A multifaceted strategy to optimize pharmacokinetics of antimicrobial therapy in patients with hospital-acquired infections-a monocentre quality improvement project.

OBJECTIVE: We assessed the efficacy of a quality improvement programme to optimize the delivery of antimicrobial therapy in critically ill patients with hospital-acquired infections (HAI). PATIENTS AND METHODS: Before-after trial in a university hospital in France. Consecutive adults receiving systemic antimicrobial therapy for HAI were included. Patients received standard care during the pre-intervention period (June 2017 to November 2017). The quality improvement programme was implemented in December 2017. During the intervention period (January 2018 to June 2019), clinicians were trained to dose adjustment based on therapeutic drug monitoring and continuous infusion of ß-lactam antibiotics. The primary endpoint was the mortality rate at day 90. RESULTS: A total of 198 patients were included (58 pre-intervention, 140 intervention). The compliance with the therapeutic drug monitoring-dose adaptation increased from 20.3% to 59.3% after the intervention (P < 0.0001). The 90-day mortality rate was 27.6% in the pre-intervention period and 17.3% in the intervention group (adjusted relative risk 0.53, 95%CI 0.27-1.07, P = 0.08). Treatment failures were observed in 22 (37.9%) patients before and 36 (25.7%) patients after the intervention (P = 0.07). CONCLUSIONS: Recommendations for therapeutic drug monitoring-dose adaptation and continuous infusion of ß-lactam antibiotics were not associated with a reduction in the 90-day mortality rate in patients with HAI.

Experience with Implementing a Beta-lactam Therapeutic Drug Monitoring Service in a Burn Intensive Care Unit: A Retrospective Chart Review.

Thermal injuries alter pharmacokinetics, complicating the prediction of standard antibiotic dose effectiveness. Therapeutic drug monitoring (TDM) has been proposed to prevent subtherapeutic dosing of antibiotic therapy, but remains scarcely studied in the burn patient population. A retrospective chart review of burn patients receiving beta-lactam TDM from 2016 to 2019 was conducted. Adult patients with thermal injury receiving cefepime, piperacillin/tazobactam, or meropenem for ≥48 hours were included. Between February 2016 and July 2017, we utilized selective TDM based on clinical judgement to guide treatment. From October 2018 until July 2019, TDM was expanded to all burn patients on beta-lactams. The primary endpoint was achievement of therapeutic concentration, and the secondary endpoints were clinical cure, culture clearance, new resistance, length of stay, and mortality. The selective (control) group included 19 patients and the universal (study) group reviewed 23 patients. In both groups, skin and lungs were the most common primary infection sources, with Pseudomonas aeruginosa as the most common species. In the universal cohort, patients were older with higher risk factors, but more frequently achieved the target drug concentration, required less days to start TDM (p < .0001), and had more frequent measurements and beta-lactam dose adjustments. Positive clinical outcome was reported in 77%, and microbial eradication in 82% of all patients. All clinical outcomes were similar between the groups. The implementation of beta-lactam TDM protocol shortened the time, increased the probability of appropriate target attainment, and individualized beta-lactam therapy in burn patients.

Beta-lactam exposure and safety in intermittent or continuous infusion in critically ill children: an observational monocenter study.

The aim of this study was to assess the pharmacokinetic (PK) exposure and clinical toxicity for three beta-lactams: cefotaxime, piperacillin/tazobactam, and meropenem, depending on two lengths of infusion: continuous and intermittent, in critically ill children. This single center observational prospective study was conducted in a pediatric intensive care unit. All hospitalized children who had one measured plasma concentration of the investigated antibiotics were included. Plasma antibiotic concentrations were interpreted by a pharmacologist, using a Bayesian approach based on previously published population pharmacokinetic models in critically ill children. Exposure was considered optimal, low, or high according to the PK target 100% fT> 4 × MIC and a trough concentration below the toxic concentration (50 mg.L-1 for cefotaxime, 150 mg.L-1 for piperacillin, and 44 mg.L-1 for meropenem). Between May 2019 and January 2020, 80 patients were included and received 106 antibiotic courses: 74 (70%) were administered in intermittent infusion (II) and 32 (30%) in continuous infusion (CI). Compared to II, CI provided more optimal PK exposure (n = 22/32, 69% for CI versus n = 35/74, 47% for II, OR 1.2, 95%CI 1.01-1.5, p = 0.04), less underexposure (n = 4/32, 13% for CI versus n = 36/74, 49% for II, OR 0.7, 95%CI 0.6-0.84, p < 0.001), and more overexposure (n = 6/32, 19% for CI versus n = 3/74, 4% for II, OR 1.2, 95%CI 1.03-1.3, p = 0.01). Five adverse events have been reported during the study period, although none has been attributed to beta-lactam treatment. CONCLUSION: CI provided a higher probability to attain an optimal PK target compared to II, but also a higher risk for overexposure. Regular therapeutic drug monitoring is recommended in critically ill children receiving beta-lactams, regardless of the length of infusion. WHAT IS KNOWN: • Since beta-lactams are time-dependent antibiotics, the probability to attain the pharmacokinetic target is higher with continuous infusion compared to that with intermittent infusion. • In daily practice, continuous or extended infusions are rarely used despite recent guidelines, and toxicity is hardly reported. WHAT IS NEW: • Continuous infusion provided a higher probability to attain an optimal pharmacokinetic target compared to intermittent infusion, but also a higher risk of overexposure. • Regular therapeutic drug monitoring is recommended in critically ill children receiving beta-lactams, regardless of the length of infusion.

Assessment of current practice for ß-lactam therapeutic drug monitoring in French ICUs in 2021: a nationwide cross-sectional survey.

BACKGROUND: Current guidelines and literature support the use of therapeutic drug monitoring (TDM) to optimize ß-lactam treatment in adult ICU patients. OBJECTIVES: To describe the current practice of ß-lactam monitoring in French ICUs. METHODS: A nationwide cross-sectional survey was conducted from February 2021 to July 2021 utilizing an online questionnaire that was sent as an email link to ICU specialists (one questionnaire per ICU). RESULTS: Overall, 119 of 221 (53.8%) French ICUs participated. Eighty-seven (75%) respondents reported having access to ß-lactam TDM, including 52 (59.8%) with on-site access. ß-Lactam concentrations were available in 24-48 h and after 48 h for 36 (41.4%) and 26 (29.9%) respondents, respectively. Most respondents (n = 61; 70.1%) reported not knowing whether the ß-lactam concentrations in the TDM results were expressed as unbound fractions or total concentrations. The 100% unbound fraction of the ß-lactam above the MIC was the most frequent pharmacokinetic and pharmacodynamic target used (n = 62; 73.0%). CONCLUSIONS: Despite the publication of international guidelines, ß-lactam TDM is not optimally used in French ICUs. The two major barriers are ß-lactam TDM interpretation and the required time for results.

Implementation of a ß-lactam therapeutic drug monitoring program: Experience from a large academic medical center.

PURPOSE: To describe the implementation and operationalization of a ß-lactam (BL) therapeutic drug monitoring (TDM) program at a large academic center. SUMMARY: BLs are the most used class of antibiotics. Suboptimal antibiotic exposure is a significant concern in hospitalized patients, particularly in those with altered pharmacokinetics. BL-TDM provides clinicians the opportunity to optimize drug concentrations to ensure maximal therapeutic efficacy while minimizing toxicity. However, BL-TDM has not been widely adopted due to the lack of access to assays. The University of Florida Shands Hospital developed a BL-TDM program in 2015. This is a consultative service primarily run by pharmacists and is conducted in all patient care areas. An analysis was performed on the first BL-TDM encounter for 1,438 patients. BL-TDM was most frequently performed for cefepime (61%, n = 882), piperacillin (15%, n = 218), and meropenem (11%, n = 151). BL-TDM was performed a median of 3 days (interquartile range, 1-5 days) from BL initiation. Among patients with available minimum inhibitory concentration (MIC) values and trough concentrations, the pharmacokinetic/pharmacodynamic (PK/PD) target of 100% fT>MIC was attained in 308 patients (88%). BL-TDM resulted in a dosage adjustment in 25% (n = 361) of patients. CONCLUSION: Implementation of a BL-TDM program requires the concerted efforts of physicians, pharmacists, nursing staff, phlebotomists, and personnel in the analytical laboratory. Standard antibiotic dosing failed to achieve optimal PK/PD targets in all patients; utilizing BL-TDM, dose adjustments were made in 1 of every 4 patients.

Suboptimal Beta-Lactam Therapy in Critically Ill Children: Risk Factors and Outcome.

OBJECTIVES: In critically ill children, severely altered pharmacokinetics may result in subtherapeutic ß-lactam antibiotic concentrations when standard pediatric dosing regimens are applied. However, it remains unclear how to recognize patients most at risk for suboptimal exposure and their outcome. This study aimed to: 1) describe target attainment for ß-lactam antibiotics in critically ill children, 2) identify risk factors for suboptimal exposure, and 3) study the association between target nonattainment and clinical outcome. DESIGN: Post hoc analysis of the "Antibiotic Dosing in Pediatric Intensive Care" study (NCT02456974, 2012-2019). Steady-state trough plasma concentrations were classified as therapeutic if greater than or equal to the minimum inhibitory concentration of the (suspected) pathogen. Factors associated with subtherapeutic concentrations and clinical outcome were identified by logistic regression analysis. SETTING: The pediatric and cardiac surgery ICU of a Belgian tertiary-care hospital. PATIENTS: One hundred fifty-seven patients (aged 1 mo to 15 yr) treated intravenously with amoxicillin-clavulanic acid, piperacillin-tazobactam, or meropenem. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three hundred eighty-two trough concentrations were obtained from 157 patients (median age, 1.25 yr; interquartile range, 0.4-4.2 yr). Subtherapeutic concentrations were measured in 39 of 60 (65%), 43 of 48 (90%), and 35 of 49 (71%) of patients treated with amoxicillin-clavulanic acid, piperacillin-tazobactam, and meropenem, respectively. Estimates of glomerular filtration rate (eGFR; 54% increase in odds for each sd increase in value, 95% CI, 0.287-0.736; p = 0.001) and the absence of vasopressor treatment (2.8-fold greater odds, 95% CI, 1.079-7.253; p = 0.034) were independently associated with target nonattainment. We failed to identify an association between antibiotic concentrations and clinical failure. CONCLUSIONS: Subtherapeutic ß-lactam concentrations are common in critically ill children and correlate with renal function. eGFR equations may be helpful in identifying patients who may require higher dosing. Future studies should focus on the impact of subtherapeutic concentrations on clinical outcome.

Antibiotic Optimization in the Intensive Care Unit.

Effective antimicrobial therapy remains paramount to successful treatment of patients with critical illness, such as pneumonia and sepsis. Unfortunately, critically ill patients often exhibit altered pharmacokinetics and pharmacodynamics (PK/PD) that make this endeavor challenging. Particularly in sepsis, alterations in volume of distribution (Vd) and protein binding lead to unpredictable effects on serum levels of various antimicrobials. Additionally, metabolic pathways and excretion may be significantly impacted due to end-organ failure. These dynamic factors may increase the likelihood of deleterious effects such as treatment failure or toxicity. Meeting these challenging scenarios has led to various strategies meant to improve clinical cure without untoward consequences. Vancomycin and ß-lactam antimicrobials are frequently utilized and have been the focus of dose optimization strategies including extended infusion (EI) or continuous infusion (CI). Available data suggests that administration of vancomycin by CI may reduce the risk of nephrotoxicity without increasing the risk of treatment failure, although retrospective data are largely utilized in supporting this method. Other efforts to optimize vancomycin have focused on transitioning from trough-based therapeutic drug monitoring (TDM) to area-under-the-curve: minimum inhibitory concentration (AUC:MIC) ratios. Despite the creation of more user-friendly methods of calculation and data suggesting reduced rates of nephrotoxicity, widespread implementation is limited, in part due to clinician comfort. Use of ß-lactams in patients with sepsis is similarly problematic due to observational data demonstrating fluctuations in serum levels in the setting of critical illness. Implementing TDM of agents such as piperacillin-tazobactam, cefepime, and meropenem has been suggested as a method of improving time above MIC (T >MIC). This practice is limited by the lack of access to commercial assays and the failure of rigorous studies to demonstrate improved treatment success. Clinicians should be aware of these challenges and should refine their dosing strategies based on individualized patient factors to reduce treatment failure.

Therapeutic Drug Monitoring of Antibiotic Drugs in Patients Receiving Continuous Renal Replacement Therapy or Intermittent Hemodialysis: A Critical Review.

PURPOSE: Antibiotics are frequently used in patients receiving intermittent or continuous renal replacement therapy (RRT). Continuous renal replacement may alter the pharmacokinetics (PK) and the ability to achieve PK/pharmacodynamic (PD) targets. Therapeutic drug monitoring (TDM) could help evaluate drug exposure and guide antibiotic dosage adjustment. The present review describes recent TDM data on antibiotic exposure and PK/PD target attainment (TA) in patients receiving intermittent or continuous RRT, proposing practical guidelines for performing TDM. METHODS: Studies on antibiotic TDM performed in patients receiving intermittent or continuous RRT published between 2000 and 2020 were searched and assessed. The authors focused on studies that reported data on PK/PD TA. TDM recommendations were based on clinically relevant PK/PD relationships and previously published guidelines. RESULTS: In total, 2383 reports were retrieved. After excluding nonrelevant publications, 139 articles were selected. Overall, 107 studies reported PK/PD TA for 24 agents. Data were available for various intermittent and continuous RRT techniques. The study design, TDM practice, and definition of PK/PD targets were inconsistent across studies. Drug exposure and TA rates were highly variable. TDM seems to be necessary to control drug exposure in patients receiving intermittent and continuous RRT techniques, especially for antibiotics with narrow therapeutic margins and in critically ill patients. Practical recommendations can provide insights on relevant PK/PD targets, sampling, and timing of TDM for various antibiotic classes. CONCLUSIONS: Highly variable antibiotic exposure and TA have been reported in patients receiving intermittent or continuous RRT. TDM for aminoglycosides, beta-lactams, glycopeptides, linezolid, and colistin is recommended in patients receiving RRT and suggested for daptomycin, fluoroquinolones, and tigecycline in critically ill patients on RRT.

Therapeutic Drug Monitoring of Antibiotics in Critically Ill Patients: Current Practice and Future Perspectives With a Focus on Clinical Outcome.

PURPOSE: Early initiation of antibiotics is essential for ameliorating infections in critically ill patients. The correct dosage of antibiotics is imperative to ensure their adequate exposure. Critically ill patients have altered pharmacokinetic parameters and are often infected by less susceptible microorganisms. Differences in drug disposition are not considered with standard doses of antibiotics. This can lead to suboptimal antibiotic exposure in critically ill patients. To overcome this problem of suboptimal dosing, therapeutic drug monitoring (TDM) is a strategy commonly used to support individualized dosing of antibiotics. It is routinely used for vancomycin and aminoglycosides in clinical practice. In recent years, it has become apparent that TDM may also be used in other antibiotics. METHODS: This review summarizes the evidence for TDM of antibiotics in critically ill patients, focuses on clinical outcomes, and summarizes possibilities for optimized TDM in the future. RESULTS AND CONCLUSION: After reviewing the literature, we can conclude that general TDM implementation is advised for glycopeptides and aminoglycosides, as evidence of the relationship between TDM and clinical outcome is present. For antibiotics, such as beta-lactams, fluoroquinolones, and linezolid, it seems rational to perform TDM in specific patient cases. TDM involving other antibiotics is supported by individual cases, specifically to decrease toxicity. When focusing on future possibilities to improve TDM of antibiotics in critically ill patients, implementation of model-informed precision dosing should be investigated because it can potentially streamline the TDM process. The logistics of TDM, such as turnaround time and available equipment, are challenging but may be overcome by rapid bioanalytical techniques or real-time monitoring of drug concentrations through biosensors in the future. Education, clinical information on targets, and clinical outcome studies are other important factors that facilitate TDM implementation.

Antibiotic Stewardship and Therapeutic Drug Monitoring of ß-Lactam Antibiotics: Is There a Link? An Opinion Paper.

PURPOSE: In critically ill patients, changes in the pharmacokinetics (PK) of ß-lactams can lead to significant variations in serum concentrations, with possibly detrimental effects on outcomes. The utilization of individually calculated doses, extended infusion regimen, and therapeutic drug monitoring (TDM)-guided dose adjustments can mitigate the PK changes and help to achieve and attain an individual PK target. METHODS: We reviewed relevant literature from 2004 to 2021 using 4 search engines (PubMed, Web of Science, Scopus, and Google Scholar). Unpublished clinical data were also examined. RESULTS: TDM-guided, individualized dosing strategies facilitated PK target attainment and improved patient outcomes. TDM-guided therapy is a core concept of individualized dosing that increases PK target attainment and identifies possible toxic ß-lactam concentrations. CONCLUSIONS: Individualized dosing and TDM facilitate the rational use of ß-lactams and are integral for antibiotic stewardship interventions in critical care, affording the optimal exposure of both pathogen and drugs, along with enhanced treatment efficacy and reduced emergence of antimicrobial resistance.

Personalized ß-lactam dosing in patients with coronavirus disease 2019 (COVID-19) and pneumonia: A retrospective analysis on pharmacokinetics and pharmacokinetic target attainment.

ABSTRACT: Pathophysiological changes are important risk factors for critically ill patients with pneumonia manifesting sub-therapeutic antibiotic exposures during empirical treatment. The effect of coronavirus disease 2019 (COVID-19) on antibiotic dosing requirements is uncertain. We aimed to determine the effect of COVID-19 on ß-lactam pharmacokinetics (PK) and PK target attainment in critically ill patients with a personalized dosing strategy.Retrospective, single-center analysis of COVID-19 ± critically ill patients with pneumonia (community-acquired pneumonia or hospital-acquired pneumonia) who received continuous infusion of a ß-lactam antibiotic with dosing personalized through dosing software and therapeutic drug monitoring. A therapeutic exposure was defined as serum concentration between (css) 4 to 8 times the EUCAST non-species related breakpoint).Data from 58 patients with pneumonia was analyzed. Nineteen patients were tested COVID-19-positive before the start of the antibiotic therapy for community-acquired pneumonia or hospital-acquired pneumonia. Therapeutic exposure was achieved in 71% of COVID-19 patients (68% considering all patients). All patients demonstrated css above the non-species-related breakpoint. Twenty percent exceeded css above the target range (24% of all patients). The median ß-lactam clearance was 49% compared to ß-lactam clearance in a standard patient without a significant difference regarding antibiotic, time of sampling or present COVID-19 infection. Median daily doses were 50% lower compared to standard bolus dosing.COVID-19 did not significantly affect ß-lactam pharmacokinetics in critically ill patients. Personalized ß-lactam dosing strategies were safe in critically ill patients and lead to high PK target attainment with less resources.

Importance of beta-lactam pharmacokinetics and pharmacodynamics on the recovery of microbial diversity in the airway of persons with cystic fibrosis.

Cystic fibrosis (CF) is a chronic lung disease characterized by acute pulmonary exacerbations (PExs) that are frequently treated with antibiotics. The impact of antibiotics on airway microbial diversity remains a critical knowledge gap. We sought to define the association between beta-lactam pharmacokinetic (PK) and pharmacodynamic target attainment on richness and alpha diversity. Twenty-seven children <18 years of age with CF participated in the prospective study. Airway samples were collected at hospital admission for PEx, end of antibiotic treatment (Tr), and >1 month in follow-up (FU). Metagenomic sequencing was performed to determine richness, alpha diversity, and the presence of antibiotic resistance genes. Free plasma beta-lactam levels were measured, and PK modeling was performed to determine time above the minimum inhibitory concentration (fT>MIC). 52% of study subjects had sufficient fT>MIC for optimal bacterial killing. There were no significant differences in demographics or PEx characteristics, except for F508del homozygosity. No significant differences were noted in richness or alpha diversity at individual time points, and both groups experienced a decrease in richness and alpha diversity at Tr compared with PEx. However, alpha diversity remained decreased at FU compared with PEx in those with sufficient fT>MIC but increased in those with insufficient fT>MIC (Shannon -0.222 vs +0.452, p=0.031, and inverse Simpson -1.376 vs +1.388, p=0.032). Fluoroquinolone resistance was also more frequently detected in those with insufficient fT>MIC (log2 fold change (log2FC) 2.29, p=0.025). These findings suggest sufficient beta-lactam fT>MIC is associated with suppressed recovery of alpha diversity following the antibiotic exposure period.

Pharmacokinetic/pharmacodynamic target attainment in critically ill renal patients on antimicrobial usage: focus on novel beta-lactams and beta lactams/beta-lactamase inhibitors.

INTRODUCTION: Several novel beta-lactams (BLs) and/or beta lactams/beta-lactamase inhibitors (BL/BLIs) have been recently developed for the management of multidrug-resistant bacterial infections. Data concerning dose optimization in critically ill patients with altered renal function are scanty. AREAS COVERED: This article provides a critical reappraisal of pharmacokinetic and clinical issues emerged with novel BLs and/or BL/BLIs in renal critically ill patients. Clinical and pharmacokinetic studies published in English until December 2020 were searched on the PubMed-MEDLINE database. EXPERT OPINION: Several issues emerged with the use of novel BLs and/or BL/BLIs in critically ill renal patients. Suboptimal clinical response rate with ceftazidime-avibactam and ceftolozane-tazobactam was reported in phase II-III trials in patients with moderate kidney injury; data on patients undergoing renal replacement therapy are limited to some case reports; dose adjustment in augmented renal clearance is provided only for cefiderocol. Implementation of altered dosing strategies (prolonged infusion and/or higher dosage) coupled with adaptive real-time therapeutic drug monitoring could represent the most effective approach in warranting optimal pharmacokinetic/pharmacodynamic targets with novel BLs and/or BL/BLIs in challenging scenarios, thus minimizing the risk of clinical failure and/or of resistance selection.

Variation in Target Attainment of Beta-Lactam Antibiotic Dosing Between International Pediatric Formularies.

As antimicrobial susceptibility of common bacterial pathogens decreases, ensuring optimal dosing may preserve the use of older antibiotics in order to limit the spread of resistance to newer agents. Beta-lactams represent the most widely prescribed antibiotic class, yet most were licensed prior to legislation changes mandating their study in children. As a result, significant heterogeneity persists in the pediatric doses used globally, along with quality of evidence used to inform dosing. This review summarizes dosing recommendations from the major pediatric reference sources and tries to answer the questions: Does beta-lactam dose heterogeneity matter? Does it impact pharmacodynamic target attainment? For three important severe clinical infections-pneumonia, sepsis, and meningitis-pharmacokinetic models were identified for common for beta-lactam antibiotics. Real-world demographics were derived from three multicenter point prevalence surveys. Simulation results were compared with minimum inhibitory concentration distributions to inform appropriateness of recommended doses in targeted and empiric treatment. While cephalosporin dosing regimens are largely adequate for target attainment, they also pose the most risk of neurotoxicity. Our review highlights aminopenicillin, piperacillin, and meropenem doses as potentially requiring review/optimization in order to preserve the use of these agents in future.

A narrative review of predictors for ß-lactam antibiotic exposure during empirical treatment in critically ill patients.

INTRODUCTION: : Emerging studies suggest that antibiotic pharmacokinetics (PK) are difficult to predict in critically ill patients. The high intra- and inter-patient PK variability makes it challenging to accurately predict the appropriate dosage required for a given patient. Identifying patients at risk could help clinicians to consider more individualized dosing regimens and perform therapeutic drug monitoring. We provide an overview of relevant predictors associated with target (non-)attainment of ß-lactam antibiotics in critically ill patients. AREAS COVERED: : This narrative review summarizes patient and clinical characteristics that can help to predict the attainment of target serum concentrations and to provide guidance on antimicrobial dose optimization. Literature was searched using Embase and Medline database, focusing on ß-lactam antibiotics in critically ill patients. EXPERT OPINION: : Adequate concentration attainment can be anticipated in critically ill patients prior to initiating empiric ß-lactam antibiotic therapy based on readily available demographic and clinical factors. Male gender, younger age, and augmented renal clearance were the most significant predictors for target non-attainment and should be considered in further investigations to develop dosing algorithms for optimal ß-lactam therapy.

Clinical and pharmacokinetic/dynamic outcomes of prolonged infusions of beta-lactam antimicrobials: An overview of systematic reviews.

OBJECTIVE: This overview of reviews aims to map and compare of objectives, methods, and findings of existing systematic reviews to develop a greater understanding of the information available about prolonged beta-lactam infusions in hospitalized patients with infection. DESIGN: Overview of systematic reviews. DATA SOURCES: Medline, Embase, PROSPERO and the Cochrane Library were systematically searched from January, 1990 to June, 2019 using a peer reviewed search strategy. Grey literature was also searched for relevant reviews. ELIGIBILITY CRITERIA FOR SELECTING REVIEWS: Systematic reviews were sought that compared two or more infusion strategies for intravenous beta-lactam antimicrobials and report clinical cure or mortality. Populations of included reviews were restricted to hospitalized patients with infection, without restrictions on age, infection type, or disease. DATA EXTRACTION AND ANALYSIS: Abstract screening, data extraction, quality and risk of bias assessment were conducted by two independent reviewers. Overlap between reviews was assessed using a modified corrected covered area. Overview findings are reported in accordance with Cochrane's recommendation for overview conduct. Clinical outcomes extracted included survival, clinical cure, treatment failure, microbiological cure, length of stay, adverse events, cost, and emergence of resistance. RESULTS: The search strategy identified 3327 unique citations from which 21 eligible reviews were included. Reviews varied by population, intervention and outcomes studied. Between reviews, overlap of primary studies was generally high, methodologic quality generally low and risk of bias variable. Nine of 14 reviews that quantitatively evaluated mortality and clinical cure identified a benefit with prolonged infusions of beta lactams when compared with intermittent infusions. Evidence of mortality and clinical cure benefit was greater among critically ill patients when compared to less sick patients and lower in randomized controlled trials when compared with observational studies. CONCLUSIONS: Findings from our review demonstrate a consistent and reproducible lack of harm with prolonged infusions of beta-lactam antibiotics with variability in effect size and significance of benefits. Despite 21 systematic reviews addressing prolonged infusions of beta-lactams, this overview supports the continued need for a definitive systematic review given variability in populations, interventions and outcomes in the current systematic reviews. Subsequent systematic reviews should have more rigorous and transparent methods, only include RCTs and evaluate the proposed benefits found in various subgroup-analyses-i.e. high risk of mortality. TRIAL REGISTRATION: Prospero registry, CRD42019117118.

Decoding the Penicillin Resistance of Streptococcus pneumoniae for Invasive and Noninvasive Infections.

This commentary explains the reasons for the extensive variations in pneumococcal penicillin resistance based on a literature review of pneumococcal penicillin-binding proteins, the pharmacodynamics and pharmacokinetics of beta-lactams, the risk factors associated with mortality, laboratory issues and challenges, including identification, susceptibility testing, and clinical reporting, and the management of invasive and noninvasive Streptococcus pneumoniae infections.

Demonstrating Feasibility of an Opportunistic Sampling Approach for Pharmacokinetic Studies of ß-Lactam Antibiotics in Critically Ill Children.

There has been increasing interest in incorporating ß-lactam precision dosing into routine clinical care, but robust population pharmacokinetic models in critically ill children are needed for these purposes. The objective of this study was to demonstrate the feasibility of an opportunistic sampling approach that utilizes scavenged residual blood for future pharmacokinetic studies of cefepime, meropenem, and piperacillin. We aimed to show that opportunistic samples would cover the full concentration-versus-time profiles and to evaluate stability of the antibiotics in whole blood and plasma to optimize future use of the opportunistic sampling approach. A prospective observational study was conducted in a single-center pediatric intensive care unit, where pediatric patients administered at least 1 dose of cefepime, meropenem, or piperacillin/tazobactam and who had residual blood scavenged from samples obtained for routine clinical care were enrolled. A total of 138 samples from 22 pediatric patients were collected in a 2-week period. For all 3 antibiotics, the samples collected covered the entire dosing intervals and were not clustered around specific times. There was high variability in the free concentrations and in the percentage of drug bound to protein. There was less than 15% degradation for meropenem or piperacillin when stored in whole blood or plasma at 4°C after 6 days. Cefepime degraded by more than 15% after 3 days. The opportunistic sampling approach is a powerful and feasible method to obtain sufficient samples to study the variability of drug concentrations and protein binding for future pharmacokinetic studies in the pediatric critical care population.

Development of a penem antibiotic against Mycobacteroides abscessus.

ß-lactams are the most widely used antibiotic class to treat bacterial infections in humans. Mycobacteroides abscessus is an emerging pulmonary pathogen resistant to most antibiotics, including penicillins and cephalosporins. With no current FDA-approved treatment and cure rates <50%, there is a pressing need for effective therapies. Here we report T405, a new ß-lactam of the penem subclass that exhibits potent activity against M. abscessus and a panel of drug-resistant strains isolated from cystic fibrosis patients. Additionally, in combination with the ß-lactamase inhibitor avibactam, the rate of spontaneous resistance of M. abscessus to T405 approached the limit of detection. Lastly, we show the favorable pharmacokinetic profile of T405 in mice and the absence of toxicity at elevated dosage, which support the clinical potential of this compound.

New ß-Lactam-ß-Lactamase Inhibitor Combinations.

The limited armamentarium against drug-resistant Gram-negative bacilli has led to the development of several novel ß-lactam-ß-lactamase inhibitor combinations (BLBLIs). In this review, we summarize their spectrum of in vitro activities, mechanisms of resistance, and pharmacokinetic-pharmacodynamic (PK-PD) characteristics. A summary of available clinical data is provided per drug. Four approved BLBLIs are discussed in detail. All are options for treating multidrug-resistant (MDR) Enterobacterales and Pseudomonas aeruginosa Ceftazidime-avibactam is a potential drug for treating Enterobacterales producing extended-spectrum ß-lactamase (ESBL), Klebsiella pneumoniae carbapenemase (KPC), AmpC, and some class D ß-lactamases (OXA-48) in addition to carbapenem-resistant Pseudomonas aeruginosa Ceftolozane-tazobactam is a treatment option mainly for carbapenem-resistant P. aeruginosa (non-carbapenemase producing), with some activity against ESBL-producing Enterobacterales Meropenem-vaborbactam has emerged as treatment option for Enterobacterales producing ESBL, KPC, or AmpC, with similar activity as meropenem against P. aeruginosa Imipenem-relebactam has documented activity against Enterobacterales producing ESBL, KPC, and AmpC, with the combination having some additional activity against P. aeruginosa relative to imipenem. None of these drugs present in vitro activity against Enterobacterales or P. aeruginosa producing metallo-ß-lactamase (MBL) or against carbapenemase-producing Acinetobacter baumannii Clinical data regarding the use of these drugs to treat MDR bacteria are limited and rely mostly on nonrandomized studies. An overview on eight BLBLIs in development is also provided. These drugs provide various levels of in vitro coverage of carbapenem-resistant Enterobacterales, with several drugs presenting in vitro activity against MBLs (cefepime-zidebactam, aztreonam-avibactam, meropenem-nacubactam, and cefepime-taniborbactam). Among these drugs, some also present in vitro activity against carbapenem-resistant P. aeruginosa (cefepime-zidebactam and cefepime-taniborbactam) and A. baumannii (cefepime-zidebactam and sulbactam-durlobactam).