to determine optimal meropenem dosing regimens required to achieve targeted cerebrospinal fluid exposures. Neurocritical care patients receiving meropenem and with a diagnosis of ventriculitis or extracranial infection were recruited from two centers to this study. Serial plasma and cerebrospinal fluid samples were collected and assayed. Population pharmacokinetic modeling and Monte Carlo dosing simulations were performed using Pmetrics. We sought to determine optimized dosing regimens that achieved meropenem cerebrospinal fluid concentrations above pathogen MICs for 40% of the dosing interval, or a higher target ratio of meropenem cerebrospinal fluid trough concentrations to pathogen MIC of ≥1. In total, 53 plasma and 34 cerebrospinal fluid samples were obtained from eight patients. Meropenem pharmacokinetics were appropriately described using a three-compartment model with linear plasma clearance scaled for creatinine clearance and cerebrospinal fluid penetration scaled for patient age. Considerable interindividual pharmacokinetic variability was apparent, particularly in the cerebrospinal fluid. Percent coefficients of variation for meropenem clearance from plasma and cerebrospinal fluid were 41.7% and 89.6%, respectively; for meropenem, the volume of distribution in plasma and cerebrospinal fluid values were 63.4% and 58.3%, respectively. High doses (up to 8 to 10 g/day) improved attainment of meropenem cerebrospinal fluid target exposures, particularly for less susceptible organisms (MICs, ≥0.25 mg/L). Standard meropenem doses of 2 g every 8 h may not achieve effective concentrations in cerebrospinal fluid in all critically ill patients. Higher doses, or alternative dosing methods (e.g., loading dose followed by continuous infusion) may be required to optimize cerebrospinal fluid exposures. Doses of up to 8 to 10 g/day either as intermittent boluses or continuous infusion would be suitable for patients with augmented renal clearance; lower doses may be considered for patients with impaired renal function as empirical suggestions. Ongoing dosing should be tailored to the individual patient circumstances. Notably, the study population was small and dosing recommendations may not be generalizable to all critically ill patients.

Therapeutic Drug Monitoring of Antibiotics: Defining the Therapeutic Range.

PURPOSE: In the present narrative review, the authors aimed to discuss the relationship between the pharmacokinetic/pharmacodynamic (PK/PD) of antibiotics and clinical response (including efficacy and toxicity). In addition, this review describes how this relationship can be applied to define the therapeutic range of a particular antibiotic (or antibiotic class) for therapeutic drug monitoring (TDM). METHODS: Relevant clinical studies that examined the relationship between PK/PD of antibiotics and clinical response (efficacy and response) were reviewed. The review (performed for studies published in English up to September 2021) assessed only commonly used antibiotics (or antibiotic classes), including aminoglycosides, beta-lactam antibiotics, daptomycin, fluoroquinolones, glycopeptides (teicoplanin and vancomycin), and linezolid. The best currently available evidence was used to define the therapeutic range for these antibiotics. RESULTS: The therapeutic range associated with maximal clinical efficacy and minimal toxicity is available for commonly used antibiotics, and these values can be implemented when TDM for antibiotics is performed. Additional data are needed to clarify the relationship between PK/PD indices and the development of antibiotic resistance. CONCLUSIONS: TDM should only be regarded as a means to achieve the main goal of providing safe and effective antibiotic therapy for all patients. The next critical step is to define exposures that can prevent the development of antibiotic resistance and include these exposures as therapeutic drug monitoring targets.

A Systematic Review of Studies Reporting Antibiotic Pharmacokinetic Data in the Cerebrospinal Fluid of Critically Ill Patients with Uninflamed Meninges.

Ventriculostomy-associated infections in critically ill patients remain therapeutically challenging because of drug- and disease-related factors that contribute to suboptimal antibiotic concentrations in cerebrospinal fluid. Optimal antibiotic dosing for the treatment and prevention of such infections should be based on robust and contextually specific pharmacokinetic data. The objects of this study were to describe and critically appraise studies with reported antibiotic concentrations or pharmacokinetic data in cerebrospinal fluid of critically ill patients without meningeal inflammation. We systematically reviewed the literature to identify published reports and studies describing antibiotic concentrations, pharmacokinetics, and pharmacokinetics/pharmacodynamics in cerebrospinal fluid of critically ill patients with uninflamed meninges. Fifty-eight articles met the inclusion criteria. There was significant heterogeneity in methodologies and results. When available, antibiotic pharmacokinetic parameters displayed large intersubject variability. Intraventricular dosing achieved substantially higher antibiotic concentrations in cerebrospinal fluid than did intravenous doses. Few studies conducted a robust pharmacokinetic analysis and described relevant clinical pharmacokinetic/pharmacodynamic indices and exposure targets in cerebrospinal fluid. Robust and clinically relevant antibiotic pharmacokinetic data describing antibiotic disposition in cerebrospinal fluid are necessary. Such studies should use a standardized approach to accurately describe pharmacokinetic variability. These data should ideally be tied to clinical outcomes whereby therapeutic targets in the cerebrospinal fluid can be better defined. Altered dosing strategies, in conjunction with exploring the utility of therapeutic drug monitoring, can then be developed to optimize antibiotic exposure with the goal of improving outcomes in this difficult-to-treat patient group.

Pharmacokinetics/Pharmacodynamics of ß-Lactams and Therapeutic Drug Monitoring: From Theory to Practical Issues in the Intensive Care Unit.

Despite therapeutic advances over recent decades, the mortality rate for sepsis and septic shock is still approximately 25% worldwide. Early administration of appropriate intravenous antibiotics in the right dose is one of the cornerstones of treatment of sepsis. ß-Lactam antibiotics are the most commonly prescribed in critically ill patients, and dosages that do not achieve specific pharmacokinetic/pharmacodynamic targets may increase the likelihood of treatment failure and even emergence of antibiotic resistance. Fluctuations in physiological parameters are often observed in critically ill patients, leading to altered pharmacokinetics and increased risk of suboptimal exposures, especially if standard dosing according to the product information is prescribed. Contemporary evidence illustrates that therapeutic ß-lactam concentrations are inconsistently achieved at steady state. This review will investigate alternative ß-lactam dose optimization strategies including prolonged infusions, guideline-based dosing, therapeutic drug monitoring (TDM), and the use of dose optimization software, all of which aim to increase the likelihood of achieving therapeutic drug concentrations and improve clinical outcomes as compared with the standard dosing approach. These dose optimization strategies have been the subject of a growing body of evidence; however, further investigation into the outcome benefits and validity of both non-TDM and TDM dosing strategies is required. For the clinician, it is important to select a feasible dosing strategy tailored for the individual patient, which will maximize the likelihood of achieving therapeutic concentrations at steady state and maintain these exposures throughout the course of therapy.

A Systematic Review of the Definitions, Determinants, and Clinical Outcomes of Antimicrobial De-escalation in the Intensive Care Unit.

Antimicrobial de-escalation (ADE) is a strategy to reduce the spectrum of antimicrobials and aims to prevent the emergence of bacterial resistance. We present a systematic review describing the definitions, determinants and outcomes associated with ADE. We included 2 randomized controlled trials and 12 cohort studies. There was considerable variability in the definition of ADE. It was more frequently performed in patients with broad-spectrum and/or appropriate antimicrobial therapy (P= .05 to .002), when more agents were used (P= .002), and in the absence of multidrug-resistant pathogens (P< .05). Where investigated, lower or improving severity scores were consistently associated with ADE (P= .04 to <.001). The pooled effect of ADE on mortality is protective (relative risk, 0.68; 95% confidence interval, .52-.88). Because the determinants of ADE are markers of clinical improvement and/or of lower risk of treatment failure this effect on mortality cannot be retained as evidence. None of the studies were designed to investigate the effect of ADE on antimicrobial resistance.

Does Critical Illness Change Levofloxacin Pharmacokinetics?

Levofloxacin is commonly used in critically ill patients for which existing data suggest nonstandard dosing regimens should be used. The objective of this study was to compare the population pharmacokinetics of levofloxacin in critically ill and in non-critically ill patients. Adult patients with a clinical indication for levofloxacin were eligible for participation in this prospective pharmacokinetic study. Patients were given 500 mg or 750 mg daily by intravenous administration with up to 11 blood samples taken on day 1 or 2 of therapy. Plasma samples were analyzed and population pharmacokinetic analysis was undertaken using Pmetrics. Thirty-five patients (18 critically ill) were included. The mean (standard deviation [SD]) age, weight, and Cockcroft-Gault creatinine clearance for the critically ill and for the non-critically ill patients were 60.3 (16.4) and 72.0 (11.6) years, 78.5 (14.8) and 70.9 (15.8) kg, and 71.9 (65.8) and 68.2 (30.1) ml/min, respectively. A two-compartment linear model best described the data. Increasing creatinine clearance was the only covariate associated with increasing drug clearance. The presence of critical illness did not significantly affect any pharmacokinetic parameter. The mean (SD) parameter estimates were as follows: clearance, 8.66 (3.85) liters/h; volume of the central compartment (Vc), 41.5 (24.5) liters; intercompartmental clearance constants from central to peripheral, 2.58 (3.51) liters/h; and peripheral to central compartments, 0.90 (0.58) liters/h. Monte Carlo dosing simulations demonstrated that achievement of therapeutic exposures was dependent on renal function, pathogen, and MIC. Critical illness appears to have no independent effect on levofloxacin pharmacokinetics that cannot be explained by altered renal function.

The ADMIN-ICU survey: a survey on antimicrobial dosing and monitoring in ICUs.

OBJECTIVES: There is little evidence and few guidelines to inform the most appropriate dosing and monitoring for antimicrobials in the ICU. We aimed to survey current practices around the world. METHODS: An online structured questionnaire was developed and sent by e-mail to obtain information on local antimicrobial prescribing practices for glycopeptides, piperacillin/tazobactam, carbapenems, aminoglycosides and colistin. RESULTS: A total of 402 professionals from 328 hospitals in 53 countries responded, of whom 78% were specialists in intensive care medicine (41% intensive care, 30% anaesthesiology, 14% internal medicine) and 12% were pharmacists. Vancomycin was used as a continuous infusion in 31% of units at a median (IQR) daily dose of 25 (25-30) mg/kg. Piperacillin/tazobactam was used as an extended infusion by 22% and as a continuous infusion by 7%. An extended infusion of carbapenem (meropenem or imipenem) was used by 27% and a continuous infusion by 5%. Colistin was used at a daily dose of 7.5 (3.9-9) million IU (MIU)/day, predominantly as a short infusion. The most commonly used aminoglycosides were gentamicin (55%) followed by amikacin (40%), with administration as a single daily dose reported in 94% of the cases. Gentamicin was used at a daily dose of 5 (5-6) mg/day and amikacin at a daily dose of 15 (15-20) mg/day. Therapeutic drug monitoring of vancomycin, piperacillin/tazobactam and meropenem was used by 74%, 1% and 2% of the respondents, respectively. Peak aminoglycoside concentrations were sampled daily by 28% and trough concentrations in all patients by 61% of the respondents. CONCLUSIONS: We found wide variability in reported practices for antibiotic dosing and monitoring. Research is required to develop evidence-based guidelines to standardize practices.

A Systematic Review of the Pharmacokinetics and Pharmacodynamics of Novel Beta-Lactams and Beta-Lactam with Beta-Lactamase Inhibitor Combinations for the Treatment of Pneumonia Caused by Carbapenem-Resistant Gram-Negative Bacteria.

BACKGROUND: Novel beta-lactams show activity against many multidrug-resistant Gram-negative bacteria that cause severe lung infections. Understanding pharmacokinetic/pharmacodynamic characteristics of these agents may help optimise outcomes in the treatment of pneumonia. OBJECTIVES: To describe and appraise studies that report pulmonary pharmacokinetic and pharmacodynamic data of cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam and meropenem/vaborbactam. METHODS: MEDLINE (PubMed), Embase, Web of Science and Scopus libraries were used for the literature search. Pulmonary population pharmacokinetic and pharmacokinetic/pharmacodynamic studies on adult patients receiving cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam, and meropenem/vaborbactam published in peer-reviewed journals were included. Two independent authors screened, reviewed and extracted data from included articles. A reporting guideline for clinical pharmacokinetic studies (ClinPK statement) was used for bias assessment. Relevant outcomes were included, such as population pharmacokinetic parameters and probability of target attainment of dosing regimens. RESULTS: Twenty-four articles were included. There was heterogeneity in study methods and reporting of results, with diversity across studies in adhering to the ClinPK statement checklist. Ceftolozane/tazobactam was the most studied agent. Only two studies collected epithelial lining fluid samples from patients with pneumonia. All the other phase I studies enrolled healthy subjects. Significant population heterogeneity was evident among available population pharmacokinetic models. Probabilities of target attainment rates above 90% using current licensed dosing regiments were reported in most studies. CONCLUSIONS: Although lung pharmacokinetics was rarely described, this review observed high target attainment using plasma pharmacokinetic data for all novel beta-lactams. Future studies should describe lung pharmacokinetics in patient populations at risk of carbapenem-resistant pathogen infections.

Safety and efficacy of outpatient parenteral antimicrobial therapy: A systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Outpatient parenteral antimicrobial therapy (OPAT) offers an alternative to inpatient (hospital bed-based) treatment of infections that require intravenous administration of antimicrobials. This meta-analysis aimed to summarise the evidence available from randomised controlled trials (RCTs) regarding the efficacy and safety of OPAT compared to inpatient parenteral antimicrobial therapy. METHODS: We searched the Cochrane Library, MEDLINE, Embase, PubMed, and Web of Sciences databases for RCTs comparing outpatient versus inpatient parenteral antimicrobial therapy. We included studies without restrictions on language or publication year. Eligibility was reviewed independently by two assessors, and data extraction was cross validated. We evaluated bias risk via the Cochrane tool and determined the evidence certainty using GRADE. Meta-analysis was conducted using a random effects model. The protocol of this review was registered on PROSPERO (CRD42023460389). RESULT: Thirteen RCTs, involving 1,310 participants were included. We found no difference in mortality (Risk Ratio [RR] 0.54, 95% Confidence Interval [CI] 0.23 to 1.26; P = 0.93), treatment failure (RR 1.0, CI 0.59 to 1.72; P = 0.99), adverse reaction related to antimicrobials (RR 0.89, CI 0.69 to 1.15; P = 0.38), and administration device (RR 0.58, CI 0.17 to 1.98; P = 0.87) between outpatient and inpatient parenteral antimicrobial therapy. The overall body of evidence had a low level of certainty. CONCLUSION: Existing evidence suggests OPAT is a safe and effective alternative to inpatient treatment. Further RCTs are warranted for a thorough comparison of inpatient and outpatient parenteral antimicrobial therapy with a high level of certainty.

Antimicrobial therapeutic drug monitoring in critically ill adult patients - An international perspective on access, utilisation, and barriers.

BACKGROUND: Therapeutic drug monitoring (TDM) is an effective method for individualising antimicrobial therapy in critically ill patients. The 2021 ADMIN-intensive care unit survey studied a wide range of intensive care unit clinicians worldwide to gain their perspectives on antimicrobial TDM. This article reports the responses from this survey relating to TDM access, utilisation, and barriers. METHODS: An online survey consisted of multiple-choice questions and 5-point Likert scales. The survey examined respondent's access to minimum inhibitory concentration (MIC) results, drug assays, and dosing software, as well as barriers to TDM. RESULTS: The survey included 538 clinicians from 409 hospitals in 45 countries, with 71% physicians and 29% pharmacists. Despite most respondents having access to assays, 21% and 26% of respondents lacked access to vancomycin and aminoglycosides, respectively. In lower-income countries, almost 40% reported no access. Delayed drug assay turnaround time was the most significant barrier to TDM, particularly in lower-income countries. Routine access to MIC results was unavailable for 41% of respondents, with 25% of lower-income country respondents having no access to MIC or susceptibility reports. CONCLUSIONS: This global survey indicated that consistent TDM usage is hindered by assay access in some sites and the timeliness of assay results in others. Addressing barriers to TDM, particularly in low-income countries, should be a priority to ensure equitable access to affordable TDM.

A Systematic Review on Antimicrobial Pharmacokinetic Differences between Asian and Non-Asian Adult Populations.

While the relevance of inter-ethnic differences to the pharmacokinetic variabilities of antimicrobials has been reported in studies recruiting healthy subjects, differences in antimicrobial pharmacokinetics between Asian and non-Asian patients with severe pathologic conditions require further investigation. For the purpose of describing the potential differences in antimicrobial pharmacokinetics between Asian and non-Asian populations, a systematic review was performed using six journal databases and six theses/dissertation databases (PROSPERO record CRD42018090054). The pharmacokinetic data of healthy volunteers and non-critically ill and critically ill patients were reviewed. Thirty studies on meropenem, imipenem, doripenem, linezolid, and vancomycin were included in the final descriptive summaries. In studies recruiting hospitalised patients, inconsistent differences in the volume of distribution (Vd) and drug clearance (CL) of the studied antimicrobials between Asian and non-Asian patients were observed. Additionally, factors other than ethnicity, such as demographic (e.g., age) or clinical (e.g., sepsis) factors, were suggested to better characterise these pharmacokinetic differences. Inconsistent differences in pharmacokinetic parameters between Asian and non-Asian subjects/patients may suggest that ethnicity is not an important predictor to characterise interindividual pharmacokinetic differences between meropenem, imipenem, doripenem, linezolid, and vancomycin. Therefore, the dosing regimens of these antimicrobials should be adjusted according to patients' demographic or clinical characteristics that can better describe pharmacokinetic differences.

In silico evaluation of a beta-lactam dosing guideline among adults with serious infections.

STUDY OBJECTIVE: The aim of this study was to compare the achievement of therapeutic pharmacokinetic-pharmacodynamic (PK-PD) exposure targets for beta-lactam antibiotics using product information dosing or guideline-based dosing for the treatment of serious infections. DESIGN: In silico study. DATA SOURCE: ID-ODSTM (Individually Designed Optimum Dosing Strategies). PATIENTS AND INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: In silico product information and guideline-based dosing simulations for cefepime, ceftazidime, flucloxacillin, meropenem, and piperacillin/tazobactam were performed using pharmacokinetic models from seriously ill patient populations. The median simulated concentration at 48 and 96 h was used to measure the probability of target attainment (PTA) to achieve predefined therapeutic and toxicity PK-PD targets. A multiple linear regression model was constructed to identify the effect of guideline-based dosing covariates on achieving pre-defined therapeutic targets. In total, 480 dosing simulations were performed. The PTA percentage with guideline-based dosing at 48 and 96 h was 80% and 68%, respectively, yielding significantly higher results when compared to product information dosing (48.45% and 49%, respectively), p < 0.001 at both time points. At 48 h, predefined toxicity thresholds were exceeded in 4.7% and 0% of simulations for guideline-based and product information-based dosing, respectively (p = 0.002). eGFR was significantly associated with the % PTA by guideline-based dosing, with eGFR values of 20 and 50 ml/min both statistically significant in leading to an increase in PTA. CONCLUSIONS: Our study demonstrated that achievement of PK-PD exposures associated with an increased likelihood of effectiveness was more likely to occur with guideline-based dosing; especially at 48 h.

Population Pharmacokinetics and Dosing Simulations of Ampicillin and Sulbactam in Hospitalised Adult Patients.

BACKGROUND: The pharmacokinetic variability of ampicillin-sulbactam in adults has not been extensively described, particularly in patients with a reduced renal function (i.e., < 60 mL/min). OBJECTIVE: This study investigated the population pharmacokinetics of ampicillin and sulbactam in patients with a wide range of renal functions and sought to define dosing approaches that have a high likelihood for optimising drug exposure. METHODS: Serial blood samples were collected from 16 adult patients receiving intravenous ampicillin-sulbactam in general wards. Total ampicillin and sulbactam concentrations were measured by chromatographic assay and pharmacokinetic parameters were estimated using Pmetrics®. Monte Carlo simulations were used to evaluate the probability of target attainment (PTA) of free ampicillin and sulbactam concentrations exceeding the minimum inhibitory concentration (MIC) for 60% and 100% of the dosing interval. Fractional target attainment (FTA) was calculated against MIC distributions of common hospital pathogens. A threshold of ≥ 90% and ≥ 95% was used to define both optimal PTA and FTA, respectively. RESULTS: The median (range) age, weight, and serum creatinine of the study population was 68 (40-82) years, 62 (40-82) kg, and 1.4 (0.6-6.4) mg/dL, respectively. The pharmacokinetics of ampicillin and sulbactam were best described by a two-compartment model with serum creatinine most closely associated with clearance for both drugs. The estimated ampicillin and sulbactam clearances were 5.58 L/h and 4.79 L/h, respectively, while the volumes of distribution were 12.6 L and 15.36 L, respectively. Approved dosing regimens of ampicillin-sulbactam were sufficient against MICs ≤ 8 and ≤ 4 mg/L, respectively. A 4-h infusion enabled optimal PTA at higher MICs. For both dosing targets, optimal FTAs were obtained against Streptococcus pneumoniae. CONCLUSION: Optimal FTAs were obtained against the susceptible MIC distributions of Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. Applying a 4-h infusion will enhance PTA and FTA, particularly at higher MICs.

Ampicillin and Ceftobiprole Combination for the Treatment of Enterococcus faecalis Invasive Infections: "The Times They Are A-Changin".

BACKGROUND: Enterococcus faecalis is responsible for a large variety of severe infections. This study is a case series reporting our experience in the treatment of E. faecalis invasive infections with ampicillin in combination with ceftobiprole (ABPR). METHODS: We retrospectively analyzed all the medical records of patients admitted to the University Hospital of Udine from January to December 2020 with a diagnosis of infective endocarditis or primary or non-primary complicated or uncomplicated bacteremia caused by E. faecalis. RESULTS: Twenty-one patients were included in the final analysis. The clinical success rate was very high, accounting for 81% of patients, and microbiological cure was obtained in 86% of patients. One relapse was recorded in one patient who did not adhere to the partial oral treatment prescribed. Therapeutic drug monitoring (TDM) was always performed for ampicillin and ceftobiprole, and serum concentrations of both drugs were compared to the MICs of the different enterococcal isolates. CONCLUSIONS: ABPR is a well-tolerated antimicrobial regimen with anti-E. faecalis activity. TDM can help clinicians optimize medical treatments to achieve the best possible efficacy with fewer side effects. ABPR might be a reasonable option for the treatment of severe invasive infections caused by E. faecalis due to the high level of enterococcal penicillin-binding protein (PBP) saturation.

Corrigendum to "Statistical analysis plan for the BLING III study: a phase 3 multicentre randomised controlled trial of continuous versus intermittent ß-lactam antibiotic infusion in critically ill patients with sepsis" [Crit Care Resusc 23(3) (2021) 273-284].

[This corrects the article DOI: 10.51893/2021.3.oa4.].

Hospital-Based Antimicrobial Stewardship Programs Used in Low- and Middle-Income Countries: A Scoping Review.

The burden of antimicrobial resistance (AMR) is considerable in many low- and middle-income countries (LMICs), and it is important to describe the antimicrobial stewardship program (ASP) activities found in these countries and report their impact. Importantly, as these programs target prescribing behavior, the factors influencing prescription of antimicrobials must also be taken into account. This scoping review aimed to (1) describe hospital-based ASP activities, (2) report methods used to measure the impact of ASPs, and (3) explore factors influencing antimicrobial prescribing behavior in LMICs. PubMed was searched from database inception until April 2021. Factors influencing antimicrobial prescribing behavior were canvassed using the Capability-Opportunity-Motivation and Behavior framework. Most of ASP studies in LMICs were predominantly conducted in tertiary care and university-based hospitals. Audit of antimicrobial prescriptions with feedback and restrictive-based strategies was the main reported activity. Total antimicrobial consumption was the main method used to measure the impact of ASPs. Positive outcomes were observed for both clinical and microbiological outcomes; however, these were measured from nonrandomized controlled trials. Dominant factors identified through the behavioral framework were a limited awareness of AMR as a local problem, a perception that overprescription of antimicrobials had limited consequences and was mainly driven by a motivation to help improve patient outcomes. In addition, antimicrobial prescribing practices were largely influenced by existing hierarchy among prescribers. Our scoping review suggests that LMICs need to evaluate antimicrobial appropriateness as an added measure to assess impact. Furthermore, improvements in the access of microbiology and diagnostic facilities and ensuring ASP champions are recruited from senior prescribers will positively influence antimicrobial prescribing behavior, helping improve stewardship of antimicrobials in these countries.

Population pharmacokinetics and dose optimization of intravenous levofloxacin in hospitalized adult patients.

Although levofloxacin has been used for the last 25 years, there are limited pharmacokinetic data to guide levofloxacin dosing in adult patients. This study aimed to develop a population pharmacokinetic model of levofloxacin for adult hospitalized patients and define dosing regimens that attain pharmacokinetic/pharmacodynamic target associated with maximum effectiveness. Blood samples were drawn from 26 patients during one dosing interval. Population pharmacokinetic modelling and dosign simulations were performed using Pmetrics®. Pathogen minimum inhibition concentration (MIC) distribution data from the European Committee on Antimicrobial Susceptibility Testing database was used to analyse fractional target attainment (FTA). A two-compartment model adequately described the data. The final model included estimated glomerular filtration rate (eGFR) to describe clearance. The population estimate for clearance was 1.12 L/h, while the volume of distribution in the central compartment and peripheral compartments were 27.6 L and 28.2 L, respectively. Our simulation demonstrated that an area under free concentration-time curve to MIC ≥ 80 was hardly achieved for pathogens with MIC ≥ 1 mg/L. Low FTA against Pseudomonas aeruginosa and Streptococcus pneumoniae were observed for patients with higher eGFR (≥ 80 mL/min/1.73m2). A daily levofloxacin dose of 1000 mg is suggested to maximise the likelihood of efficacy for adult patients.