Cefepime-Taniborbactam in Complicated Urinary Tract Infection.

BACKGROUND: Carbapenem-resistant Enterobacterales species and multidrug-resistant Pseudomonas aeruginosa are global health threats. Cefepime-taniborbactam is an investigational ß-lactam and ß-lactamase inhibitor combination with activity against Enterobacterales species and P. aeruginosa expressing serine and metallo-ß-lactamases. METHODS: In this phase 3, double-blind, randomized trial, we assigned hospitalized adults with complicated urinary tract infection (UTI), including acute pyelonephritis, in a 2:1 ratio to receive intravenous cefepime-taniborbactam (2.5 g) or meropenem (1 g) every 8 hours for 7 days; this duration could be extended up to 14 days in case of bacteremia. The primary outcome was both microbiologic and clinical success (composite success) on trial days 19 to 23 in the microbiologic intention-to-treat (microITT) population (patients who had a qualifying gram-negative pathogen against which both study drugs were active). A prespecified superiority analysis of the primary outcome was performed after confirmation of noninferiority. RESULTS: Of the 661 patients who underwent randomization, 436 (66.0%) were included in the microITT population. The mean age of the patients was 56.2 years, and 38.1% were 65 years of age or older. In the microITT population, 57.8% of the patients had complicated UTI, 42.2% had acute pyelonephritis, and 13.1% had bacteremia. Composite success occurred in 207 of 293 patients (70.6%) in the cefepime-taniborbactam group and in 83 of 143 patients (58.0%) in the meropenem group. Cefepime-taniborbactam was superior to meropenem regarding the primary outcome (treatment difference, 12.6 percentage points; 95% confidence interval, 3.1 to 22.2; P = 0.009). Differences in treatment response were sustained at late follow-up (trial days 28 to 35), when cefepime-taniborbactam had higher composite success and clinical success. Adverse events occurred in 35.5% and 29.0% of patients in the cefepime-taniborbactam group and the meropenem group, respectively, with headache, diarrhea, constipation, hypertension, and nausea the most frequently reported; the frequency of serious adverse events was similar in the two groups. CONCLUSIONS: Cefepime-taniborbactam was superior to meropenem for the treatment of complicated UTI that included acute pyelonephritis, with a safety profile similar to that of meropenem. (Funded by Venatorx Pharmaceuticals and others; CERTAIN-1 ClinicalTrials.gov number, NCT03840148.).

Oral Tebipenem Pivoxil Hydrobromide in Complicated Urinary Tract Infection.

BACKGROUND: There is a need for oral antibiotic agents that are effective against multidrug-resistant gram-negative uropathogens. Tebipenem pivoxil hydrobromide is an orally bioavailable carbapenem with activity against uropathogenic Enterobacterales, including extended-spectrum beta-lactamase-producing and fluoroquinolone-resistant strains. METHODS: In this phase 3, international, double-blind, double-dummy trial, we evaluated the efficacy and safety of orally administered tebipenem pivoxil hydrobromide as compared with intravenous ertapenem in patients with complicated urinary tract infection or acute pyelonephritis. Patients were randomly assigned, in a 1:1 ratio, to receive oral tebipenem pivoxil hydrobromide (at a dose of 600 mg every 8 hours) or intravenous ertapenem (at a dose of 1 g every 24 hours) for 7 to 10 days (or up to 14 days in patients with bacteremia). The primary efficacy end point was overall response (a composite of clinical cure and favorable microbiologic response) at a test-of-cure visit (on day 19, within a ±2-day window) in the microbiologic intention-to-treat population. The noninferiority margin was 12.5%. RESULTS: A total of 1372 hospitalized adult patients were enrolled; 868 patients (63.3%) were included in the microbiologic intention-to-treat population (50.8% of whom had complicated urinary tract infections and 49.2% of whom had pyelonephritis). An overall response was seen in 264 of 449 patients (58.8%) who received tebipenem pivoxil hydrobromide, as compared with 258 of 419 patients (61.6%) who received ertapenem (weighted difference, -3.3 percentage points; 95% confidence interval [CI], -9.7 to 3.2). Clinical cure at the test-of-cure visit was observed in 93.1% of the patients in the microbiologic intention-to-treat population who received tebipenem pivoxil hydrobromide and 93.6% of patients who received ertapenem (weighted difference, -0.6 percentage point; 95% CI, -4.0 to 2.8); the majority of patients with microbiologic response failures at the test-of-cure visit were asymptomatic patients with recurrent bacteriuria. Secondary and subgroup analyses were supportive of the primary analysis. Adverse events were observed in 25.7% of patients who received tebipenem pivoxil hydrobromide and in 25.6% of patients who received ertapenem; the most common adverse events were mild diarrhea and headache. CONCLUSIONS: Oral tebipenem pivoxil hydrobromide was noninferior to intravenous ertapenem in the treatment of complicated urinary tract infection and acute pyelonephritis and had a similar safety profile. (Funded by Spero Therapeutics and the Department of Health and Human Services; ADAPT-PO ClinicalTrials.gov number, NCT03788967.).

Food and Drug Administration Public Workshop Summary-Development Considerations of Antifungal Drugs to Address Unmet Medical Need.

Pressing challenges in the treatment of invasive fungal infections (IFIs) include emerging and rare pathogens, resistant/refractory infections, and antifungal armamentarium limited by toxicity, drug-drug interactions, and lack of oral formulations. Development of new antifungal drugs is hampered by the limitations of the available diagnostics, clinical trial endpoints, prolonged trial duration, difficulties in patient recruitment, including subpopulations (eg, pediatrics), and heterogeneity of the IFIs. On 4 August 2020, the US Food and Drug Administration convened a workshop that included IFI experts from academia, industry, and other government agencies to discuss the IFI landscape, unmet need, and potential strategies to facilitate the development of antifungal drugs for treatment and prophylaxis. This article summarizes the key topics presented and discussed during the workshop, such as incentives and research support for drug developers, nonclinical development, clinical trial design challenges, lessons learned from industry, and potential collaborations to facilitate antifungal drug development.

An open randomized multicentre Phase 2 trial to assess the safety of DAV132 and its efficacy to protect gut microbiota diversity in hospitalized patients treated with fluoroquinolones.

BACKGROUND: DAV132 (colon-targeted adsorbent) has prevented antibiotic-induced effects on microbiota in healthy volunteers. OBJECTIVES: To assess DAV132 safety and biological efficacy in patients. PATIENTS AND METHODS: An open-label, randomized [stratification: fluoroquinolone (FQ) indication] multicentre trial comparing DAV132 (7.5 g, 3 times a day, orally) with No-DAV132 in hospitalized patients requiring 5-21 day treatment with FQs and at risk of Clostridioides difficile infection (CDI). FQ and DAV132 were started simultaneously, DAV132 was administered for 48 h more, and patients were followed up for 51 days. The primary endpoint was the rate of adverse events (AEs) independently adjudicated as related to DAV132 and/or FQ. The planned sample size of 260 patients would provide a 95% CI of ±11.4%, assuming a 33% treatment-related AE rate. Plasma and faecal FQ concentrations, intestinal microbiota diversity, intestinal colonization with C. difficile, MDR bacteria and yeasts, and ex vivo resistance to C. difficile faecal colonization were assessed. RESULTS: Two hundred and forty-three patients (median age 71 years; 96% with chronic comorbidity) were included (No-DAV132, n = 120; DAV132, n = 123). DAV132- and/or FQ-related AEs did not differ significantly: 18 (14.8%) versus 13 (10.8%) in DAV132 versus No-DAV132 patients (difference 3.9%; 95% CI: -4.7 to 12.6). Day 4 FQ plasma levels were unaffected. DAV132 was associated with a >98% reduction in faecal FQ levels (Day 4 to end of treatment; P < 0.001), less impaired microbiota diversity (Shannon index; P = 0.003), increased ex vivo resistance to C. difficile colonization (P = 0.0003) and less frequent FQ-induced VRE acquisition (P = 0.01). CONCLUSIONS: In FQ-treated hospitalized patients, DAV132 was well tolerated, and FQ plasma concentrations unaffected. DAV132 preserved intestinal microbiota diversity and C. difficile colonization resistance.

First-in-Human Evaluation of the Safety, Tolerability, and Pharmacokinetics of SPR720, a Novel Oral Bacterial DNA Gyrase (GyrB) Inhibitor for Mycobacterial Infections.

SPR720 (phosphate prodrug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for nontuberculous mycobacterial pulmonary disease (NTM-PD) and pulmonary tuberculosis. SPR719 has demonstrated activity against clinically relevant mycobacteria in vitro and in murine and hollow-fiber infection models. This phase 1 randomized, double-blind, placebo-controlled, single ascending dose (SAD)/multiple ascending dose (MAD) trial evaluated the safety, tolerability, and pharmacokinetics of SPR720/SPR719. A total of 96 healthy volunteers (n = 8/cohort, 3:1 randomization) received SPR720 (or placebo) as single oral doses ranging from 100 to 2,000 mg or repeat total daily doses ranging from 500 to 1,500 mg for 7 or 14 days. SPR720 was well tolerated at daily doses of up to 1,000 mg for up to 14 days. Across SAD/MAD cohorts, the most common adverse events (AEs) were gastrointestinal (nausea, vomiting, and diarrhea) and headache, all of mild or moderate severity and dose dependent. No serious AEs were reported. The median SPR719 Tmax ranged from 2.8 to 8.0 h across cohorts, and the t1/2 ranged from 2.9 to 4.5 h and was shown to be dose independent. Dosing with food decreased SPR719 plasma exposure by approximately 20%. In the MAD cohorts, SPR719 plasma exposure declined approximately 40% between days 1 and 7, suggesting induction of an elimination pathway. However, plasma AUC0-24 was comparable between days 7 and 14. The results of this first-in-human study suggest that predicted therapeutic exposures of SPR719 can be attained with a once-daily oral administration of SPR720. (This study has been registered at ClinicalTrials.gov under registration no. NCT03796910.).

Pharmacodynamics of Cefepime Combined with the Novel Extended-Spectrum-ß-Lactamase (ESBL) Inhibitor Enmetazobactam for Murine Pneumonia Caused by ESBL-Producing Klebsiella pneumoniae.

Klebsiella pneumoniae strains that produce extended-spectrum beta lactamases (ESBLs) are a persistent public health threat. There are relatively few therapeutic options, and there is undue reliance on carbapenems. Alternative therapeutic options are urgently required. A combination of cefepime and the novel beta lactamase inhibitor enmetazobactam is being developed for the treatment of serious infections caused by ESBL-producing organisms. The pharmacokinetics-pharmacodynamics (PK-PD) of cefepime-enmetazobactam against ESBL-producing K. pneumoniae was studied in a neutropenic murine pneumonia model. Dose-ranging studies were performed. Dose fractionation studies were performed to define the relevant PD index for the inhibitor. The partitioning of cefepime and enmetazobactam into the lung was determined by comparing the area under the concentration-time curve (AUC) in plasma and epithelial lining fluid. The magnitude of drug exposure for cefepime-enmetazobactam required for logarithmic killing in the lung was defined using 3 ESBL-producing strains. Cefepime, given as 100 mg/kg of body weight every 8 h intravenously (q8h i.v.), had minimal antimicrobial effect. When this background regimen of cefepime was combined with enmetazobactam, a half-maximal effect was induced with enmetazobactam at 4.71 mg/kg q8h i.v. The dose fractionation study suggested both fT > threshold and fAUC:MIC are relevant PD indices. The AUCELF:AUCplasma ratio for cefepime and enmetazobactam was 73.4% and 61.5%, respectively. A ≥2-log kill in the lung was achieved with a plasma and ELF cefepime fT > MIC of ≥20% and enmetazobactam fT > 2 mg/liter of ≥20% of the dosing interval. These data and analyses provide the underpinning evidence for the combined use of cefepime and enmetazobactam for nosocomial pneumonia.

Evidence-Based Study Design for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia.

BACKGROUND: The US Food and Drug Administration solicited evidence-based recommendations to improve guidance for studies of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). METHODS: We analyzed 7 HABP/VABP datasets to explore novel noninferiority study endpoints and designs, focusing on alternatives to all-cause mortality (ACM). RESULTS: ACM at day 28 differed for ventilated HABP (27.8%), VABP (18.0%), and nonventilated HABP (14.5%). A "mortality-plus" (ACM+) composite endpoint was constructed by combining ACM with patient-relevant, infection-related adverse events from the Medical Dictionary for Regulatory Activities toxic/septic shock standardized query. The ACM+ rate was 3-10 percentage points above that of ACM across the studies and treatment groups. Predictors of higher ACM/ACM+ rates included older age and elevated acute physiology and chronic health evaluation (APACHE) II score. Only patients in the nonventilated HABP group were able to report pneumonia symptom changes. CONCLUSIONS: If disease groups and patient characteristics in future studies produce an ACM rate so low (<10%-15%) that a fixed noninferiority margin of 10% cannot be justified (requiring an odds ratio analysis), an ACM+ endpoint could lower sample size. Enrichment of studies with patients with a higher severity of illness would increase ACM. Data on symptom resolution in nonventilated HABP support development of a patient-reported outcome instrument.

Fosfomycin for Injection (ZTI-01) Versus Piperacillin-tazobactam for the Treatment of Complicated Urinary Tract Infection Including Acute Pyelonephritis: ZEUS, A Phase 2/3 Randomized Trial.

BACKGROUND: ZTI-01 (fosfomycin for injection) is an epoxide antibiotic with a differentiated mechanism of action (MOA) inhibiting an early step in bacterial cell wall synthesis. ZTI-01 has broad in vitro spectrum of activity, including multidrug-resistant Gram-negative pathogens, and is being developed for treatment of complicated urinary tract infection (cUTI) and acute pyelonephritis (AP) in the United States. METHODS: Hospitalized adults with suspected or microbiologically confirmed cUTI/AP were randomized 1:1 to 6 g ZTI-01 q8h or 4.5 g intravenous (IV) piperacillin-tazobactam (PIP-TAZ) q8h for a fixed 7-day course (no oral switch); patients with concomitant bacteremia could receive up to 14 days. RESULTS: Of 465 randomized patients, 233 and 231 were treated with ZTI-01 and PIP-TAZ, respectively. In the microbiologic modified intent-to-treat (m-MITT) population, ZTI-01 met the primary objective of noninferiority compared with PIP-TAZ with overall success rates of 64.7% (119/184 patients) vs 54.5% (97/178 patients), respectively; treatment difference was 10.2% (95% confidence interval [CI]: -0.4, 20.8). Clinical cure rates at test of cure (TOC, day 19-21) were high and similar between treatments (90.8% [167/184] vs 91.6% [163/178], respectively). In post hoc analysis using unique pathogens typed by pulsed-field gel electrophoresis, overall success rates at TOC in m-MITT were 69.0% (127/184) for ZTI-01 versus 57.3% (102/178) for PIP-TAZ (difference 11.7% 95% CI: 1.3, 22.1). ZTI-01 was well tolerated. Most treatment-emergent adverse events, including hypokalemia and elevated serum aminotransferases, were mild and transient. CONCLUSIONS: ZTI-01 was effective for treatment of cUTI including AP and offers a new IV therapeutic option with a differentiated MOA for patients with serious Gram-negative infections. CLINICAL TRIAL REGISTRATION: NCT02753946.

Safety, Pharmacokinetics, and Food Effect of Tebipenem Pivoxil Hydrobromide after Single and Multiple Ascending Oral Doses in Healthy Adult Subjects.

Tebipenem pivoxil hydrobromide (TBPM-PI-HBr, formerly SPR994) is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) Gram-negative pathogens, including quinolone-resistant and extended-spectrum-ß-lactamase-producing Enterobacteriaceae The safety and pharmacokinetics (PK) of tebipenem were studied after administration of single and multiple ascending oral doses of TBPM-PI-HBr in fed and fasted states. Healthy adults received single oral doses of TBPM-PI-HBr at 100 mg to 900 mg or placebo (n = 108) or multiple doses of 300 mg or 600 mg every 8 h or placebo (n = 16) for 14 days. In the single-ascending-dose (SAD) phase, mean tebipenem plasma concentrations increased in a linear and dose proportional manner for doses of 100 to 900 mg and were comparable in the fasted and fed states for the 300- and 600-mg doses. In the MAD phase, tebipenem maximum concentration (Cmax) was reached within 1.5 h and was dose proportional on day 1 and higher than dose proportional (2.7-fold) on day 14. AUC was more than 2-fold greater on day 1 (2.7-fold) and day 14 (2.5-fold) for 600 mg q8h than for 300 mg q8h. Approximately 55% to 60% of tebipenem was recovered in the urine. TBPM-PI-HBr was well tolerated; mild, transient diarrhea was the most commonly reported adverse event. TBPM-PI-HBr provides an orally bioavailable carbapenem option to treat serious infections caused by MDR Enterobacteriaceae and has the potential to decrease the need for intravenous antibiotic therapy in the hospital or outpatient setting. (This study has been registered at ClinicalTrials.gov under identifier NCT03395249.).

Pharmacodynamics of Tebipenem: New Options for Oral Treatment of Multidrug-Resistant Gram-Negative Infections.

Tebipenem pivoxil HBr (TBPM-PI-HBr) is a novel orally bioavailable carbapenem. The active moiety is tebipenem. Tebipenem pivoxil is licensed for use in Japan in children with ear, nose, and throat infections and respiratory infections. The HBr salt was designed to improve drug substance and drug product properties, including stability. TBPM-PI-HBr is now being developed as an agent for the treatment of complicated urinary tract infections (cUTI) in adults. The pharmacokinetics-pharmacodynamics of tebipenem were studied in a well-characterized neutropenic murine thigh infection model. Plasma drug concentrations were measured using liquid chromatography-tandem mass spectrometry. Dose fractionation experiments were performed after establishing dose-response relationships. The magnitude of drug exposure required for stasis was established using 11 strains of Enterobacteriaceae (Escherichia coli, n = 6; Klebsiella pneumoniae, n = 5) with a variety of resistance mechanisms. The relationship between drug exposure and the emergence of resistance was established in a hollow-fiber infection model (HFIM). Tebipenem exhibited time-dependent pharmacodynamics that were best described by the free drug area under the concentration-time curve (fAUC0-24)/MIC corrected for the length of the dosing interval (fAUC0-24/MIC · 1/tau). The pharmacodynamics of tebipenem versus E. coli and K. pneumoniae were comparable, as was the response of strains possessing extended-spectrum ß-lactamases versus the wild type. The median fAUC0-24/MIC · 1/tau value for the achievement of stasis in the 11 strains was 23. Progressively more fractionated regimens in the HFIM resulted in the suppression of resistance. An fAUC0-24/MIC · 1/tau value of 34.58 to 51.87 resulted in logarithmic killing and the suppression of resistance. These data and analyses will be used to define the regimen for a phase III study of adult patients with cUTI.

Software for Dosage Individualization of Voriconazole: a Prospective Clinical Study.

Voriconazole is a first-line antifungal agent. Therapeutic drug monitoring is a standard of care. The best way to adjust dosages to achieve desired drug exposure endpoints is unclear due to nonlinear and variable pharmacokinetics. Previously described software was used to prospectively adjust voriconazole dosages. The CYP2C19, CYP3A4, and CYP3A5 genotypes were determined. The primary endpoint was the proportion of patients with a Cmin at 120 h in the range 1 to 3 mg/liter using software to adjust voriconazole dosages. A total of 19 patients were enrolled, and 14 were evaluable. Of these, 12/14 (85.7%; 95% confidence interval = 57.2 to 98.2%) had a Cmin at 120 h posttreatment initiation of 1 to 3 mg/liter, which was higher than the a priori expected proportion of 33%. There was no association of CYP genotype-derived metabolizer phenotype with voriconazole AUC. Software can be used to adjust the dosages of voriconazole to achieve drug exposures that are safe and effective. (The clinical trial discussed in this paper has been registered in the European Clinical Trials Database under EudraCT no. 2013-0025878-34 and in the ISRCTN registry under no. ISRCTN83902726.).

Subgroup analysis and interpretation for phase 3 confirmatory trials: White paper of the EFSPI/PSI working group on subgroup analysis.

Subgroup by treatment interaction assessments are routinely performed when analysing clinical trials and are particularly important for phase 3 trials where the results may affect regulatory labelling. Interpretation of such interactions is particularly difficult, as on one hand the subgroup finding can be due to chance, but equally such analyses are known to have a low chance of detecting differential treatment effects across subgroup levels, so may overlook important differences in therapeutic efficacy. EMA have therefore issued draft guidance on the use of subgroup analyses in this setting. Although this guidance provided clear proposals on the importance of pre-specification of likely subgroup effects and how to use this when interpreting trial results, it is less clear which analysis methods would be reasonable, and how to interpret apparent subgroup effects in terms of whether further evaluation or action is necessary. A PSI/EFSPI Working Group has therefore been investigating a focused set of analysis approaches to assess treatment effect heterogeneity across subgroups in confirmatory clinical trials that take account of the number of subgroups explored and also investigating the ability of each method to detect such subgroup heterogeneity. This evaluation has shown that the plotting of standardised effects, bias-adjusted bootstrapping method and SIDES method all perform more favourably than traditional approaches such as investigating all subgroup-by-treatment interactions individually or applying a global test of interaction. Therefore, these approaches should be considered to aid interpretation and provide context for observed results from subgroup analyses conducted for phase 3 clinical trials.

Optimizing the Design and Analysis of Clinical Trials for Antibacterials Against Multidrug-resistant Organisms: A White Paper From COMBACTE's STAT-Net.

Innovations are urgently required for clinical development of antibacterials against multidrug-resistant organisms. Therefore, a European, public-private working group (STAT-Net; part of Combatting Bacterial Resistance in Europe [COMBACTE]), has reviewed and tested several innovative trials designs and analytical methods for randomized clinical trials, which has resulted in 8 recommendations. The first 3 focus on pharmacokinetic and pharmacodynamic modeling, emphasizing the pertinence of population-based pharmacokinetic models, regulatory procedures for the reassessment of old antibiotics, and rigorous quality improvement. Recommendations 4 and 5 address the need for more sensitive primary end points through the use of rank-based or time-dependent composite end points. Recommendation 6 relates to the applicability of hierarchical nested-trial designs, and the last 2 recommendations propose the incorporation of historical or concomitant trial data through Bayesian methods and/or platform trials. Although not all of these recommendations are directly applicable, they provide a solid, evidence-based approach to develop new, and established, antibacterials and address this public health challenge.

Progress in the Fight Against Multidrug-Resistant Bacteria 2005-2016: Modern Noninferiority Trial Designs Enable Antibiotic Development in Advance of Epidemic Bacterial Resistance.

From a public health perspective, new antibacterial agents should be evaluated and approved for use before widespread resistance to existing agents emerges. However, for multidrug-resistant pathogens, demonstration of superior efficacy of a new agent over a current standard-of-care agent is routinely feasible only when epidemic spread of these dangerous organisms has already occurred. One solution to enable proactive drug development is to evaluate new antibiotics with improved in vitro activity against MDR pathogens using recently updated guidelines for active control, noninferiority trials of selected severe infections caused by more susceptible pathogens. Such trials are feasible because they enroll patients with infections due to pathogens with a "usual drug resistance" phenotype that will be responsive to widely registered standard-of-care comparator antibiotics. Such anticipatory drug development has constructively reshaped the antibiotic pipeline and offers the best chance of making safe and efficacious antibiotics available to the public ahead of epidemic resistance.

Efficient Delivery of Investigational Antibacterial Agents via Sustainable Clinical Trial Networks.

The economics of antibiotics can be improved by infectious diseases-specific clinical trial networks. While developers would still need to implement an independent phase 1 program as well as studies focused on highly resistant pathogens, standardized procedures in a network focused on usual drug resistance phenotype isolates would permit sharing of controls and would predictably generate high-quality pivotal data for product registration while creating cost and time savings in the range of 30%-40%. This would reduce economic barriers to antibiotic development and contribute to public health.

Confidence intervals for the difference between independent binomial proportions: comparison using a graphical approach and moving averages.

This paper uses graphical methods to illustrate and compare the coverage properties of a number of methods for calculating confidence intervals for the difference between two independent binomial proportions. We investigate both small-sample and large-sample properties of both two-sided and one-sided coverage, with an emphasis on asymptotic methods. In terms of aligning the smoothed coverage probability surface with the nominal confidence level, we find that the score-based methods on the whole have the best two-sided coverage, although they have slight deficiencies for confidence levels of 90% or lower. For an easily taught, hand-calculated method, the Brown-Li 'Jeffreys' method appears to perform reasonably well, and in most situations, it has better one-sided coverage than the widely recommended alternatives. In general, we find that the one-sided properties of many of the available methods are surprisingly poor. In fact, almost none of the existing asymptotic methods achieve equal coverage on both sides of the interval, even with large sample sizes, and consequently if used as a non-inferiority test, the type I error rate (which is equal to the one-sided non-coverage probability) can be inflated. The only exception is the Gart-Nam 'skewness-corrected' method, which we express using modified notation in order to include a bias correction for improved small-sample performance, and an optional continuity correction for those seeking more conservative coverage. Using a weighted average of two complementary methods, we also define a new hybrid method that almost matches the performance of the Gart-Nam interval.

Statistical considerations associated with a comprehensive regulatory framework to address the unmet need for new antibacterial therapies.

At present, there are situations in antibiotic drug development where the low number of enrollable patients with key problem pathogens makes it impossible to conduct fully powered non-inferiority trials in the traditional way. Recent regulatory changes have begun to address this situation. In parallel, statistical issues regarding the application of alternative techniques, balancing the unmet need with the level of certainty in the approval process, and the use of additional sources of data are critical areas to increase development feasibility. Although such approaches increase uncertainty compared with a traditional development program, this will be necessary to allow new agents to be made available. Identification of these risks and explicit discussion around requirements in these areas should help clarify the situation, and hence, the feasibility of developing drugs to treat the most concerning pathogens before the unmet need becomes even more acute than at present.

Exeporfinium chloride (XF-73) nasal gel significantly reduces Staphylococcus aureus nasal carriage in cardiac surgery patients throughout surgery and the early recovery period: results from a randomized placebo-controlled Phase 2 study.

Staphylococcus aureus nasal carriers were randomized (1:1) to XF-73 or placebo nasal gel, administered 5x over ∼24hrs pre-cardiac surgery. S. aureus burden rapidly decreased after 2 doses (-2.2log10 CFU/mL; placebo -0.01log10 CFU/mL) and was maintained to 6 days post-surgery. Among XF-73 patients, 46.5% received post-operative anti-staphylococcal antibiotics versus 70% in placebo (P = 0.045).

Exeporfinium chloride (XF-73) nasal gel dosed over 24 hours prior to surgery significantly reduced Staphylococcus aureus nasal carriage in cardiac surgery patients: Safety and efficacy results from a randomized placebo-controlled phase 2 study.

We studied 83 cardiac-surgery patients with nasal S. aureus carriage who received 4 intranasal administrations of XF-73 nasal gel or placebo <24 hours before surgery. One hour before surgery, patients exhibited a S. aureus nasal carriage reduction of 2.5 log10 with XF-73 compared to 0.4 log10 CFU/mL for those who received placebo (95% CI, -2.7 to -1.5; P < .0001).

The Value of the Information That Can Be Generated: Optimizing Study Design to Enable the Study of Treatments Addressing an Unmet Need for Rare Pathogens.

In traditional phase 3 trials confirming safety and efficacy of new treatments relative to a comparator, a 1-sided type I error rate of 2.5% is traditionally used and typically leads to minimum sizes of 300-600 subjects per study. However, for rare pathogens, it may be necessary to work with data from as few as 50-100 subjects. For areas with a high unmet need, there is a balance between traditional type I error and power and enabling feasible studies. In such cases, an alternative 1-sided alpha level of 5% or 10% should be considered, and we review herein the implications of such approaches. Resolving this question requires engagement of patients, the medical community, regulatory agencies, and trial sponsors.