Oral Antibiotics and Risk of Serious Cutaneous Adverse Drug Reactions.

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.

Fosfomycin and nitrofurantoin: classic antibiotics and perspectives.

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.

Twice-Daily Nitrofurantoin Administration Following Short-term Transurethral Catheterization After Pelvic Reconstructive Surgery: A Randomized Clinical Trial.

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.

Adverse effects of chronic nitrofurantoin therapy in women with recurrent urinary tract infections in an outpatient setting.

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.

Reversible lung fibrosis in a 6-year-old girl after long term nitrofurantoin treatment.

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.

CombiANT: Antibiotic interaction testing made easy.

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.

Interstitial Lung Disease Secondary to Long-Term Nitrofurantoin Use.

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.

Assessment of contribution of BCRP to intestinal absorption of various drugs using portal-systemic blood concentration difference model in mice.

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 (Rbcrp ). Ciprofloxacin and nitrofurantoin showed the low Rbcrp 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 Rbcrp values were 0.42 and 0.79, respectively, indicating the high contribution of BCRP to their oral absorption. Furthermore, in vivo Rbcrp 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.

The Role of Ciprofloxacin Resistance and Extended-spectrum beta-lactamase (ESBL) Positivity in Infective Complications Following Prostate Biopsy.

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.

Effectiveness of extended- versus normal-release nitrofurantoin for cystitis: an instrumental variable analysis.

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.

Urinary antibacterial activity of fosfomycin and nitrofurantoin at registered dosages in healthy volunteers.

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.

The pharmacokinetics of nitrofurantoin in healthy female volunteers: a randomized crossover study.

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.

Retrospective evaluation of nitrofurantoin and pivmecillinam for the treatment of lower urinary tract infections in men.

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.

Altered methotrexate clearance in the treatment of CNS lymphoma with concurrent use of nitrofurantoin for a urinary tract infection.

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.

Cross-over data supporting long-term antibiotic treatment in patients with painful lower urinary tract symptoms, pyuria and negative urinalysis.

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.

Long-term prescribing of nitrofurantoin for urinary tract infections (UTI) in veterans with spinal cord injury (SCI).

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.

Five-day nitrofurantoin is better than single-dose fosfomycin at resolving UTI symptoms.

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.

Nitrofurantoin: friend or foe?

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.

Effect of 5-Day Nitrofurantoin vs Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in Women: A Randomized Clinical Trial.

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.