Effect of C-Reactive Protein-Guided Antibiotic Treatment Duration, 7-Day Treatment, or 14-Day Treatment on 30-Day Clinical Failure Rate in Patients With Uncomplicated Gram-Negative Bacteremia: A Randomized Clinical Trial.

Importance: Antibiotic overuse drives antibiotic resistance. Gram-negative bacteremia is a common infection that results in substantial antibiotic use. Objective: To compare the clinical effectiveness of C-reactive protein (CRP)-guided, 7-day, and 14-day antibiotic durations 30, 60, and 90 days after treatment initiation. Design, Setting, and Participants: Multicenter, noninferiority, point-of-care randomized clinical trial including adults hospitalized with gram-negative bacteremia conducted in 3 Swiss tertiary care hospitals between April 2017 and May 2019, with follow-up until August 2019. Patients and physicians were blinded between randomization and antibiotic discontinuation. Adults (aged ≥18 years) were eligible for randomization on day 5 (±1 d) of microbiologically efficacious therapy for fermenting, gram-negative bacteria in blood culture(s) if they were afebrile for 24 hours without evidence for complicated infection (eg, abscess) or severe immunosuppression. Intervention: Randomization in a 1:1:1 ratio to an individualized CRP-guided antibiotic treatment duration (discontinuation once CRP declined by 75% from peak; n = 170), fixed 7-day treatment duration (n = 169), or fixed 14-day treatment duration (n = 165). Main Outcomes and Measures: The primary outcome was the clinical failure rate at day 30, defined as the presence of at least 1 of the following, with a non-inferiority margin of 10%: recurrent bacteremia, local suppurative complication, distant complication (growth of the same organism causing the initial bacteremia), restarting gram-negative-directed antibiotic therapy due to clinical worsening suspected to be due to the initial organism, or death due to any cause. Secondary outcomes included the clinical failure rate on day 90 of follow-up. Results: Among 504 patients randomized (median [interquartile range] age, 79 [68-86] years; 306 of 503 [61%] were women), 493 (98%) completed 30-day follow-up and 448 (89%) completed 90-day follow-up. Median antibiotic duration in the CRP group was 7 (interquartile range, 6-10; range, 5-28) days; 34 of the 164 patients (21%) who completed the 30-day follow-up had protocol violations related to treatment assignment. The primary outcome occurred in 4 of 164 (2.4%) patients in the CRP group, 11 of 166 (6.6%) in the 7-day group, and 9 of 163 (5.5%) in the 14-day group (difference in CRP vs 14-day group, -3.1% [1-sided 97.5% CI, -∞ to 1.1]; P < .001; difference in 7-day vs 14-day group, 1.1% [1-sided 97.5% CI, -∞ to 6.3]; P < .001). By day 90, clinical failure occurred in 10 of 143 patients (7.0%) in the CRP group, 16 of 151 (10.6%) in the 7-day group, and 16 of 153 (10.5%) in the 14-day group. Conclusions and Relevance: Among adults with uncomplicated gram-negative bacteremia, 30-day rates of clinical failure for CRP-guided antibiotic treatment duration and fixed 7-day treatment were noninferior to fixed 14-day treatment. However, interpretation is limited by the large noninferiority margin compared with the low observed event rate, as well as low adherence and wide range of treatment durations in the CRP-guided group. Trial Registration: ClinicalTrials.gov Identifier: NCT03101072.

Analysis of the clinical antibacterial and antituberculosis pipeline.

This analysis of the global clinical antibacterial pipeline was done in support of the Global Action Plan on Antimicrobial Resistance. The study analysed to what extent antibacterial and antimycobacterial drugs for systemic human use as well as oral non-systemic antibacterial drugs for Clostridium difficile infections were active against pathogens included in the WHO priority pathogen list and their innovativeness measured by their absence of cross-resistance (new class, target, mode of action). As of July 1, 2018, 30 new chemical entity (NCE) antibacterial drugs, ten biologics, ten NCEs against Mycobacterium tuberculosis, and four NCEs against C difficile were identified. Of the 30 NCEs, 11 are expected to have some activity against at least one critical priority pathogen expressing carbapenem resistance. The clinical pipeline is dominated by derivatives of established classes and most development candidates display limited innovation. New antibacterial drugs without pre-existing cross-resistance are under-represented and are urgently needed, especially for geographical regions with high resistance rates among Gram-negative bacteria and M tuberculosis.

PIRATE project: point-of-care, informatics-based randomised controlled trial for decreasing overuse of antibiotic therapy in Gram-negative bacteraemia.

INTRODUCTION: Antibiotic overuse drives antibiotic resistance. The optimal duration of antibiotic therapy for Gram-negative bacteraemia (GNB), a common community and hospital-associated infection, remains unknown and unstudied via randomised controlled trials (RCTs). METHODS AND ANALYSIS: This investigator-initiated, multicentre, non-inferiority, informatics-based point-of-care RCT will randomly assign adult hospitalised patients receiving microbiologically efficacious antibiotic(s) for GNB to (1) 14 days of antibiotic therapy, (2) 7 days of therapy or (3) an individualised duration determined by clinical response and 75% reduction in peak C reactive protein (CRP) values. The randomisation will occur in equal proportions (1:1:1) on day 5 (±1) of efficacious antibiotic therapy as determined by antibiogram; patients, their physicians and study investigators will be blind to treatment duration allocation until the day of antibiotic discontinuation. Immunosuppressed patients and those with GNB due to complicated infections (endocarditis, osteomyelitis, etc) and/or non-fermenting bacilli (Acinetobacter spp, Burkholderia spp, Pseudomonas spp) Brucella spp, Fusobacterium spp or polymicrobial growth with Gram-positive organisms will be ineligible. The primary outcome is incidence of clinical failure at day 30; secondary outcomes include clinical failure, all-cause mortality and incidence of Clostridiumdifficile infection in the 90-day study period. An interim safety analysis will be performed after the first 150 patients have been followed for ≤30 days. Given a chosen margin of 10%, the required sample size to determine non-inferiority is roughly 500 patients. Analyses will be performed on both intention-to-treat and per-protocol populations. ETHICS AND DISSEMINATION: Ethics approval was obtained from the cantonal ethics committees of all three participating sites. Results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: This trial is registered at www.clinicaltrials.gov (NCT03101072; pre-results).

Therapeutic drug monitoring of the ß-lactam antibiotics: what is the evidence and which patients should we be using it for?

Traditional antibiotic dosing was not designed for today's escalating antibiotic resistance, lack of novel antibiotics and growing complexity in patient populations. Dosing that ensures optimal antibiotic exposures should be considered essential to increase the likelihood of effective patient treatment. Given the variability in these exposures across different patients, a 'one-dose-fits-all' approach is increasingly problematic. Therapeutic drug monitoring (TDM) of the ß-lactams, the most widely used antibiotic class, is underutilized in certain populations. Clinical experience with ß-lactam TDM remains relatively scarce. Patients most likely to benefit from such an intervention include the critically ill, the obese, the elderly and those with cystic fibrosis. Most centres actively performing ß-lactam TDM target a minimum 100% of the time during the dosing interval that the free (unbound) concentration of antibiotic exceeds the MIC of the pathogen (100% fT>MIC), which is higher than a traditional target supported by in vitro data. Ideally, isolated pathogens should undergo MIC testing along with TDM on a regular basis, allowing clinicians to address the triad of bug, drug and patient ('mug') in equal measure.

Impact of outpatient antibiotic use on carriage of ampicillin-resistant Escherichia coli.

Studies about the relationship between antibiotic consumption and carriage of antibiotic-resistant Escherichia coli in individual patients have yielded conflicting results. The goal of this study was to identify individual- and household-level factors associated with carriage of ampicillin (AMP)-resistant E. coli during consumption of a course of oral antibiotics. We enrolled outpatients and their families in a prospective household study of AMP-resistant or AMP-susceptible E. coli carriage. Two kinds of index patients were identified. Group 1 consisted of outpatients who were being initiated on a new antibiotic course at the time of a clinic visit, and group 2 consisted of outpatients not starting antibiotics. Each participant was asked to submit three stool swab samples (at baseline, week 1, and week 4) and to complete a questionnaire. Antimicrobial susceptibility testing was performed on each phenotypically distinct E. coli colony. The study included 149 group 1 households (total, 570 participants) and 38 group 2 households (total, 131 participants). AMP-resistant E. coli was recovered from 29% of stool samples. Observed associations with antibiotic exposure varied by drug class. Penicillins, which were the most frequently prescribed drug class, were associated with a modest increase in AMP-resistant E. coli carriage and a modest decrease in AMP-susceptible E. coli carriage. Neither change by itself was statistically significant. Macrolides were associated with reduced carriage of both AMP-resistant E. coli and AMP-susceptible E. coli (P < 0.05). Both AMP-resistant and AMP-susceptible E. coli demonstrated household clustering (P < 0.001). In summary, the overall effect of antibiotics on individual risk of carriage of AMP-resistant E. coli was small. However, even a modest alteration of the competitive balance between AMP-resistant and AMP-susceptible E. coli may promote population spread of resistant E. coli. Examining changes in both resistant and susceptible organisms in antibiotic-treated individuals and their close contacts improves understanding of antibiotic selection pressure.

Adequacy of antimicrobial treatment and outcome of Staphylococcus aureus bacteremia in 9 Western European countries.

BACKGROUND: Little is known about the incidence of inadequate treatment of severe Staphylococcus aureus infection in Europe. We aimed to evaluate the adequacy of antibiotic therapy for S. aureus bacteremia (SAB), to identify determinants of inadequate treatment, and to determine the effect of inadequate treatment on patient outcome in a representative selection of hospitals in 9 Western European countries. METHODS: In this retrospective cohort study, all adult patients with SAB (due to methicillin-susceptible S. aureus [MSSA] or methicillin-resistant S. aureus [MRSA]) who were admitted to 60 randomly selected hospitals from 1 November 2007 through 31 December 2007 were included. Adequate antimicrobial therapy was defined as intravenous administration of at least 1 antibiotic to which the isolate showed in vitro susceptibility that was initiated within 2 days after onset of SAB. RESULTS: A total of 334 SAB episodes (257 due to MSSA and 77 due to MRSA) were included. Ninety-four patients (28%) received inadequate empirical therapy (21% in the MSSA group and 52% in the MRSA group). Both length of stay before SAB onset and methicillin-resistant infection were associated with inadequate therapy, with adjusted odds ratios (ORs) of 1.01 (95% confidence interval [CI], 1.00-1.03) and 3.7 (95% CI, 2.2-6.4), respectively. Age (OR, 1.06; 95% CI, 1.03-1.10), Charlson comorbidity score (OR, 2.1; 95% CI, 1.2-3.6), severe sepsis or septic shock (OR, 2.7; 95% CI, 1.5-4.8), and intensive care unit stay at onset of SAB (OR, 2.9; 95% CI, 1.5-5.6) but not inadequate treatment (OR, 0.7; 95% CI, 0.4-1.3) were associated with increased 30-day mortality. CONCLUSION: Inadequate empirical antimicrobial therapy for SAB is common in Western Europe and is strongly associated with infection caused by MRSA. In this study, inadequate treatment was not associated with increased 30-day mortality rates.