Impact of the 2019 Food and Drug Administration Guidance for Uncomplicated Urinary Tract Infection on Treatment Response Rates: A Reanalysis of a Clinical Trial of Nitrofurantoin vs Fosfomycin.

Background: Current US Food and Administration (FDA) guidance recommends that the primary efficacy endpoint for uncomplicated urinary tract infection (uUTI) clinical trials be a composite of clinical and microbiological responses. We applied these criteria to a previous clinical trial to determine the impact on treatment outcomes. Methods: We conducted a patient-level reanalysis of a randomized clinical trial of nitrofurantoin versus fosfomycin for treatment of uUTI in nonpregnant adult women. Women were included in the reanalysis if they had 2 or more signs/symptoms of uUTI and a single bacterial species isolated from baseline urine culture at ≥105 colony-forming units (CFU)/mL. The applied primary efficacy endpoint-therapeutic response-required both clinical resolution of signs/symptoms and reduction of the infecting bacterial pathogen to <103 CFU/mL at day 14 post-treatment completion. Results: Two hundred eleven of 513 (41%) patients were eligible for inclusion in the reanalysis. Among these patients, 74% (76/103) and 69% (75/108) in the nitrofurantoin and fosfomycin groups, respectively, achieved clinical resolution by day 14. Similarly, 70% (72/103) and 67% (72/108) in each group achieved microbiological success at day 14. As such, 59% (61/103) and 57% (62/108) of women in each group met the primary efficacy endpoint-therapeutic success-at day 14. In comparison, 75% and 66% of patients in each group achieved clinical resolution at day 14 in the initial clinical trial. Conclusions: Applying current FDA guidance resulted in lower composite efficacy rates than clinical resolution alone as observed in the initial clinical trial. This may limit the ability to compare antibiotic treatment effects between historical and future clinical trials.

Efficacy and Safety of Gepotidacin as Treatment of Uncomplicated Urogenital Gonorrhea (EAGLE-1): Design of a Randomized, Comparator-Controlled, Phase 3 Study.

INTRODUCTION: Gonorrhea, caused by Neisseria gonorrhoeae (NG), is the second most common bacterial sexually transmitted infection (STI). Rates of antimicrobial resistance to standard care are increasing worldwide, with many antibiotic classes now ineffective against NG. Gepotidacin is a first-in-class, bactericidal, triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by inhibition of two enzymes, where a single target-specific mutation does not significantly impact susceptibility. Gepotidacin confers activity against NG, including most strains resistant to marketed antibiotics. Here, we describe the design of a phase 3 clinical trial (EAGLE-1; NCT04010539) evaluating gepotidacin for the treatment of uncomplicated urogenital gonorrhea. METHODS: This phase 3, randomized, multicenter, sponsor-blinded, noninferiority study across six countries is comparing the efficacy of gepotidacin with ceftriaxone plus azithromycin in 400 patients with uncomplicated urogenital gonorrhea (microbiological intent-to-treat population) and assessing the safety of gepotidacin in approximately 600 patients (intent-to-treat population). Eligible participants 12 years of age or older with clinical suspicion of urogenital gonococcal infection and a NG-positive urogenital sample and/or purulent discharge are randomized 1:1 to receive oral gepotidacin (2 × 3000 mg 10-12 h apart) or ceftriaxone (500 mg, intramuscular) plus azithromycin (1 g, oral). The primary endpoint is culture-confirmed bacterial eradication of NG from the urogenital site at the test-of-cure (days 4-8) visit. PLANNED OUTCOMES: This trial was designed in accordance with US Food and Drug Administration (2015) and European Medicines Agency (2011) guidance, particularly the primary endpoint and microbiological evaluability requirements. This study will help characterize the risk-benefit profile of gepotidacin for treating uncomplicated urogenital gonorrhea. Gepotidacin is an important potential treatment for gonorrhea to help address the urgent unmet need of multidrug resistance and the increasingly limited number of oral treatment options. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04010539.

A paradigm shift in cystic fibrosis nutritional care: Clinicians' views on the management of patients with overweight and obesity.

BACKGROUND: Overweight and obesity among people with cystic fibrosis (pwCF) has become more prevalent since the widespread adoption of CF transmembrane conductance regulator (CFTR) modulator therapies and presents a new challenge for nutritional care. We aimed to explore how clinicians working in CF care approach the management of adults with overweight and obesity. METHODS: We conducted semi-structured interviews with n = 20 clinicians (n = 6 physiotherapists, n = 6 doctors and n = 8 dietitians) working in 15 adult CF centres in the United Kingdom. The interviews explored their perspectives and current practices caring for people with CF and overweight/obesity. Data were analysed using reflexive thematic analysis. RESULTS: Four main themes were identified: 1) challenges of raising the topic of overweight and obesity in the CF clinic (e.g., clinician-patient rapport and concerns around weight stigma); 2) the changing landscape of assessment due to CF-specific causes of weight gain: (e.g., impact of CFTR modulators and CF legacy diet) 3) presence of clinical equipoise for weight management due to the lack of CF-specific evidence on the consequences of obesity and intentional weight loss (e.g., unclear consequences on respiratory outcomes and risk of weight related co-morbidities) and 4) opportunities for a safe, effective, and acceptable weight management treatment for people with CF (e.g., working collaboratively with current multidisciplinary CF care). CONCLUSIONS: Approaching weight management in the CF setting is complex. Trials are needed to assess the equipoise of weight management interventions in this group and CF-specific issues should be considered when developing such interventions.

Respiratory Viruses and Cystic Fibrosis.

The threat of respiratory virus infection to human health and well-being has been clearly highlighted by the coronavirus disease 2019 (COVID-19) pandemic. For people with cystic fibrosis (CF), the clinical significance of viral infections long predated the emergence of severe acute respiratory syndrome coronavirus 2. This article reviews the epidemiology, diagnosis, and treatment of respiratory virus infection in the context of CF as well as the current understanding of interactions between viruses and other microorganisms in the CF lung. The incidence of respiratory virus infection in CF varies by age with young children typically experiencing more frequent episodes than adolescents and adults. At all ages, respiratory viruses are very common in CF and are associated with pulmonary exacerbations. Respiratory viruses are identified at up to 69% of exacerbations, while viruses are also frequently detected during clinical stability. The full impact of COVID-19 in CF is yet to be established. Early studies found that rates of COVID-19 were lower in CF cohorts than in the general population. The reasons for this are unclear but may be related to the effects of shielding, infection control practices, maintenance CF therapies, or the inflammatory milieu in the CF lung. Observational studies have consistently identified that prior solid organ transplantation is a key risk factor for poor outcomes from COVID-19 in CF. Several key priorities for future research are highlighted. First, the impact of highly effective CFTR modulator therapy on the epidemiology and pathophysiology of viral infections in CF requires investigation. Second, the impact of respiratory viruses on the development and dynamics of the CF lung microbiota is poorly understood and viral infection may have important interactions with bacteria and fungi in the airway. Finally, bacteriophages represent a key focus of future investigation both for their role in transmission of antimicrobial resistance and as a promising treatment modality for multiresistant pathogens.

Clinical associations with carriage of pulmonary Stenotrophomonas maltophilia.

BACKGROUND: Stenotrophomonas maltophilia causes opportunistic respiratory infections and is associated with declining lung function in patients with cystic fibrosis (CF). Risk factors for carrying S. maltophilia remain unclear. METHODS: We conducted a retrospective study of patients yielding ⩾1 respiratory S. maltophilia isolate at the Oxford University Hospitals Trust between 2014 and 2019 and a cohort study of S. maltophilia carriage in CF patients attending annual review in 2018. RESULTS: Seven hundred and forty isolates were identified from 238 patients (median 1.0 isolate/patient). Predisposing conditions included invasive ventilation (29.8%), CF (25.6%) and non-CF bronchiectasis (24.4%). The rates of Stenotrophomonas isolates and co-trimoxazole resistance were stable over time. About 10.8% of isolates were co-trimoxazole-resistant, with resistance more common in CF than in other diagnoses (29.5% vs 5.8%, p < 0.001). No clinical features were significantly associated with S. maltophilia carriage in the CF population. DISCUSSION: We present new insight into the epidemiology of Stenotrophomonas colonisation/infection and identify increased co-trimoxazole resistance in CF isolates.

How good is end of life care for patients dying with cystic fibrosis?

BACKGROUND: Cystic Fibrosis (CF) is a life-limiting illness. Audit of the care of patients dying of CF has not been published to date. METHODS: Newcastle and Oxford teams adapted the National Audit of Care at the End of Life and agreed additional questions that were particularly pertinent for patients dying as a consequence of their CF. Data were extracted and analysed for 15 patients. RESULTS: On recognition that the patient was dying, the CF teams were less good at reviewing the need for physiological observations (50% vs national 70%) but better at reviewing the need for capillary blood glucose monitoring, oxygen support and intravenous antibiotics compared with the national average for all patients.On recognition that the patient was dying, the CF teams were better at assessing pain (87% vs national 80%) and breathlessness (93% vs national 73%), but less good at assessing nausea and vomiting (47% vs national 74%).There was documented evidence that 100% of families and 64% of patients were aware that the patient was at risk of dying. CONCLUSION: Comparing care of this sample of patients dying with CF against the national data is a useful first step in understanding that many aspects of care are of high quality. This audit identifies the need to offer earlier conversations to patients as their voices may be missing from the conversation. Undertaking a national audit would provide a more reliable and a fuller picture.

Diagnosis of cystic fibrosis in adulthood and eligibility for novel CFTR modulator therapy.

BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive condition that primarily manifests as a chronic respiratory disease. CF is usually diagnosed in early childhood or through newborn screening although in a small but important group, diagnosis is not made until adulthood. Highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are now available for most genetic causes of CF highlighting the importance of identifying people with late presentations of CF. AIM: We aimed to identify the clinical characteristics of people diagnosed with CF in adulthood and their resulting eligibility for novel CFTR modulator therapies. DESIGN: Retrospective single-centre cohort study. METHODS: Patients diagnosed with CF at age 18 years or older were identified from a patient database. Paper and electronic medical records were reviewed and clinical, microbiological and radiological data at diagnosis were recorded. RESULTS: Nineteen patients were identified. Median age at diagnosis was 38 years (range: 19-71) and 9 (47%) were female. All patients had a history of chronic respiratory symptoms and 18/19 (94%) had radiological evidence of bronchiectasis. All patients had two pathogenic CFTR mutations identified with 16/19 (84%) compound heterozygotes for the F508del mutation. The majority of patients had a CFTR genotype considered eligible for CFTR modulator therapy (84% and 89% according to European and US licences, respectively). CONCLUSIONS: Adult patients with unexplained chronic bronchiectasis should be thoroughly investigated for CF. A low index of suspicion will help to identify adults with undiagnosed CF who are likely to benefit from CFTR modulator therapy.

Using a learning health system to understand the mismatch between medicines supply and actual medicines use among adults with cystic fibrosis.

BACKGROUND: Studies in separate cohorts suggest possible discrepancies between inhaled medicines supplied (median 50-60%) and medicines used (median 30-40%). We performed the first study that directly compares CF medicine supply against use to identify the cost of excess medicines supply. METHODS: This cross-sectional study included participants from 12 UK adult centres with ≥1 year of continuous adherence data from data-logging nebulisers. Medicine supply was measured as medication possession ratio (MPR) for a 1-year period from the first suitable supply date. Medicine use was measured as electronic data capture (EDC) adherence over the same period. The cost of excess medicines was calculated as whole excess box(es) supplied after accounting for the discrepancy between EDC adherence and MPR with 20% contingency. RESULTS: Among 275 participants, 133 (48.4%) were females and mean age was 30 years (95% CI 29-31 years). Median EDC adherence was 57% (IQR 23-86%), median MPR was 74% (IQR 46-96%) and the discrepancy between measures was median 14% (IQR 2-29%). Even with 20% contingency, mean potential cost of excess medicines was £1,124 (95% CI £855-1,394), ranging from £183 (95% CI £29-338) for EDC adherence ≥80% to £2,017 (95% CI £1,507-2,526) for EDC adherence <50%. CONCLUSIONS: This study provides a conservative estimate of excess inhaled medicines supply cost among adults with CF in the UK. The excess supply cost was highest among those with lowest EDC adherence, highlighting the importance of adherence support and supplying medicine according to actual use. MPR provides information about medicine supply but over-estimates actual medicine use.

Epidemiology of Mycobacterium abscessus in England: an observational study.

BACKGROUND: Mycobacterium abscessus has emerged as a significant clinical concern following reports that it is readily transmissible in health-care settings between patients with cystic fibrosis. We linked routinely collected whole-genome sequencing and health-care usage data with the aim of investigating the extent to which such transmission explains acquisition in patients with and without cystic fibrosis in England. METHODS: In this retrospective observational study, we analysed consecutive M abscessus whole-genome sequencing data from England (beginning of February, 2015, to Nov 14, 2019) to identify genomically similar isolates. Linkage to a national health-care usage database was used to investigate possible contacts between patients. Multivariable regression analysis was done to investigate factors associated with acquisition of a genomically clustered strain (genomic distance <25 single nucleotide polymorphisms [SNPs]). FINDINGS: 2297 isolates from 906 patients underwent whole-genome sequencing as part of the routine Public Health England diagnostic service. Of 14 genomic clusters containing isolates from ten or more patients, all but one contained patients with cystic fibrosis and patients without cystic fibrosis. Patients with cystic fibrosis were equally likely to have clustered isolates (258 [60%] of 431 patients) as those without cystic fibrosis (322 [63%] of 513 patients; p=0·38). High-density phylogenetic clusters were randomly distributed over a wide geographical area. Most isolates with a closest genetic neighbour consistent with potential transmission had no identifiable relevant epidemiological contacts. Having a clustered isolate was independently associated with increasing age (adjusted odds ratio 1·14 per 10 years, 95% CI 1·04-1·26), but not time spent as an hospital inpatient or outpatient. We identified two sibling pairs with cystic fibrosis with genetically highly divergent isolates and one pair with closely related isolates, and 25 uninfected presumed household contacts with cystic fibrosis. INTERPRETATION: Previously identified widely disseminated dominant clones of M abscessus are not restricted to patients with cystic fibrosis and occur in other chronic respiratory diseases. Although our analysis showed a small number of cases where person-to-person transmission could not be excluded, it did not support this being a major mechanism for M abscessus dissemination at a national level in England. Overall, these data should reassure patients and clinicians that the risk of acquisition from other patients in health-care settings is relatively low and motivate future research efforts to focus on identifying routes of acquisition outside of the cystic fibrosis health-care-associated niche. FUNDING: The National Institute for Health Research, Health Data Research UK, The Wellcome Trust, The Medical Research Council, and Public Health England.

Successful awake proning is associated with improved clinical outcomes in patients with COVID-19: single-centre high-dependency unit experience.

The SARS-CoV-2 can lead to severe illness with COVID-19. Outcomes of patients requiring mechanical ventilation are poor. Awake proning in COVID-19 improves oxygenation, but on data clinical outcomes is limited. This single-centre retrospective study aimed to assess whether successful awake proning of patients with COVID-19, requiring respiratory support (continuous positive airways pressure (CPAP) or high-flow nasal oxygen (HFNO)) on a respiratory high-dependency unit (HDU), is associated with improved outcomes. HDU care included awake proning by respiratory physiotherapists. Of 565 patients admitted with COVID-19, 71 (12.6%) were managed on the respiratory HDU, with 48 of these (67.6%) requiring respiratory support. Patients managed with CPAP alone 22/48 (45.8%) were significantly less likely to die than patients who required transfer onto HFNO 26/48 (54.2%): CPAP mortality 36.4%; HFNO mortality 69.2%, (p=0.023); however, multivariate analysis demonstrated that increasing age and the inability to awake prone were the only independent predictors of COVID-19 mortality. The mortality of patients with COVID-19 requiring respiratory support is considerable. Data from our cohort managed on HDU show that CPAP and awake proning are possible in a selected population of COVID-19, and may be useful. Further prospective studies are required.

Outcomes of pulmonary Mycobacterium abscessus infection.

Background: Treatment of Mycobacterium abscessus pulmonary disease (PD) is challenging with frequent side effects and uncertain rates of success. Methods: We performed a retrospective review of all patients at our center with at least one respiratory sample positive for M. abscessus between 2014 and 2019. Electronic health records were reviewed to determine factors associated with M. abscessus infection and clinical outcomes. Results: Thirty-seven patients were identified including 24 with cystic fibrosis (CF), 10 with bronchiectasis, two with chronic obstructive PD (COPD), and one with asthma. American Thoracic Society/Infectious Diseases Society of America criteria for nontuberculous mycobacteria PD were met in 21/37 (56.8%) of cases. Evidence of Aspergillus lung disease was noted in 18 (75.0%) CF patients compared with 3 (23.1%) non-CF patients (P = 0.005). Induction therapy for M. abscessus was given to 22/37 (59.5%) patients (18/24 [75%] with CF and 4/13 [30.8%] without CF). Median duration of induction therapy was 6 weeks (range 3-12). Maintenance antibiotic therapy was prescribed to 17/22 (77.3%) of treated patients. Culture conversion was seen in 15/24 (62.5%) of CF patients compared with 3/13 (23.1%) in the non-CF group (P = 0.034). Culture conversion occurred in 10/22 (45.5%) of treated patients compared with 8/15 (53.3%) untreated patients. Three patients (8.1%) died during follow-up: one with CF and two with COPD. Conclusions: Culture conversion following isolation of M. abscessus from respiratory samples not only is more common in CF than in patients without CF but also frequently occurs spontaneously in both groups. Targeted treatment for M. abscessus did not clearly impact rates of culture conversion.

Gastrointestinal malignancy in cystic fibrosis.

Cystic fibrosis (CF) is a multisystem disease affecting the gastrointestinal (GI) tract as well as the lungs. As survival has increased significantly over the past few decades, complications not seen previously have become apparent. There is an overall increased rate of malignancy in CF, particularly from the GI tract and in the post-transplant population. The most common sites of malignancy are the pancreatico-biliary and digestive tract, as well as an increased rate of testicular cancer. Using an illustrative case of metastatic oesophageal malignancy which initially appeared to be hepatic in origin, we have reviewed the literature surrounding malignancy in CF with a particular focus on the GI tract.

Confidence and skills for cystic fibrosis end-of-life care.

OBJECTIVES: Optimal cystic fibrosis (CF) end-of-life care (EOLC) is a challenge. There is little formal guidance about who should deliver this and how CF multi-disciplinary teams should interact with specialist palliative care. We assessed the knowledge, experience and preparedness of both CF and palliative care professionals for CF EOLC. METHODS: An electronic questionnaire was distributed to all members of the Oxford adult CF and palliative care teams. RESULTS: 35 of a possible 63 members responded (19 CF team; 16 palliative care). Levels of preparedness were low in both groups. Only 11% of CF and 19% of palliative care team members felt fully prepared for EOLC in adult CF. 58% of CF members had no (21%) or minimal (37%) general palliative care training. Similarly, 69% of the palliative care team had no CF-specific training. All respondents desired additional education. CF team members preferred further education in general EOLC while palliative care team members emphasised a need for more CF-specific knowledge. CONCLUSIONS: Few members of either the CF or palliative care teams felt fully prepared to deliver CF EOLC and many desired additional educations. They expressed complementary knowledge gaps, which suggests both could benefit from increased collaboration and sharing of specialist knowledge.

The diagnosis and management of respiratory viral infections in cystic fibrosis.

INTRODUCTION: Respiratory viruses, such as those that cause influenza and the common cold, are a regular feature of life for the entire human population. Among people with CF, these viruses are associated with prolonged respiratory illness and show a clear association with pulmonary exacerbations which in turn are associated with lung function decline and risk of death. Human rhinovirus is the most commonly encountered respiratory viral pathogen in CF although adenovirus, bocavirus, coronavirus, influenza, parainfluenza, metapneumovirus and respiratory syncytial virus are all also responsible for infections in this population. Areas covered: This article reviews the epidemiology, clinical impact and therapeutic options for respiratory virus infection in both children and adults with CF. Expert commentary: The management of CF to date has largely focused on airway clearance strategies, nutritional support and aggressive antibacterial therapy. We highlight the significant role that respiratory viruses play in CF lung disease and argue that these pathogens represent an under-exploited target in the battle to control patients' symptoms and disease progression.

Severe Achromobacter xylosoxidans infection and loss of sputum bacterial diversity in an adult patient with cystic fibrosis.

Achromobacter spp. are emerging pathogens in the lungs of patients with cystic fibrosis. We report the case of an adult patient with cystic fibrosis and chronic A. xylosoxidans infection who experienced rapid, progressive clinical deterioration. Metagenomic analysis of the sputum revealed that the airway microbiota was almost entirely dominated by A. xylosoxidans. We review the impact of this organism on lung function and the airway microbiome in cystic fibrosis, and discuss the potential for cross-infection between patients.

An international, multicentre evaluation and description of Burkholderia pseudomallei infection in cystic fibrosis.

BACKGROUND: Several cases of Burkholderia pseudomallei infection in CF have been previously reported. We aimed to identify all cases globally, risk factors for acquisition, clinical consequences, and optimal treatment strategies. METHODS: We performed a literature search to identify all published cases of B. pseudomallei infection in CF. In addition we hand-searched respiratory journals, and contacted experts in infectious diseases and CF around the world. Supervising clinicians for identified cases were contacted and contemporaneous clinical data was requested. RESULTS: 25 culture-confirmed cases were identified. The median age at acquisition was 21 years, mean FEV1 % predicted was 60 %, and mean BMI was 19.5 kg/m(2). The location of acquisition was northern Australia or south-east Asia for most. 19 patients (76 %) developed chronic infection, which was usually associated with clinical decline. Successful eradication strategies included a minimum of two weeks of intravenous ceftazidime, followed by a consolidation phase with trimethoprim/sulfamethoxazole, and this resulted in a higher chance of success when instituted early. Three cases of lung transplantation have been recorded in the setting of chronic B. pseudomallei infection. CONCLUSION: Chronic carriage of B. pseudomallei in patients with CF appears common after infection, in contrast to the non-CF population. This is often associated with an accelerated clinical decline. Lung transplantation has been performed in select cases of chronic B. pseudomallei infection.