In women with uncomplicated UTIs, gepotidacin was noninferior to nitrofurantoin for therapeutic response at 10 to 13 d.

SOURCE CITATION: Wagenlehner F, Perry CR, Hooton TM, et al. Oral gepotidacin versus nitrofurantoin in patients with uncomplicated urinary tract infection (EAGLE-2 and EAGLE-3): two randomised, controlled, double-blind, double-dummy, phase 3, non-inferiority trials. Lancet. 2024;403:741-755. 38342126.

Safety and efficacy evaluation of low-dose trimethoprim-sulfamethoxazole for prophylaxis of Pneumocystis pneumonia in HIV uninfected patients undergoing hemodialysis: a retrospective observational study.

BACKGROUND: Pneumocystis pneumonia (PCP) is a potentially life-threatening infection. Trimethoprim-sulfamethoxazole (TMP-SMX) is considered as the first regimen for PCP prophylaxis according to several guidelines. The recommended prophylactic dose of TMP-SMX has been determined based on patients with normal renal function, but the appropriate dosage for patients undergoing hemodialysis is unknown. The aim of this study was to investigate the efficacy and safety of low-dose TMP-SMX in patients undergoing hemodialysis. METHODS: HIV-uninfected adult patients who were undergoing hemodialysis and administered TMP-SMX for PCP prophylaxis, were included, and divided into standard-dose (≥6 single strength (SS, TMP-SMX 80 mg/400 mg tablets/week) and low-dose groups (< 6 SS tablets/week). The endpoints were cumulative incidence of PCP and cumulative discontinuation rate of TMP-SMX due to adverse events. For comparison of the groups, we employed the chi-squared test for categorical variables and the Mann-Whitney U test for continuous variables. Risk factors for the endpoints were evaluated using the Cox Fine and Gray method. RESULTS: The median age of the 81 patients included in the study was 67 years (IQR: 60-76 years), and 52 patients (64.2%) were men. No patients in either group developed PCP during the observation period. The yearly cumulative incidence of discontinuation was 12.1% (95% confidence interval [CI]: 0.027-0.29) in the low-dose group and 35.6% (95% CI: 0.20-0.52) in the standard-dose group (P = 0.019). The adjusted hazard ratio of the low-dose group compared to standard-dose group was 0.18 (95% CI: 0.04-0.86, P = 0.032). CONCLUSIONS: None of the study patients developed PCP, and the cumulative discontinuation rate of TMP-SMX due to adverse events was significantly lower in the low-dose group compared to that in the standard-dose group (P = 0.032). These results indicate that low-dose TMP-SMX is an appropriate regimen to maintain a balance between PCP prophylaxis and prevention of adverse events due to TMP-SMX administration. These findings can guide health care professionals to determine TMP-SMX dosage when considering PCP prophylaxis for patients undergoing hemodialysis.

The Significance of Age and Causative Bacterial Morphology in the Choice of an Antimicrobial Agent to Treat Acute Uncomplicated Cystitis.

Differentiating patients by age and causative bacterial morphology might aid in making the appropriate choice of antimicrobial agent when treating acute uncomplicated cystitis. In this retrospective analysis, the non-susceptibility rates of the causative bacteria to cefcapene-pivoxil (CFPN-PI) and levofloxacin (LVFX) were determined after dividing patients with acute uncomplicated cystitis by age group (15-54 and 55-74 years old) and by bacterial morphology: gram-positive cocci (GPC) or gram-negative rod (GNR). The overall non-susceptibility rates for CFPN-PI and LVFX were 19.4% and 15.3%, respectively. When the subjects were divided by age, only the non-susceptibility rate for LVFX in the younger group significantly decreased (to 8.7%). When the groups were divided by both age and bacterial morphology, the younger GNR group had non-susceptibility rates of 6.9% to CFPN-PI and 7.8% to LVFX, whereas the younger GPC group showed 10.2% non-susceptibility to LVFX. The older GNR group showed 9.8% non-susceptibility to CFPN-PI, while the older GPC group showed 7.2% non-susceptibility to LVFX. All the non-susceptibility rates were lower than 10.2% in the sub-divided groups. Differentiating patients by age and the morphology of causative bacteria can aid in making the appropriate choice of antimicrobial agent and may improve treatment outcomes in patients with acute uncomplicated cystitis.

Validating an empiric sulfadiazine-trimethoprim dosage regimen for treatment of Escherichia coli and Staphylococcus delphini infections in mink (Neovison vison).

Antimicrobial agents are used extensively off-label in mink, as almost no agents are registered for this animal species. Pharmacokinetic (PK) and pharmacodynamic (PD) data are required to determine antimicrobial dosages specifically targeting mink bacterial pathogens. The aims of this study were to assess, in a PKPD framework, the empirical dosage regimen for a combination of trimethoprim (TMP) and sulfadiazine (SDZ) in mink, and secondarily to produce data for future setting of clinical breakpoints. TMP and SDZ PK parameters were obtained experimentally in 22 minks following IV or oral administration of TMP/SDZ (30 mg/kg, i.e. 5 mg/kg TMP and 25 mg/kg SDZ). fAUC/MIC with a target value of 24 hr was selected as the PKPD index predictive of TMP/SDZ efficacy. Using a modeling approach, PKPD cutoffs for TMP and SDZ were determined as 0.062 and 16 mg/L, respectively. By incorporating an anticipated potentiation effect of SDZ on TMP against Escherichia coli and Staphylococcus delphini, the PKPD cutoff of TMP was revised to 0.312 mg/L, which is above the tentative epidemiological cutoffs (TECOFF) for these species. The current empirical TMP/SDZ dosage regimen (30 mg/kg, PO, once daily) therefore appears adequate for treatment of wild-type E. coli and S. delphini infections in mink.

Drug-Drug Binary Solids of Nitrofurantoin and Trimethoprim: Crystal Engineering and Pharmaceutical Properties.

With the aim of developing multidrug solids through a tuned crystal engineering approach, we have selected two antiurinary infective drugs, namely, nitrofurantoin (NF) and trimethoprim (TMP) and isolated eight binary drug-drug solid solvates along with a nonsolvated cocrystal. Crystal structure analyses were performed for eight of these solids and rationalized in terms of known supramolecular synthons formed by pyrimidine, imide, and amine functionalities. Notably, the TMP-NF anhydrous cocrystal and its ionic cocrystal hydrate exhibit enhanced equilibrium solubilities compared to pure NF or the simple NF hydrate. Furthermore, the ionic cocrystal hydrate exhibits greater antibacterial activity against the Gram-negative bacteria, E. coli, compared to the parent TMP and NF at the lowest concentration of 3.9 µg/mL. This study indicates initial pathways using the cocrystal methodology that would help to eventually arrive at an antiurinary cocrystal with optimal properties.

High-throughput identification and rational design of synergistic small-molecule pairs for combating and bypassing antibiotic resistance.

Antibiotic-resistant infections kill approximately 23,000 people and cost $20,000,000,000 each year in the United States alone despite the widespread use of small-molecule antimicrobial combination therapy. Antibiotic combinations typically have an additive effect: the efficacy of the combination matches the sum of the efficacies of each antibiotic when used alone. Small molecules can also act synergistically when the efficacy of the combination is greater than the additive efficacy. However, synergistic combinations are rare and have been historically difficult to identify. High-throughput identification of synergistic pairs is limited by the scale of potential combinations: a modest collection of 1,000 small molecules involves 1 million pairwise combinations. Here, we describe a high-throughput method for rapid identification of synergistic small-molecule pairs, the overlap2 method (O2M). O2M extracts patterns from chemical-genetic datasets, which are created when a collection of mutants is grown in the presence of hundreds of different small molecules, producing a precise set of phenotypes induced by each small molecule across the mutant set. The identification of mutants that show the same phenotype when treated with known synergistic molecules allows us to pinpoint additional molecule combinations that also act synergistically. As a proof of concept, we focus on combinations with the antibiotics trimethoprim and sulfamethizole, which had been standard treatment against urinary tract infections until widespread resistance decreased efficacy. Using O2M, we screened a library of 2,000 small molecules and identified several that synergize with the antibiotic trimethoprim and/or sulfamethizole. The most potent of these synergistic interactions is with the antiviral drug azidothymidine (AZT). We then demonstrate that understanding the molecular mechanism underlying small-molecule synergistic interactions allows the rational design of additional combinations that bypass drug resistance. Trimethoprim and sulfamethizole are both folate biosynthesis inhibitors. We find that this activity disrupts nucleotide homeostasis, which blocks DNA replication in the presence of AZT. Building on these data, we show that other small molecules that disrupt nucleotide homeostasis through other mechanisms (hydroxyurea and floxuridine) also act synergistically with AZT. These novel combinations inhibit the growth and virulence of trimethoprim-resistant clinical Escherichia coli and Klebsiella pneumoniae isolates, suggesting that they may be able to be rapidly advanced into clinical use. In sum, we present a generalizable method to screen for novel synergistic combinations, to identify particular mechanisms resulting in synergy, and to use the mechanistic knowledge to rationally design new combinations that bypass drug resistance.

Spontaneous community-acquired PVL-producing Staphylococcus aureus mediastinitis in an immunocompetent adult - a case report.

BACKGROUND: Mediastinitis caused by hematogenous spread of an infection is rare. We report the first known case of community-acquired mediastinitis from hematogenous origin in an immunocompetent adult. This rare invasive infection was due to Panton-Valentine Leucocidin-producing (PVL+) methicillin-susceptible Staphylococcus aureus (MSSA). CASE PRESENTATION: A 22-year-old obese man without other medical history was hospitalized for febrile precordial chest pain. He reported a cutaneous back abscess 3 weeks before. CT-scan was consistent with mediastinitis and blood cultures grew for a PVL+ MSSA. Intravenous clindamycin (600 mg t.i.d) and cloxacillin (2 g q.i.d.), secondary changed for fosfomycin (4 g q.i.d.) because of a related toxidermia, was administered. Surgical drainage was performed and confirmed the presence of a mediastinal abscess associated with a fistula between the mediastinum and right pleural space. All local bacteriological samples also grew for PVL+ MSSA. In addition to clindamycin, intravenous fosfomycin was switched to trimethoprim-sulfamethoxazole after 4 weeks for a total of 10 weeks of antibiotics. CONCLUSIONS: We present the first community-acquired mediastinitis of hematogenous origin with PVL+ MSSA. Clinical evolution was favorable after surgical drainage and 10 weeks of antibiotics. The specific virulence of MSSA PVL+ strains played presumably a key role in this rare invasive clinical presentation.

Effectiveness of Methenamine for UTI Prevention in Older Adults.

Background: Methenamine is a drug used for the prevention of lower urinary tract infections (UTIs). However, efficacy has not been established in older adults or patients with varying degrees of kidney function. Objective: To evaluate the effectiveness of methenamine for the prevention of UTI in adults 60 years and older. Methods: This was a retrospective, pre-post, observational study. The study included primary care patients 60 years and older who were taking methenamine between January 1, 2015, and September 30, 2018. The primary outcome was the time to first UTI after methenamine initiation compared with the average time between UTIs in the 12 months prior to methenamine initiation. Results: Of 434 patients reviewed, 150 met inclusion criteria. The average time to UTI was 3.3 months prior to methenamine initiation compared with 5.5 months after methenamine initiation (P = 0.0004). There were 33 patients (22%) who did not have a UTI after methenamine initiation. Also, 14 patients (9.3%) had a calculated CrCl <30 mL/min at baseline. The average time to UTI in these patients was 3.3 months prior to methenamine initiation compared with 12.7 months after initiation (P < 0.0001). Conclusion and Relevance: Methenamine use was associated with a longer time to UTI in older adults with varying degrees of kidney function. The effectiveness of methenamine appeared to be similar regardless of kidney function, which is new evidence. Because of a lack of acquired resistance, methenamine may be an effective option for UTI prophylaxis in older adults.

Immunotherapy to reduce frequency of urinary tract infections in people with neurogenic bladder dysfunction; a pilot randomised, placebo-controlled trial.

OBJECTIVE: To establish the feasibility of a randomized, placebo-controlled trial to investigate the effect of a specific immunotherapy bacterial lysate OM-89 (Uro-Vaxom®) in reducing the frequency of urinary tract infections in people with neurogenic bladder dysfunction. DESIGN: A parallel-group, double-blind, randomized, placebo-controlled trial. SETTING: Patients at home, recruited through out-patient contact, social media and patient support groups. SUBJECTS: People with a spinal cord injury, multiple sclerosis, transverse myelitis or cauda equina syndrome who had suffered three or more clinically diagnosed urinary tract infections treated with antibiotics over the preceding 12 months. INTERVENTIONS: All participants took one capsule of oral OM-89 immunotherapy (6 mg) or matching Placebo (randomisation ratio 1:1), once daily in the morning for 3 months. MAIN MEASURES: The primary outcome was occurrence of a symptomatic urinary tract infection treated with an antibiotic, assessed at 3 and 6 months. Feasibility measures included recruitment, retention and practical difficulties. RESULTS: Of 115 patients screened, 49 were recruited, one withdrew before randomization, and 23 were allocated to the control group receiving matching placebo. Six participants, all in the control group, discontinued the intervention; all participants provided full data at both follow-up times. Over 6 months, 18/25 active group patients had 55 infections, and 18/23 control group patients had 47 infections. Most research and clinical procedures were practical, and acceptable to participants. CONCLUSION: It is feasible to undertake a larger trial. We recommend broader inclusion criteria to increase eligibility and generalizability.

Optimizing dosing of nitrofurantoin from a PK/PD point of view: What do we need to know?

Nitrofurantoin is an old antibiotic and an important first-line oral antibiotic for the treatment of uncomplicated urinary tract infections. However despite its long term use for over 60 years, little information is available with respect to its dose justification and this may be the reason of highly variable recommended doses and dosing schedules. Furthermore, nitrofurantoin is not a uniform product -crystal sizes of nitrofurantoin, and therefore pharmacokinetic properties, differ significantly by product. Moreover, pharmacokinetic profiling of some products is even lacking, or difficult to interpret because of its unstable chemical properties. Pharmacokinetic and pharmacodynamic data is now slowly becoming available. This review provides an overview of nitrofurantoins antibacterial, pharmacokinetic and pharmacodynamic properties. This shows that a clear rationale of current dosing regimens is scanty.

Legionella pneumonia: increased risk after COVID-19 lockdown? Italy, May to June 2020.

We report a case of Legionella pneumonia in a dishwasher of a restaurant in Rome, Italy, just after the end of the lockdown that was in place to control the SARS-CoV-2 epidemic. The case highlights the importance of strict monitoring of water and air systems immediately before reopening business or public sector buildings, and the need to consider Legionella infections among the differential diagnosis of respiratory infections after lockdown due to the ongoing COVID-19 pandemic.

Treatment duration of pivmecillinam in men, non-pregnant and pregnant women for community-acquired urinary tract infections caused by Escherichia coli: a retrospective Danish cohort study.

OBJECTIVES: To evaluate the importance of treatment duration for therapeutic efficacy of pivmecillinam for community-acquired urinary tract infections (UTIs) caused by Escherichia coli. METHODS: A retrospective cohort study was conducted between 1 January 2010 and 30 September 2016 in adults with community-acquired E. coli bacteriuria, treated empirically with pivmecillinam. Regimens of 3, 5 and 7 days were compared using clinical treatment failure (i.e. redemption of a new antibiotic or hospitalization due to UTI) within 14 and 30 days as outcome. HR and risk difference with 95% CI were estimated for treatment failure. Results were stratified by age (18-50, 51-70, >70 years) and sex. RESULTS: Of the 21864 cases of E. coli UTI that were analysed, 2524 (11.5%) were in men. In 954 cases (4.4%) E. coli produced ESBL and 125 (13.1%) of the cases were in men. The 3 day regimen increased the risk of treatment failure for all groups. The risk differences between the 3 and 5 day regimens were <10% for women, but >10% for men. Comparing the 7 day and 5 day regimens, only women aged >50 years demonstrated an increased risk of treatment failure within 14 days with the 5 day regimen, but not within 30 days. CONCLUSIONS: With the current data, where data on clinical classification of the E. coli UTI were missing, a 5 day treatment with pivmecillinam at 400 mg three times daily seems to be the rational recommendation for lower UTI in men, pregnant women and women >50 years old. A 3 day regimen seems sufficient for non-pregnant women <50 years old.

A co-infection of varicella-zoster virus and Pneumocystis jirovecii in a non-HIV immunocompromised patient: a case report.

BACKGROUND: Varicella-zoster virus (VZV) causes herpes zoster. Pneumocystis jirovecii (PJ) also causes pneumonia in immunocompromised hosts. Although both cause opportunistic infections, it is rare to have a co-infection in a non-human immunodeficiency virus carrier. CASE PRESENTATION: An 84-year-old woman with hemolytic anemia referred because of acute respiratory failure. She had received prednisolone without PJ pneumonia prevention. She developed dyspnea and desaturation while eating, and thus was treated based on a presumptive diagnosis of aspiration pneumonia. Physical examination revealed a vesicular rash on the left side of her neck suggesting herpes zoster infection. Polymerase chain reaction of her sputum for PJ and VZV was positive, which confirmed a diagnosis of pneumonia due to PJ and VZV co-infection. Despite acyclovir and sulfamethoxazole and trimethoprim administration, she died on hospital day 19. CONCLUSIONS: Clinicians should suspect PJP when patients on systemic corticosteroids develop pneumonia and they have not received prophylactic treatment for PJP in non-HIV carriers. When such patients have a VZV rash, clinicians should aggressively seek signs of opportunistic infections. Our case hereby highlights the importance of recognizing the possibility of a VZV and PJ co-infection.

Long-term antibiotics for preventing recurrent urinary tract infection in children.

BACKGROUND: Urinary tract infection (UTI) is common in children. Symptoms include fever, lethargy, anorexia, and vomiting. UTI is caused by Escherichia coli in over 80% of cases and treatment is a course of antibiotics. Due to acute illness caused by UTI and the risk of pyelonephritis-induced permanent kidney damage, many children are given long-term (several months to 2 years) antibiotics aimed at preventing recurrence. This is the third update of a review first published in 2001 and updated in 2006, and 2011. OBJECTIVES: To assess whether long-term antibiotic prophylaxis was more effective than placebo/no treatment in preventing recurrence of UTI in children, and if so which antibiotic in clinical use was the most effective. We also assessed the harms of long-term antibiotic treatment. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 30 July 2018 through contact with the Cochrane Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: Randomised comparisons of antibiotics with other antibiotics, placebo or no treatment to prevent recurrent UTI in children. DATA COLLECTION AND ANALYSIS: Two authors independently assessed and extracted information for the initial and previous updates. A random-effects model was used to estimate risk ratio (RR) and risk difference (RD) for recurrent UTI with 95% confidence intervals (CI). MAIN RESULTS: In this update sixteen studies (2036 children randomised, 1977 analysed) were included. Seven studies (612 children) compared two or more types of antibiotics, six (1088 children) compared antibiotics with placebo or no treatment, one four-armed study compared circumcision with and without antibiotic treatment, one study compared dose of antibiotic, and one three-armed study compared two different antibiotics as well as no treatment. Of the sixteen included studies only one study was judged to be at low risk of bias for all domains, with the majority judged to be at unclear risk of bias due to very poorly reported methodology. The number of studies judged to be a low risk of bias was: selection bias (7); performance bias (4); detection bias (1); attrition bias (6); reporting bias (7); and other bias (2). The number of studies judged to be at high risk of bias was: selection bias (0); performance bias (5); detection bias (1); attrition bias (4); reporting bias (6); and other bias (1).Compared to placebo/no treatment, antibiotics lead to a modest decrease in the number of repeat symptomatic UTI in children; however the estimate from combining all studies was not certain and the confidence interval indicates low precision indicating that antibiotics may make little or no difference to risk of repeat infection (RR 0.75, 95% CI 0.28 to 1.98). When we combined only the data from studies with concealed treatment allocation, there was a similar reduction in risk of repeat symptomatic UTI in children taking antibiotics (RR 0.68) and we have greater certainty in this estimate because of the more robust study designs, the confidence interval is smaller and it does not include the point of no effect (95% CI 0.48 to 0.95). The estimated reduction in risk of repeat symptomatic UTI for children taking antibiotics was similar in children with vesicoureteric reflux (VUR) (RR 0.65, 95% CI 0.39 to 1.07) compared to those without VUR (RR 0.56, 95% CI 0.15 to 2.12) however there was considerable uncertainty due to imprecision from fewer events in the smaller group of children with VUR. There was no consistency in occurrence of adverse events, with one study having more events in the placebo group and a second study having more events in the antibiotics group. Three studies reported data for antibiotic resistance with the analysis estimating the risk of a UTI caused by a bacteria resistant to the prophylactic antibiotic being almost 2.5 times greater in children on antibiotics than for children on placebo or no treatment (RR 2.40, 95% CI 0.62 to 9.26). However the confidence interval is wide, showing imprecision and there may be little or no difference between the two groups.Eight studies involving 659 children compared one antibiotic with another but few studies compared the same combination for the same outcome so little data could be pooled. Two studies reported microbial resistance data and analysis showed that treatment with nitrofurantoin may lead to a lower risk of a UTI caused by a bacteria resistant to the treatment drug compared to children given trimethoprim-sulphamethoxazole as their prophylactic treatment (RR 0.54, 95% CI 0.31 to 0.92). AUTHORS' CONCLUSIONS: Long-term antibiotics may reduce the risk of repeat symptomatic UTI in children who have had one or more previous UTIs but the benefit may be small and must be considered together with the increased risk of microbial resistance.

Antimicrobial agents for preventing urinary tract infections in adults undergoing cystoscopy.

BACKGROUND: Cystoscopy is commonly performed for diagnostic purposes to inspect the interior lining of the bladder. One disadvantage of cystoscopy is the risk of symptomatic urinary tract infection (UTI) due to pre-existing colonization or by introduction of bacteria at the time of the procedure. However, the incidence of symptomatic UTI following cystoscopy is low. Currently, there is no consensus on whether antimicrobial agents should be used to prevent symptomatic UTI for cystoscopy. OBJECTIVES: To assess the effects of antimicrobial agents compared with placebo or no treatment for prevention of UTI in adults undergoing cystoscopy. SEARCH METHODS: We comprehensively searched electronic databases of the Cochrane Library, PubMed, Embase, LILACS, and CINAHL. We searched the WHO ICTRP and ClinicalTrials.gov for ongoing trials. We used no language or date restrictions in the electronic searches. We searched the reference lists of identified articles and contacted authors for related information. The last search of the electronic databases was 4 February 2019. SELECTION CRITERIA: We included randomized controlled trials (RCTs) or quasi-RCTs that compared any prophylactic antibiotic versus placebo, no treatment, or other non-antibiotic prophylaxis in adults undergoing cystoscopy. There was no restriction on the dose, frequency, formulation, duration, or mode of administration of the antibiotics. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcomes were systemic UTI, symptomatic UTI (composite of systemic and/or localized UTI), and serious adverse events. Secondary outcomes were minor adverse events, localized UTI, asymptomatic bacteriuria, and bacterial resistance. We assessed the quality of evidence using GRADE. MAIN RESULTS: We included 20 RCTs and two quasi-RCTs with 7711 participants, all of which compared antibiotic prophylaxis with placebo or no treatment control. We found no studies comparing antibiotic prophylaxis with non-antibiotic prophylaxis.Primary outcomesSystemic UTI: antibiotic prophylaxis may have little or no effect on the risk of systemic UTI compared with placebo or no treatment (risk ratio (RR) 1.12, 95% confidence interval (CI) 0.38 to 3.32; 5 RCTs; 504 participants; low-quality evidence); this corresponds to two more people (95% CI 12 fewer to 46 more) per 1000 people developing a systemic UTI. We downgraded the quality of the evidence for study limitations and imprecision.Symptomatic UTI: antibiotic prophylaxis may reduce the risk of symptomatic UTI (RR 0.49, 95% CI 0.28 to 0.86; 11 RCTs; 5441 participants; low-quality evidence); this corresponds to 30 fewer people (95% CI 42 fewer to 8 fewer) per 1000 people developing a symptomatic UTI when provided with antibiotic prophylaxis. We downgraded the quality of the evidence for study limitations and potential publication bias.Serious adverse events: the studies reported no serious adverse events in either the intervention group or control group and no effect size could be calculated. Antibiotic prophylaxis may have little or no effect on serious adverse events (4 RCTs, 630 participants; very low-quality evidence), but we are very uncertain of this finding. We downgraded the quality of the evidence for study limitations and very serious imprecision.Secondary outcomesMinor adverse events: prophylactic antibiotics may have little or no effect on minor adverse events when compared with placebo or no treatment (RR 2.82, 95% CI 0.54 to 14.80; 4 RCTs; 630 participants; low-quality evidence). We downgraded the quality of the evidence for study limitations and imprecision.Localized UTI: prophylactic antibiotics may have little or no effect on the risk of localized UTI (RR 1.0, 95% CI 0.06 to 15.77; 1 RCT; 200 participants; very low-quality evidence), but we were very uncertain of this finding. We downgraded the quality of the evidence for study limitations and very serious imprecision.Bacterial resistance: prophylactic antibiotics may increase bacterial resistance (RR 1.73, 95% CI 1.04 to 2.87; 38 participants; 2 RCTs; very low-quality evidence), but we were uncertain of this finding. We downgraded the quality of the evidence for study limitations, indirectness, and imprecision.We were able to perform few secondary analyses; these did not suggest any subgroup effects. AUTHORS' CONCLUSIONS: Antibiotic prophylaxis may reduce the risk of symptomatic UTI but not systemic UTIs. Serious and minor adverse events may not be increased with the use of antibiotic prophylaxis. The findings are informed by low- and very low-quality evidence ratings for all outcomes.

Should I stay or should I go? A qualitative study exploring participation in a urology clinical trial.

INTRODUCTION AND HYPOTHESIS: The aim of this study was to identify modifiable factors to improve recruitment in a urology clinical trial of women with recurrent urinary tract infection (rUTI). An embedded qualitative study was conducted with patients and recruiting clinicians in the first 8 months of the trial. We present a matrix of factors influencing how patients make decisions about trial participation. METHODS: This was a qualitative study using telephone interviews. When they were first approached about the trial, women were asked to complete an expression of interest form if they wished to be contacted for an interview. Data were analysed thematically. NVivo 10 software (Qualitative data analysis software. 10th ed: QSR International Pty Ltd; 2012) was used as a management tool. RESULTS: Thirty patients and 11 clinicians were interviewed. Influences on patient participation included the impact of rUTI on quality of life (QoL), understanding of antibiotic resistance, and previous experiences with antibiotics either positive or negative. Very few women who declined the trial agreed to be interviewed. However, some of those who participated had reservations about it. These included the perceived risk of trying a new treatment, trial length, and the burden of participating. One person interviewed left the trial because of repeated infections and difficulties getting general practitioner appointments. CONCLUSIONS: A combination of factors worked to influence women to decide to participate, to remain in, or to leave the trial. A better understanding of how these factors interact and work can assist in the recruitment and retention of individual trial participants.

Methenamine's journey of 160 years: Repurposal of an old urinary antiseptic for treatment and hypoxic radiosensitization of cancers and glioblastoma.

Methenamine (hexamethylenetetramine, hexamine, urotropine) is a compound discovered in 1859, which is still currently being used as a urinary antiseptic. Methenamine is highly soluble in water and polar solvents, and its molecular constitution is similar to adamantane compounds with tetrahedral cage like structure. In acidic conditions, methenamine decomposes to formaldehyde and ammonia. Recently, methenamine has gained a renewal of interest due to antibiotic-resistant bacteria urinary tract infections; interestingly, bacteria cannot gain resistance to formaldehyde. In 1968, David and Burkitt reported remarkable regression of four Burkitt Lymphoma patients in eight subjects who were treated with septicemine (a solution containing 6.3 g of methenamine iodomethylate and 1 g of methenamine sodium benzoate in 100 cc distilled water). Unfortunately, these striking observations did not gain interest in the medical community; despite experimental models that showed that methenamine synergized with hyperthermia, radiation, and chemotherapy to block cancer growth. As the hypoxic core of tumours have an acidic pH, it would be plausible to expect that methenamine would selectively target dormant, non-proliferative, and treatment-resistant cancer clones in large tumours. Moreover, previous data suggests that methenamine can be safely used intravenously and for treatment of infections of the central nervous system. It may therefore be an effective adjuvant in treatment of systemic cancers and glioblastoma.

Susceptibility of the Index Urinary Tract Infection to Prophylactic Antibiotics Is a Predictive Factor of Breakthrough Urinary Tract Infection in Children with Primary Vesicoureteral Reflux Receiving Continuous Antibiotic Prophylaxis.

BACKGROUND: Few studies have reported on breakthrough urinary tract infection (UTI) associated with the susceptibility of index UTI to prophylactic antibiotics in children with primary vesicoureteral reflux (VUR) receiving continuous antibiotic prophylaxis (CAP). We assessed the impact of the susceptibility of index UTI to prophylactic antibiotics in breakthrough UTIs in children with primary VUR receiving CAP. METHODS: We retrospectively reviewed the medical records of 81 children with primary VUR who were diagnosed after febrile or symptomatic UTI and subsequently received trimethoprim-sulfamethoxazole (TMP-SMX) as CAP between January 2010 and December 2013. We allocated children to a susceptible group or a resistant group based on the susceptibility of index UTI to TMP-SMX. We evaluated patient demographics and clinical outcomes after CAP according to the susceptibility of index UTI to TMP-SMX. Multivariate analysis was used to identify the predictive factors for breakthrough UTI. RESULTS: Of the 81 children, 42 were classified into the susceptible group and 39 into the resistant group. The proportion of breakthrough UTI was 31.0% (13/42) in the susceptible group and 53.8% (21/39) in the resistant group (P = 0.037). Progression of renal scarring was observed in 0% of children in the susceptible group and 15% in the resistant group (P = 0.053). Multivariate analysis showed that TMP-SMX resistance and initial renal scarring were significant predictors of breakthrough UTI. CONCLUSION: Susceptibility of index UTI to prophylactic antibiotics is a risk factor of breakthrough UTI and is associated with poor clinical outcomes in children with primary VUR receiving CAP.

[Acute and recurrent urinary tract infections in women presenting in primary practice]. / Akute und rezidivierende Harnwegsinfekte der Frau in der allgemeinmedizinischen Praxis.

Acute and recurrent urinary tract infections in women presenting in primary practice Abstract. Acute and recurrent urinary tract infections in women of all age groups are becoming an increasing problem in primary care and medical practice. Symptoms can be relieved by a guideline-oriented acute therapy and a multimodal infection prophylaxis. The restoration of the body's natural defence mechanisms plays a central role. This article informs about the causes, the basic diagnostic examinations and the practical use of therapeutic and prophylactic measures.

Ibuprofen versus pivmecillinam for uncomplicated urinary tract infection in women-A double-blind, randomized non-inferiority trial.

BACKGROUND: Although uncomplicated urinary tract infections (UTIs) are often self-limiting, most patients will be prescribed antibiotic treatment. We assessed whether treatment with ibuprofen was non-inferior to pivmecillinam in achieving symptomatic resolution by day 4, with a non-inferiority margin of 10%. METHODS AND FINDINGS: This was a randomized, controlled, double-blind non-inferiority trial. We recruited patients from 16 sites in a general practice setting in Norway, Sweden, and Denmark. Non-pregnant women aged 18-60 years presenting with symptoms of uncomplicated UTI were screened for eligibility from 11 April 2013 to 22 April 2016. Patients with informed consent were randomized (1:1 ratio) to treatment with either 600 mg ibuprofen or 200 mg pivmecillinam 3 times a day for 3 days. The patient, treating physician, and study personnel were blinded to treatment allocation. The primary outcome was the proportion of patients who felt cured by day 4, as assessed from a patient diary. Secondary outcomes included the proportion of patients in need of secondary treatment with antibiotics and cases of pyelonephritis. A total of 383 women were randomly assigned to treatment with either ibuprofen (n = 194, 181 analyzed) or pivmecillinam (n = 189, 178 analyzed). By day 4, 38.7% of the patients in the ibuprofen group felt cured versus 73.6% in the pivmecillinam group. The adjusted risk difference with 90% confidence interval was 35% (27% to 43%) in favor of pivmecillinam, which crossed the prespecified non-inferiority margin. Secondary endpoints were generally in favor of pivmecillinam. After 4 weeks' follow-up, 53% of patients in the ibuprofen group recovered without antibiotic treatment. Seven cases of pyelonephritis occurred, all in the ibuprofen group, giving a number needed to harm of 26 (95% CI 13 to 103). Five of these patients were hospitalized and classified as having serious adverse events; 2 recovered as outpatients. A limitation of the study was the extensive list of exclusion criteria, eliminating almost half of the patients screened. We did not register symptoms in the screening process; hence, we do not know the symptom burden for those who declined to participate. This might make our results less generalizable. CONCLUSIONS: Ibuprofen was inferior to pivmecillinam for treating uncomplicated UTIs. More than half of the women in the ibuprofen group recovered without antibiotics. However, pyelonephritis occurred in 7 out of 181 women using ibuprofen. Until we can identify those women who will develop complications, we cannot recommend ibuprofen alone as initial treatment to women with uncomplicated UTIs. TRIAL REGISTRATION: ClinicalTrials.gov NCT01849926 EU Clinical Trials Register (EU-CTR), EudraCT Number 2012-002776-14.