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Study question Can treatment of the symptoms of uncomplicated urinary tract infection (UTI) with ibuprofen reduce the rate of antibiotic prescriptions without a significant increase in symptoms, recurrences, or complications?Methods Women aged 18-65 with typical symptoms of UTI and without risk factors or complications were recruited in 42 German general practices and randomly assigned to treatment with a single dose of fosfomycin 3 g (n=246; 243 analysed) or ibuprofen 3×400 mg (n=248; 241 analysed) for three days (and the respective placebo dummies in both groups). In both groups additional antibiotic treatment was subsequently prescribed as necessary for persistent, worsening, or recurrent symptoms. The primary endpoints were the number of all courses of antibiotic treatment on days 0-28 (for UTI or other conditions) and burden of symptoms on days 0-7. The symptom score included dysuria, frequency/urgency, and low abdominal pain.Study answer and limitations The 248 women in the ibuprofen group received significantly fewer course of antibiotics, had a significantly higher total burden of symptoms, and more had pyelonephritis. Four serious adverse events occurred that lead to hospital referrals; one of these was potentially related to the trial drug. Results have to be interpreted carefully as they might apply to women with mild to moderate symptoms rather than to all those with an uncomplicated UTI.What this paper adds Two thirds of women with uncomplicated UTI treated symptomatically with ibuprofen recovered without any antibiotics. Initial symptomatic treatment is a possible approach to be discussed with women willing to avoid immediate antibiotics and to accept a somewhat higher burden of symptoms.Funding, competing interests, data sharing German Federal Ministry of Education and Research (BMBF) No 01KG1105. Patient level data are available from the corresponding author. Patient consent was not obtained but the data are anonymised and risk of identification is low.Trial registration No ClinicalTrialGov Identifier NCT01488955.

Abstract Background ZTI-01 (fosfomycin for injection) is an epoxide antibiotic with a differentiated mechanism of action (MOA) inhibiting an early step in bacterial cell wall synthesis. ZTI-01 has broad in vitro spectrum of activity, including multidrug-resistant Gram-negative pathogens, and is being developed for treatment of complicated urinary tract infection (cUTI) and acute pyelonephritis (AP) in the United States. Methods Hospitalized adults with suspected or microbiologically confirmed cUTI/AP were randomized 1:1 to 6 g ZTI-01 q8h or 4.5 g intravenous (IV) piperacillin-tazobactam (PIP-TAZ) q8h for a fixed 7-day course (no oral switch); patients with concomitant bacteremia could receive up to 14 days. Results Of 465 randomized patients, 233 and 231 were treated with ZTI-01 and PIP-TAZ, respectively. In the microbiologic modified intent-to-treat (m-MITT) population, ZTI-01 met the primary objective of noninferiority compared with PIP-TAZ with overall success rates of 64.7% (119/184 patients) vs 54.5% (97/178 patients), respectively; treatment difference was 10.2% (95% confidence interval [CI]: −0.4, 20.8). Clinical cure rates at test of cure (TOC, day 19–21) were high and similar between treatments (90.8% [167/184] vs 91.6% [163/178], respectively). In post hoc analysis using unique pathogens typed by pulsed-field gel electrophoresis, overall success rates at TOC in m-MITT were 69.0% (127/184) for ZTI-01 versus 57.3% (102/178) for PIP-TAZ (difference 11.7% 95% CI: 1.3, 22.1). ZTI-01 was well tolerated. Most treatment-emergent adverse events, including hypokalemia and elevated serum aminotransferases, were mild and transient. Conclusions ZTI-01 was effective for treatment of cUTI including AP and offers a new IV therapeutic option with a differentiated MOA for patients with serious Gram-negative infections. Clinical Trial Registration NCT02753946 ZEUS, a Phase 2/3 trial, studied ZTI-01 (fosfomycin for injection) in the treatment of hospitalized adults with complicated urinary tract infection and acute pyelonephritis versus piperacillin-tazobactam. ZTI-01 was non-inferior to piperacillin-tazobactam and was well tolerated.

Fecal microbiota transplantation (FMT) is a potential therapeutic approach to restore normal intestinal microbiota in patients with ulcerative colitis (UC), which is associated with dysbiosis; however, treatment efficacy remains unclear. Hence, we studied the impact of antibiotic pretreatment with amoxicillin, fosfomycin, and metronidazole (AFM therapy) and FMT versus AFM alone.MethodsAFM therapy was administered to patients for 2 weeks until 2 days before FMT. Patients' spouses or relatives were selected as donor candidates. Donor fecal samples were collected on the day of administration and transferred into the patient's colon by colonoscopy within 6 hours. Microbiome analysis was performed by 16S rRNA next-generation sequencing.ResultsPatients with mild-to-severe active UC (combination-therapy group, n = 21; AFM monotherapy group, n = 20) were included. Thirty-six patients completed this assessment (combination-therapy group, n = 17; AFM monotherapy group, n = 19). A higher clinical response was observed after combination therapy compared with AFM monotherapy at 4 weeks after treatment. After the 2-week AFM therapy, the Bacteroidetes composition was nearly abolished. The Bacteroidetes proportion recovered in clinical responders at 4 weeks after FMT was not observed in the AFM monotherapy group. Persistent antimicrobial-associated dysbiosis found in the AFM monotherapy group was reversed by FMT. The recovery rate of Bacteroidetes at 4 weeks after FMT correlated with endoscopic severity.ConclusionsFMT following antimicrobial bowel cleansing synergistically contributes to the recovery of the Bacteroidetes composition, which is associated with clinical response and UC severity. Thus, this therapeutic protocol may be useful for managing UC.

Abstract Background: This clinical trial evaluated the pharmacokinetics and safety/tolerability of amikacin/fosfomycin solution using a vibrating plate nebulizer, in mechanically ventilated patients with ventilator-associated tracheobronchitis (VAT) or ventilator-associated pneumonia (VAP). Methods: Nine adult patients were consented to receive three escalating doses of a combination of 50 mg/mL amikacin and 20 mg/mL fosfomycin; doses were separated by 24±2 hr. On day 3, patients received two blinded, randomized treatments (amikacin/fosfomycin and volume-matched placebo), separated by 2 hr. All treatments were administered with a single-patient, multitreatment nebulizer (Investigational eFlow® Inline Nebulizer System; PARI Pharma GmbH, positioned in the inspiratory limb tubing between the ventilator and the patient. The nebulizer remained in-line until all treatments had been delivered. Concentrations of amikacin and fosfomycin were measured in tracheal aspirate and plasma samples obtained during the 24 hr after each dose. Results: Fifteen minutes after dosing with the 300/120 mg amikacin/fosfomycin combination, tracheal aspirate amikacin concentrations±SD were 12,390±3,986 μg/g, and fosfomycin concentrations were 6,174±2,548 μg/g (n=6). Airway clearance was rapid. Plasma concentrations were subtherapeutic; the highest observed amikacin plasma concentration was 1.4 μg/mL, and the highest observed fosfomycin plasma concentration was 0.8 μg/mL. Administration time was approximately 2 min/mL. No adverse effects on respiratory rate, peak airway pressures, or oxygenation were observed during or following drug or placebo administration. Conclusions: High tracheal aspirate concentrations of amikacin and fosfomycin were achieved in mechanically ventilated patients with VAT or VAP after aerosolized administration with an inline nebulizer system. Airway clearance was rapid. No adverse respiratory effects were noted during or following drug administration.

Fosfomycin/tobramycin for inhalation (FTI), a unique, broad-spectrum antibiotic combination, may have therapeutic potential for patients with cystic fibrosis (CF). To evaluate safety and efficacy of FTI (160/40 mg or 80/20 mg), administered twice daily for 28 days versus placebo, in patients greater than or equal to 18 years of age, with CF, chronic Pseudomonas aeruginosa (PA) airway infection, and FEV(1) greater than or equal to 25% and less than or equal to 75% predicted. This double-blind, placebo-controlled, multicenter study assessed whether FTI/placebo maintained FEV(1) % predicted improvements achieved following a 28-day, open-label, run-in course of aztreonam for inhalation solution (AZLI). A total of 119 patients were randomized to FTI (160/40 mg: n = 41; 80/20 mg: n = 38) or placebo (n = 40). Mean age was 32 years and mean FEV(1) was 49% predicted at screening. Relative improvements in FEV(1) % predicted achieved by the AZLI run-in were maintained in FTI groups compared with placebo (160/40 mg vs. placebo: 6.2% treatment difference favoring FTI, P = 0.002 [primary endpoint]; 80/20 mg vs. placebo: 7.5% treatment difference favoring FTI, P < 0.001). The treatment effect on mean PA sputum density was statistically significant for the FTI 80/20 mg group versus placebo (-1.04 log(10) PA colony-forming units/g sputum difference, favoring FTI; P = 0.01). Adverse events, primarily cough, were consistent with CF disease. Respiratory events, including dyspnea and wheezing, were less common with FTI 80/20 mg than FTI 160/40 mg. No clinically significant differences between groups were reported for laboratory values. FTI maintained the substantial improvements in FEV(1) % predicted achieved during the AZLI run-in and was well tolerated. FTI is a promising antipseudomonal therapy for patients with CF.

Safe and effective antimalarial drugs with new methods of action are urgently needed. Fosmidomycin inhibits the synthesis of isoprenoid by Plasmodium falciparum, and suppresses the growth of multidrug-resistant strains in vitro. Our aim was to assess the efficacy and tolerability of fosmidomycin in adults with malaria in Gabon. We administered the drug for 5, 4, or 3 days (1–2 g every 8 h), in nine, eight, and ten evaluable patients, respectively. All treatment regimens were well tolerated. Cure rates by day 14 were 89% (eight of nine), 88% (seven of eight), and 60% (six of ten), for treatment durations of 5, 4, and 3 days, respectively. These data suggest that fosmidomycin is a safe and effective treatment for uncomplicated malaria if given for 4 days or more.

The purpose of this paper was to compare the efficacy of a single dose of 3 g of fosfomycin to that of a 7-day regimen of amoxicillin-clavulanate in the treatment of asymptomatic bacteriuria during pregnancy. A randomised, prospective, interventional, analytical, longitudinal study was undertaken, in which the efficacy of two antibiotic regimens (one short and the other long) in the treatment of pregnant women with asymptomatic bacteriuria is compared. One hundred and nine patients were randomly assigned to two groups: 56 were treated with amoxicillin-clavulanate and 53 with fosfomycin. The two groups were similar in terms of co-morbidity, treatments received during pregnancy, obstetric, gynaecological and surgical history and laboratory data. The efficacy of the two regimens was similar and the eradication rate was over 80% in both groups (P = 0.720) (relative risk [RR] 1.195, 95% confidence interval [CI]: 0.451-3.165). The number of reinfections was greater in the amoxicillin-clavulanate group (P = 0.045). The secondary effects were lower in the fosfomycin group (P = 0.008). There were no significant differences in the number of persistences (P = 0.39), development of symptomatic urinary infections (P = 0.319) or recurrences (P = 0.96). Treatment with a single dose of fosfomycin is as effective as the standard course of treatment with amoxicillin-clavulanate and may be preferable due to its simpler administration and the smaller number of reinfections.

Background Uncomplicated urinary tract infections (UTI) are usually treated with antibiotics as recommended by primary care guidelines. Antibiotic treatment supports clinical cure in individual patients but also leads to emerging resistance rates in the population. We designed a comparative effectiveness study to investigate whether the use of antibiotics for uncomplicated UTI could be reduced by initial treatment with ibuprofen, reserving antibiotic treatment to patients who return due to ongoing or recurrent symptoms. Methods/design This is a randomized-controlled, double-blind, double dummy multicentre trial assessing the comparative effectiveness of immediate vs. conditional antibiotic therapy in uncomplicated UTI. Women > 18 and < 65 years, presenting at general practices with at least one of the typical symptoms dysuria or frequency/urgency of micturition, will be screened and enrolled into the trial. During an 18- months recruitment period, a total of 494 patients will have to be recruited in 45 general practices in Lower Saxony. Participating patients receive either immediate antibiotic therapy with fosfomycin-trometamol 1x3g or initial symptomatic treatment with ibuprofen 3x400mg for 3 days. The ibuprofen group will be provided with antibiotic therapy only if needed, i.e. for persistent or worsening symptoms. For a combined primary endpoint, we choose the number of all antibiotic prescriptions regardless of the medical indication day 0–28 and the “disease burden”, defined as a weighted sum of the daily total symptom scores from day 0 to day 7. The study is considered positive if superiority of conditional antibiotic treatment with respect to the first primary endpoint and non-inferiority of conditional antibiotic treatment with respect to the second primary endpoint is proven. Discussion This study aims at investigating whether the use of antibiotics for uncomplicated UTI could be reduced by initial treatment with ibuprofen. The comparative effectiveness design was chosen to prove the effectiveness of two therapeutic strategies instead of the pure drug efficacy. Trial registration Clinicaltrials.Gov: NCT01488955

Background The present study investigated the formulation, development, and characterization of Fosfomycin pessaries for the treatment of genitourinary tract infections. To achieve higher local concentration and to avoid the systemic exposure of the body towards Fosfomycin, vaginal pessaries have been developed in this research work. Methodology The Fosfomycin pessaries were prepared using the hand rolling method. After the formulation of the Fosfomycin pessaries, pre-formulation studies were conducted to evaluate the drug-excipient compatibility, followed by in vivo studies. Results The pre-formulation studies using FTIR (Fourier Transform Infra-Red) spectrophotometric analysis showed no significant interaction of Fosfomycin with the base and formation of Fosfomycin pessaries. Furthermore, DSC (differential scanning calorimetry) and TGA (thermogravimetric analysis) analysis confirm the formulation stability. The physicochemical analysis of Fosfomycin pessaries, including liquefaction time and breaking force, showed the formulation within the pharmacopeia standard range. Furthermore, the pharmacokinetic and in vitro release studies showed that Fosfomycin pessaries, in contrast to the Fosfomycin suspension, exhibited higher elimination time, higher absorption rate, and area under the curve. The antibacterial results of the Fosfomycin pessaries showed significant activity against E. coli using in vitro and in vivo studies. Conclusion The in vitro and in vivo results revealed that Fosfomycin pessaries have improved pharmacokinetics and increased antibacterial activity.

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.