Beta-lactam dosing during continuous renal replacement therapy: a survey of practices in french intensive care units.

BACKGROUND: Little information is available on current practice in beta-lactam dosing during continuous renal replacement therapy (CRRT). Optimized dosing is essential for improving outcomes, and there is no consensus on the appropriate dose regimens. The objective of the present study was to describe current practice for beta-lactam dosing during CRRT in intensive care units (ICUs). METHODS: We conducted a nationwide survey by e-mailing an online questionnaire to physicians working in ICUs in France. The questionnaire included three sections: demographic characteristics, CRRT practices, and beta-lactam dosing regimens during CRRT. RESULTS: 157 intensivists completed the questionnaire. Continuous venovenous hemofiltration was the most frequently used CRRT technique, and citrate was the most regularly used anticoagulant. The median prescribed dose at baseline was 30 mL/kg/h. The majority of prescribers (57%) did not reduce beta-lactam dosing during CRRT. The tools were used to adapt dosing regimens during CRRT included guidelines, therapeutic drug monitoring (TDM), and data from the literature. When TDM was used, 100% T > 4 time the MIC was the most common mentioned pharmacokinetic/pharmacodynamic target (53%). Pharmacokinetic software tools were rarely used. Prolonged or continuous infusions were widely used during CRRT (88%). Institutional guidelines on beta-lactam dosing during CRRT were rare. 41% of physicians sometimes consulted another specialist before adapting the dose of antibiotic during CRRT. CONCLUSIONS: Our present results highlight the wide range of beta-lactam dosing practices adopted during CRRT. Personalized TDM and the implementation of Bayesian software appear to be essential for optimizing beta-lactam dosing regimens and improving patient outcomes.

Evaluation of Antibiotic Allergies in Surgical Patients.

Antibiotic administration in the perioperative period is the foundation of preventing surgical site infections. ß-Lactam antibiotics, notably the first-generation cephalosporin cefazolin, are the drugs of choice for this indication. However, reported antibiotic allergies often result in the use of suboptimal alternative agents that can lead to an increased risk of infection and adverse effects. A comprehensive allergy history and risk stratification should be completed preoperatively to determine whether or not a patient can be rechallenged with a ß-lactam antibiotic and what testing may be necessary prior to administration. Nursing staff can play a critical role in understanding the implications and management of reported antibiotic allergies in surgical patients in order to optimize patient care.

Single versus combination intravenous anti-pseudomonal antibiotic therapy for people with cystic fibrosis.

BACKGROUND: The choice of antibiotic, and the use of single or combined therapy are controversial areas in the treatment of respiratory infection due to Pseudomonas aeruginosa in cystic fibrosis (CF). Advantages of combination therapy include wider range of modes of action, possible synergy and reduction of resistant organisms; advantages of monotherapy include lower cost, ease of administration and reduction of drug-related toxicity. Current evidence does not provide a clear answer and the use of intravenous antibiotic therapy in CF requires further evaluation. This is an update of a previously published review. OBJECTIVES: To assess the effectiveness of single compared to combination intravenous anti-pseudomonal antibiotic therapy for treating people with CF. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search of the Group's Trials Register: 07 October 2020. We also searched online trials registries on 16 November 2020. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing a single intravenous anti-pseudomonal antibiotic with a combination of that antibiotic plus a second anti-pseudomonal antibiotic in people with CF. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We assessed the certainty of the data using GRADE. MAIN RESULTS: We identified 59 trials, of which we included eight trials (356 participants) comparing a single anti-pseudomonal agent to a combination of the same antibiotic and one other. There was a wide variation in the individual antibiotics used in each trial. In total, the trials included seven comparisons of a beta-lactam antibiotic (penicillin-related or third generation cephalosporin) with a beta-lactam-aminoglycoside combination and three comparisons of an aminoglycoside with a beta-lactam-aminoglycoside combination.  There was considerable heterogeneity amongst these trials, leading to difficulties in performing the review and interpreting the results. These results should be interpreted cautiously. Six of the included trials were published between 1977 and 1988; these were single-centre trials with flaws in the randomisation process and small sample size. Overall, the methodological quality was poor and the certainty of the evidence ranged from low to moderate. The review did not find any differences between monotherapy and combination therapy in either the short term or in the long term for the outcomes of different lung function measures, bacteriological outcome measures, need for additional treatment, adverse effects, quality of life or symptom scores. AUTHORS' CONCLUSIONS: The results of this review are inconclusive. The review raises important methodological issues. There is a need for an RCT which needs to be well-designed in terms of adequate randomisation allocation, blinding, power and long-term follow-up. Results need to be standardised to a consistent method of reporting, in order to validate the pooling of results from multiple trials.

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.

Discontinuing ß-lactam treatment after 3 days for patients with community-acquired pneumonia in non-critical care wards (PTC): a double-blind, randomised, placebo-controlled, non-inferiority trial.

BACKGROUND: Shortening the duration of antibiotic therapy for patients admitted to hospital with community-acquired pneumonia should help reduce antibiotic consumption and thus bacterial resistance, adverse events, and related costs. We aimed to assess the need for an additional 5-day course of ß-lactam therapy among patients with community-acquired pneumonia who were stable after 3 days of treatment. METHODS: We did this double-blind, randomised, placebo-controlled, non-inferiority trial (the Pneumonia Short Treatment [PTC]) in 16 centres in France. Adult patients (aged ≥18 years) admitted to hospital with moderately severe community-acquired pneumonia (defined as patients admitted to a non-critical care unit) and who met prespecified clinical stability criteria after 3 days of treatment with ß-lactam therapy were randomly assigned (1:1) to receive ß-lactam therapy (oral amoxicillin 1 g plus clavulanate 125 mg three times a day) or matched placebo for 5 extra days. Randomisation was done using a web-based system with permuted blocks with random sizes and stratified by randomisation site and Pneumonia Severity Index score. Participants, clinicians, and study staff were masked to treatment allocation. The primary outcome was cure 15 days after first antibiotic intake, defined by apyrexia (temperature ≤37·8°C), resolution or improvement of respiratory symptoms, and no additional antibiotic treatment for any cause. A non-inferiority margin of 10 percentage points was chosen. The primary outcome was assessed in all patients who were randomly assigned and received any treatment (intention-to-treat [ITT] population) and in all patients who received their assigned treatment (per-protocol population). Safety was assessed in the ITT population. This study is registered with ClinicalTrials.gov, NCT01963442, and is now complete. FINDINGS: Between Dec 19, 2013, and Feb 1, 2018, 706 patients were assessed for eligibility, and after 3 days of ß-lactam treatment, 310 eligible patients were randomly assigned to receive either placebo (n=157) or ß-lactam treatment (n=153). Seven patients withdrew consent before taking any study drug, five in the placebo group and two in the ß-lactam group. In the ITT population, median age was 73·0 years (IQR 57·0-84·0) and 123 (41%) of 303 participants were female. In the ITT analysis, cure at day 15 occurred in 117 (77%) of 152 participants in the placebo group and 102 (68%) of 151 participants in the ß-lactam group (between-group difference of 9·42%, 95% CI -0·38 to 20·04), indicating non-inferiority. In the per-protocol analysis, 113 (78%) of 145 participants in the placebo treatment group and 100 (68%) of 146 participants in the ß-lactam treatment group were cured at day 15 (difference of 9·44% [95% CI -0·15 to 20·34]), indicating non-inferiority. Incidence of adverse events was similar between the treatment groups (22 [14%] of 152 in the placebo group and 29 [19%] of 151 in the ß-lactam group). The most common adverse events were digestive disorders, reported in 17 (11%) of 152 patients in the placebo group and 28 (19%) of 151 patients in the ß-lactam group. By day 30, three (2%) patients had died in the placebo group (one due to bacteraemia due to Staphylococcus aureus, one due to cardiogenic shock after acute pulmonary oedema, and one due to heart failure associated with acute renal failure) and two (1%) in the ß-lactam group (due to pneumonia recurrence and possible acute pulmonary oedema). INTERPRETATION: Among patients admitted to hospital with community-acquired pneumonia who met clinical stability criteria, discontinuing ß-lactam treatment after 3 days was non-inferior to 8 days of treatment. These findings could allow substantial reduction of antibiotic consumption. FUNDING: French Ministry of Health.

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.

Implementation of EMR-based standardized antibiotic desensitization protocols and its impact on providers.

Background: As desensitization protocols become more readily available and published, more institutions are implementing them and searching for ways to streamline the process. There have been no published studies to date on the effect that electronic medical record systems (EMR) have on the safety and efficiency of ß-lactam antibiotic desensitization. Objective: The purpose of this study was to evaluate the changes in workflow, efficiency, and medical errors after implementation of ß-lactam antibiotic desensitization. Methods: A collaborative effort between the Allergy/Immunology Division and the Pharmacy Department led to the creation and implementation of antibiotic desensitization order sets. Pre- and postimplementation of ß-lactam antibiotic surveys were sent to pharmacists and allergy/immunology fellows and attendings at a single-center tertiary care center. Results: There were only 26 valid respondents (12.3%) to both the pre- and postimplementation surveys. The percentage of respondents who thought that the time needed to prepare desensitization materials was < 4 hours increased from 23% to 77% (p < 0.001). The percentage of respondents who thought that the time needed to input electronic desensitization orders was < 1 hour increased from 19% to 54% (p = 0.002). The percentage of respondents who identified zero errors increased from 42% to 92% (p = 0.001). The perception of the overall desensitization process efficiency significantly increased (p < 0.001). Conclusion: Creation of standardized electronic ß-lactam antibiotic desensitization order sets significantly decreased the time taken to order and prepare materials and increased overall efficiency.

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.

From Therapeutic Drug Monitoring to Model-Informed Precision Dosing for Antibiotics.

Therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD) have evolved as important tools to inform rational dosing of antibiotics in individual patients with infections. In particular, critically ill patients display altered, highly variable pharmacokinetics and often suffer from infections caused by less susceptible bacteria. Consequently, TDM has been used to individualize dosing in this patient group for many years. More recently, there has been increasing research on the use of MIPD software to streamline the TDM process, which can increase the flexibility and precision of dose individualization but also requires adequate model validation and re-evaluation of existing workflows. In parallel, new minimally invasive and noninvasive technologies such as microneedle-based sensors are being developed, which-together with MIPD software-have the potential to revolutionize how patients are dosed with antibiotics. Nonetheless, carefully designed clinical trials to evaluate the benefit of TDM and MIPD approaches are still sparse, but are critically needed to justify the implementation of TDM and MIPD in clinical practice. The present review summarizes the clinical pharmacology of antibiotics, conventional TDM and MIPD approaches, and evidence of the value of TDM/MIPD for aminoglycosides, beta-lactams, glycopeptides, and linezolid, for which precision dosing approaches have been recommended.

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.

Daptomycin-based aminoglycoside-sparing therapy for streptococcal endocarditis: a retrospective multicenter study.

Streptococci still represent common etiologic agents of infective endocarditis (IE). Although renal failure is frequently reported as an aminoglycoside-associated adverse event, last international guidelines recommend a beta-lactam/gentamicin combination therapy. We retrospectively evaluated the use of daptomycin-based aminoglycoside-sparing combination therapy for the treatment of streptococcal IE in seven referral hospitals in Italy. Retrospective, multicenter, observational study. All patients with streptococcal IE admitted from 2016 to 2018 were enrolled. Mortality and incidence of acute kidney injury (AKI) were compared between Group A (standard of care, SoC) and Group B (daptomycin-based aminoglycoside-sparing combination therapy). Fifty-four patients were enrolled, 33 in Group A and 21 in Group B. Mortality was 2/33 (6%) in Group A and 0 in Group B (p = 0.681); AKI incidence was 8/33 (24%) in Group A and 0 in Group B (p = 0.04). Daptomycin-based aminoglycoside-sparing combination therapy appears to be promising for the treatment of streptococcal endocarditis because of similar efficacy compared with SoC and significantly reduced incidence of AKI.

Intravenous push versus intravenous piggyback beta-lactams for the empiric management of gram-negative bacteremia.

WHAT IS KNOWN AND OBJECTIVE: Nationwide shortages of small-volume parenteral solutions (SVPS) compelled hospitals to develop strategies including the use of intravenous push (IVP) administration of antibiotics to reserve SVPS for absolute necessities. It is unknown if administration of beta-lactam antibiotics (BL) via IVP results in worse clinical outcomes compared to intravenous piggyback (IVPB) due to the potential inability to achieve pharmacodynamic targets. METHODS: Our health-system implemented a mandatory IVP action plan for BL from October 2017 to September 2018. This was a retrospective study of adult patients with GNB who received empiric therapy with IVPB (30 minutes) or IVP (5 minutes) cefepime (FEP) or meropenem (MEM) for at least 2 days. Endpoints included clinical response, microbiological clearance and mortality. All data are presented as n (%) or median (interquartile range). RESULTS: The final cohort included 213 patients (IVPB n = 105, IVP n = 108). The primary source of bacteremia was urinary, with Escherichia coli being the primary pathogen. Escalation of therapy was similar between groups (15 [14%] vs 11 [10%], P = .36) at a median of 3 days (P = .68). No significant differences were observed in any secondary endpoints including microbiological clearance, bacteremia recurrence, time to defervescence, WBC normalization, vasopressor duration or in-hospital mortality. WHAT IS NEW AND CONCLUSION: Our findings suggest no differences in clinical response with the use of IVP compared to IVPB FEP and MEM for treatment of GNB. This form of administration may be considered as a fluid conservation strategy in times of shortage.

Association Between the Prothrombin Time-International Normalized Ratio and Concomitant Use of Antibiotics in Warfarin Users: Focus on Type of Antibiotic and Susceptibility of Bacteroides fragilis to Antibiotics.

BACKGROUND: The difference in type of antibiotics and susceptibility of Bacteroides fragilis to antibiotics may influence warfarin anticoagulation. However, these influences have not been clarified in clinical settings. OBJECTIVES: This study aimed to investigate association the between the prothrombin time-international normalized ratio (PT-INR) and concomitant use of antibiotics in a real-world population of warfarin users. METHODS: This was a single-center cohort study using data from health records and included patients who received ß-lactams (BLs)/fluoroquinolones (FQs) during ongoing warfarin treatment (2011-2015) at Hamamatsu University Hospital in Japan. Antibiotics were categorized into those to which B fragilis is susceptible (BLsus, FQsus) and those to which it is not (BLnon, FQnon) and into those given orally (BLpo, FQpo) or intravenously (BLiv, FQiv). Outcomes were excessive PT-INR and changes in PT-INR, defined as the ratio (INR ratio) and difference (ΔINR) of maximum PT-INR and baseline PT-INR. Excessive PT-INR was graded as INR ratio of >1.5 or >2.5. RESULTS: A total of 1185 warfarin users were included. The proportion of INR ratio >2.5 in FQiv was higher than in BLiv (95% CI: 1.59-46.5). The proportions with an INR ratio of >1.5 in BLsus and FQsus were higher than in BLnon (1.72-14.1) and FQnon (1.05-9.36), respectively. ΔINR values in FQpo, FQiv, and FQsus were higher than those in BLpo, BLiv, and FQnon, respectively. CONCLUSIONS AND RELEVANCE: Concomitant use of FQs, or of antibiotics to which B fragilis is susceptible is associated with higher risk of excessive anticoagulation. These findings would contribute to safe and proper antibiotic treatment in warfarin users.

Short-course aminoglycosides as adjunctive empirical therapy in patients with Gram-negative bloodstream infection, a cohort study.

OBJECTIVE: Short-course aminoglycosides as adjunctive empirical therapy to ß-lactams in patients with a clinical suspicion of sepsis are used to broaden antibiotic susceptibility coverage and to enhance bacterial killing. We quantified the impact of this approach on 30-day mortality in a subset of sepsis patients with a Gram-negative bloodstream infection. METHODS: From a prospective cohort study conducted in seven hospitals in the Netherlands between June 2013 and November 2015, we selected all patients with Gram-negative bloodstream infection (GN-BSI). Short-course aminoglycoside therapy was defined as tobramycin, gentamicin or amikacin initiated within a 48-hour time window around blood-culture obtainment, and prescribed for a maximum of 2 days. The outcome of interest was 30-day all-cause mortality. Confounders were selected a priori for adjustment using a propensity score analysis with inverse probability weighting. RESULTS: A total of 626 individuals with GN-BSI who received ß-lactams were included; 156 (24.9%) also received aminoglycosides for a median of 1 day. Patients receiving aminoglycosides more often had septic shock (31/156, 19.9% versus 34/470, 7.2%) and had an eight-fold lower risk of inappropriate treatment (3/156, 1.9% versus 69/470, 14.7%). Thirty-day mortality was 17.3% (27/156) and 13.6% (64/470) for patients receiving and not receiving aminoglycosides, respectively; yielding crude and adjusted odds ratios for 30-day mortality for patients treated with aminoglycosides of 1.33 (95% CI 0.80-2.15) and 1.57 (0.84-2.93), respectively. CONCLUSIONS: Short-course adjunctive aminoglycoside treatment as part of empirical therapy with ß-lactam antibiotics in patients with GN-BSI did not result in improved outcomes, despite better antibiotic coverage of pathogens.

Loading dose and efficacy of continuous or extended infusion of beta-lactams compared with intermittent administration in patients with critical illnesses: A subgroup meta-analysis and meta-regression analysis.

WHAT IS KNOWN AND OBJECTIVE: The role of continuous/extended beta-lactam infusions (CEIs) in improving clinical outcomes among critically ill patients remains controversial. Therefore, we aimed to compare the clinical efficacy of CEI versus intermittent administration (IA) of beta-lactams by performing a systematic review and meta-analysis. METHODS: PubMed, the Cochrane Library and Embase were searched from inception until December 2018 for studies comparing clinical outcomes of CEI versus IA in critically ill patients. The meta-analysis included 18 randomized controlled trials (RCTs) and 13 non-RCTs. RESULTS AND DISCUSSION: For CEI versus IA, the summary relative risk (RR) for overall mortality and clinical cure was 0.82 (95% confidence interval [CI]: 0.72-0.94) and 1.31 (95% CI: 1.15-1.49), respectively. Subgroup and meta-regression analyses of the loading dose revealed a significantly increased clinical cure rate in the loading-dose group (RR: 1.44, 95% CI: 1.22-1.69), which remained significant after adjustments for beta-lactam type, and association between clinical cure and loading dose for clinical cure (RR: 1.47, 95% CI: 1.20-1.80; p = .001). Subgroup analysis of administration type indicated that both groups had low mortality and high clinical cure rates; however, the heterogeneity analysis did not support an association across continuous infusion and extended infusion groups. Subgroup analysis of the Acute Physiology and Chronic Health Evaluation (APACHE) score was conducted; according to APACHE scores ≥ 16, overall mortality and clinical cure significantly differed between CEI and IA. WHAT IS NEW AND CONCLUSION: CEIs with loading-dose treatment may significantly improve the clinical outcomes in critically ill sepsis or septic shock patients.

Population pharmacokinetic models of first choice beta-lactam antibiotics for severe infections treatment: What antibiotic regimen to prescribe in children?

BACKGROUND: To perform a review describing the pharmacokinetic (PK) parameters and covariates of interest of the eight first choice ß-lactams (BL) antibiotics for treatment of severe infections in pediatric population. Pediatric sepsis and septic shock reportedly affect 30% of children admitted to pediatric intensive care units, with a 25% mortality rate. Eight BL are included as first choice antibiotic for severe infections in pediatric population in the World Health Organization model list of essential medicines for children. METHODS: The PubMed/Medline databases was searched and included studies if they described a population PK model of piperacillin, amoxicillin, ampicillin, cefotaxime, ceftriaxone, cloxacillin, imipenem or meropenem in neonates or children. We compared the PK parameters for each drug. We analysed the used covariates to estimate PK parameters. We compared the pharmacokinetics/pharmacodynamics (PK/PD) targets and the drug dosing recommendations. RESULTS: Thirty-four studies met inclusion criteria with seven studies for piperacillin, five for amoxicillin, three for ampicillin, three for cefotaxime, two for ceftriaxone, two for imipenem and twelve for meropenem. None met inclusion criteria for cloxacillin. Ages ranged from 0-19.1 years with 12 studies including preterm. Body weight, age and renal function were the three major covariates in neonates and children. Different PK/PD targets were observed (between 40% to 100% of the dosing regimen interval of time over which the unbound (or free) drug concentration remains above the minimal inhibitory concentration (MIC) (fT>MIC) or four times the MIC (fT>4xMIC)). Several drug-dosing regimens were fond recommended according to the age and pathogens MIC using intermittent, timed or continuous infusions. CONCLUSIONS: Consensus is lacking on the optimal dosing regimens for these eight first choice antibiotics. A more personalized approach to antibiotic drugs dosing with individual characteristics of patient and pathogen susceptibility is required. According PK/PD targets and used dosing regimens, prospective clinical studies are required to investigate clinical cure, patient survival and emergence of antimicrobial resistance.

[Antibiotic stewardship - recent developments]. / Aktuelle Entwicklungen im Bereich Antibiotic Stewardship.

Both in hospitals and outpatient settings, fewer fluoroquinolones have been prescribed in Germany in recent years. The consumption of cephalosporins also decreased somewhat in favor of penicillin derivatives. The aminoglycosides, which have only rarely been prescribed, can now be used again as a suitable alternative - but only parenterally - due to their relatively favorable activity and low resistance rates among typical urinary tract infection pathogens. In acute severe infection such as sepsis, addition, e. g. of tobramycin, to a suitable betalactam of a single dose has been discussed as a useful option, but the evidence for such a recommendation is weak. There is little news about the rational use of antibiotics in hematology-oncology patients. In the case of fever and neutropenia, the initial empirical regimens of choice remain piperacillin-tazobactam or a pseudomonas-active carbapenem as monotherapy. These betalactams should be given with extended infusion times, e. g. over 4 hours. Linezolid should be considered as a reserve drug and not be used empirically, but only in targeted therapy. With regard to an alleged penicillin allergy, the risk of true allergic reactions can be differentiated by careful taking of the history; on that ground patient subgroups can be defined that may be re-exposed without further allergological examinations.

Oral beta-lactam step down in bacteremic E. coli urinary tract infections.

BACKGROUND: Literature is scarce regarding oral step down to beta-lactams in bacteremic urinary tract infections. Oral fluoroquinolones are an accepted and common step down for bacteremic urinary tract infections; however, their use is associated with mounting safety concerns. We compared clinical cure in patients with E. coli bacteremic urinary tract infections who were stepped down to oral beta-lactams compared to oral fluoroquinolones. METHODS: This multicentre retrospective cohort study included patients with first positive concurrent urine and blood cultures from January 2016 to December 2016. Patients were included if they received empiric intravenous beta-lactam therapy with step down to either oral beta-lactam or fluoroquinolone for treatment completion. The primary outcome was clinical cure. Secondary outcomes were length of hospitalization, all-cause mortality and C. difficile infection. Multivariate analysis and propensity score were used to control for confounding. RESULTS: A total of 207 patients were identified with bacteremic E.coli urinary tract infections. Clinical cure was achieved in 72/77 (94%) in the oral beta-lactam group versus 127/130 (98%) in the oral fluoroquinolone group (absolute difference - 4.2, 95% confidence interval [CI] -10.3 to 1.9%, p = 0.13). The adjusted odds ratio (OR) for clinical cure with oral beta-lactams was 0.31 (95% CI 0.05-1.90, p = 0.21); propensity score adjusted analysis showed a similar result. There was no statistically significant difference in secondary outcomes. CONCLUSIONS: Oral beta-lactams appear to be a safe and effective step down option in bacteremic E. coli urinary tract infections compared to oral fluoroquinolones.