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Purpose: Nitrofurantoin (NITRO), a long-standing antibiotic to treat urinary tract infections, is activated by Nitro reductases. This activation mechanism has led to its exploration for repositioning applications in controlling and treating breast cancer, which express a Nitro reductase gene., Methods: NITRO Cubosomes were developed using hot homogenization according to 2 3 -full factorial design. The factors studied included the ratio of drug to oily phase (1:10 and 2:10), the ratio of oily to aqueous phase (1:10 and 1:5), and the ratio of Glyceryl mono-oleate (GMO) to Poloxamer 407 (PX407) (0.25:1 and 0.5:1). A total of 8 systems were proposed and evaluated by measuring particle size, zeta potential, polydispersity index, and percentage of entrapment efficiency., Results: S6 (1:10 drug: oily phase, 1:5 oily: aqueous phase and 0.5:1 GMO: PX407) with particle size 45.5 ±c1.1 nm and an entrapment efficiency of 98.6 ± 1.8% exhibited highest desirability and was selected for further analysis. The morphology of S6 was examined using TEM microscopy. The activation of NITRO from S6 reflected on intracellular viability of MCF-7 breast cancer cell line was investigated by an MTT assay. The findings indicated that S6 had the lowest IC50 value (83.99 ± 0.15 μg g/mL) compared to Free NITRO (174.54 ± 1.36 μg g/mL), suggesting enhanced efficacy compared to free NITRO., Conclusion: Nitrofurantoin cubosomes can be candidates for repositioning in breast cancer management after encouraging further stability and in-vivo studies., Competing Interests: The author(s) report no conflicts of interest in this work., (© 2024 Louis et al.)

Importance: Serious cutaneous adverse drug reactions (cADRs) are potentially life-threatening drug hypersensitivity reactions involving the skin and internal organs. Antibiotics are a recognized cause of these reactions, but no studies have compared relative risks across antibiotic classes., Objectives: To explore the risk of serious cADRs associated with commonly prescribed oral antibiotics, and to characterize outcomes of patients hospitalized for them., Design, Setting, and Participants: Nested case-control study using population-based linked administrative datasets among adults aged 66 years or older who received at least 1 oral antibiotic between 2002 and 2022 in Ontario, Canada. Cases were those who had an emergency department (ED) visit or hospitalization for serious cADRs within 60 days of the prescription, and each case was matched with up to 4 controls who did not., Exposure: Various classes of oral antibiotics., Main Outcomes and Measures: Conditional logistic regression estimate of the association between different classes of oral antibiotics and serious cADRs, using macrolides as the reference group., Results: During the 20-year study period, we identified 21 758 older adults (median age, 75 years; 64.1% female) who had an ED visit or hospitalization for serious cADRs following antibiotic therapy and 87 025 matched controls who did not. In the primary analysis, sulfonamide antibiotics (adjusted odds ratio [aOR], 2.9; 95% CI, 2.7-3.1) and cephalosporins (aOR, 2.6; 95% CI, 2.5-2.8) were most strongly associated with serious cADRs relative to macrolides. Additional associations were evident with nitrofurantoin (aOR, 2.2; 95% CI, 2.1-2.4), penicillins (aOR, 1.4; 95% CI, 1.3-1.5), and fluoroquinolones (aOR, 1.3; 95% CI, 1.2-1.4). The crude rate of ED visits or hospitalization for cADRs was highest for cephalosporins (4.92 per 1000 prescriptions; 95% CI, 4.86-4.99) and sulfonamide antibiotics (3.22 per 1000 prescriptions; 95% CI, 3.15-3.28). Among the 2852 case patients hospitalized for cADRs, the median length of stay was 6 days (IQR, 3-13 days), 9.6% required transfer to a critical care unit, and 5.3% died in the hospital., Conclusion and Relevance: Commonly prescribed oral antibiotics are associated with an increased risk of serious cADRs compared with macrolides, with sulfonamides and cephalosporins carrying the highest risk. Prescribers should preferentially use lower-risk antibiotics when clinically appropriate.

Antibiotics are essential molecules for the treatment and prophylaxis of many infectious diseases. However, drugs that combat microbial infections can become a human health threat due to their high and often indiscriminate consumption, considered one of the factors of antimicrobial resistance (AMR) emergence. The AMR crisis, the decrease in new drug development by the pharmaceutical industry, and reduced economic incentives for research have all reduced the options for treating infections, and new strategies are necessary, including the return of some traditional but "forgotten" antibiotics. However, prescriptions for these older drugs including nitrofurantoin and oral fosfomycin, have been based on the results of pioneer studies, and the limited knowledge generated 50-70 years ago may not be enough. To avoid harming patients and further increasing multidrug resistance, systematic evaluation is required, mainly for the drugs prescribed for community-acquired infections, such as urinary tract infections (UTI). Therefore, this review has the objective of reporting the use of two classic drugs from the nitrofuran and phosphonic acid classes for UTI control nowadays. Furthermore, we also explore new approaches used for these antibiotics, including new combination regimes for spectral amplification, and the prospects for reducing bacterial resistance in the fight against bacteria responsible for UTI., (© 2021. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.)

Purpose: To review the frequency of adverse events reported with nitrofurantoin (NF) in perimenopausal and menopausal women on prolonged daily prophylaxis in an outpatient setting., Methods: Electronic medical records of women aged 50-95 prescribed NF by 2 primary urology providers for at least 3 consecutive months from 2006 to 2018 were retrospectively reviewed. Demographics, reason for the initiation, dose and duration of therapy, explanation of therapy interruptions, occurrence of adverse events, comorbid conditions, and relevant lab and imaging results were recorded. The number of months on prolonged therapy were summed., Results: Of the 221 patients included, 167 (77%) were prescribed 100 mg of NF daily with a mean duration of therapy of 1.5 years. The most common indication for therapy was recurrent urinary tract infection prophylaxis. Breakthrough urinary tract infections developed in 88 (40%) patients on prolonged NF therapy but only 10 were not restarted on NF. Four patients (1.8%) were determined to have pulmonary adverse events and 1 (0.4%) developed elevated liver function tests., Conclusion: In peri-menopausal and menopausal women, the risks and benefits of chronic NF therapy should be weighed by the clinician and patient prior to prescribing long term NF. Patients must be educated about the potential NF toxicities and clinically monitored for signs and symptoms of potential adverse events while on chronic NF therapy., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The objective of this study was to evaluate if twice-daily nitrofurantoin for 5 days after discontinuation of transurethral catheterization decreases the rate of urinary tract infection (UTI) in women with postoperative urinary retention (POUR) after pelvic reconstructive surgery., Methods: This was a double-blind, placebo-controlled, randomized trial conducted across 2 clinical sites between October 2017 and April 2019. Women with acute POUR after pelvic reconstructive surgery were included and randomized to nitrofurantoin (100 mg) or placebo twice-daily for 5 days. The primary outcome was clinically suspected UTI (defined as dysuria, frequency, and irritation in the absence of vaginal discharge) and/or culture-proven UTI (defined as greater than 105 colony forming units of a single organism) within 30 days of surgery. Secondary outcomes included evaluation of adverse events related to study medication and medication adherence., Results: Data from 164 participants were eligible for intention-to-treat analysis (nitrofurantoin, n = 82; placebo, n = 82). There were no significant demographic or intraoperative differences except for body mass index and race. Median duration of catheterization was 3 days (interquartile range, 2-5 days, P = 0.12). Fifteen women in the nitrofurantoin group and 14 women in the placebo group experienced UTI within 30 days (18.3% vs 17.1%; P = 0.84; odds ratio, 1.09; 95% confidence interval, 0.49-2.43). There were no study medication allergies; however, nausea was the most common intolerance. Most women in each group completed the study drug treatment (91.5% vs 86.4%, P = 0.30)., Conclusions: Nitrofurantoin prophylaxis after transurethral catheter removal did not reduce the risk of UTI in women with acute POUR after pelvic reconstructive surgery., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2021 American Urogynecologic Society. All rights reserved.)

Background: Pulmonary side effects are well known, including lung fibrosis, in elderly patients treated with long-term nitrofurantoin to prevent urinary tract infections and secondary renal injury. However, pulmonary side effects have only been reported rarely in paediatric cases, despite nitrofurantoin being a first line prophylactic treatment of recurrent childhood urinary tract infection., Case Presentations: A 6-year-old girl was admitted to the hospital with dyspnea, general fatigue, loss of appetite and need for nasal oxygen treatment after long-term nitrofurantoin treatment. A computed tomography scan of the chest showed lung fibrosis. A biopsy confirmed this diagnosis. We suspected the fibrosis to be caused by the nitrofurantoin treatment. Thorough examinations reveal no other explanations. Nitrofurantoin was discontinued and the girl was treated with methylprednisolone. After 17 month a new scan and lung function test showed total regression of the lung fibrosis., Conclusions: This case underlines that risk of severe side effects should be taken in to account before initiation of long-term nitrofurantoin treatment in children.

Antibiotic combination therapies are important for the efficient treatment of many types of infections, including those caused by antibiotic-resistant pathogens. Combination treatment strategies are typically used under the assumption that synergies are conserved across species and strains, even though recent results show that the combined treatment effect is determined by specific drug-strain interactions that can vary extensively and unpredictably, both between and within bacterial species. To address this problem, we present a new method in which antibiotic synergy is rapidly quantified on a case-by-case basis, allowing for improved combination therapy. The novel CombiANT methodology consists of a 3D-printed agar plate insert that produces defined diffusion landscapes of 3 antibiotics, permitting synergy quantification between all 3 antibiotic pairs with a single test. Automated image analysis yields fractional inhibitory concentration indices (FICis) with high accuracy and precision. A technical validation with 3 major pathogens, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus, showed equivalent performance to checkerboard methodology, with the advantage of strongly reduced assay complexity and costs for CombiANT. A synergy screening of 10 antibiotic combinations for 12 E. coli urinary tract infection (UTI) clinical isolates illustrates the need for refined combination treatment strategies. For example, combinations of trimethoprim (TMP) + nitrofurantoin (NIT) and TMP + mecillinam (MEC) showed synergy, but only for certain individual isolates, whereas MEC + NIT combinations showed antagonistic interactions across all tested strains. These data suggest that the CombiANT methodology could allow personalized clinical synergy testing and large-scale screening. We anticipate that CombiANT will greatly facilitate clinical and basic research of antibiotic synergy., Competing Interests: The authors of this manuscript have the following competing interests: A patent comprising the described method has been filed by the authors and is pending under number 640 SE 2050304-1.

BACKGROUND Interstitial lung disease, also known as diffuse parenchymal lung disease, is a group of diseases that affects the interstitium of the lungs and can lead to progressive fibrosis of the lungs. The potential causes of interstitial lung disease are broad and includes infection, malignancy, autoimmune/connective tissues diseases, inhaled substances, and certain medications. One of the medications that can cause interstitial lung disease is nitrofurantoin. CASE REPORT A 88-year-old man with recurrent urinary tract infections was treated with long-term nitrofurantoin prophylactic therapy. He took 100 mg of nitrofurantoin on a daily basis for over 10 years as prophylactic therapy for recurrent urinary tract infections, and subsequently developed chronic respiratory failure requiring supplemental oxygen. Chest radiography and high-resolution computed tomography imaging were performed and revealed pulmonary fibrosis consistent with interstitial lung disease. CONCLUSIONS Although nitrofurantoin is one of the most commonly used antibiotics in the treatment of urinary tract infections and is often considered a relatively safe medication, long-term use can lead to the development of interstitial lung disease.

Purpose: To evaluate ciprofloxacin resistance (CR) and extended-spectrum beta-lactamase (ESBL) positivity in the rectal flora, antibiotic prophylaxis received, and post-biopsy infectious complications in patients undergoing prostate biopsy., Material & Methods: Rectal swab samples collected from 99 patients suspected of prostate cancer two days before prostate biopsy were tested for microbial susceptibility and ESBL production. All patients were given standard ciprofloxacin and ornidazole prophylaxis. Ten days post-biopsy, the patients were contacted by phone and asked about the presence of fever and/or symptoms of urinary tract infection., Results: Escherichia coli (E.coli) was the most common isolate detected in 82 (75%) of the rectal swab samples. Ciprofloxacin resistance was detected in 33% and ESBL positivity in 22% of the isolated E.coli strains. No microorganisms other than E.coli were detected in blood, urine, and rectal swab cultures of patients who developed post-biopsy complications. CR E.coli strains also showed resistance to other antimicrobial agents. The lowest resistance rates were to amikacin (n = 2, 7.4%) and nitrofurantoin (n = 1, 3.7%). Seven patients (7.6%) developed infectious complications. There was no significant difference in probability of hospitalization between patients with CR strains (14.3%) and those with ciprofloxacin-susceptible strains (14.3% vs. 4.7%; p = 0.194). However, strains that were both CR and ESBL-positive were associated with significantly higher probability of hospitalization compared to ciprofloxacin-susceptible strains (28.6% vs. 3.8%; p = 0.009)., Conclusion: The higher rate of infectious complications with CR and ESBL-positive strains suggests that the agents used for antibiotic prophylaxis should be reevaluated. It is important to consider local resistance data when using extended-spectrum agents to treat patients presenting with post-biopsy infectious complications.

Prediction of the intestinal absorption of new chemical entities (NCEs) is still difficult, in part because drug efflux transporters, including breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp), restrict their intestinal permeability. We have demonstrated that the absorptive quotient (AQ) obtained from the in vitro Caco-2 permeability study would be a valuable parameter for estimating the impact of BCRP on the intestinal absorption of drugs. In this study, in order to assess the correlation between the in vitro AQ for BCRP and in vivo contribution of BCRP on drug absorption, we evaluated the oral absorption of various compounds by portal-systemic blood concentration (P-S) difference method in wild-type (WT), Bcrp(-/-), and Mdr1a/1b(-/-) mice. In addition, we also calculated a rate of BCRP contribution ( R bcrp ). Ciprofloxacin and nitrofurantoin showed the low R bcrp value (0.05 and 0.15), and their apparent fractions of intestinal absorption in WT mice were 46.5% and 63.7%, respectively. These results suggest that BCRP hardly affects their intestinal absorption in mice. On the other hand, the apparent fraction of intestinal absorption of topotecan and sulfasalazine was significantly lower in WT mice than in Bcrp(-/-) mice. Moreover, their R bcrp values were 0.42 and 0.79, respectively, indicating the high contribution of BCRP to their oral absorption. Furthermore, in vivo R bcrp calculated in this study was almost comparable to in vitro AQ obtained from Caco-2 permeability study. This study provides useful concepts in assessing the contribution of BCRP on intestinal absorption in drug discovery and development process., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This work did not involve studies with human subjects., (© 2019 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Background: It is unknown whether nitrofurantoin 50 mg normal-release every 6 h (NF50) and nitrofurantoin 100 mg extended-release every 12 h (NF100) are equally effective for treating cystitis in primary care. In the Netherlands, GP prescription of either option largely depends on pharmacy procurement, rather than on patient-related factors., Methods: GP data between January 2013 and July 2018 were retrospectively collected. Inclusion criteria were the use of nitrofurantoin for uncomplicated cystitis, complicated cystitis or cystitis in pregnancy. Criteria for early and late failure were a second antibiotic prescription for cystitis or pyelonephritis within 14 and 28 days post-prescription, respectively. Crude and confounder-adjusted (CA) risk differences (RDs) were estimated using linear regression. Instrumental variable analysis and CA instrumental variable analysis used GP practice proportion of NF50 versus NF100 use as the instrumental variable., Results: For uncomplicated cystitis (n=46855), treatment with NF50 and NF100 resulted in late failure in 9.7% and 9.6%, respectively. The CA RD, instrumental variable RD and CA instrumental variable RD were 0.2% (95% CI=-0.5 to 0.8), -0.7% (95% CI=-1.7 to 0.3) and 0.0% (95% CI=-0.9 to 1.0), respectively. In complicated cystitis (n=10767), late failure occurred in 10.9% and 11.1% after using NF50 and NF100, respectively [CA RD=0.5% (95% CI=-1.2 to 1.8), instrumental variable RD=-0.8% (95% CI=-3.4 to 1.8) and CA instrumental variable RD=-0.3% (95% CI=-3.0 to 2.4)]. For cystitis in pregnancy (n=1087), NF50 and NF100 resulted in late failure in 13.4% and 7.8%, respectively [CA RD=-5.4% (95% CI=-10.0 to -1.4), instrumental variable RD=-8.9% (95% CI=-16.0 to -1.8) and CA instrumental variable RD=-8.9% (95% CI=-16.0 to -1.7)]. No differences were observed in early failure., Conclusions: In patients with cystitis in pregnancy, NF100 was associated with a lower incidence of late clinical failure compared with NF50. We found no differences in clinical failure between NF50 and NF100 for uncomplicated and complicated cystitis., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Given emerging uropathogen resistance to more recent antibiotics, old antibiotics used for uncomplicated urinary tract infection (UTI) warrant re-examination. In this study, the urinary antibacterial activities of fosfomycin and nitrofurantoin were investigated by determining the urinary inhibitory titre and urinary bactericidal titre against uropathogens in urine samples from female volunteers following administration of single-dose fosfomycin (3 g) or nitrofurantoin (50 mg q6h or 100 mg q8h). Urine samples were collected over 48 h (fosfomycin) or 6 or 8 h (nitrofurantoin), with drug levels quantified with every void. Fosfomycin concentrations ranged from <0.75 mg/L [lower limit of quantification (LLOQ)] to 5729.9 mg/L and nitrofurantoin concentrations ranged from <4 mg/L (LLOQ) to 176.3 mg/L (50 mg q6h) or 209.4 mg/L (100 mg q8h). There was discrepancy in the response to fosfomycin between Escherichia coli and Klebsiella pneumoniae, with fosfomycin displaying strong bactericidal activity for 48 h against E. coli but moderate bactericidal activity for 18 h against K. pneumoniae. This effect was not related to the strain's baseline minimum inhibitory concentration but rather to the presence of a resistant subpopulation. Maximum titres of nitrofurantoin were obtained during the first 2 h, but no antibacterial effect was found in most samples regardless of the dose. In the rare samples in which antibacterial activity was detectable, titres were comparable for both species tested. These findings confirm doubts regarding fosfomycin administration in UTIs caused by K. pneumoniae and reveal a discrepancy between nitrofurantoin's measurable ex vivo activity and its clinical effect over multiple dosing intervals., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Methotrexate is a widely used chemotherapy agent with a propensity for drug interactions placing the patient at risk for toxicities. There are several modes for altering methotrexate clearance including concomitant drugs leading to toxic effects on the kidneys, medications producing an acidic urine pH, and agents interfering with methotrexate transporters including the organic anion transporter and breast cancer resistance protein efflux pump. We report a case of a patient with central nervous system non-Hodgkin's lymphoma receiving high-dose methotrexate and being concomitantly treated for a urinary tract infection with nitrofurantoin. Subsequently, her initial methotrexate clearance was altered by the introduction of nitrofurantoin and returned to baseline when her nitrofurantoin was discontinued. This is the first case report describing the altered methotrexate clearance from concurrent administration of methotrexate and nitrofurantoin.

Context/objective: To evaluate the impact of long-term nitrofurantoin for UTI prophylaxis in veterans with SCI., Design: Matched pairs study., Setting: Veterans cared for at VA facilities from 10/1/2012-9/30/2013., Participants: Veterans., Interventions: n/a., Outcomes Measures: UTI, positive urine cultures, resistant cultures., Methods: Cases receiving long-term nitrofurantoin (≥90 days supply) were matched to controls by facility. Controls were patients who did not receive long-term nitrofurantoin with a history of ≥3 positive urine cultures and at least one diagnosis of UTI or asymptomatic bacteriuria in the previous year., Results: 122 SCI cases were identified and matched to 196 controls. After adjusting for differences in baseline demographic characteristics, UTIs were less frequent in cases (OR = 0.60 [95% CI 0.44-0.72]). Cases had a greater mean number of days between positive urine cultures as compared to controls (<0.0001). Cases were more likely to have isolates resistant to nitrofurantoin (P ≤ 0.0001); however, the frequency of multi-drug resistant organisms isolated from the urine was not significantly different., Conclusions: Long-term prescription of nitrofurantoin may reduce UTIs in veterans with SCI and there is no evidence that it promotes multi-drug resistance. Future prospective studies should be conducted prior to incorporating routine use of long-term nitrofurantoin into clinical care.

Background: Use of nitrofurantoin has increased significantly since its recent repositioning as a first-line agent for uncomplicated cystitis by multiple guidelines. However, current dosing regimens were developed in an era before robust pharmacokinetic testing and may not be optimal. Furthermore, formulations have been modified over the years., Objectives: To reassess the plasma and urinary pharmacokinetic profile of macrocrystalline nitrofurantoin in two commonly used dosing regimens., Methods: In this open-label, randomized crossover pharmacokinetic trial, 12 healthy adult female volunteers were randomized to receive oral nitrofurantoin 100 mg q8h on days 1 and 2 and, after a washout period, 50 mg q6h on days 30 and 31, or the same dosing schemes in reversed order. Urine and blood were collected at steady state and analysed by UPLC. Pharmacokinetic analysis was performed by WinNonlin., Results: Plasma peak concentrations were low (mean 0.33 mg/L, SD 0.08, and 0.69 mg/L, SD 0.35, after 50 and 100 mg, respectively) and dose dependent. The AUC0-24 was higher (6.49 versus 4.43 mg·h/L, P = 0.021) for the 100 mg q8h dosing regimen, but the dose-normalized AUC was similar for the two regimens. In contrast, urinary concentrations were dose independent: increasing the nitrofurantoin dose delayed the time to peak urinary concentration, while steady-state AUC0-24 values remained unchanged (943.49 and 855.95 mg·h/L at 50 mg q6h and 100 mg q8h, respectively)., Conclusions: Plasma concentrations were relatively low and dose dependent. The dose-independent urinary concentrations suggest that excretion of nitrofurantoin into the urine is saturable. Pharmacodynamic studies are urgently required to determine the impact of these findings., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: To measure the effects of an unplanned, sudden cessation of treatment in an unselected group of patients with chronic painful LUTS managed with protracted antimicrobial treatment and to report these observational data collected from a cross-over process., Materials and Methods: The imposition of a guideline resulted in the immediate cessation of antibiotic treatment in a cohort of patients with chronic painful LUTS and microscopic pyuria. Patients were assessed before treatment withdrawal, whilst off treatment, and following reinstatement. Outcome measures included a validated symptom score, microscopic enumeration of urinary white cells and uroepithelial cells, and routine urine culture., Results: These patients had reported treatment-resistant, painful LUTS for a mean of 6.5 years before treatment at this centre. Treatment was stopped in 221 patients (female = 210; male = 11; mean age = 56 years; SD = 17.81). Sixty-six per cent of women were post-menopausal. After unplanned treatment cessation, 199 patients (90%; female = 188; male = 9) reported deterioration. Eleven patients required hospital care in association with disease recurrence, including acute urinary tract infection (UTI) and urosepsis. Symptom scores increased after cessation and recovered on reinitiating treatment (F = 33; df = 2; p < 0.001). Urinary leucocyte (F = 3.7; df = 2; p = 0.026) and urothelial cells counts mirrored symptomatic changes (F = 6.0; df = 2; p = 0.003). Routine urine culture results did not reflect changes in disease status., Conclusion: These data support the hypothesis that treating painful LUTS associated with pyuria with long-term antimicrobial courses, despite negative urine culture, is effective. The microscopy of fresh unspun, unstained urine to count white cells and epithelial cells offers a valid method of monitoring disease. An unplanned cessation of antibiotic therapy produced a resurgence of symptoms and lower urinary tract inflammation in patients with chronic LUTS, supporting an infective aetiology below the level of routine detection.

Objectives: This study aimed to retrospectively assess the clinical outcome with nitrofurantoin and pivmecillinam for lower urinary tract infections (UTI) in men. Patients treated with trimethoprim were also included for comparison., Methods: All prescriptions of the study antibiotics to adult men in Uppsala County, Sweden, during 2012 were extracted. Data on patient characteristics, therapy, clinical outcome and microbiological results were obtained from the electronic medical records. The relative impact of antibiotic therapy, patient factors and pathogens on clinical outcome was assessed with univariate logistic regression using a 95% confidence interval (CI)., Results: 832 prescriptions were identified, and 171 patients treated with nitrofurantoin (n = 69), pivmecillinam (n = 57) and trimethoprim (n = 45) met the inclusion criteria. Treatment failure occurred in one patient treated with nitrofurantoin and in four patients treated with pivmecillinam. New prescriptions of UTI antibiotics and relapse within 3 months after completion of therapy were more frequent with nitrofurantoin (34% and 15%) and pivmecillinam (30% and 17%) than trimethoprim (22 and 7%). However, these differences were not statistically significant and substantial heterogeneity was noted between the treatment groups. Urinary tract catheterization was associated with a higher risk for new antibiotic prescriptions (OR 2.34, 95% CI 1.14-4.80; P = 0.022) and prostate cancer was associated with a higher incidence of relapse (OR 3.01, 95% CI 1.09-8.29; P = 0.042)., Conclusions: The clinical outcome with nitrofurantoin and pivmecillinam was acceptable in comparison with the results of previous studies. These antibiotics are suitable for empirical treatment of lower UTI in men considering their high activity against Escherichia coli and limited impact on the intestinal microbiota., Competing Interests: The authors have declared that no competing interests exist.

Review of : Huttner A et al Effect of 5-day nitrofurantoin vs single dose fosfomycin on clinical resolution of uncomplicated lower urinary tract infection in women. JAMA 2018;319(17):1781-9., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Single institution studies suggest a benefit of a week of preoperative antibiotics prior to percutaneous nephrolithotomy. These studies are limited by lower quality methodology, such as the inclusion of heterogeneous populations or nonstandard definitions of sepsis. The AUA (American Urological Association) Best Practice Statement recommends less than 24 hours of intravenous antibiotics but to our knowledge no other data exist on the duration or benefit of preoperative antibiotics. Using CONSORT (Consolidated Reporting of Trials) guidelines we sought to perform a rigorous multi-institutional trial to assess preoperative antibiotics in patients in whom percutaneous nephrolithotomy was planned and who were at low risk for infection., Materials and Methods: This randomized controlled trial enrolled patients undergoing percutaneous nephrolithotomy who were at low risk, defined as negative preoperative urine cultures and no urinary drain. Of the subjects 43 were randomized to nitrofurantoin 100 mg twice daily for 7 days preoperatively while a control arm of 43 received no oral antibiotics. All subjects received perioperative doses of ampicillin and gentamicin. Prone percutaneous nephrolithotomy was performed by urologists blinded to randomization. The primary outcome was the development of sepsis., Results: A total of 86 subjects were enrolled. Preoperative patient characteristics were similar in the treatment and control cohorts with a stone size of 19 and 17 mm, respectively (p = 0.47). Intraoperative characteristics also did not differ. The sepsis rate was not statistically different between the treatment and control groups (12% and 14%, respectively, 95% CI -0.163-0.122, p = 1.0). Other infectious parameters and complications were similar, including intensive care admission, fever, hypotension and leukocytosis., Conclusions: Our study demonstrated no advantage to providing 1 week of preoperative oral antibiotics in patients at low risk for infectious complications who undergo percutaneous nephrolithotomy. Perioperative antibiotics according to the AUA Best Practice Statement appear sufficient., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Nitrofurantoin remains the gold standard treatment of uncomplicated cystitis as well as prophylactic treatment of recurrent urinary tract infections. Drug-induced hepatotoxicity presents in acute (3 in 1 000 000) and chronic (1 in 1500) forms. We present a patient with acute liver failure after 5 days of treatment. A 69-year-old man admitted for chronic obstructive pulmonary disease exacerbation 5 days into treatment for cystitis with nitrofurantoin. On admission he was noted to be jaundiced with elevated liver enzymes and normal international normalised ratio. Investigation for infectious, autoimmune and cholestatic causes of hepatotoxicity was negative. The patient improved after discontinuation of the drug and 10 days of methylprednisolone. There are scant data on acute liver failure in the setting of short-term nitrofurantoin administration. The mechanism of toxicity remains unclear, but is hypothesised to be an autoimmune process in which steroids may play a role in treatment. Diagnosis is one of exclusion as the only definitive method of diagnosis is rechallenge., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Although intestinal and urinary microbiome perturbations are associated with nephrolithiasis, whether antibiotics are a risk factor for this condition remains unknown. Methods We determined the association between 12 classes of oral antibiotics and nephrolithiasis in a population-based, case-control study nested within 641 general practices providing electronic health record data for >13 million children and adults from 1994 to 2015 in the United Kingdom. We used incidence density sampling to match 25,981 patients with nephrolithiasis to 259,797 controls by age, sex, and practice at date of diagnosis (index date). Conditional logistic regression models were adjusted for the rate of health care encounters, comorbidities, urinary tract infections, and use of thiazide and loop diuretics, proton-pump inhibitors, and statins. Results Exposure to any of five different antibiotic classes 3-12 months before index date was associated with nephrolithiasis. The adjusted odds ratio (95% confidence interval) was 2.33 (2.19 to 2.48) for sulfas, 1.88 (1.75 to 2.01) for cephalosporins, 1.67 (1.54 to 1.81) for fluoroquinolones, 1.70 (1.55 to 1.88) for nitrofurantoin/methenamine, and 1.27 (1.18 to 1.36) for broad-spectrum penicillins. In exploratory analyses, the magnitude of associations was greatest for exposure at younger ages ( P <0.001) and 3-6 months before index date ( P <0.001), with all but broad-spectrum penicillins remaining statistically significant 3-5 years from exposure. Conclusions Oral antibiotics associated with increased odds of nephrolithiasis, with the greatest odds for recent exposure and exposure at younger age. These results have implications for disease pathogenesis and the rising incidence of nephrolithiasis, particularly among children., (Copyright © 2018 by the American Society of Nephrology.)

Importance: The use of nitrofurantoin and fosfomycin has increased since guidelines began recommending them as first-line therapy for lower urinary tract infection (UTI)., Objective: To compare the clinical and microbiologic efficacy of nitrofurantoin and fosfomycin in women with uncomplicated cystitis., Design, Setting, and Participants: Multinational, open-label, analyst-blinded, randomized clinical trial including 513 nonpregnant women aged 18 years and older with symptoms of lower UTI (dysuria, urgency, frequency, or suprapubic tenderness), a positive urine dipstick result (with detection of nitrites or leukocyte esterase), and no known colonization or previous infection with uropathogens resistant to the study antibiotics. Recruitment took place from October 2013 through April 2017 at hospital units and outpatient clinics in Geneva, Switzerland; Lodz, Poland; and Petah-Tiqva, Israel., Interventions: Participants were randomized in a 1:1 ratio to oral nitrofurantoin, 100 mg 3 times a day for 5 days (n = 255), or a single 3-g dose of oral fosfomycin (n = 258). They returned 14 and 28 days after therapy completion for clinical evaluation and urine culture collection., Main Outcomes and Measures: The primary outcome was clinical response in the 28 days following therapy completion, defined as clinical resolution (complete resolution of symptoms and signs of UTI without prior failure), failure (need for additional or change in antibiotic treatment due to UTI or discontinuation due to lack of efficacy), or indeterminate (persistence of symptoms without objective evidence of infection). Secondary outcomes included bacteriologic response and incidence of adverse events., Results: Among 513 patients who were randomized (median age, 44 years [interquartile range, 31-64]), 475 (93%) completed the trial and 377 (73%) had a confirmed positive baseline culture. Clinical resolution through day 28 was achieved in 171 of 244 patients (70%) receiving nitrofurantoin vs 139 of 241 patients (58%) receiving fosfomycin (difference, 12% [95% CI, 4%-21%]; P = .004). Microbiologic resolution occurred in 129 of 175 (74%) vs 103 of 163 (63%), respectively (difference, 11% [95% CI, 1%-20%]; P = .04). Adverse events were few and primarily gastrointestinal; the most common were nausea and diarrhea (7/248 [3%] and 3/248 [1%] in the nitrofurantoin group vs 5/247 [2%] and 5/247 [1%] in the fosfomycin group, respectively)., Conclusions and Relevance: Among women with uncomplicated UTI, 5-day nitrofurantoin, compared with single-dose fosfomycin, resulted in a significantly greater likelihood of clinical and microbiologic resolution at 28 days after therapy completion., Trial Registration: ClinicalTrials.gov Identifier: NCT01966653.

Vancomycin-resistant enterococci (VRE) are a growing healthcare concern, and since 2012 the incidence has increased eightfold in Denmark. Treatment options for infections with ampicillin-resistant VRE are sparse, and there are no Danish guidelines concerning this topic. For treatment of uncomplicated VRE urinary tract infections, ciprofloxacin or nitrofurantoin can be used. The mainstay of treatment of bacteraemia and other severe infections caused by VRE is linezolid or high-dose daptomycin. Combination treatment is recommended for complicated infections and/or prolonged therapy.

Porous implants or implantable scaffolds used for tissue regeneration can encourage tissue growth inside the implant and provide extended drug release. Water-soluble polymers incorporated into a biodegradable or inert implant matrix may leach out upon contact with biological fluids and thereby gradually increasing the porosity of the implant and simultaneously release drug from the implant matrix. Different molecular weight grades of methylcellulose (MC) and hydroxypropyl methylcellulose (HPMC) were mixed with polylactide and extruded into model implants containing nitrofurantoin as a model drug. The effect of the leached pore formers on the implant porosity and the rheology of the implant microenvironment in vitro was investigated and it was shown that HPMC pore formers had the greatest effect on the surrounding viscosity, with higher drug release and pore forming ability as compared to the MC pore formers. The highest molecular weight HPMC led to the most significant increase in viscosity of the implant microenvironment, while the highest drug release was achieved with the lowest molecular weight HPMC. The data suggested that the microenvironmental rheology of the implant, both in the formed pores and in biological fluids in the immediate vicinity of the implant could be an important factor affecting the diffusion of the drug and other molecules in the implantation site., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Nitrofurantoin is one of the most common drugs implicated in drug-induced pulmonary toxicities, the manifestations of which range from dose-independent acute self-limiting reactions to chronic dose-dependent pathologies. The severity of these pulmonary adverse effects may range from trivial hypersensitivity reactions to extensive and irreversible lung fibrosis leading to respiratory failure and death. Symptomatic and supportive treatment in addition to discontinuation of the drug usually suffices for the management of mild reactions. Corticosteroids have been traditionally used to relieve the symptoms and hasten the resolution of pulmonary lesions in case of severe toxicities. However conclusive evidence in the form of controlled studies in favor of this routine use is lacking. We report a case of an elderly lady who presented to us in respiratory failure due to nitrofurantoin induced chronic lung disease. The patient's symptoms and blood gas abnormalities resolved spontaneously over the course of 6 months after stopping the drug. Radiological lesions including those suggestive of apparently permanent fibrosis also resolved during this time. Corticosteroids, inhalational or systemic, were not used. Spontaneous normalization of clinico-radiological features in nitrofurantoin induced chronic lung disease presenting with respiratory failure has rarely been reported previously. The related literature is also reviewed.

Objectives: Nitrofurantoin is widely used in the prophylaxis of urinary-tract infections. The aim of this study was to develop and characterize innovative transdermal formulations of nitrofurantoin, to increase the patient compliance and decrease the adverse effects such as nausea and vomiting which limit the drug use in long-term., Methods: Nitrofurantoin loaded microemulsion, gel (hydrogel, lipogel and DMSO gel) and film formulations were prepared and characterized via several parameters. Ex-vivo drug permeation studies were performed to determine the amount of drug permeated through the rat skin. In in-vivo studies, in order to detect nitrofurantoin in urine, the selected formulations were applied to male Wistar rats transdermally. Also, skin irritation tests (transepidermal water loss and erythema) were performed., Results: All nitrofurantoin loaded formulations were prepared successfully and were stable at +4°C for 3 months. 13%, 16%, 32.5%, 36.5% and 39% of drugs permeated through the rat skin in the 168th hour for hydrogel, lipogel, film, microemulsion and DMSO gel, respectively. Only with film and DMSO gel formulations, nitrofurantoin was detected in urine. Transepidermal water loss was increased compared to basal level in film type formulations (p&lt;0.05). However, in erythema experiments there was no difference (p&gt;0.05)., Conclusion: There is no approved transdermal formulation of nitrofurantion on the market. Therefore, the prepared film formulations could be an alternative due to their high penetration through the rat skin, the presence of nitrofurantoin in urine and because they cause no irritation on the skin., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Aims: To describe prescribing for women with suspected urinary tract infections, including suspected uncomplicated cystitis, in New Zealand., Methods: Randomly selected community pharmacies participated in the study. Women attending the pharmacy in a 2-week period in 2012 for prescribed or non-prescription treatment of symptoms suggesting a urinary tract infection, or prophylaxis of a urinary tract infection, were invited to self-complete a questionnaire. Analysis focused on prescribing for women with symptoms of cystitis without complicating features., Results: Valid questionnaires arising from a prescription treatment were received from 789 patients from 139 pharmacies. Questionnaire data indicated that 17% of women had symptoms of cystitis without complicating features. Most prescribing was for a first-line agent, trimethoprim (59%) or nitrofurantoin (14%), but norfloxacin was also common (21%). Women with self-reported antibiotic use for suspected cystitis in the past 6 months were more likely to be prescribed norfloxacin than those with no such use. Many prescriptions were for a dose or duration outside those recommended in New Zealand guidelines., Conclusions: While use of first-line agents is generally high, norfloxacin use could be reduced further. There is scope to understand clinical practice that deviates from guideline use regarding dose and duration.

We previously reported that 28-day exposure to hepatocarcinogens that facilitate cell proliferation specifically alters the expression of G1/S checkpoint-related genes and proteins, induces aberrant early expression of ubiquitin D (UBD) at the G2 phase, and increases apoptosis in the rat liver, indicating G1/S and spindle checkpoint dysfunction. The present study aimed to determine the time of onset of carcinogen-specific cell-cycle disruption after repeated administration of renal carcinogens for up to 28 days. Rats were orally administered the renal carcinogens nitrofurantoin (NFT), 1-amino-2,4-dibromoantraquinone (ADAQ), and 1,2,3-trichloropropane (TCP) or the non-carcinogenic renal toxicants 1-chloro-2-propanol, triamterene, and carboxin for 3, 7 or 28 days. Both immunohistochemical single-molecule analysis and real-time RT-PCR analysis revealed that carcinogen-specific expression changes were not observed after 28 days of administration. However, the renal carcinogens ADAQ and TCP specifically reduced the number of cells expressing phosphorylated-histone H3 at Ser10 in both UBD(+) cells and proliferating cells, suggestive of insufficient UBD expression at the M phase and early transition of proliferating cells from the M phase, without increasing apoptosis, after 28 days of administration. In contrast, NFT, which has marginal carcinogenic potential, did not induce such cellular responses. These results suggest that it may take 28 days to induce spindle checkpoint dysfunction by renal carcinogens; however, induction of apoptosis may not be essential. Thus, induction of spindle checkpoint dysfunction may be dependent on carcinogenic potential of carcinogen examined, and marginal carcinogens may not exert sufficient responses even after 28 days of administration.

Background: Existing approaches for the screening and treatment of asymptomatic bacteriuria in pregnancy are based on trials that were done more than 30 years ago. In this study, we reassessed the consequences of treated and untreated asymptomatic bacteriuria in pregnancy., Methods: In this multicentre prospective cohort study with an embedded randomised controlled trial, we screened women (aged ≥18 years) at eight hospitals and five ultrasound centres in the Netherlands with a singleton pregnancy between 16 and 22 weeks' gestation for asymptomatic bacteriuria. Screening was done with a single dipslide and two culture media. Dipslides were judged positive when the colony concentration was at least 1×10(5) colony-forming units (CFU) per mL of a single microorganism or when two different colony types were present but one had a concentration of at least 1×10(5) CFU per mL. Asymptomatic bacteriuria-positive women were eligible to participate in the randomised controlled trial comparing nitrofurantoin with placebo treatment. In this trial, participants were randomly assigned 1:1 to receive either nitrofurantoin 100 mg or identical placebo tablets, and were instructed to self-administer these tablets twice daily for 5 consecutive days. Randomisation was done by a web-based application with a computer-generated list with random block sizes of two, four, or six participants rendered by an independent data manager. 1 week after the end of treatment, they provided us with a follow-up dipslide. Women, treating physicians, and researchers all remained unaware of the bacteriuria status and treatment allocation. Women who refused to participate in the randomised controlled trial did not receive any antibiotics, but their outcomes were collected for analysis in the cohort study. We compared untreated and placebo-treated asymptomatic bacteriuria-positive women with asymptomatic bacteriuria-negative women and nitrofurantoin-treated asymptomatic bacteriuria-positive women. The primary endpoint was a composite of pyelonephritis with or without preterm birth at less than 34 weeks, analysed by intention to treat at 6 weeks post-partum. This trial is registered with the Dutch Trial Registry, number NTR3068., Findings: Between Oct 11, 2011, and June 10, 2013, we enrolled 5621 women into our screening cohort, of whom 5132 were eligible for screening. After exclusions for contaminated dipslides and patients lost to follow-up, in our final cohort of 4283 women, 248 were asymptomatic bacteriuria positive, of whom 40 were randomly assigned to nitrofurantoin and 45 to placebo for the randomised controlled trial, whereas the other 163 asymptomatic bacteriuria-positive women were followed without treatment. The proportion of women with pyelonephritis, preterm birth, or both did not differ between untreated or placebo-treated asymptomatic bacteriuria-positive women and asymptomatic bacteriuria-negative women (6 [2·9%] of 208 vs 77 [1·9%] of 4035; adjusted odds ratio [OR] 1·5, 95% CI 0·6-3·5) nor between asymptomatic bacteriuria-positive women treated with nitrofurantoin versus those who were untreated or received placebo (1 [2·5%] of 40 vs 6 [2·9%] of 208; risk difference -0·4, 95% CI -3·6 to 9·4). Untreated or placebo-treated asymptomatic bacteriuria-positive women developed pyelonephritis in five [2·4%] of 208 cases, compared with 24 [0·6%] of 4035 asymptomatic bacteriuria-negative women (adjusted OR 3·9, 95% CI 1·4-11·4)., Interpretation: In women with an uncomplicated singleton pregnancy, asymptomatic bacteriuria is not associated with preterm birth. Asymptomatic bacteriuria showed a significant association with pyelonephritis, but the absolute risk of pyelonephritis in untreated asymptomatic bacteriuria is low. These findings question a routine screen-treat-policy for asymptomatic bacteriuria in pregnancy., Funding: ZonMw (the Netherlands Organisation for Health Research and Development)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: The objective was to study changes in the faecal microbiota of patients with uncomplicated urinary tract infections (UTIs) treated with nitrofurantoin and of non-treated healthy controls using 16S rRNA analysis., Methods: Serial stool samples were collected from patients receiving nitrofurantoin treatment at different timepoints [before treatment (day 1; T1), within 48 h of end of treatment (days 5-15; T2) and 28 days after treatment (days 31-43; T3)], as well as from healthy controls. Direct DNA extraction (PowerSoil DNA Isolation Kit, MoBio Laboratories, Carlsbad, CA, USA) from stool samples was followed by pyrosequencing (454 GS FLX Titanium) of the V3-V5 region of the bacterial 16S rRNA gene., Results: Among UTI patients, mean proportions of the Actinobacteria phylum increased by 19.6% in the first follow-up sample (T2) in comparison with the pretreatment baseline stool sample (T1) (P = 0.026). However, proportions of Actinobacteria reversed to 'normal' pre-antibiotic levels, with a mean difference of 1.0% compared with baseline proportions, in the second follow-up sample (T3). The increase in Actinobacteria was specifically due to an increase in the Bifidobacteriaceae family (Bifidobacterium genus), which constituted 81.0% (95% CI ±7.4%) of this phylum., Conclusions: No significant impact was observed other than a temporary increase in the beneficial Bifidobacterium genus following nitrofurantoin treatment, which supports its reintroduction into clinical use., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The aim of the present study was to grind nitrofurantoin (NF) with HPMC solution and to determine the dissolution and bioavailability of the enteric pellets prepared with the NF cogrounds and other excipients. During milling, crystalline transformation occurred--the aciform microcrystalline monohydrate II replaced the coarse crystal anhydrate β and the particle size markedly reduced. In vitro test demonstrated that the enteric pellets prepared with NF cogrounds (4 h) revealed a faster dissolution than the commercial tablet and 50% was released within 30 min in the basic medium. Finally, an in vivo test was conducted in beagle dogs. The Cmax and AUC(0 → 24) of the pellets were 2.19 ± 0.74 μg/ml and 6.73 ± 4.71 μg/ml h, respectively, while the corresponding values were 0.49 ± 0.42 μg/ml and 1.38 ± 1.17 μg/ml h for the tablet. Thus, the bioavailability of the pellets was increased significantly. In conclusion, the wet grinding that reduced the particle size and created the microcrystalline played a major role in the acceleration of the dissolution of NF and, consequently, enhanced the bioavailability, and the wet grinding process offers an alternative approach to improve the dissolution and bioavailability of drugs with poor aqueous solubility.

Nitrofurantoin is commonly prescribed to treat urinary tract infections (UTI). Reported adverse effects include gastrointestinal, pulmonary, hepatic and neurological disorders. We report a case of a 67-year-old woman treated for UTI with nitrofurantoin who presented with antineutrophilic cytoplasmic antibody (ANCA)-associated renal and skin vasculitis 3 days after starting treatment. The symptoms resolved following withdrawal of the drug and treatment with steroids. This is the first reported case of nitrofurantoin causing ANCA-associated vasculitis., (2015 BMJ Publishing Group Ltd.)

Background & Objectives: This cross-sectional study was conducted at a tertiary care centre in Puducherry, south India, with the aim of finding the profile of the paediatric urinary tract infection (UTI), bacterial pathogens involved, and also to observe vesicoureteric reflux (VUR) and renal scarring in these patients., Methods: A total of 524 paediatric patients ≤13 yr, suspected to have UTI, were included in the study. Urine samples were collected, processed for uropathogen isolation and antibiotic susceptibility test was performed as per the Clinical and Laboratory Standards Institute (CLSI) guidelines. Thirty two culture proven children with UTI underwent micturating cysto-urethrography (MCU) and dimercaptosuccinic acid (DMSA) scanning was done for 69 children., Results: o0 f the 524 children, 186 (35.4%) had culture proven UTI with 105 (56.4%) being infants, 50 (27.4%) between 1-5 yr, 30 (16.12%) between 5-13 yr and 129 (69.35%) males. Posterior urethral valve (PUV) was noted in three, hydronephrosis in one, VUR in 18 and renal scarring in 33. VUR as well as renal scarring were more in males >1 yr of age. A significant association (P=0.0054) was noted with a combined sensitivity and specificity of these investigations being 83 and 90 per cent, respectively of the MCU and DMSA scans for detecting VUR. Escherichia coli was the most common pathogen isolated, sensitive to nitrofurantoin, followed by cefoperazone-sulbactam, aminoglycosides and meropenem., Interpretation & Conclusions: Our results indicate that UTI varies with age and gender and extensive evaluation is required in boys over one year of age with UTI. This study also highlights the better efficacy of aminoglycosides, cefoperazone-sulbactam and nitrofurantoin in vitro compared with meropenem in Gram-negative uropathogens.

The aim of the present work was to investigate the potential of three-dimensional (3D) printing as a manufacturing method for products intended for personalized treatments by exploring the production of novel polylactide-based feedstock materials for 3D printing purposes. Nitrofurantoin (NF) and hydroxyapatite (HA) were successfully mixed and extruded with up to 30% drug load with and without addition of 5% HA in polylactide strands, which were subsequently 3D-printed into model disc geometries (10 × 2 mm). X-ray powder diffraction analysis showed that NF maintained its anhydrate solid form during the processing. Release of NF from the disks was dependent on the drug loading in a concentration-dependent manner as a higher level of released drug was observed from disks with higher drug loads. Disks with 30% drug loading were able to prevent surface-associated and planktonic growth of Staphylococcus aureus over a period of 7 days. At 10% drug loading, the disks did not inhibit planktonic growth, but still inhibited surface-associated growth. Elemental analysis indicated the presence of microdomains of solid drug supporting the observed slow and partial drug release. This work demonstrates the potential of custom-made, drug-loaded feedstock materials for 3D printing of pharmaceutical products for controlled release., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Purpose: The treatment of urinary tract infections (UTI) with antibiotics is commonly used, but recurrence and antibiotic resistance have been growing and concerning clinicians. We studied whether the rapid onset of a protective biofilm may be responsible for the lack of effectiveness of antibiotics against selected bacteria., Materials and Methods: Two established uropathogenic Escherichia coli strains, UTI89 and CFT073, and two Pseudomonas aeruginosa strains, PA01 and Boston-41501, were studied to establish a reliable biofilm formation process. Bacterial growth (BG) was determined by optical density at 600 nm (OD 600) using a spectrophotometer, while biofilm formation (BF) using crystal violet staining was measured at OD 550. Next, these bacterial strains were treated with clinically relevant antibiotics, ciprofloxacin HCl (200 ng/mL and 2 μg/mL), nitrofurantoin (20 µg/mL and 40 µg/mL) and ampicillin (50 µg/mL) at time points of 0 (T0) or after 6 hours of culture (T6). All measurements, including controls (bacteria -1% DMSO), were done in triplicates and repeated three times for consistency., Results: The tested antibiotics effectively inhibited both BG and BF when administered at T0 for UPEC strains, but not when the antibiotic administration started 6 hours later. For Pseudomonas strains, only Ciprofloxacin was able to significantly inhibit bacterial growth at T0 but only at the higher concentration of 2 µg/mL for T6., Conclusion: When established UPEC and Pseudomonas bacteria were allowed to culture for 6 hours before initialization of treatment, the therapeutic effect of selected antibiotics was greatly suppressed when compared to immediate treatment, probably as a result of the protective nature of the biofilm.

A 70-year-old woman presented with progressive skin lesions on the face, limbs and trunk in the absence of systemic illness. Three months earlier, she had been prescribed six months prophylactic nitrofurantoin for recurrent urinary tract infections, treated with nitrofurantoin and trimethoprim. Positive immunology and histological inflammatory changes in a skin biopsy were consistent with a diagnosis of sub-acute cutaneous lupus erythematosus. Following treatment with topical steroids, the skin lesions regressed, but alopecia followed and required hydroxychloroquine. One year later, there are no new skin lesions and no evidence of systemic lupus erythematosus. Nitrofurantoin is associated with many side effects and hypersensitivity reactions. Possible drug-induced lupus reactions due to nitrofurantoin include pneumonitis, blood disorders and hepatotoxicity. This is the only published case of isolated sub-acute cutaneous lupus following maintenance nitrofurantoin., (© The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

With increase of multi-drug resistant Escherichia coli in community-acquired urinary tract infections (CA-UTI), other treatment option with a therapeutic efficacy and a low antibiotic selective pressure is necessary. In this study, we evaluated in vitro susceptibility of E. coli isolates from CA-UTI to fosfomycin (FM), nitrofurantoin (NI), temocillin (TMO) as well as trimethoprim-sulfamethoxazole (SMX), ciprofloxacin (CIP) and cefepime (FEP). The minimal inhibitory concentrations were determined by E-test or agar dilution method according to the Clinical and Laboratory Standards Institute guidelines, using 346 E. coli collected in 12 Korean hospitals from March 2010 to February 2011. FM, NI and TMO showed an excellent susceptibility profile; FM 100% (346/346), TMO 96.8% (335/346), and NI 99.4% (344/346). Conversely, resistance rates of CIP and SMX were 22% (76/346) and 29.2% (101/349), respectively. FEP still retained an activity of 98.5%. In Korea, NI and TMO in addition to FM are a good therapeutic option for uncomplicated CA-UTI, especially for lower UTI.

High-density lipoprotein cholesterol (HDL-C) concentration is an independent risk factor for cardiovascular disease. Fibrates are widely used in the management of atherogenic dyslipidemia, principally for their triglyceride-lowering and HDL-C-raising effects. Fibrates may cause paradoxical reductions in HDL-C. These reductions are usually modest, but significant reductions have been observed. The molecular mechanism for these paradoxical reductions remains unexplained despite advances in our understanding of lipid metabolism. This review considers possible mechanisms for this effect, illustrated by a patient with an observed reduction in HDL-C of 88% after introduction of fenofibrate., (Copyright © 2014 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Question: My patient has a urinary tract infection and is currently breastfeeding. Her son is only 3 weeks old. Is nitrofurantoin a safe antibiotic for treatment?, Answer: The use of nitrofurantoin in breastfeeding mothers is generally safe, as only small amounts transfer into the breast milk. Despite the lack of documented reports, there is a risk of hemolytic anemia in all newborns exposed to nitrofurantoin owing to their glutathione instability, especially in infants with glucose-6-phosphate dehydrogenase deficiency. Although some suggest that nitrofurantoin be avoided in infants younger than 1 month, studies have noted that glutathione stability might be established by the eighth day of life. In infants younger than 1 month, an alternative antibiotic might be preferred; however, if an alternative were not available, the use of nitrofurantoin would not be a reason to avoid breastfeeding. In any such case the suckling infant should be monitored by his or her physician., (Copyright© the College of Family Physicians of Canada.)

The use of three-dimensional (3D) printing technologies is transforming the way that materials are turned into functional devices. We demonstrate in the current study the incorporation of anti-microbial nitrofurantoin in a polymer carrier material and subsequent 3D printing of a model structure, which resulted in an inhibition of biofilm colonization. The approach taken is very promising and can open up new avenues to manufacture functional medical devices in the future., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Angiotensin-converting enzyme inhibitors (ACEi) can reduce urine output, especially when treatment is first started. Since bacterial clearance from the urinary tract is dependent on urine output, it was hypothesized that ACEi may also increase the risk of urinary tract infections (UTIs)., Objective: Our objective was to assess the risk of UTIs associated with ACEi therapy initiation in the general population., Methods: A prescription sequence symmetry analysis was performed with the Dutch 'InterAction Database' (IADB.nl) pharmacy prescription database. We selected all patients from the IADB who were incident users of both ACEi and nitrofurantoin (a proxy for UTIs). A relatively short maximum time-span of 4 weeks between both prescriptions was used to limit time-variant confounding. The sequence ratio was calculated by dividing the number of individuals starting ACEi first and nitrofurantoin second by the number of individuals starting nitrofurantoin treatment first and ACEi second. We adjusted for trends in prescribing and estimated 95 % confidence intervals using exact confidence intervals for binomial distributions. To evaluate whether the effect is specific to ACEi and to assess whether the possible mechanism behind an increased risk of UTIs is related to the renin-angiotensin-aldosterone system, we also estimated the risk for β-adrenoceptor antagonists (β-blockers)., Results: In total, 22,959 incident users of ACEi therapy were eligible for analysis. Of these, 161 patients started ACEi therapy within 4 weeks prior to or after nitrofurantoin therapy initiation. A total of 101 (63 %) started ACEi therapy first followed by nitrofurantoin treatment, while 60 (37 %) patients started nitrofurantoin treatment first, which corresponds to a statistically significant adjusted sequence ratio (ASR) of 1.68 (95 % CI 1.21-2.36). No association was found between β-blockers and UTI treatment (ASR 1.01, 95 % CI 0.74-1.38)., Conclusions: A significant excess of patients received UTI medication prescriptions following the first month after ACEi initiation. This prescription sequence asymmetry suggests that ACEi initiation increases the risk of developing UTIs.