Systematic Review and Meta-Analysis of Antimicrobial Treatment Effect Estimation in Complicated Urinary Tract Infection

Abstract

bNoninferiority trial design and analyses are commonly used to establish the effectiveness of a new antimicrobial drug for treatment of serious infections such as complicated urinary tract infection (cUTI). A systematic review and meta-analysis were conducted to estimate the treatment effects of three potential active comparator drugs for the design of a noninferiority trial. The systematic review identified no placebo trials of cUTI, four clinical trials of cUTI with uncomplicated urinary tract infection as a proxy for placebo, and nine trials with reports of treatment effect estimates for doripenem, levofloxacin, or imipenem-cilastatin. In the meta-analysis, the primary efficacy endpoint of interest was the microbiological eradication rate at the test-of-cure visit in the microbiological intent-to-treat population. The estimated eradication rates and corresponding 95% confidence intervals (CI) were 31.8% (26.5% to 37.2%) for placebo, 81% (77.7% to 84.2%) for doripenem, 79% (75.9% to 82.2%) for levofloxacin, and 80.5% (71.9% to 89.1%) for imipenem-cilastatin. The treatment effect estimates were 40.5% for doripenem, 38.7% for levofloxacin, 34.7% for imipenem-cilastatin, and 40.8% overall. These treatment effect estimates can be used to inform the design and analysis of future noninferiority trials in cUTI study populations. Complicated urinary tract infections (cUTI) occur in persons with structural or functional abnormalities of the urinary tract and in hospitalized patients with significant medical or surgical comorbidities (1, 2). These infections are a major cause of hospital admission, morbidity, mortality, and excess health care costs (3-6). National and international treatment guidance for urinary tract infections includes recommendations for targeted and empirical treatment of the major causative pathogens, including Escherichia coli, Klebsiella pneumoniae, and non-Enterobacteriaceae organisms such as Pseudomonas aeruginosa (7-9).Of notable concern for the clinical care of patients with cUTI and other serious infections is effective antimicrobial treatment amid the emergence and spread of drug-resistant pathogens (10, 11). To demonstrate efficacy of a new or test antimicrobial agent for the treatment of adult subjects with cUTI, randomized parallel-group noninferiority phase 3 trials have traditionally been used to meet regulatory requirements for approval of the test drug (12). An active-comparator, noninferiority study design is generally used in cUTI trials given the ethical implications of placebo treatment (13,14). In order to conduct a noninferiority trial, an estimate of the treatment effect of the planned antimicrobial comparator must be obtained from historical data (12). Once an estimate of the treatment effect of the antimicrobial comparator is determined, the largest clinically acceptable difference of the test drug compared to the comparator must be decided. This decision is critical to the design, analysis, and interpretation of a noninferiority trial.We conducted a systematic review and me...

Assessment of Outpatient and Inpatient Antibiotic Treatment Patterns and Health Care Costs of Patients with Complicated Urinary Tract Infections

“…1,2,7,8 With the increasing prevalence of antimicrobial resistance, the treatment of cUTIs has become more challenging, leading to the need to develop new antimicrobial treatments. 9,10 There are few real-world data regarding the characteristics of patients with cUTIs, their outpatient and inpatient treatment patterns, and the costs associated with the management of cUTIs. The objectives of the present study were to describe the characteristics, treatment patterns, and total costs associated with cUTI patients who received outpatient treatment only compared with those who required emergency services or hospitalization due to presumed treatment failure after outpatient treatment.…”

Outcomes of high-dose levofloxacin therapy remain bound to the levofloxacin minimum inhibitory concentration in complicated urinary tract infections

“…A recent meta-analysis examined multiple cUTI trials before ASPECT-cUTI and identified microbiological eradication rates at the TOC visit in the microbiological intent-to-treat population of 81% for doripenem, 79% for levofloxacin, and 80.5% for imipenem-cilastatin, confirming that levofloxacin has a place in the armamentarium for cUTI [21]. In an era of increasing and evolving antibiotic resistance, however, decisions about clinical usefulness must be made at the local hospital and individual patient level [22].…”

Systematic Review and Meta-Analysis To Estimate Antibacterial Treatment Effect in Acute Bacterial Skin and Skin Structure Infection

“…While the placebo response rate in uSSTI should not be interpreted as the true placebo response rate in ABSSSI, we assumed that the use of this proxy for the placebo treatment response, resulting in an overestimation of the ABSSSI placebo treatment response, is a conservative approach in estimating antibacterial efficacy relative to that of placebo. Based on the uncertainty of the true placebo effect and the use of the FDA guidance, each ABSSSI treatment effect estimate is conservative, given that the overestimation of the ABSSSI placebo treatment response results in a conservative underestimation of the ABSSSI treatment effect (14,22,58). The second major finding from our study is the evidence and assessment of heterogeneity in these historical clinical trials as relevant and informative to future ABSSSI clinical trials.…”

“…The placebo search was extended to include clinical trials reporting a placebo treatment response in uncomplicated skin and soft tissue infections (uSSTI) as a proxy for placebo in ABSSSI (search A2). This strategy, which comprised use of a proxy for placebo effect estimation, has been recommended in the FDA guidance for noninferiority trials and has been used for placebo treatment effect estimation for trials in complicated urinary tract infections (13,21,22). Given that historical studies published in 1937 reported relatively high response rates in the treatment of erysipelas with UV light, an additional search (search C) was conducted to identify clinical trials of nonantibacterial treatment in uSSTI and in ABSSSI (4,23,24).…”