Review of the In Vitro Microbiological Activity of Mecillinam Against Common Uropathogens in Uncomplicated Urinary Tract Infection: Focus on Resistant Pathogens.

Antimicrobial resistance in uropathogens commonly causing urinary tract infections (UTIs) is a growing problem internationally. Pivmecillinam, the oral prodrug of mecillinam, has been used for over 40 years, primarily in Northern Europe and Canada. It is recommended in several countries as a first-line agent for the treatment of uncomplicated UTIs (uUTIs) and is now approved in the United States. We performed a structured literature search to review the available evidence on susceptibility of common uUTI-causing uropathogens to mecillinam. Among 38 studies included in this literature review, susceptibility rates for Escherichia coli to mecillinam-including resistant phenotypes such as extended-spectrum ß-lactamase-producing E. coli-exceed 90% in most studies. High rates of susceptibility were also reported among many other uropathogens including Klebsiella spp., Enterobacter spp., and Citrobacter spp. In the current prescribing climate within the United States, pivmecillinam represents a viable first-line treatment option for patients with uUTI.

Development of Predictive Models to Inform a Novel Risk Categorization Framework for Antibiotic Resistance in Escherichia coli-Caused Uncomplicated Urinary Tract Infection.

BACKGROUND: In clinical practice, challenges in identifying patients with uncomplicated urinary tract infections (uUTIs) at risk of antibiotic nonsusceptibility may lead to inappropriate prescribing and contribute to antibiotic resistance. We developed predictive models to quantify risk of nonsusceptibility to 4 commonly prescribed antibiotic classes for uUTI, identify predictors of nonsusceptibility to each class, and construct a corresponding risk categorization framework for nonsusceptibility. METHODS: Eligible females aged ≥12 years with Escherichia coli-caused uUTI were identified from Optum's de-identified Electronic Health Record dataset (1 October 2015-29 February 2020). Four predictive models were developed to predict nonsusceptibility to each antibiotic class and a risk categorization framework was developed to classify patients' isolates as low, moderate, and high risk of nonsusceptibility to each antibiotic class. RESULTS: Predictive models were developed among 87 487 patients. Key predictors of having a nonsusceptible isolate to ≥3 antibiotic classes included number of previous UTI episodes, prior ß-lactam nonsusceptibility, prior fluoroquinolone treatment, Census Bureau region, and race. The risk categorization framework classified 8.1%, 14.4%, 17.4%, and 6.3% of patients as having isolates at high risk of nonsusceptibility to nitrofurantoin, trimethoprim-sulfamethoxazole, ß-lactams, and fluoroquinolones, respectively. Across classes, the proportion of patients categorized as having high-risk isolates was 3- to 12-fold higher among patients with nonsusceptible isolates versus susceptible isolates. CONCLUSIONS: Our predictive models highlight factors that increase risk of nonsusceptibility to antibiotics for uUTIs, while the risk categorization framework contextualizes risk of nonsusceptibility to these treatments. Our findings provide valuable insight to clinicians treating uUTIs and may help inform empiric prescribing in this population.

The emotional impact of uncomplicated urinary tract infections in women in China and Japan: a qualitative study.

BACKGROUND: Uncomplicated urinary tract infections (uUTIs) are one of the most common community-acquired infections, particularly among women. Common symptoms of UTI include dysuria, urinary urgency and increased frequency, and lower abdominal pain. With appropriate treatment, symptoms may resolve in a few days. However, there is a lack of research on the emotional impact of this disease. We conducted a qualitative, interview-based study to gain a greater understanding of the emotional impact of uUTIs in women in China and Japan. METHODS: A qualitative, exploratory, in-depth, interview-based study was conducted between 19 November 2020 and 25 February 2021. Women aged ≥ 18 years who experienced ≥ 1 uUTI and received antibiotic treatment in the past year were eligible for inclusion. Participants must have experienced ≥ 1 of the following symptoms during a uUTI episode: urinary urgency, frequency, dysuria, or lower abdominal/suprapubic pain. Participants who reported back pain or fever (indicative of complicated UTI) were excluded. Participants with recurrent or sporadic UTIs were included, with specific screening criteria used to ensure capture of both groups. Following a screening call, a structured, in-depth telephone interview (~ 30 min in duration) was conducted by three female external moderators trained in qualitative interviewing, assisted by an interview guide. Interviews were analysed individually and thematically, with the results presented within the identified themes. RESULTS: A total of 65 women with uUTI completed the in-depth telephone interview: 40 (62%) from China and 25 (38%) from Japan. Participants reported that the symptoms of uUTI affected multiple aspects of their lives, and described feelings of embarrassment, frustration, guilt, dread, and loneliness associated with symptoms that interfered with relationships, work and daily activities, and sleep. Participants reported seeking healthcare from several different points of contact, from local pharmacies to hospitals. CONCLUSIONS: Our analysis highlights the profound emotional impact of uUTIs in women in China and Japan, and the journey these participants take before their initial interaction with a healthcare professional. These insights emphasise the need to better understand the full impact of uUTI, and the role of healthcare professionals in improved patient education and support.

Prevalence, regional distribution, and trends of antimicrobial resistance among female outpatients with urine Klebsiella spp. isolates: a multicenter evaluation in the United States between 2011 and 2019.

BACKGROUND: Antimicrobial resistance research in uncomplicated urinary tract infection typically focuses on the main causative pathogen, Escherichia coli; however, little is known about the antimicrobial resistance burden of Klebsiella species, which can also cause uncomplicated urinary tract infections. This retrospective cohort study assessed the prevalence and geographic distribution of antimicrobial resistance among Klebsiella species and antimicrobial resistance trends for K. pneumoniae in the United States (2011-2019). METHODS: K. pneumoniae and K. oxytoca urine isolates (30-day, non-duplicate) among female outpatients (aged ≥ 12 years) with presumed uUTI at 304 centers in the United States were classified by resistance phenotype(s): not susceptible to nitrofurantoin, trimethoprim/sulfamethoxazole, or fluoroquinolone, extended-spectrum ß-lactamase-positive/not susceptible; and multidrug-resistant based on ≥ 2 and ≥ 3 resistance phenotypes. Antimicrobial resistance prevalence by census division and age, as well as antimicrobial resistance trends over time for Klebsiella species, were assessed using generalized estimating equations. RESULTS: 270,552 Klebsiella species isolates were evaluated (250,719 K. pneumoniae; 19,833 K. oxytoca). The most frequent resistance phenotypes in 2019 were nitrofurantoin not susceptible (Klebsiella species: 54.0%; K. pneumoniae: 57.3%; K. oxytoca: 15.1%) and trimethoprim/sulfamethoxazole not susceptible (Klebsiella species: 10.4%; K. pneumoniae: 10.6%; K. oxytoca: 8.6%). Extended-spectrum ß-lactamase-positive/not susceptible prevalence was 5.4%, 5.3%, and 6.8%, respectively. K. pneumoniae resistance phenotype prevalence varied (p < 0.0001) geographically and by age, and increased over time (except for the nitrofurantoin not susceptible phenotype, which was stable and > 50% throughout). CONCLUSIONS: There is a high antimicrobial resistance prevalence and increasing antimicrobial resistance trends among K. pneumoniae isolates from female outpatients in the United States with presumed uncomplicated urinary tract infection. Awareness of K. pneumoniae antimicrobial resistance helps to optimize empiric uncomplicated urinary tract infection treatment.

Treating urinary tract infections in the era of antibiotic resistance.

INTRODUCTION: Urinary tract infections (UTIs) are associated with 25-40% of antibiotics consumed in primary care and are, therefore, driving antibiotic resistance. The worldwide increase in antibiotic resistance especially in Escherichia coli has complicated the treatment choices for UTIs and absence of effective oral antibiotics may lead to increasing need for more effective treatments. AREAS COVERED: In this review we focus on the importance of the correct diagnosis of UTI as based on proof of urinary pathogens in the urine and discuss diagnostic measures including microscopy, dipstick, and culture. Antibiotic treatment can often await diagnostic measures with pain relief such as ibuprofen. The risk of an uncomplicated UTI leading to pyelonephritis is low (1-2%) and presence of bacteria in the bladder leaves some time for the immune system to react. Three antibiotics are recommended as based on their activity, and low propensity to select for resistance, i.e. nitrofurantoin, fosfomycin, and pivmecillinam, and in general, 3-5 days of treatment will suffice. EXPERT OPINION: Understanding the usual benign course of uUTIs can help reduce antibiotic treatment in many cases, e.g. starting treatment by pain relief and awaiting the course of infection without antibiotics. Better rapid tests in primary care are urgently needed to enforce such policies.

Phytotherapy (BNO 1045) of Acute Lower Uncomplicated Urinary Tract Infection in Women Normalizes Local Host Responses.

INTRODUCTION: Acute lower uncomplicated urinary tract infection (uUTI) affects a large proportion of women. Increased antimicrobial resistance has created an urgent need for novel therapeutics and the phytotherapeutic drug BNO 1045 (Canephron® N) has previously been shown to be noninferior to standard antimicrobial stewardship. This sub-analysis from a randomized, double-blind, controlled phase III noninferiority clinical trial using BNO 1045 versus fosfomycin to treat uUTI aimed to determine how urine cytokine levels are altered by the two different treatments. METHODS: Urine samples from a predefined subset of women diagnosed with uUTI (18-70 years) and treated with BNO 1045 (n = 58) or fosfomycin (n = 69) were analyzed for urine levels of IL-6 and IL-8, using analyte-to-creatinine ratios. RESULTS: BNO 1045 treatment showed similar effects to fosfomycin treatment in reducing both urine IL-6 and IL-8 levels. Mean IL-6 and IL-8 levels were markedly reduced in all patients regardless of treatment. BNO 1045 treatment decreased urine IL-8 significantly (p = 0.0142) and showed a trend toward reduction of urine IL-6 (p = 0.0551). Fosfomycin treatment reduced both IL-6 and IL-8 levels significantly (p = 0.0038, <0.0001 respectively). CONCLUSION: BNO 1045 is, in addition to reducing symptoms, comparable to fosfomycin treatment in reducing the local inflammatory response associated with uUTI.

Linguistic and clinical validation of the Turkish version of Acute Cystitis Symptom Score for the diagnosis and patient-reported outcome in acute uncomplicated cystitis.

PURPOSE: The Acute Cystitis Symptom Score (ACSS) was developed as a self-reporting questionnaire for diagnosing and monitoring acute uncomplicated cystitis (AC) in female patients. The study aims at the translation of the ACSS into Turkish from the original Uzbek including its linguistic, cognitive and clinical validation. MATERIALS AND METHODS: After forward and backward translation of the ACSS from Uzbek to Turkish and vice versa, the cognitive assessment of the Turkish ACSS was performed on 12 female subjects to achieve the final study version. RESULTS: The clinical validation was performed on a total of 120 female respondents including 64 Patients with AC and 56 controls without AC. For clinical diagnosis of AC, the predefined summary score of the typical symptoms of >6 showed high values (95% confidence interval) for sensitivity (0.88 [0.77-0.94]), specificity (0.98 [0.91-1.00]), and diagnostic accuracy (0.93 [0.86-0.97]). All patients were followed up between five to nine days after the baseline visit. Forty-four (68.75%) patients used antimicrobial treatment, whereas the rest (31.25%) preferred non-antimicrobial treatment. The severity scores of the typical symptoms and the quality of life were reduced significantly at follow-up. Using different (favored) thresholds for successful and non-successful treatment a clinical success rate between 54.7% and 64.1% (60.9%) was achieved. CONCLUSIONS: After translation from the original Uzbek and cognitive assessment, the Turkish ACSS showed similar good results for clinical diagnosis and patient-reported outcome as in other languages validated so far and could therefore now be used for clinical studies as well as in everyday practice.

Nitrofurantoin for the treatment of uncomplicated urinary tract infection in female patients: the impact of dosing regimen, age, and renal function on drug exposure.

PURPOSE: The aim of this study is to determine nitrofurantoin exposure in female patients with different age and renal function with complaints of an uncomplicated UTI. Also the nitrofurantoin exposure in relation to the dosage regimen will be studied. METHODS: Eight general practitioners (GP) participated in the study and included 38 patients with symptoms of an uncomplicated UTI, treated either with a dose of 50 mg q6h or 100 mg q12h, upon the discretion of the GP. Nitrofurantoin exposure was quantified in the patient's 24-h urine samples by UHPLC-UV and the area under the curve was calculated. RESULTS: The 38 patients provided a range of 2-17 urine samples. The urine nitrofurantoin exposure was 1028 mg h/L for the patients receiving 50 mg q6h and 1036 mg h/L for those treated with 100 mg q12h (p = 0.97) and was not affected by age and eGFR (p = 0.64 and p = 0.34, respectively). CONCLUSION: The data obtained do not support the discouragement of nitrofurantoin use in the elderly and in patients with impaired renal function. Since only a small number of patients were included, a larger study with more patients is warranted to evaluate nitrofurantoin exposure and adverse effects.

Unmet needs in uncomplicated urinary tract infection in the United States and Germany: a physician survey.

BACKGROUND: Uncomplicated urinary tract infections (uUTIs/acute cystitis) are among the most common infections in women worldwide. There are differences in uUTI treatment guidelines between countries and understanding the needs of physicians in diverse healthcare systems is important for developing new treatments. We performed a survey of physicians in the United States (US) and Germany to understand their perceptions of, and management approaches to uUTI. METHODS: This was a cross-sectional online survey of physicians in the US and Germany who were actively treating patients with uUTI (≥ 10 patients/month). Physicians were recruited via a specialist panel and the survey was piloted with 2 physicians (1 US, 1 Germany) prior to study commencement. Data were analyzed with descriptive statistics. RESULTS: A total of 300 physicians were surveyed (n = 200 US, n = 100 Germany). Across countries and specialties, physicians estimated 16-43% of patients did not receive complete relief from initial therapy and 33-37% had recurrent infections. Urine culture and susceptibility testing was more common in the US and among urologists. The most commonly selected first-line therapy was trimethoprim-sulfamethoxazole in the US (76%) and fosfomycin in Germany (61%). Ciprofloxacin was the most selected following multiple treatment failures (51% US, 45% Germany). Overall, 35% of US and 45% of German physicians agreed with the statement "I feel there is a good selection of treatment options" and ≥ 50% felt that current treatments provided good symptom relief. More than 90% of physicians included symptom relief amongst their top 3 treatment goals. The overall impact of symptoms on patients' lives was rated "a great deal" by 51% of US and 38% of German physicians, increasing with each treatment failure. Most physicians (> 80%) agreed that antimicrobial resistance (AMR) is serious, but fewer (56% US, 46% Germany) had a high level of confidence in their knowledge of AMR. CONCLUSIONS: Treatment goals for uUTI were similar in the US and Germany, although with nuances to disease management approaches. Physicians recognized that treatment failures have a significant impact on patients' lives and that AMR is a serious problem, though many did not have confidence in their own knowledge of AMR.

A Possible Case of Nitrofurantoin-Associated Immune Thrombocytopenia in a Healthy 45-Year-Old Caucasian Female.

Patients presenting with immune thrombocytopenia (ITP) may have an associated underlying medical condition or medication exposure serving as the cause of their disease, but oftentimes, ITP is due to an idiopathic, autoimmune cause. While molecular mimicry is recognized as the pathogenesis behind infectious-related causes of ITP, drug-induced ITP is likely due to hapten formation, leading to an inappropriate immune-mediated response. Several drugs are associated with the development of ITP. Nitrofurantoin, a commonly prescribed antibiotic for the treatment of uncomplicated urinary tract infections (UTIs), is a medication not previously associated with the development of ITP, with only one case reporting the development of thrombotic thrombocytopenic purpura (TTP) after nitrofurantoin use. Herein, we report a case of a middle-aged Caucasian female with a history of anxiety and hypothyroidism who developed ITP following exposure to nitrofurantoin three weeks prior to presentation. The patient presented with signs and symptoms consistent with ITP: an isolated low platelet count of 1 x 109/L, petechia, fatigue, normal coagulation parameters, recurrent epistaxis, and melena. Subsequently, she was hospitalized for five days, receiving a total of four units of platelets during her stay. She was started on daily high-dose intravenous corticosteroids and received a one-time dose of intravenous immunoglobulin (IVIG). After achieving a platelet count greater than 30 x 109/L, she was discharged from inpatient care, having responded well to corticosteroid treatment. Upon follow-up with outpatient hematology, her platelet levels were maintained above 150 x 109/L, with full resolution of her acute illness. An autoimmune laboratory workup was negative except for an isolated, newly positive antinuclear antibody IgG with an elevated titer of 1:640, leading to the conclusion that an immunological response to nitrofurantoin had occurred. To our knowledge, this is the first report that describes an association between nitrofurantoin use and ITP. We hope this report aids clinicians in recognizing the various immune-mediated adverse reactions associated with nitrofurantoin.

Sulopenem or Ciprofloxacin for the Treatment of Uncomplicated Urinary Tract Infections in Women: A Phase 3, Randomized Trial.

BACKGROUND: There are limited treatment options for uncomplicated urinary tract infection (uUTI) caused by resistant pathogens. Sulopenem etzadroxil/probenecid (sulopenem) is an oral thiopenem antibiotic active against multidrug-resistant pathogens that cause uUTIs. METHODS: Patients with uUTI were randomized to 5 days of sulopenem or 3 days of ciprofloxacin. The primary endpoint was overall success, defined as both clinical and microbiologic response at day 12. In patients with ciprofloxacin-nonsusceptible baseline pathogens, sulopenem was compared for superiority over ciprofloxacin; in patients with ciprofloxacin-susceptible pathogens, the agents were compared for noninferiority. Using prespecified hierarchical statistical testing, the primary endpoint was tested in the combined population if either superiority or noninferiority was declared in the nonsusceptible or susceptible population, respectively. RESULTS: In the nonsusceptible population, sulopenem was superior to ciprofloxacin, 62.6% vs 36.0% (difference, 26.6%; 95% confidence interval [CI], 15.1 to 7.4; P <.001). In the susceptible population, sulopenem was not noninferior to ciprofloxacin, 66.8% vs 78.6% (difference, -11.8%; 95% CI, -18.0 to 5.6). The difference was driven by a higher rate of asymptomatic bacteriuria (ASB) post-treatment in patients on sulopenem. In the combined analysis, sulopenem was noninferior to ciprofloxacin, 65.6% vs 67.9% (difference, -2.3%; 95% CI, -7.9 to 3.3). Diarrhea occurred more frequently with sulopenem (12.4% vs 2.5%). CONCLUSIONS: Sulopenem was noninferior to ciprofloxacin in the treatment of uUTIs. Sulopenem was superior to ciprofloxacin in patients with uUTIs due to ciprofloxacin-nonsusceptible pathogens. Sulopenem was not noninferior in patients with ciprofloxacin-susceptible pathogens, driven largely by a lower rate of ASB in those who received ciprofloxacin. CLINICAL TRIAL REGISTRATION: NCT03354598.

Impact of suboptimal or inappropriate treatment on healthcare resource use and cost among patients with uncomplicated urinary tract infection: an analysis of integrated delivery network electronic health records.

BACKGROUND: Although uncomplicated urinary tract infections (uUTIs; occurring in female patients without urological abnormalities or history of urological procedures or complicating comorbidities) are one of the most common community infections in the United States (US), limited data are available concerning associations between antibiotic resistance, suboptimal prescribing, and the economic burden of uUTI. We examined the prevalence of suboptimal antibiotic prescribing and antibiotic resistance and its effects on healthcare resource use and costs. METHODS: This retrospective cohort study utilized electronic health record data from a large Mid-Atlantic US integrated delivery network database, collected July 2016-March 2020. Female patients aged ≥ 12 years with a uUTI, who received ≥ 1 oral antibiotic treatment within ± 5 days of index uUTI diagnosis, and had ≥ 1 urine culture with antimicrobial susceptibility test, were eligible for inclusion in the study. The study examined the proportion of antibiotics that were inappropriately or suboptimally prescribed among patients with confirmed uUTI, and total healthcare costs (all-cause and UTI-related) within 6 months after a uUTI, stratified by antibiotic susceptibility and/or inappropriate or suboptimal treatment. Patient outcomes were assessed after 1:1 propensity score matching of patients with antibiotic-susceptible versus not-susceptible isolates and then by other covariates (e.g., demographics and recent healthcare use). A similar propensity score calculation was used to analyze the effect of inappropriate/suboptimal treatment on health outcomes. Costs were adjusted to 2020 US dollars ($). RESULTS: Among 2565 patients with a uUTI included in the analysis, the most commonly prescribed antibiotics were nitrofurantoin (61%), trimethoprim-sulfamethoxazole (19%), and ciprofloxacin (15%). More than one-third of the sample (40.2%) had isolates that were not-susceptible to ≥ 1 antibiotic indicated for treating patients with uUTI. Two-thirds (66.6%) of study-eligible patients were prescribed appropriate treatment; 29.9% and 11.9% were prescribed suboptimal and/or inappropriate treatment, respectively. Inappropriate or suboptimally prescribed patients had greater all-cause and UTI-related costs compared with appropriately prescribed patients. Differences were most striking among patients with antibiotic not-susceptible isolates. CONCLUSIONS: These findings highlight how the increasing prevalence of antibiotic resistance combined with suboptimal treatment of patients with uUTI increases the burden on healthcare systems. The finding underlines the need for improved prescribing accuracy by better understanding regional resistance rates and developing improved diagnostic tests.

Design of Two Phase III, Randomized, Multicenter Studies Comparing Gepotidacin with Nitrofurantoin for the Treatment of Uncomplicated Urinary Tract Infection in Female Participants.

BACKGROUND: Uncomplicated urinary tract infections (uUTIs) are among the most common community-acquired infections for women worldwide. Treatment options are increasingly limited by antibiotic resistance; novel oral antibiotics are urgently needed. Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial deoxyribonucleic acid (DNA) replication by a distinct mechanism of action, which confers activity against most strains of target pathogens, such as Escherichia coli and Staphylococcus saprophyticus, including those resistant to current antibiotics. Here, we describe the designs of two near-identical phase III clinical trials (EAGLE-2 and EAGLE-3) evaluating gepotidacin for the treatment of uUTI. METHODS: These are phase III, randomized, multicenter, parallel-group, double-blind, double-dummy, comparator-controlled, noninferiority studies, comparing the efficacy and safety of gepotidacin to nitrofurantoin in the treatment of uUTI. Eligible participants are women aged ≥ 12 years with ≥ 2 uUTI symptoms, randomized (1:1) to receive oral gepotidacin (1500 mg) plus placebo or nitrofurantoin (100 mg) plus placebo, twice daily for 5 days. The primary therapeutic endpoint is composite clinical and microbiological efficacy, with noninferiority comparisons made in individuals with a qualifying (≥ 105 colony-forming units/mL urine) nitrofurantoin-susceptible uropathogen. RESULTS: These trials were designed in accordance with US Food and Drug Administration (2019) and European Medicines Agency (2018) guidance, particularly the composite endpoint and microbiological evaluability requirements. Across the trials ~ 5000 participants are planned to be enrolled from > 200 centers globally. CONCLUSIONS: Gepotidacin represents an important potential treatment option being evaluated to address the need for novel oral antibiotics to treat uUTI. These trials are registered at ClinicalTrials.gov ( https://clinicaltrials.gov/ ) where the full protocols can be accessed under trial IDs: NCT04020341 (EAGLE-2) and NCT04187144 (EAGLE-3).

Efficacy of Single Dose of Fosfomycin Versus a Five-Day Course of Ciprofloxacin in Patients With Uncomplicated Urinary Tract Infection.

INTRODUCTION AND OBJECTIVE: Treatment has become more challenging due to an aging population, polypharmacy and high prevalence of comorbid illness, antimicrobial antibiotic allergy or sensitivity, an increase in the number of individuals with underlying immunological or structural abnormalities, as well as the frequency of multidrug-resistant infections. Many multidrug-resistant bacteria are still susceptible to nitrofurantoin and fosfomycin, two ancient medicines. Their high urine concentrations and low toxicity give them an advantage over newer medications. This study aimed to compare the efficacy of a single dose of fosfomycin versus a five-day course of ciprofloxacin in patients with uncomplicated urinary tract infections. Methodology and data collection procedure: This randomized control trial was conducted in the Department of Medicine, Benazir Bhutto Hospital, Rawalpindi. A total of 46 patients were enrolled. Patients were divided randomly into two groups by using the lottery method. In group A, patients were given a single 3 g dose of oral fosfomycin. In group B, patients were given oral ciprofloxacin (500 mg) daily for five days. Then patients were followed-up in the Outpatient Department (OPD) for 28 days. After 28 days, patients were evaluated for resolution of symptoms (as per operational definition). Patients in whom symptoms would not be resolved were managed as per standard protocol. All this information was recorded on proforma. RESULTS: The average age of the patients in group A was 39.41±9.80 years while in group B that was 41.32±17.76 years. In both groups, 23 females were equally divided. The mean duration of symptoms in group A was 4.78±1.98 days while in group B was 4.95±1.29 days. The minimum duration of symptoms was three days and the maximum was 10 days. In group A, there were 15 (65.21%) patients with efficacy achieved, and among eight (34.78%) patients, efficacy was not achieved while in group B, there were 15 (65.21%) patients in which efficacy was achieved, and among eight (34.78%) patients, efficacy was not achieved. There was no significant association between efficacy and study groups as the p-value was not significant (p=0.87).  Conclusion: The conclusion of the study was that in the treatment of simple urinary infections, a single dose of fosfomycin had equal efficacy and tolerability as a five-day course of ciprofloxacin.

Linguistic validation and cognitive assessment of the French version of the Acute Cystitis Symptom Score questionnaire.

INTRODUCTION: The Acute Cystitis Symptom Score (ACSS) questionnaire first developed in Russian and Uzbek languages and now available in many other languages can be used for clinical diagnostics and patient-reported outcome (PRO) in female patients with acute uncomplicated cystitis (AUC). The aim of the current study was the linguistic validation and cognitive assessment of the French version of the ACSS questionnaire according to internationally accepted guidelines. METHODS: After two forward translations from Russian into the French language and backward translation into Russian and Uzbek, the two original languages, the scientific committee (SC) performed a slightly adapted French version, which finally was cognitively assessed by female subjects with different ages and educational levels and medical professionals, such as nurses, physicians, and pharmacists. RESULTS: All comments of the female subjects and professionals were discussed within the SC and after slight, but necessary adaptations, the SC agreed on the final study version of the French ACSS. CONCLUSION: Now, the linguistically validated and cognitively assessed French version of the ACSS can be used for clinical studies and practice.

Dose Selection for Phase III Clinical Evaluation of Gepotidacin (GSK2140944) in the Treatment of Uncomplicated Urinary Tract Infections.

Antibiotics are the current standard-of-care treatment for uncomplicated urinary tract infections (uUTIs). However, increasing rates of bacterial antibiotic resistance necessitate novel therapeutic options. Gepotidacin is a first-in-class triazaacenaphthylene antibiotic that selectively inhibits bacterial DNA replication by interaction with the bacterial subunits of DNA gyrase (GyrA) and topoisomerase IV (ParC). Gepotidacin is currently in clinical development for the treatment of uUTIs and other infections. In this article, we review data for gepotidacin from nonclinical studies, including in vitro activity, in vivo animal efficacy, and pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) models that informed dose selection for phase III clinical evaluation of gepotidacin. Based on this translational package of data, a gepotidacin 1,500-mg oral dose twice daily for 5 days was selected for two ongoing, randomized, multicenter, parallel-group, double-blind, double-dummy, active-comparator phase III clinical studies evaluating the safety and efficacy of gepotidacin in adolescent and adult female participants with uUTIs (ClinicalTrials.gov identifiers NCT04020341 and NCT04187144).

A global perspective on improving patient care in uncomplicated urinary tract infection: expert consensus and practical guidance.

OBJECTIVES: Uncomplicated urinary tract infections (uUTIs) are a common problem in female patients. Management is mainly based on empirical prescribing, but there are concerns about overtreatment and antimicrobial resistance (AMR), especially in patients with recurrent uUTIs. METHODS: A multidisciplinary panel of experts met to discuss diagnosis, treatment, prevention, guidelines, AMR, clinical trial design and the impact of COVID-19 on clinical practice. RESULTS: Symptoms remain the cornerstone of uUTI diagnosis, and urine culture is necessary only when empirical treatment fails or rapid recurrence of symptoms or AMR is suspected. Specific antimicrobials are first-line therapy (typically nitrofurantoin, fosfomycin, trimethoprim/sulfamethoxazole and pivmecillinam, dependent on availability and local resistance data). Fluoroquinolones are not first-line options for uUTIs primarily due to safety concerns but also rising resistance rates. High-quality data to support most non-antimicrobial approaches are lacking. Local AMR data specific to community-acquired uUTIs are needed, but representative information is difficult to obtain; instead, identification of risk factors for AMR can provide a basis to guide empirical antimicrobial prescribing. The COVID-19 pandemic has impacted the management of uUTIs in some countries and may have long-lasting implications for future models of care. CONCLUSION: Management of uUTIs in female patients can be improved without increasing complexity, including simplified diagnosis and empirical antimicrobial prescribing based on patient characteristics, including a review of recent antimicrobial use and past pathogen resistance profiles, drug availability and guidelines. Current data for non-antimicrobial approaches are limited. The influence of COVID-19 on telehealth could provide an opportunity to enhance patient care in the long term.

Antimicrobial Resistance Trends in Urine Escherichia coli Isolates From Adult and Adolescent Females in the United States From 2011 to 2019: Rising ESBL Strains and Impact on Patient Management.

BACKGROUND: Uncomplicated urinary tract infection (uUTI) is predominantly caused by Escherichia coli, which has increasing antimicrobial resistance (AMR) at the United States (US)-community level. As uUTI is often treated empirically, assessing AMR is challenging, and there are limited contemporary data characterizing period prevalence in the US. METHODS: This was a retrospective study of AMR using Becton, Dickinson and Company Insights Research Database (Franklin Lakes, New Jersey, US) data collected 2011-2019. Thirty-day, nonduplicate Escherichia coli urine isolates from US female outpatients (aged ≥12 years) were included. Isolates were evaluated for nonsusceptibility (intermediate/resistant) to trimethoprim-sulfamethoxazole, fluoroquinolones, or nitrofurantoin, and assessed for extended-spectrum ß-lactamase production (ESBL+) and for ≥2 or ≥3 drug-resistance phenotypes. Generalized estimating equations were used to model AMR trends over time and by US census region. RESULTS: Among 1 513 882 E. coli isolates, the overall prevalence of isolates nonsusceptible to trimethoprim-sulfamethoxazole, fluoroquinolones, and nitrofurantoin was 25.4%, 21.1%, and 3.8%, respectively. Among the isolates, 6.4% were ESBL+, 14.4% had ≥2 drug-resistance phenotypes, and 3.8% had ≥3. Modeling demonstrated a relative average yearly increase of 7.7% (95% confidence interval [CI], 7.2-8.2%) for ESBL+ isolates and 2.7% (95% CI, 2.2-3.2%) for ≥3 drug-phenotypes (both P < .0001). Modeling also demonstrated significant variation in AMR prevalence between US census regions (P < .001). CONCLUSIONS: Period prevalence of AMR among US outpatient urine-isolated E. coli was high, and for multidrug-resistance phenotypes increased during the study period with significant variation between census regions. Knowledge of regional AMR rates helps inform empiric treatment of community-onset uUTI and highlights the AMR burden to physicians.

Adherence to guideline recommendations for urinary tract infections in adult women: a cross-sectional study.

AIM: To study whether changes in drug preferences in the Dutch guideline for the treatment of Urinary Tract Infection (UTI) for General Practitioners (GPs) in 2013, resulted in corresponding changes in antibiotic dispensing. BACKGROUND: For the treatment of uncomplicated UTI, nitrofurantoin remained the first choice, while fosfomycin became the second choice and changed ranks with trimethoprim. For a subsequent febrile UTI, ciprofloxacin became the first choice and changed ranks with amoxicillin/clavulanic acid, co-trimoxazole remained the third choice. METHODS: In this observational cross-sectional study, routinely collected dispensing data from the Dutch Foundation of Pharmaceutical Statistics from 2012 to 2017 were used. The number of women 18 years and older, treated with one of the guideline antibiotics for uncomplicated UTI and subsequent febrile UTI were analysed annually. Proportions were calculated. Data were stratified for age categories. Failure of uncomplicated UTI treatment was defined as the dispensing of an antibiotic for febrile UTI within 14 days after the dispensing of an antibiotic for uncomplicated UTI. FINDINGS: Data were available from 81% of all pharmacies in 2012 to 89% in 2017. Percentages of women dispensed nitrofurantoin were relatively stable with 87.4% in 2012 and 84.4% in 2017. Percentages of women dispensed fosfomycin increased from 5.4% in 2012 to 21.8% in 2017, whereas percentages of women dispensed trimethoprim decreased from 17.8% to 8.0%. Within age categories, the percentage of women dispensed fosfomycin increased from 12.4% in women 18-30 years old to 36.7% in women above 80 years old. Percentages of women dispensed antibiotics for febrile UTI remained stable at 5% annually. Percentages of women receiving ciprofloxacin increased from 1.9% in 2012 to 3.3% in 2017, while those receiving amoxicillin/clavulanic acid decreased from 2.9% to 1.8%. New guideline recommendations resulted in corresponding changes in dispensed antibiotics for uncomplicated UTI and subsequent febrile UTI. Drug choices differed for age categories.

The Clinical Efficacy of Nitrofurantoin for Treating Uncomplicated Urinary Tract Infection in Adults: A Systematic Review of Randomized Control Trials.

OBJECTIVE: To provide an updated systematic review of randomized control trials (RCTs) to investigate the clinical and microbiological efficacy of nitrofurantoin compared to other antibiotics or placebo for treatment of uncomplicated urinary tract infections (uUTI). A secondary aim is to assess whether nitrofurantoin use is associated with increased side effects compared to other treatment regimens. SUMMARY: The review was performed according to PRISMA guidelines. We searched 4 databases for articles published from database inception to May 6, 2020: (1) PubMed electronic database of the National Library of Medicine, (2) Web of Science, (3) Embase, and (4) Cochrane Library. Nine RCTs were selected for the review. RCTs were a mixture of double-blind, single-blind, and open-label trials. The most common comparators were trimethoprim-sulfamethoxazole and fosfomycin tromethamine. Overall study quality was poor with a high risk of bias. The clinical cure rates in nitrofurantoin ranged from 51 to 94% depending on the length of follow-up, and bacteriological cure rates ranged from 61 to 92%. Overall the evidence suggests that nitrofurantoin is at least comparable with other uUTI treatments in terms of efficacy. Patients taking nitrofurantoin reported fewer side effects than other drugs and the most commonly reported were gastrointestinal and central nervous system symptoms. Key Messages: Evidence on the clinical and bacteriological efficacy of nitrofurantoin is sparse, with a lack of new data, and hampered by high risk of bias. Although no firm conclusions can be made on the current base of evidence, the studies generally suggest that nitrofurantoin is at least comparable to other common uUTI treatments in terms of clinical and bacteriological cure. More robust research with well-designed double-blinded RCTs is needed.