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Background. Beta-lactam antibiotics are a commonly used treatment for severe sepsis, with intermittent bolus dosing standard therapy, despite a strong theoretical rationale for continuous administration. The aim of this trial was to determine the clinical and pharmacokinetic differences between continuous and intermittent dosing in patients with severe sepsis. Methods. This was a prospective, double-blind, randomized controlled trial of continuous infusion versus intermittent bolus dosing of piperacillin-tazobactam, meropenem, and ticarcillin-clavulanate conducted in 5 intensive care units across Australia and Hong Kong. The primary pharmacokinetic outcome on treatment analysis was plasma antibiotic concentration above the minimum inhibitory concentration (MIC) on days 3 and 4. The assessed clinical outcomes were clinical response 7–14 days after study drug cessation, ICU-free days at day 28 and hospital survival. Results. Sixty patients were enrolled with 30 patients each allocated to the intervention and control groups. Plasma antibiotic concentrations exceeded the MIC in 82% of patients (18 of 22) in the continuous arm versus 29% (6 of 21) in the intermittent arm (P = .001). Clinical cure was higher in the continuous group (70% vs 43%; P = .037), but ICU-free days (19.5 vs 17 days; P = .14) did not significantly differ between groups. Survival to hospital discharge was 90% in the continuous group versus 80% in the intermittent group (P = .47). Conclusions. Continuous administration of beta-lactam antibiotics achieved higher plasma antibiotic concentrations than intermittent administration with improvement in clinical cure. This study provides a strong rationale for further multicenter trials with sufficient power to identify differences in patient-centered endpoints.

Background Critically ill patients undergo extensive physiological alterations that will have impact on antibiotic pharmacokinetics. Up to 60% of intensive care unit (ICU) patients meet the pharmacodynamic targets of beta-lactam antibiotics, with only 30% in fluoroquinolones. Not reaching these targets might increase the chance of therapeutic failure, resulting in increased mortality and morbidity, and antibiotic resistance. The DOLPHIN trial was designed to demonstrate the added value of therapeutic drug monitoring (TDM) of beta-lactam and fluoroquinolones in critically ill patients in the ICU. Methods A multi-centre, randomised controlled trial (RCT) was designed to assess the efficacy and cost-effectiveness of model-based TDM of beta-lactam and fluoroquinolones. Four hundred fifty patients will be included within 24 months after start of inclusion. Eligible patients will be randomly allocated to either study group: the intervention group (active TDM) or the control group (non-TDM). In the intervention group dose adjustment of the study antibiotics (cefotaxime, ceftazidime, ceftriaxone, cefuroxime, amoxicillin, amoxicillin with clavulanic acid, flucloxacillin, piperacillin with tazobactam, meropenem, and ciprofloxacin) on day 1, 3, and 5 is performed based upon TDM with a Bayesian model. The primary outcome will be ICU length of stay. Other outcomes amongst all survival, disease severity, safety, quality of life after ICU discharge, and cost effectiveness will be included. Discussion No trial has investigated the effect of early TDM of beta-lactam and fluoroquinolones on clinical outcome in critically ill patients. The findings from the DOLPHIN trial will possibly lead to new insights in clinical management of critically ill patients receiving antibiotics. In short, to TDM or not to TDM? Trial registration EudraCT number: 2017–004677-14 . Sponsor protocol name: DOLPHIN. Registered 6 March 2018 . Protocol Version 6, Protocol date: 27 November 2019.

Continuous infusion of β-lactam antibiotics may improve outcomes because of time-dependent antibacterial activity compared with intermittent dosing. To evaluate the efficacy of continuous versus intermittent infusion in patients with severe sepsis. We conducted a randomized controlled trial in 25 intensive care units (ICUs). Participants commenced on piperacillin-tazobactam, ticarcillin-clavulanate, or meropenem were randomized to receive the prescribed antibiotic via continuous or 30-minute intermittent infusion for the remainder of the treatment course or until ICU discharge. The primary outcome was the number of alive ICU-free days at Day 28. Secondary outcomes were 90-day survival, clinical cure 14 days post antibiotic cessation, alive organ failure-free days at Day 14, and duration of bacteremia. We enrolled 432 eligible participants with a median age of 64 years and an Acute Physiology and Chronic Health Evaluation II score of 20. There was no difference in ICU-free days: 18 days (interquartile range, 2-24) and 20 days (interquartile range, 3-24) in the continuous and intermittent groups (P = 0.38). There was no difference in 90-day survival: 74.3% (156 of 210) and 72.5% (158 of 218); hazard ratio, 0.91 (95% confidence interval, 0.63-1.31; P = 0.61). Clinical cure was 52.4% (111 of 212) and 49.5% (109 of 220); odds ratio, 1.12 (95% confidence interval, 0.77-1.63; P = 0.56). There was no difference in organ failure-free days (6 d; P = 0.27) and duration of bacteremia (0 d; P = 0.24). In critically ill patients with severe sepsis, there was no difference in outcomes between β-lactam antibiotic administration by continuous and intermittent infusion. Australian New Zealand Clinical Trials Registry number (ACT RN12612000138886).

Antimicrobial choices for community-acquired pneumonia in hospitalized patients who do not require ICU-level care continue to be debated. In this trial, empirical beta-lactam–based therapy with or without a macrolide was compared with fluoroquinolones as initial treatment. Community-acquired pneumonia (CAP) is a leading cause of hospitalization and death worldwide. 1 – 3 Most guidelines recommend that antibiotic treatment be based on the severity of disease at presentation, assessed either on the basis of the level of care needed or on the basis of a prognostic risk score. 4 – 6 For patients with clinically suspected CAP who are admitted to a non–intensive-care-unit (ICU) ward, guidelines recommend either combination therapy with a beta-lactam plus a macrolide or plus ciprofloxacin or monotherapy with moxifloxacin or levofloxacin for empirical treatment. These guidelines have increased the use of macrolides and fluoroquinolones, although these antibiotic classes . . .

Background Sepsis and septic shock are significant global healthcare challenges with high mortality rates. Effective management requires timely and adequate antimicrobial therapy. Beta-lactam antibiotics, commonly used in patients with sepsis, are crucial for treating these infections. However, standard dosing often leads to insufficient plasma levels due to dynamic physiological changes in critically ill patients. Previous randomized controlled trials highlighted the need for timely dose adjustments to improve clinical outcomes. This is the study protocol for the BULLSEYE trial in which we aim to optimize antibiotic treatment during the initial 48 h of sepsis by comparing standard to double dosing of beta-lactam antibiotics. Methods This open-label, multicenter, randomized controlled trial will compare standard to double dosing of beta-lactam antibiotics (cefuroxime, ceftazidime, ceftriaxone, cefotaxime, amoxicillin, amoxicillin/clavulanic acid, flucloxacillin, meropenem, and piperacillin/clavulanic acid) in critically ill patients with septic shock. Participants will be randomized into two arms: the control arm receiving standard care, and the intervention arm receiving double antibiotic doses for 48 h, irrespective of renal function. Following this period, all patients will receive standard doses as per local protocol. The primary outcome is all cause 28-day mortality, with secondary outcomes including 90-day, 365-day, hospital and ICU mortality, hospital and ICU length of stay, SOFA scores, time to shock reversal, microbiological eradication, clinical cure, pharmacodynamic target attainment, safety, quality of life, and medical consumption. Discussion The BULLSEYE trial aims to improve sepsis treatment in critically ill patients. Despite anticipated recruitment challenges, its large sample size ensures robust comparability. This pivotal trial could significantly impact sepsis treatment, leading to better clinical outcomes. Trial registration EU_CT 2024–512950-13–00. Protocol version 2.3, protocol date 09–12-2024. Prospectively registered on 09–01-2025 at Clinicaltrails.gov nr. NCT06766461.

Background Due to limited therapeutic options, the spread of extended-spectrum beta-lactamases (ESBLs) have become a major public health concern. We conducted a prospective, randomized, open-label comparison of the therapeutic efficacy of piperacillin-tazobactam (PTZ), cefepime, and ertapenem in febrile nosocomial urinary tract infection with ESBL-producing Escherichia coli (ESBL-EC). Methods This study was conducted at three university hospitals between January 2013 and August 2015. Hospitalized adult patients presenting with fever were screened for healthcare-associated urinary tract infection (HA-UTI). When ESBL-EC was solely detected and susceptible to a randomized antibiotic in vitro, the case was included in the final analysis. Participants were treated for 10–14 days with PTZ, cefepime, or ertapenem. Results A total of 66 participants were evenly assigned to the PTZ and ertapenem treatment groups. After the recruitment of six participants, assignment to the cefepime treatment group was stopped because of an unexpectedly high treatment failure rate. The baseline characteristics of these participants did not differ from participants in other treatment groups. The clinical and microbiological response to PTZ treatment was estimated to be 94% and was similar to the response to ertapenem treatment. The efficacy of cefepime was 33.3%. In the cefepime group, age, Charlson comorbidity index, genotype, and minimal inhibitory concentration (MIC) did not significantly affect the success of treatment. Similarly, genotype seemed to be irrelevant with respect to clinical outcome in the PTZ group. Expired cases tended to involve septic shock with a high Charlson comorbidity index and high MIC. Conclusion Results from this study suggest that PTZ is effective in the treatment of urinary tract infection caused by ESBL-EC when the in vitro test indicates susceptibility. In addition, cefepime should not be used as an alternative treatment for urinary tract infection caused by ESBL-EC. Trial registration The trial was registered with the Clinical Research Information Service of Korea Centers for Disease Control and Prevention. (KCT0001895)

Background Methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia is a serious infection resulting in 20–50 % 90-day mortality. The limitations of vancomycin, the current standard therapy for MRSA, make treatment difficult. The only other approved drug for treatment of MRSA bacteraemia, daptomycin, has not been shown to be superior to vancomycin. Surprisingly, there has been consistent in-vitro and in-vivo laboratory data demonstrating synergy between vancomycin or daptomycin and an anti-staphylococcal β-lactam antibiotic. There is also growing clinical data to support such combinations, including a recent pilot randomised controlled trial (RCT) that demonstrated a trend towards a reduction in the duration of bacteraemia in patients treated with vancomycin plus flucloxacillin compared to vancomycin alone. Our aim is to determine whether the addition of an anti-staphylococcal penicillin to standard therapy results in improved clinical outcomes in MRSA bacteraemia. Methods/Design We will perform an open-label, parallel-group, randomised (1:1) controlled trial at 29 sites in Australia, New Zealand, Singapore, and Israel. Adults (aged 18 years or older) with MRSA grown from at least one blood culture and able to be randomised within 72 hours of the index blood culture collection will be eligible for inclusion. Participants will be randomised to vancomycin or daptomycin (standard therapy) given intravenously or to standard therapy plus 7 days of an anti-staphylococcal β-lactam (flucloxacillin, cloxacillin, or cefazolin). The primary endpoint will be a composite outcome at 90 days of (1) all-cause mortality, (2) persistent bacteraemia at day 5 or beyond, (3) microbiological relapse, or (4) microbiological treatment failure. The recruitment target of 440 patients is based on an expected failure rate for the primary outcome of 30 % in the control arm and the ability to detect a clinically meaningful absolute decrease of 12.5 %, with a two-sided alpha of 0.05, a power of 80 %, and assuming 10 % of patients will not be evaluable for the primary endpoint. Discussion Key potential advantages of adding anti-staphylococcal β-lactams to standard therapy for MRSA bacteraemia include their safety profile, low cost, and wide availability. Trial registration ClinicalTrials.gov Identifier: NCT02365493 . Registered 24 February 2015.

Antibiotic resistance is a major threat to public health. Treatment strategies involving shorter antibiotic courses have been proposed as a strategy to lower the potential for antibiotic resistance. Pediatric community-acquired pneumonia (CAP) is often treated with 10 days of antibiotics. Shorter treatment strategies may be effective and lead to less resistance. The impact of duration of treatment on the respiratory microbiome is unknown. Data are from children ( n  = 171), ages 6 to 71 months, enrolled in the SCOUT-CAP trial (NCT02891915). Children with CAP were randomized to a short (5 days) versus standard (10 days) beta-lactam treatment strategy. Throat swabs were collected at enrollment and the end of the study and used for shotgun metagenomic sequencing. The number of beta-lactam and multidrug efflux resistance genes per prokaryotic cell (RGPC) was significantly lower in children receiving the short compared to standard treatment strategy at the end of the study (Wilcoxon rank sum test, P  < 0.05 for each). Wilcoxon effect sizes were small for beta-lactam ( r : 0.15; 95% confidence interval [CI], 0.01 to 0.29) and medium for multidrug efflux RGPC ( r : 0.23; 95% CI, 0.09 to 0.37). Analyses comparing the resistome at the beginning and end of the trial indicated that in contrast to the standard strategy group, the resistome significantly differed in children receiving the short course strategy. Relative abundances of commensals such as Neisseria subflava were higher in children receiving the standard strategy, and Prevotella species and Veillonella parvula were higher in children receiving the short course strategy. We conclude that children receiving 5 days of beta-lactam therapy for CAP had a significantly lower abundance of antibiotic resistance determinants than those receiving standard 10-day treatment. These data provide an additional rationale for reductions in antibiotic use when feasible. IMPORTANCE Antibiotic resistance is a major threat to public health. Treatment strategies involving shorter antibiotic courses have been proposed as a strategy to lower the potential for antibiotic resistance. We examined relationships between the duration of antibiotic treatment and its impact on resistance genes and bacteria in the respiratory microbiome using data from a randomized controlled trial of beta-lactam therapy for pediatric pneumonia. The randomized design provides reliable evidence of the effectiveness of interventions and minimizes the potential for confounding. Children receiving 5 days of therapy for pneumonia had a lower prevalence of two different types of resistance genes than did those receiving the 10-day treatment. Our data also suggest that children receiving longer durations of therapy have a greater abundance of antibiotic resistance genes for a longer period of time than do children receiving shorter durations of therapy. These data provide an additional rationale for reductions in antibiotic use.

Background Atypical pathogens (AP), present in some patients with community-acquired pneumonia (CAP), are intrinsically resistant to betalactam drugs, the mainstay of empirical antibiotic treatment. Adding antibiotic coverage for AP increases the risk of adverse effects and antimicrobial selection pressure, while withholding such coverage may worsen the prognosis if an AP is causative. A clinical model predicting the presence of AP would allow targeting atypical coverage for patients most likely to benefit. Methods This is a secondary analysis of a multicentric randomized controlled trial that included 580 adults patients hospitalized for CAP. A predictive score was built using independent predictive factors for AP identified through multivariate analysis. Accuracy of the score was assessed using area under the receiver operating curve (AUROC), sensitivity, and specificity. Results Prevalence of AP was 5.3%. Age < 75 years (OR 2.7, 95% CI 1.2–6.2), heart failure (OR 2.6, 95% CI 1.1–6.1), absence of chest pain (OR 3.0, 95% CI 1.1–8.2), natremia < 135 mmol/L (OR 3.0, 95% CI 1.4–6.6) and contracting the disease in autumn (OR 2.7, 95% CI 1.3–5.9) were independently associated with AP. A predictive score using these factors had an AUROC of 0.78 (95% CI 0.71–0.85). A score of 0 or 1 (present in 33% of patients) had 100% sensitivity and 35% specificity. Conclusion Use of a score built on easily obtained clinical and laboratory data would allow safe withholding of atypical antibiotic coverage in a significant number of patients, with an expected positive impact on bacterial resistance and drug adverse effects. Trial registration: NCT00818610.

Background Carbapenem antibiotics are considered the treatment of choice for serious extended-spectrum beta-lactamase (ESBL)-producing Gram-negative bacteria (GNB) infections. The study objectives were to evaluate efficacy and safety of de-escalation therapy to ertapenem for treatment of infections caused by extended-spectrum-β-lactamase-producing Enterobacteriaceae. Methods We conducted a randomized controlled trial of adult patients with documented ESBL-producing Enterobacteriaceae infections who had received any group 2 carbapenem for less than 96 h. In the intervention group, the previously-prescribed group 2 carbapenem was de-escalated to ertapenem. In the control group, the group 2 carbapenem was continued. Results During June 2011–December 2014, 32 patients were randomized to the de-escalation group and 34 to the control group. Most common sites of infection were urinary tract infection (42%). Characteristics of both groups were comparable. By using a 15% predefined margin, ertapenem was non-inferior to control group regarding the clinical cure rate (%Δ = 14.0 [95% confidence interval: −2.4 to 31.1]), the microbiological eradication rate (%Δ = 4.1 [−5.0 to 13.4]), and the superimposed infection rate (%Δ = −16.5 [−38.4 to 5.3]). Patients in the de-escalation group had a significantly lower 28-day mortality rate (9.4% vs. 29.4%; P  = .05), a significantly shorter median length of stay (16.5 days [4.0–73.25] vs. 20.0 days [1.0–112.25]; P  = .04), and a significantly lower defined daily dose of carbapenem use (12.9 ± 8.9 vs. 18.4 ± 12.6; P  = .05). Conclusions Ertapenem could be safely used as de-escalation therapy for ESBL-producing Enterobacteriaceae infections, once the susceptibility profiles are known. Future studies are needed to investigate ertapenem efficacy against ESBL-producing Enterobacteriaceae pneumonia to determine its applicability in life-threatening conditions. Trial registration ClinicalTrials.gov identifier: NCT01297842 . Registered on 14 February 2011. First patient enrolled on 27 June 2011.