Proposed primary endpoints for use in clinical trials that compare treatment options for bloodstream infection in adults: a consensus definition

BackgroundThe risk of endocarditis among patients with Staphylococcus aureus bacteremia is not uniform, and a number of different scores have been developed to identify patients whose risk is less than 5%. The optimal echocardiography strategy for these patients is uncertain.MethodsWe used decision analysis and Monte Carlo simulation using input parameters taken from the existing literature. The model examined patients with S aureus bacteremia whose risk of endocarditis is less than 5%, generally those with nosocomial or healthcare-acquired bacteremia, no intracardiac prosthetic devices, and a brief duration of bacteremia. We examined 6 echocardiography strategies, including the use of transesophageal echocardiography, transthoracic echocardiography, both modalities, and neither. The outcome of the model was 90-day survival.ResultsThe optimal echocardiography strategy varied with the risk of endocarditis and the procedural mortality associated with transesophageal echocardiography. No echocardiography strategy offered an absolute benefit in 90-day survival of more than 0.5% compared with the strategy of not performing echocardiography and treating with short-course therapy. Strategies using transesophageal echocardiography were never preferred if the mortality of this procedure was greater than 0.5%.ConclusionsIn patients identified to be at low risk of endocarditis, the choice of echocardiography strategy appears to exert a very small influence on 90-day survival. This finding may render test-treatment trials unfeasible and should prompt clinicians to focus on other, more important, management considerations in these patients.

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“…The binary outcome of 90-day survival was chosen to reflect the recognized outcome measures of bacteremia trials [10]. …”

Section: Methodsmentioning

confidence: 99%

Benefit of Echocardiography in Patients With Staphylococcus aureus Bacteremia at Low Risk of Endocarditis

Heriot

Tong

Cheng

et al. 2018

Open Forum Infectious Diseases

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“…Mortality endpoints are not very sensitive, while clinical cure endpoints are subjective, microbiological cure is not viable, and antibiotic- or ventilation-free days are ambiguous (Table 2). It will not be easy to reach consensus, but Delphi processes like the one recently published on endpoints for BSIs [3] are a step in the right direction. In this review, the authors concluded that it is unlikely for one endpoint to capture all relevant information and proposed to use composite endpoints.…”

Section: Possible Solutions (And Their Potential Shortcomings)mentioning

confidence: 99%

“…In two recent systematic reviews [3, 9], it is proposed to combine mortality and microbiological endpoints for BSIs, and mortality and clinical cure for HAP/VAP, respectively. However, both groups agree more debate is required to improve definitions of clinical cure and to finalize discussions on the importance of patient-centered outcomes versus microbiological or clinical response, as well as the role of safety endpoints.…”

Section: Components Of Composite Endpointsmentioning

confidence: 99%

“…The Delphi process is one of the possible ways to come to a consensus on new endpoints. This effort has already been initiated for circulatory failure in sepsis [22] and BSI [3], and is ongoing for HAP/VAP by our group [9]. …”

Section: Role Of the Clinicianmentioning

confidence: 99%

“…This has resulted in inconsistencies in how trials are designed and reported, raising questions about internal validity and making interpretations across trials difficult. A recent Delphi process (see definition in Table 1) to define standardized endpoints for trials on antibiotic therapy for bloodstream infections (BSIs) identified that no well-validated primary endpoints existed; mortality or clinical cure, at hospital discharge or up to 12 weeks after treatment, were the most common primary endpoints [3]. As another example, the US Food and Drug Administration (FDA) recommends all-cause mortality as the primary efficacy endpoint for trials on hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) [4], whereas the European Medicines Agency recommends clinical outcome at the test of cure visit for these type of infectious syndromes.…”

Section: Introductionmentioning

confidence: 99%

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Appropriate endpoints for evaluation of new antibiotic therapies for severe infections: a perspective from COMBACTE’s STAT-Net

et al. 2017

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PurposeIn this era of rising antimicrobial resistance, slowly refilling antibiotic development pipelines, and an aging population, we need to ensure that randomized clinical trials (RCTs) determine the added benefit of new antibiotic agents effectively and in a valid way, especially for severely ill patients. Unfortunately, universally accepted endpoints for the evaluation of new drugs in severe infections are lacking.MethodsWe review and discuss the current practices and challenges regarding endpoints in RCTs in this field and propose novel approaches.ResultsUsual endpoints actually recommended for drug development suffer from important flaws. Mortality requires large sample size and only partly related to the infectious process. Clinical cure rate is highly subjective in critically ill patients where symptoms may be related to other intercurrent events. Currently, composite endpoints, hierarchical nested designs, and competing risks analysis seem to be the most promising new tools for designing and analyzing clinical trials in this area, although they require further validation.ConclusionRegulatory authorities, pharmaceutical companies, and clinicians need to agree on the most appropriate clinical endpoints for severe infections to ensure efficient approval of new, effective antibiotic agents.

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Oral β-Lactam Antibiotics vs Fluoroquinolones or Trimethoprim-Sulfamethoxazole for Definitive Treatment of Enterobacterales Bacteremia From a Urine Source

et al. 2020

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IMPORTANCE Oral β-lactam antibiotics are traditionally not recommended to treat Enterobacterales bacteremia because of concerns over subtherapeutic serum concentrations, but there is a lack of outcomes data, specifically after initial treatment with parenteral antibiotics. Given the limited data and increasing limitations of fluoroquinolones or trimethoprim-sulfamethoxazole (TMP-SMX), oral β-lactam antibiotics may be a valuable additional treatment option. OBJECTIVE To compare definitive therapy with oral β-lactam antibiotics vs fluoroquinolones or TMP-SMX for Enterobacterales bacteremia from a suspected urine source. DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort study was conducted from January 1, 2007, to September 30, 2015, at 114 Veterans Affairs hospitals among 4089 adults with Escherichia coli, Klebsiella spp, or Proteus spp bacteremia and matching urine culture results. Additional inclusion criteria were receipt of active parenteral antibiotic(s) followed by conversion to an oral antibiotic. Exclusion criteria were previous Enterobacterales bacteremia, urologic abscess, or chronic prostatitis. Data were analyzed from April 15, 2019, to July 26, 2020. EXPOSURES Conversion of therapy to an oral β-lactam antibiotic vs fluoroquinolones or TMP-SMX after 1 to 5 days of parenteral antibiotics. MAIN OUTCOMES AND MEASURES The main outcome was a composite of either 30-day all-cause mortality or 30-day recurrent bacteremia. Propensity-based overlap weights were used to adjust for differences between groups. Log binomial regression models were used to estimate adjusted relative risks (aRRs) and adjusted risk differences (aRDs). RESULTS Of the 4089 eligible patients (3731 men [91.2%]; median age, 71 years [interquartile range, 63-81 years]), 955 received an oral β-lactam antibiotic, and 3134 received fluoroquinolones or TMP-SMX. The primary outcome occurred for 42 patients (4.4%) who received β-lactam antibiotics and 94 patients (3.0%) who received fluoroquinolones or TMP-SMX (aRD, 0.99% [95% CI, −0.42% to 2.40%]; aRR, 1.31 [95% CI, 0.87-1.95]). Mortality rates were 3.0% (n = 29) for patients receiving β-lactam antibiotics vs 2.6% (n = 82) for those receiving fluoroquinolones or TMP-SMX (aRD, 0.06% [95% CI, −1.13% to 1.26%]; aRR, 1.02 [95% CI, 0.67-1.56]). Recurrent bacteremia rates were 1.5% (n = 14) among those receiving β-lactam antibiotics vs 0.4% (n = 12) among those receiving fluoroquinolones or TMP-SMX (aRD, 1.03% [95% CI, 0.24%-1.82%]; aRR, 3.43 [95% CI, 0.42-27.90]). CONCLUSIONS AND RELEVANCE In this cohort study of adults with E coli, Klebsiella spp, or Proteus spp bacteremia from a suspected urine source, the relative risk of recurrent bacteremia was not significantly higher with β-lactam antibiotics compared with fluoroquinolones or TMP-SMX, and the absolute risk and risk difference were small (ie, <3%). No significant difference in mortality was observed. Oral β-lactam antibiotics may be a reasonable step-down treatment option, primarily (continued) Key Points Question Are mortality and recurren...

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Proposed primary endpoints for use in clinical trials that compare treatment options for bloodstream infection in adults: a consensus definition

Cited by 64 publications

References 41 publications

Benefit of Echocardiography in Patients With Staphylococcus aureus Bacteremia at Low Risk of Endocarditis

Benefit of Echocardiography in Patients With Staphylococcus aureus Bacteremia at Low Risk of Endocarditis

Appropriate endpoints for evaluation of new antibiotic therapies for severe infections: a perspective from COMBACTE’s STAT-Net

Oral β-Lactam Antibiotics vs Fluoroquinolones or Trimethoprim-Sulfamethoxazole for Definitive Treatment of Enterobacterales Bacteremia From a Urine Source

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