Back to the Future: Intravenous Fosfomycin is Safe and Effective for the Treatment of Complicated Infections in Children.

BACKGROUND: Despite its broad spectrum and excellent safety profile, fosfomycin is still rarely used in pediatrics, with very limited experience from clinicians. METHODS: We retrospectively reviewed the medical records of all children admitted to Bambino Gesù Children's Hospital, IRCCS, Rome, Italy, and treated with fosfomycin for any serious infection. Children with immunodeficiency and oncologic diseases were excluded. Of each, we reported and analyzed demographic and clinical data. RESULTS: The clinical charts of 20 patients were reviewed and analyzed. The mean age was 10.2 years. Most children were males (85%). Most patients treated had an osteo-articular infection (65%). In our sample, 7 patients (35%) had an underlying comorbidity. The causative agent was isolated in 14 cases (70%). All patients were treated with a combination of 2-3 antibiotics, including fosfomycin. The average duration of antibiotic treatment was 18 days. After treatment, 8 patients (40%) experienced a mild adverse reaction, possibly correlated with the administration of fosfomycin. All patients were discharged in good clinical condition. CONCLUSIONS: The present study reports on a sample of pediatric patients with complicated infections where administration of fosfomycin led to eradication of the disease with little or no side effects. Role of the underlying condition and concomitant medication in causing the reaction could not be ruled out. These data suggest that fosfomycin is an effective and safe antibiotic in the pediatric population, particularly for deep-seated infections sustained by multi-drug resistant pathogens.

Parenteral Fosfomycin in Gastrointestinal Surgery: A Systematic Review.

BACKGROUND: To investigate if perioperative parenteral administration of fosfomycin given before or during gastrointestinal surgery could protect against postoperative infectious complications and characterise the administration of fosfomycin and its harms. METHODS: This systematic review included original studies on gastrointestinal surgery where parental administration of fosfomycin was given before or during surgery to≥5 patients. We searched three databases on March 24 2023 and registered the protocol before data extraction (CRD42020201268). Risk of bias was assessed with Cochrane Handbook risk of bias assessment tool or the Newcastle-Ottawa Scale. A narrative description was undertaken. For infectious complications, results from emergency and elective surgery were presented separately. RESULTS: We included 15 unique studies, reporting on 1,029 patients that received fosfomycin before or during gastrointestinal surgery. Almost half of the studies were conducted in the 1980s to early 1990s, and typically a dose of 4 g fosfomycin was given before surgery co-administered with metronidazole and often repeated postoperatively. The risk of bias across studies was moderate to high. The rates of infectious complications were low after fosfomycin; the surgical site infection rate was 0-1% in emergency surgery and 0-10% in elective surgery. If reported, harms were few and mild and typically related to the gastrointestinal system. CONCLUSION: There were few postoperative infectious complications after perioperative parenteral administration of one or more doses of 4 g fosfomycin supplemented with metronidazole in various gastrointestinal procedures. Fosfomycin was associated with few and mild harms.

Fosfomycin-induced agranulocytosis: a case report and review of the literature.

BACKGROUND: The intravenous form of fosfomycin, a bactericide antibiotic used to treat multiresistant bacterial infections is little prescribed. The most common reported adverse effects are hypokaliemia and hypernatremia. We describe a case of agranulocytosis, a rarely described side effect that may be fatal. CASE PRESENTATION: A 45 year-old woman was admitted to the intensive care unit for post-surgical meningitis following meningioma resection. Meropenem and vancomycin were first introduced. A DRESS-syndrom with meropenem was suspected. Neutropenia was diagnosed three days after the introduction of parenteral fosfomycin and agranulocytosis four days later. Eosinophilia was also observed. A bone marrow aspiration was performed showing a disappearance of the neutrophil granulocyte line and a significant eosinophilia. Meropenem was discontinued. Fosfomycin was maintained and filgrastim was added. As filgrastim had no effect, the relationship with fosfomycin was suspected, so it was then withheld. An increase of the neutrophil count was observed. Because of the complexity of the case, the unfavorable course of the illness and the urgent need for revision surgery, a rechallenge with fosfomycin was done followed by a decrease of the neutrophil count. CONCLUSION: This is the third paper reporting agranulocytosis induced by fosfomycin, and the first detailed description of a case. Based on chronological and semiological criteria and bibliographic data, the event was qualified as probable with the Naranjo adverse drug probability scale. Literature data is scarce. The summary of product characteristics mentions that only a few cases of transient neutropenia and agranulocytosis have been reported. An analysis of the FDA Adverse Event Reporting System Database highlighted a higher than expected frequency of agranulocytosis in patients treated with fosfomycin. Parenteral fosfomycin is often used in patients receiving other medications, so that it is rarely the only suspect. In our case, the results of the bone marrow aspiration, the sudden drop of the neutrophil count with concomitant eosinophilia and the absence of improvement despite the dose decrease, point towards an immuno-allergic mechanism. However, the overlap between the suspected DRESS induced by meropenem and the agranulocytosis do not allow to conclude with certainty on the causality. Awareness should be raised about this side effect.

Effectiveness of fosfomycin trometamol as oral step-down therapy for bacteraemic urinary tract infections due to MDR Escherichia coli: a post hoc analysis of the FOREST randomized trial.

BACKGROUND: Fosfomycin is a potentially attractive option as step-down therapy for bacteraemic urinary tract infections (BUTI), but available data are scarce. Our objective was to compare the effectiveness and safety of fosfomycin trometamol and other oral drugs as step-down therapy in patients with BUTI due to MDR Escherichia coli (MDR-Ec). METHODS: Participants in the FOREST trial (comparing IV fosfomycin with ceftriaxone or meropenem for BUTI caused by MDR-Ec in 22 Spanish hospitals from June 2014 to December 2018) who were stepped-down to oral fosfomycin (3 g q48h) or other drugs were included. The primary endpoint was clinical and microbiological cure (CMC) 5-7 days after finalization of treatment. A multivariate analysis was performed using logistic regression to estimate the association of oral step-down with fosfomycin with CMC adjusted for confounders. RESULTS: Overall, 61 patients switched to oral fosfomycin trometamol and 47 to other drugs (cefuroxime axetil, 28; amoxicillin/clavulanic acid and trimethoprim/sulfamethoxazole, 7 each; ciprofloxacin, 5) were included. CMC was reached by 48/61 patients (78.7%) treated with fosfomycin trometamol and 38/47 (80.9%) with other drugs (difference, -2.2; 95% CI: -17.5 to 13.1; P = 0.38). Subgroup analyses provided similar results. Relapses occurred in 9/61 (15.0%) and 2/47 (4.3%) of patients, respectively (P = 0.03). The adjusted OR for CMC was 1.11 (95% CI: 0.42-3.29, P = 0.75). No relevant differences in adverse events were seen. CONCLUSIONS: Fosfomycin trometamol might be a reasonable option as step-down therapy in patients with BUTI due to MDR-Ec but the higher rate of relapses would need further assessment.

Effectiveness of fosfomycin-based antimicrobial prophylaxis for transrectal ultrasound-guided prostate biopsy: A Korean multicenter study.

PURPOSE: Recent studies have highlighted increasing infectious complications due to fluoroquinolone (FQ)-resistant organisms in men undergoing transrectal ultrasound-guided prostate biopsy (TRUSPB). This study investigated whether fosfomycin (FM)-based antibiotic prophylaxis reduces infections after TRUSPB and identified risk factors for infective complications. MATERIALS AND METHODS: A multicenter study was conducted in the Republic of Korea from January 2018 to December 2021. Patients undergoing prostate biopsy with FQ or FM-based prophylaxis were included. The primary outcome was the post-biopsy infectious complication rate after FQ (group 1) or FM-based antibiotic prophylaxis with FM alone (group 2) or FQ and FM (group 3). Risk factors for infectious complications after TRUSPB were secondary outcomes. RESULTS: Patients (n=2,595) undergoing prostate biopsy were divided into three groups according to the type of prophylactic antibiotics. Group 1 (n=417) received FQ before TRUSPB. Group 2 (n=795) received FM only and group 3 (n=1,383) received FM and FQ before TRUSPB. The overall post-biopsy infectious complication rate was 1.27%. The infectious complication rates were 2.4%, 1.9%, and 0.5% in groups 1, 2, and 3, respectively (p=0.002). In multivariable analysis, predictors of post-biopsy infectious complications included an association with health care utilization (adjusted odds ratio [OR], 4.66; 95% confidence interval [CI], 1.74-12.4; p=0.002) and combination antibiotic prophylaxis (FQ and FM) (adjusted OR, 0.26; 95% CI, 0.09-0.69; p=0.007). CONCLUSIONS: In comparison with monotherapy with FM or FQ, combination antibiotic prophylaxis (FQ and FM) showed a lower rate of infectious complications after TRUSPB. Utilization of health care was an independent risk factor for infectious complications after TRUSPB.

A multicentre, retrospective audit of fosfomycin use for urinary tract infections in Australian children and adolescents.

BACKGROUND: Urinary tract infections (UTIs) due to MDR organisms are increasingly common. The lack of paediatric data on efficacious antibiotics makes UTI treatment particularly challenging. Data on the efficacy of fosfomycin use for UTI in children are variable. METHODS: We conducted a retrospective audit of children aged 0-18 years who were treated with fosfomycin for UTI at seven tertiary paediatric hospitals in Australia over a 7 year period, from 2014 to 2020. RESULTS: Ninety-one children with a median age of 5 years (range 2 months to 18 years) received oral fosfomycin for UTI. The majority (57/91, 63%) had one or more comorbidity, with the most common being renal tract anomalies (24/91, 26%). Fifty-nine (65%) had febrile UTI, 14/91 (15%) had pyelonephritis and 1/91 (1%) was bacteraemic. A majority (80/91, 88%) of urinary cultures had an ESBL-producing Gram-negative pathogen isolated. Fosfomycin susceptibility was evident in all 80 isolates tested. For uncomplicated UTI, the most common dose in children aged <1, 1-12 and >12 years was 1, 2 and 3 g, respectively. For complicated UTI, doses of 2 and 3 g were most common. The median duration of fosfomycin administration was 5 days (range 1-82). Clinical cure was achieved in 84/90 (93%); the six with treatment failure had underlying comorbidities. Overall, 2/91 (2%) children experienced drug-related adverse effects comprising gastrointestinal symptoms in both, which resolved after treatment discontinuation. CONCLUSIONS: Fosfomycin is well tolerated and associated with favourable treatment outcomes in children with UTI. Further research on the optimal dosing strategy is required.

Real-life experience with IV fosfomycin in Canada: Results from the Canadian LEadership on Antimicrobial Real-life usage (CLEAR) registry.

OBJECTIVES: Data on the use of intravenous (IV) fosfomycin in Canada are limited. Using data captured by the Canadian LEadership on Antimicrobial Real-life usage (CLEAR) registry, we report the use of IV fosfomycin in Canadian patients. METHODS: The CLEAR registry uses the web-based data management program, REDCapTM (https://rcsurvey.radyfhs.umanitoba.ca/surveys/?s=F7JXNDFXEF) to facilitate clinicians' entering of details associated with their clinical experiences using IV fosfomycin. RESULTS: Data were available for 59 patients treated with IV fosfomycin. The most common infections treated were: bacteraemia or sepsis (25.4% of patients), complicated urinary tract infection (20.3%), ventilator-associated bacterial pneumonia (18.6%), and hospital-acquired pneumonia (13.6%). IV fosfomycin was used to treat Gram-negative (88.1%) and Gram-positive (10.2%) infections. The most common pathogens treated were carbapenem-resistant Enterobacterales (44.1%), multidrug-resistant Pseudomonas aeruginosa (18.6%), vancomycin-resistant Enterococcus faecium (5.1%), and methicillin-resistant Staphylococcus aureus (3.4%). IV fosfomycin was primarily used due to resistance to initially prescribed therapies (69.5%), frequently in combination with other agents (86.4%). Microbiological success (eradication/presumed eradication) occurred in 77.4% of patients, and clinical success (clinical cure/improvement) occurred in 62.5%. Overall, 15.3% of patients died because of their infection. Adverse effects were not documented in 73.1% of patients, and no patient discontinued therapy because of an adverse effect. CONCLUSIONS: In Canada, IV fosfomycin is used primarily as directed therapy to treat a variety of severe infections caused by Gram-negative and Gram-positive bacteria. It is primarily used in patients infected with bacteria resistant to other agents and as part of combination therapy. Its use is associated with relatively high microbiological and clinical cure rates, and it has an excellent safety profile.

Emerging issues on Staphylococcus aureus endocarditis and the role in therapy of daptomycin plus fosfomycin.

INTRODUCTION: Methicillin-resistant and -susceptible Staphylococcus aureus (MRSA/MSSA) infections are a major global health-care problem. Bacteremia with S. aureus exhibits high rates of morbidity and mortality and can cause complicated infections such as infective endocarditis (IE). The emerging resistance profile of S. aureus is worrisome, and several international agencies have appealed for new treatment approaches to be developed. AREAS COVERED: Daptomycin presents a rapid bactericidal effect against MRSA and has been considered at least as effective as vancomycin in treating MRSA bacteremia. However, therapy failure is often related to deep-seated infections, e.g. endocarditis, with high bacterial inocula and daptomycin regimens <10 mg/kg/day. Current antibiotic options for treating invasive S. aureus infections have limitations in monotherapy. Daptomycin in combination with other antibiotics, e.g. fosfomycin, may be effective in improving clinical outcomes in patients with MRSA IE. EXPERT OPINION: Exploring therapeutic combinations has shown fosfomycin to have a unique mechanism of action and to be the most effective option in preventing the onset of resistance to and optimizing the efficacy of daptomycin, suggesting the synergistic combination of fosfomycin with daptomycin is a useful alternative treatment option for MSSA or MRSA IE.

First trimester pregnancy exposure to fosfomycin and risk of major congenital anomaly: a comparative study in the EFEMERIS database.

PURPOSE: Fosfomycin trometamol has been recommended as first-line bactericidal antibiotic for urinary tract infections in pregnant women since 2015 in France. However, studies assessing fosfomycin safety in pregnancy are sparse. This study aimed to assess the risk of major Congenital Anomaly (CA) after fosfomycin exposure during the first trimester of pregnancy. METHODS: We performed a comparative study in EFEMERIS, the French database including expecting mothers covered by the French Health Insurance System of Haute-Garonne from July 1st, 2004 to December 31th, 2018. EFEMERIS contains prescribed and dispensed reimbursed medications during pregnancy and pregnancy outcomes. Logistic regressions have been conducted to compare three groups: (1) pregnancies exposed at least once to fosfomycin; (2) pregnancies exposed at least once to nitrofurantoin; and (3) pregnancies exposed neither to fosfomycin nor to nitrofurantoin, another antibiotic prescribed for urinary infections, before and during pregnancy. RESULTS: A total of 2724 (2.0%) pregnant women received at least one fosfomycin prescription during the first trimester, 650 (0.5%) received nitrofurantoin during the first trimester, and 133,502 (97.5%) pregnant women were not exposed to fosfomycin nor to nitrofurantoin. First trimester pregnancy exposure to fosfomycin was not associated with an increased risk of major CA, compared to first trimester exposure to nitrofurantoin (2.0% versus 2.5%; ORa = 0.80 [0.44-1.47]), or to pregnancies unexposed to fosfomycin and nitrofurantoin (2.0% versus 2.1%; ORa = 0.97 [0.73-1.30]). CONCLUSION: This is the first large comparative study assessing fosfomycin safety in pregnancy. It does not exhibit an increased risk of major CA after fosfomycin exposure during the first trimester of pregnancy.

Efficacy and safety of intravenous fosfomycin for the treatment of carbapenem-resistant Klebsiella pneumoniae.

The aim of the study was to evaluate clinical and microbiological efficacy and safety of intravenous fosfomycin for the treatment of carbapenem-resistant K. pneumoniae infections. All adult inpatients receiving 48 h of intravenous fosfomycin, alone or combined with other antibiotics were included in the study. Overall favorable clinical response rate was 75.3% among 94 patients. Clinical response rates were 92.3%, 72.2% and 56.0% for urinary tract infections, bacteremia and pneumonia, respectively. Microbiological eradication was achieved in 55 of 86 patients. 30-day mortality was 33.0%. Adverse events were generally mild. Common adverse events were hypokalemia (37.2%) and hypernatremia (22.3%). Intravenous fosfomycin is an effective antibiotic option with a good safety profile for the treatment of carbapenem-resistant K. pneumoniae infections. The most favorable clinical and microbiological responses are obtained in urinary tract infections. The efficacy of the drug in more severe infections, such as pneumonia and bacteremia, is comparable to the literature.

[Rationale for choosing an antibiotic for the treatment of cystitis: recommendations of clinical pharmacologists: A review].

In recent years, the harmonization of domestic and foreign clinical recommendations for the treatment of cystitis has been achieved. Nitrofurans and fosfomycin trometamol are recommended as first line therapy antibiotics, and oral 3rd generation of cephalosporins are recommended as alternative antibiotics; fluoroquinolones are excluded from the recommended medications due to an unfavorable safety profile. The main rationale for inclusion of antibiotics in the recommendations as a first line therapy of cystitis is the level of resistance of uropathogens to antibiotics, primarily Escherichia coli. Stable low level of resistance of E. coli in Russia was noted to nitrofurans and fosfomycin (5%), higher to cephalosporins. Among nitrofurans, furazidine is characterized by higher activity against E. coli compared to nitrofurantoin. The potassium salt of furazidine in dosage form with magnesium carbonate is preferred, since it is characterized by higher bioavailability and provides a therapeutic level of concentrations in urine above the MIC during the entire dosing period. Due to the global increase in the resistance of uropathogens observed in recent years, experts have begun to pay more and more attention to the ecological safety of antimicrobial therapy in order to minimize the risk of concomitant (collateral) damage, contributing to the selection of multi-drug resistant strains of microorganisms. In the latest WHO document of 2021, experts divided antibiotics into three groups (ACCESS, WATCH, RESERVE) according to the priority of choice. The ACCESS group of drugs for the treatment of cystitis includes nitrofurantoin and furazidine as agents with minimal collateral effect, while fosfomycin trometamol and cephalosporins are listed in the WATCH group. Thus, from the standpoint of ecological safety, WHO experts recommend prescribing nitrofurans in the treatment of cystitis in the first line of therapy.

Randomised controlled trial of fosfomycin in neonatal sepsis: pharmacokinetics and safety in relation to sodium overload.

OBJECTIVE: To assess pharmacokinetics and changes to sodium levels in addition to adverse events (AEs) associated with fosfomycin among neonates with clinical sepsis. DESIGN: A single-centre open-label randomised controlled trial. SETTING: Kilifi County Hospital, Kenya. PATIENTS: 120 neonates aged ≤28 days admitted being treated with standard-of-care (SOC) antibiotics for sepsis: ampicillin and gentamicin between March 2018 and February 2019. INTERVENTION: We randomly assigned half the participants to receive additional intravenous then oral fosfomycin at 100 mg/kg two times per day for up to 7 days (SOC-F) and followed up for 28 days. MAIN OUTCOMES AND MEASURES: Serum sodium, AEs and fosfomycin pharmacokinetics. RESULTS: 61 and 59 infants aged 0-23 days were assigned to SOC-F and SOC, respectively. There was no evidence of impact of fosfomycin on serum sodium or gastrointestinal side effects. We observed 35 AEs among 25 SOC-F participants and 50 AEs among 34 SOC participants during 1560 and 1565 infant-days observation, respectively (2.2 vs 3.2 events/100 infant-days; incidence rate difference -0.95 events/100 infant-days (95% CI -2.1 to 0.20)). Four SOC-F and 3 SOC participants died. From 238 pharmacokinetic samples, modelling suggests an intravenous dose of 150 mg/kg two times per day is required for pharmacodynamic target attainment in most children, reduced to 100 mg/kg two times per day in neonates aged <7 days or weighing <1500 g. CONCLUSION AND RELEVANCE: Fosfomycin offers potential as an affordable regimen with a simple dosing schedule for neonatal sepsis. Further research on its safety is needed in larger cohorts of hospitalised neonates, including very preterm neonates or those critically ill. Resistance suppression would only be achieved for the most sensitive of organisms so fosfomycin is recommended to be used in combination with another antimicrobial. TRIAL REGISTRATION NUMBER: NCT03453177.

Fosfomycin therapeutic drug monitoring in real-life: development and validation of a LC-MS/MS method on plasma samples.

Individualization of fosfomycin dosing based on therapeutic drug monitoring (TDM) of plasma concentrations could reduce drug-related adverse events and improve clinical outcome in complex clinical conditions. Quantification of fosfomycin in plasma samples was performed by a rapid ultraperformance liquid chromatography mass spectrometry method. Sample preparation involved protein precipitation with [13C3]-fosfomycin benzylamine salt as internal standard. The calibration curve ranged from 2 to 800 mg/L. Within- and between-day precision and accuracy, sensitivity, selectivity, dilution integrity, recovery were investigated and the results met the acceptance criteria. In patients, multiple drug dosing (every 6 or 8 hours) or in continuous administration were adopted, resulting in a large interpatient variability in drug concentrations (from 7.4 mg/L and 644.6 mg/L; CV: 91.1%). In critical care patient setting TDM can represent an important tool to identify the best fosfomycin dosing in single patients, taking into consideration clinical characteristics, infection sites and susceptibility of the treated pathogens.

Evaluation of efficacy and safety of fosfomycin versus nitrofurantoin for the treatment of uncomplicated lower urinary tract infection (UTI) in women - A systematic review and meta-analysis.

Urinary tract infections (UTI) are among the most frequent medical conditions requiring outpatient treatment. Single dose oral fosfomycin (300 mg) and the older nitrofurantoin (100 mg for 5 days) have been found to be more effective than other first-line drugs in multiple studies. This systematic review and meta-analysis were carried out with the objective of evaluating their comparative efficacy and safety in the management of uncomplicated UTI. Two authors independently searched PubMed, Cochrane Central, Embase, and Google Scholar till Nov 2020 using MeSH terms and free text. Randomized controlled trials (RCTs) comparing both drugs for efficacy and safety in uncomplicated UTI in adult women were included. The primary outcome measures were microbiological and clinical cure rates. The search resulted in n = 663 studies out of which only four studies (three for treatment of uncomplicated UTI in women and one for asymptomatic bacteriuria in pregnancy) satisfied the selection criteria. No significant differences in clinical, (RR 0.95, 95% CI - 0.81, 1.12) and microbiological cure, (RR 0.96, 95% CI - 0.84, 1.08) were found within 4 weeks of treatment. The incidence of adverse events was found to be more in fosfomycin relative to the nitrofurantoin group (RR 1.05, 95% CI - 0.59, 1.87). Hence, single-dose fosfomycin presents a potentially useful and safe treatment option for the treatment of uncomplicated UTI in women and asymptomatic bacteriuria in pregnancy.

Fosfomycin Vs Ciprofloxacin as Oral Step-Down Treatment for Escherichia coli Febrile Urinary Tract Infections in Women: A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial.

BACKGROUND: We aimed to determine the noninferiority of fosfomycin compared to ciprofloxacin as an oral step-down treatment for Escherichia coli febrile urinary tract infections (fUTIs) in women. METHODS: This was a double-blind, randomized, controlled trial in 15 Dutch hospitals. Adult women who were receiving 2-5 days of empirical intravenous antimicrobials for E. coli fUTI were assigned to step-down treatment with once-daily 3g fosfomycin or twice-daily 0.5g ciprofloxacin for 10 days of total antibiotic treatment. For the primary end point, clinical cure at days 6-10 post-end of treatment (PET), a noninferiority margin of 10% was chosen. The trial was registered on Trialregister.nl (NTR6449). RESULTS: After enrollment of 97 patients between 2017 and 2020, the trial ended prematurely because of the coronavirus disease 2019 pandemic. The primary end point was met in 36 of 48 patients (75.0%) assigned to fosfomycin and 30 of 46 patients (65.2%) assigned to ciprofloxacin (risk difference [RD], 9.6%; 95% confidence interval [CI]: -8.8% to 28.0%). In patients assigned to fosfomycin and ciprofloxacin, microbiological cure at days 6-10 PET occurred in 29 of 37 (78.4%) and 33 of 35 (94.3%; RD, -16.2%; 95% CI: -32.7 to -0.0%). Any gastrointestinal adverse event was reported in 25 of 48 (52.1%) and 14 of 46 (30.4%) patients (RD, 20.8%; 95% CI: 1.6% to 40.0%), respectively. CONCLUSIONS: Fosfomycin is noninferior to ciprofloxacin as oral step-down treatment for fUTI caused by E. coli in women. Fosfomycin use is associated with more gastrointestinal events. CLINICAL TRIAL REGISTRATION: Trial NL6275 (NTR6449).

[The efficiency of combined regimens for the treatment of urinary tract infections in women using the herbal drug Canephron N].

INTRODUCTION: Currently, empiric antibiotic therapy is considered the standard for acute cystitis. However, additional treatment may be required to alleviate the patient's condition and shorten the time to subjective recovery. AIM: To evaluate the efficiency of the combined administration of fosfomycin trometamol and herbal drug Canephron N in comparison with a single oral dose of fosfomycin trometamol in women with uncomplicated bacterial cystitis. MATERIALS AND METHODS: A randomized, comparative, open-label study was carried put between January 2018 and June 2019. The study included 112 women with symptoms of acute uncomplicated cystitis, who were randomized between two groups in a 1:1 ratio. In the main group, patients received a single oral dose of fosfomycin in combination with Canephron N (2 tablets t.i.d. for 2 weeks), while in the control group patients received only a single dose of fosfomycin (3 g). Symptoms were assessed using the Russian version of the Acute Cystitis Symptom Score (ACSS), completed daily for a week. Also, all patients underwent urine analysis on the 1st, 3rd, 5th and 7th days of therapy. The mean time to complete recovery based on the ACSS questionnaire and the time to resolution of pyuria were compared using the Mann-Whitney U test. Comparison of the proportion of patients with complete cure, according to the questionnaire, or with the elimination of pyuria was carried out using the chi-square test. RESULTS: The final analysis included 46 patients who received fosfomycin in combination with Canephron and 47 patients who received fosfomycin as monotherapy. In the group of combination therapy, patient-reported complete recovery (assessed by the ACSS questionnaire) was seen on average after 1 day, while in patients treated with monotherapy, the median time to subjective recovery was 3 days (p=0.00012). A significant difference between the groups in the proportion of patients with complete resolution of symptoms of acute cystitis was observed on days 1, 2, and 3 (p<0.05). The therapy was well tolerated in both groups. The most frequent adverse events were dyspepsia (8.7% in the combination group compared to 6.4% in the control group) and headache (in 4.3% and 6.4% of patients, respectively). CONCLUSION: the combined use of fosfomycin trometamol and the herbal drug Canephron N allows to reduce the duration of symptoms in patients with acute cystitis, thereby accelerating return to their usual lifestyle patterns.

Efficacy and safety of intravenous fosfomycin for the treatment of difficult-to-treat Gram-negative bacterial infections.

We reviewed the efficacy and safety of intravenous (IV) fosfomycin for the treatment of infections caused by Gram-negative bacteria (GNB) with difficult-to-treat resistance (DTR). Data were retrospectively retrieved for all hospitalized patients who received IV fosfomycin for ≥48 h for the treatment of a DTR GNB between September 27, 2017 and January 31, 2020. A total of 30 patients were included, of which 63.3% were males, and the median age was 63.5 years (IQR 46-73). The median Charlson Comorbidity Score was 6 (IQR 3.8-9). The urinary tract (56.7%) was the most frequent site of infection, and the most frequent target organisms were Klebsiella pneumoniae (56.7%), and Escherichia coli (23.3%). The majority (76.%) received IV fosfomycin in combination with other antibacterial agents. Clinical improvement was observed in 22 (73.3%), eradication of baseline pathogens in 20 (66.7%), 30-day all-cause mortality in 7 (23.3%), and documented emergent resistance to fosfomycin in 5 (16.7%) patients. Treatment-related adverse events were infrequent and generally mild or moderate in severity. In conclusion, IV fosfomycin is a potentially efficacious and safe treatment option for the treatment of DTR GNB infections. Randomized trials are urgently required to confirm the utility of IV fosfomycin as monotherapy and in combination with other agents.

[Rationale for the choice of an antibiotic for urinary tract infections with an emphasis on the environmental safety of therapy].

Difficulties in prescribing antibiotics for lower urinary tract infections (UTI) are associated with a fact that such patients can be treated not only by urologists, but also by general practitioners, internists, pediatricians, and gynecologists. Therefore, it is important to adapt the practical recommendations for the treatment of cystitis for different medical disciplines. When creating clinical guidelines, experts take into account the different factors in choosing antibiotic therapy. First of all, pharmacokinetics is of importance and drugs with renal excretion should be preferred. Secondly, the natural activity of the antibiotic against the pathogens, which cause cystitis, has to be considered. In uncomplicated infections, E. coli predominates, while in complicated and recurrent infections E. coli and other enterobacteria are commonly isolated, as well as Enterococci. In addition, local resistance pattern is reviewed. In the Russian Federation E. coli has minimal resistance to nitrofurans and fosfomycin. Lastly, antibiotics can negatively affect the gastrointestinal and urinary tract microbiota and contribute to the increase of antibiotic resistance and the selection of antibiotic-resistant strains, therefore the environmental safety of therapy should be considered. The effect of antibiotics on the resident flora of the gastrointestinal tract, urinary tract and vagina is called collateral effect, or concomitant (parallel) damage, and it may exceed the therapeutic effect of some antibiotics. Cephalosporins and fluoroquinolones can cause ecologically unfavorable effects with the risk of selection of resistant strains; therefore, these drugs are currently considered as second-line agents for UTI. When choosing an antibiotic, preference should be given to drugs with the narrow spectrum and minimal collateral damage, i.e., the principle of "minimum sufficiency" is of importance. Nitrofurans and fosfomycin trometamol are the optimal drugs in terms of efficiency and environmental safety in UTI. WHO experts consider nitrofurans as the most environmentally safe antibiotics with a minimally sufficient spectrum of activity. The environmental safety of antimicrobial therapy is an important component of preventing antibiotic resistance at the global and local levels.

Herbal treatment with uva ursi extract versus fosfomycin in women with uncomplicated urinary tract infection in primary care: a randomized controlled trial.

OBJECTIVE: We explored whether initial treatment with the herbal drug uva ursi (UU) reduces antibiotic use in women with uncomplicated urinary tract infection (UTI) without increasing symptom burden and complication frequency compared with antibiotic treatment. METHODS: A double-blind randomized controlled trial was conducted in 42 family practices in Germany. The participants were adult women with suspected uncomplicated UTIs receiving either UU 105 mg 3 × 2 tablets for 5 days (intervention) or fosfomycin a 3-g single dose (control), and their respective placebos. Participants and investigators were blinded. The primary outcome included (1) antibiotic courses day 0-28 as superiority, and (2) symptom burden (sum of daily symptom scores) day 0-7, as non-inferiority outcome (margin 125%). Clinicaltrials.gov: NCT03151603. RESULTS: Overall, 398 patients were randomly allocated to groups receiving UU (n = 207) and fosfomycin (n = 191). The number of antibiotic courses was 63.6% lower (95% CI 53.6%-71.4%; p < 0.0001) in the UU group than in the fosfomycin group. The ratio of total symptom burden in the UU group compared with control was 136.5% (95% CI 122.7-151.9; p 0.95), failing non-inferiority. Eight women developed pyelonephritis in the UU group compared with two in the fosfomycin group (mean difference 2.8; 95% CI 0.2-5.9; p 0.067). Adverse events were similar between the groups. DISCUSSION: In women with uncomplicated UTIs, initial treatment with UU reduced antibiotic use but led to a higher symptom burden and more safety concerns than fosfomycin.

Elimination of fosfomycin during dialysis with the Genius system in septic patients.

To assess fosfomycin (FOS) elimination in patients with sepsis and acute kidney injury (AKI) undergoing slow-extended daily dialysis (SLEDD) with the Genius system in a prospective observational study. After ethics committee approval ten patients with sepsis and AKI stage 3 underwent daily SLEDD sessions of eight hours. FOS was applied i.v. at doses of 3 × 5 g per day. FOS serum levels were measured pre- and post hemofilter before, during, and after SLEDD sessions, and instantaneous clearance was calculated. In five of the patients, we analyzed FOS levels after the first dose, in the other five patients serum levels were measured during ongoing therapy. FOS was eliminated rapidly via the hemofilter. FOS clearance decreased from 152 ± 10 mL/min (start of SLEED session) to 43 ± 38 mL/min (end of SLEDD session). In 3/5 first-dose patients after 4-6 h of SLEDD the FOS serum level fell below the EUCAST breakpoint of 32 mg/L for Enterobacterales and Staphylococcus species. In all patients with ongoing fosfomycin therapy serum levels were high and above the breakpoint at all times. FOS toxicity or adverse effects were not observed. FOS serum concentrations exhibit wide variability in critically ill patients with sepsis and AKI. FOS is eliminated rapidly during SLEDD. A loading dose of 5 g is not sufficient to achieve serum levels above the EUCAST breakpoint for common bacteria in all patients, considering that T > MIC > 70% of the dosing interval indicates sufficient plasma levels. We thus recommend a loading dose of 8 g followed by a maintenance dose of 5 g after a SLEDD session in anuric patients. We strongly recommend therapeutic drug monitoring of FOS levels in critically ill patients with AKI and dialysis therapy.