FDA, CDC, and NIH Co-sponsored Public Workshop Summary-Development Considerations of Antimicrobial Drugs for the Treatment of Gonorrhea.

There is an unmet need for developing drugs for the treatment of gonorrhea, due to rapidly evolving resistance of Neisseria gonorrhoeae against antimicrobial drugs used for empiric therapy, an increase in globally reported multidrug resistant cases, and the limited available therapeutic options. Furthermore, few drugs are under development. Development of antimicrobials is hampered by challenges in clinical trial design, limitations of available diagnostics, changes in and varying standards of care, lack of robust animal models, and clinically relevant pharmacodynamic targets.

Moving Beyond Mortality: Development and Application of a Desirability of Outcome Ranking (DOOR) Endpoint for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia.

Background: Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) are frequently caused by multidrug-resistant organisms. Patient-centered endpoints in clinical trials are needed to develop new antibiotics for HABP/VABP. Desirability of outcome ranking (DOOR) is a paradigm for the design, analysis, and interpretation of clinical trials based on a patient-centered, benefit-risk evaluation.

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.

Antibiotics needed to treat multidrug-resistant infections in neonates.

Infections remain a leading cause of death in neonates. The sparse antibiotic development pipeline and challenges in conducting neonatal research have resulted in few effective antibiotics being adequately studied to treat multidrug-resistant (MDR) infections in neonates, despite the increasing global mortality burden caused by antimicrobial resistance. Of 40 antibiotics approved for use in adults since 2000, only four have included dosing information for neonates in their labelling.

Improving Traditional Registrational Trial End Points: Development and Application of a Desirability of Outcome Ranking End Point for Complicated Urinary Tract Infection Clinical Trials.

Background: Traditional end points used in registrational randomized, controlled trials (RCTs) often do not allow for complete interpretation of the full range of potential clinical outcomes. Desirability of outcome ranking (DOOR) is an approach to the design and analysis of clinical trials that incorporates benefits and risks of novel treatment strategies and provides a global assessment of patient experience.

Methods: Through a multidisciplinary committee of experts in infectious diseases, clinical trial design, drug regulation, and patient experience, we developed a DOOR end point for infectious disease syndromes and demonstrated how this could be applied to 3 registrational drug trials (ZEUS, APEKS-cUTI, and DORI-05) for complicated urinary tract infections (cUTIs).

Cefiderocol Dosing for Patients Receiving Continuous Renal Replacement Therapy.

In this report, we describe our scientific approach for including effluent flow rate (Q )-based dosing recommendations of cefiderocol for patients receiving continuous renal replacement therapy (CRRT) in the product labeling. The total clearance (CL) of cefiderocol in patients receiving CRRT was estimated as the sum of patients' nonrenal clearance (CL ) and extracorporeal clearance by CRRT (CL ), based on the following rationale: (a) The renal clearance (CL ) of cefiderocol is assumed to be negligible in patients receiving CRRT, (b) CL represents the CRRT patients' own remaining systemic clearance and is estimated from the observed clearance in participants with creatinine clearance (CLcr) < 15 mL/minute without undergoing hemodialysis, and (c) CL was estimated by the product of unbound (free) fraction of plasma drug concentration (f ) and Q because the free fraction of low-molecular-weight compounds like cefiderocol (752 Da) can be completely filtered by CRRT, regardless of CRRT modality. Hence, cefiderocol CL in CRRT patients was calculated by the equation of CL = CL  + f  × Q .

FDA Public Workshop Summary-Coccidioidomycosis (Valley Fever): Considerations for Development of Antifungal Drugs.

Coccidioidomycosis is a fungal disease endemic to the southwestern United States, Mexico, and Central and South America. Prevalence rates are increasing steadily, and new endemic areas of Coccidioides are emerging. Standard treatment is often administered for months to decades, and intolerance to medications and treatment failures are common.

US Food and Drug Administration (FDA): Benefit-Risk Considerations for Cefiderocol (Fetroja®).

In November 2019, the Food and Drug Administration (FDA) approved cefiderocol for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by susceptible gram-negative bacteria in adults with limited to no alternative treatment options based on a randomized, double-blind, noninferiority cUTI trial (APEKS-cUTI). In a randomized, open-label trial (CREDIBLE-CR) in patients with cUTI, nosocomial pneumonia, bloodstream infections, or sepsis due to carbapenem-resistant gram-negative bacteria, an increase in all-cause mortality was observed in patients treated with cefiderocol as compared to best available therapy. The cause of the increased mortality was not established, but some deaths were attributed to treatment failure.

Trends in Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia Trials.

Background: New drug development for hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) is critical. Challenges remain in the conduct of HABP/VABP trials, especially in the contexts of enrollment, endpoints, nonstudy antibacterial drug therapy, and antimicrobial resistance.

Methods: Four Phase 3 noninferiority trials (n = 2433 participants) submitted to the Food and Drug Administration after 2015 were analyzed for enrollment statistics, participant characteristics associated with 28-day all-cause mortality (ACM), microbiology, and receipt of nonstudy antibacterial drugs.

Concordance of Early and Late End Points for Community-acquired Bacterial Pneumonia Trials.

Background: While there are ongoing regulatory convergence efforts, differences remain in primary end points recommended for community-acquired bacterial pneumonia (CABP) trials. The US Food and Drug Administration (FDA) recommends assessing CABP symptom resolution at an early time point (3-5 days after randomization). Other regulatory agencies recommend assessing overall clinical response at a later time point (5-10 days after therapy ends).

Achieving Regulatory Alignment for Anti-Infective Clinical Trials.

The growing concern of antimicrobial resistance coupled with the dearth of new antibacterial agents in development is a major public health threat. Multiple stakeholder efforts are underway to address the various challenges facing this field; while some progress has been made, antibacterial drug development continues to be a challenging area. The economic issues encountered in this space are probably today the most cogent; however, there are many other aspects that continue to pose challenges to enterprises engaging in this area, from the difficulties in discovering and advancing new classes of products to scientific issues with clinical trial design and feasibility in conducting these trials.

Pediatric Antibacterial and Antifungal Trials From 2007 to 2017.

Background And Objectives: The impact of the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) on pediatric antibacterial or antifungal drug trials is unknown. Our objective was to identify and characterize trials conducted under the BPCA and/or the PREA.

Methods: Pediatric antibacterial and antifungal drug trials with industry or US federal funding registered in clinicaltrials.

Facilitators and barriers to the successful implementation of pediatric antibacterial drug trials: Findings from CTTI's survey of investigators.

An urgent need exists to develop new antibacterial drugs for children. We conducted research with investigators of pediatric antibacterial drug trials to identify facilitators and barriers in the conduct of these trials. Seventy-three investigators completed an online survey assessing the importance of 15 facilitators (grouped in 5 topical categories) and the severity of 36 barriers (grouped in 6 topical categories) to implementing pediatric antibacterial drug trials.

Parents' perceived obstacles to pediatric clinical trial participation: Findings from the clinical trials transformation initiative.

Enrollment of children into pediatric clinical trials remains challenging. More effective strategies to improve recruitment of children into trials are needed. This study used in-depth qualitative interviews with parents who were approached to enroll their children in a clinical trial in order to gain an understanding of the barriers to pediatric clinical trial participation.

Perceived barriers to pediatrician and family practitioner participation in pediatric clinical trials: Findings from the Clinical Trials Transformation Initiative.

Despite legislation to stimulate pediatric drug development through clinical trials, enrolling children in trials continues to be challenging. Non-investigator (those who have never served as a clinical trial investigator) providers are essential to recruitment of pediatric patients, but little is known regarding the specific barriers that limit pediatric providers from participating in and referring their patients to clinical trials. We conducted an online survey of pediatric providers from a wide variety of practice types across the United States to evaluate their attitudes and awareness of pediatric clinical trials.

Advancing Pediatric Antibacterial Drug Development: A Critical Need to Reinvent our Approach.

The Clinical Trials Transformation Initiative convened with several groups in the pediatric antibacterial drug development community with the goal of identifying challenges and recommending ways to improve current practice. Attention to 5 major areas hold the promise of making new antibiotics available for use in children as soon as possible after they are approved for use in adults.

Adverse Events Associated with Fosfomycin Use: Review of the Literature and Analyses of the FDA Adverse Event Reporting System Database.

Introduction: The growing problem of antibacterial resistance resulted in an increased interest in fosfomycin, especially its parenteral formulation. We reviewed fosfomycin safety profile using the Food and Drug Administration Adverse Event (AE) Reporting System (FAERS) and published literature.

Methods: We conducted a FAERS search and disproportionality analysis of all fosfomycin-associated AEs.

Hypoglycemia in patients treated with linezolid.

Hypoglycemia was not previously known to be a linezolid-associated adverse reaction. A case report describing symptomatic hypoglycemia in a linezolid recipient prompted a review of the US Food and Drug Administration Adverse Event Reporting System, which demonstrated a relationship between linezolid and hypoglycemia. A warning with this information was added to the linezolid package insert.

Use of an active surveillance system by the FDA to observe patterns of quinine sulfate use and adverse hematologic outcomes in CMS Medicare data.

Purpose: In 2005, the Food and Drug Administration approved Qualaquin (quinine) for treatment of malaria and later ordered unapproved quinine formulations off the market. In 2009, labeling for Qualaquin added a warning for use for leg cramps, as serious hematologic reactions could occur. We examined quinine use trends among Medicare beneficiaries focusing on indications for use and associations with adverse hematologic outcomes.

Hypersensitivity reactions associated with fidaxomicin use.

We report hypersensitivity reactions associated with fidaxomicin, an antibacterial drug approved for the treatment of Clostridium difficile-associated diarrhea. These reactions are viewed as significant because of severity and unexpected because fidaxomicin is minimally absorbed. The fidaxomicin labeling was revised to include information about the possibility of hypersensitivity reactions.