New Medicines Committee Briefing. July Fosfomycin trometamol for the treatment of multidrug resistant urinary tract infection

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New Medicines Committee Briefing July 2014 Fosfomycin trometamol for the treatment of multidrug resistant urinary tract infection (unlicensed indication) Fosfomycin trometamol to be reviewed for use within: Primary Care Secondary Care Summary: Fosfomycin trometamol is a broad spectrum antibiotic that has a UK marketing authorisation for treating acute lower uncomplicated urinary tract infections (UTI). Fosfomycin is not available commercially as a licensed product in the UK and, currently, the only means of obtaining it is to order from a 'specials' supplier. The Management of infection guidance for primary care for consultation and local adaptation, recommends fosfomycin to be considered for treating adults with uncomplicated UTIs (no fever or flank pain) due to extended spectrum beta-lactamase-producing (ESBL) Escherichia coli. 1 No randomised controlled trials were identified that assessed the clinical efficacy of oral fosfomycin for treating urinary tract infections caused by multidrug-resistant bacteria. Treatment with fosfomycin trometamol was associated with a clinical success rate between 77.8% and 94.2% in the 3 small observational studies. 2 There was no statistically significant difference in clinical success rates between fosfomycin trometamol and carbapenems. 3 Clinical success rates were similar with fosfomycin trometamol and co-amoxiclav. 4 APPROVED 30/07/14: WITH RESTRICTION: AT THE RECOMMENDATION OF MICROBIOLOGIST IN LINE WITH PROFORMA (AMBER 2) 1

Application: Microbiology: Consultant submitting application: Dr Krishna Banavathi (Consultant Microbiologist) Dr Vasile Laza Stanca (Consultant Microbiologist) Clinical Director supporting application: Dr Gavin Russell (Medical Director) Dr Banavathi noted that the treatment of multidrug resistant organisms (ESBL, Amp-C, carbapenemase producers and other multidrug resistant mechanisms) mostly enterobacteriacea (E.coli and Klebsiella species) causing UTI is a challenge with very limited choices of antibiotics active against such pathogens. He also noted that patient co-morbidities like renal insufficiency and patient s intolerability to certain medications compound the issue. On such occasions patients can only be treated with IV antibiotics usually at the hospital even though the patients are not acutely unwell. Dr Banavathi stated that the use of fosfomycin for the treatment of UTI have been discussed at the Local Health Economy Antimicrobial Group meeting. The sensitivities to fosfomycin will not be released by the laboratory and the GP will only prescribe after discussion with consultant/microbiologist. It will be the responsibility of the consultant to go through the different options for oral treatment and decide on the suitability of prescribing fosfomycin. The Fosfomycin profoma will then be completed and signed by the GP mentioning the name of consultant/microbiologist recommending its use. It was agreed at the Local Health Economy Antimicrobial Group meeting to designate some community pharmacies to hold small stock of fosfomycin and the dispensing of the drug will be restricted (only dispensed against both FP10 and the profoma). Approximately 50-100 patients will be treated with fosfomycin per year across the whole health economy. Background: Fosfomycin is an orally active, bactericidal, broad spectrum antibiotic which is active against virtually all strains of E. coli, including those producing ESBLs. It is has UK marketing authorisation for treating acute lower uncomplicated urinary tract infection but no longer licensed in the UK due to lack of commercial success, but is available from specialist drug importers (e.g. IDIS). It is widely used in Europe, and increasingly is being recommended for use by microbiologists in the UK. It is well absorbed after oral administration, and is excreted unchanged in the urine. Typically there are high urine levels after a single 3g dose, with the concentration in urine remaining above the MIC of sensitive organisms for 48 hours. The Management of infection guidance for primary care for consultation and local adaptation, published by the Health Protection Agency in February 2013 states that following advice from a microbiologist; fosfomycin or nitrofurantoin should be considered for treating adults with uncomplicated UTIs (no fever or flank pain) due to ESBL Escherichia coli. 1 2

Current formulary status: The North Staffordshire Joint Formulary currently lists the following: 5.1.13 Urinary tract infections Nitrofurantoin Indication: 5 MONURIL is indicated in the treatment of acute lower uncomplicated urinary tract infections, caused by pathogens sensitive to fosfomycin. Contraindications Known hypersensitivity to fosfomycin Renal insufficiency with egfr < 20ml/min Cautions Pregnancy and breast feeding Adverse effects Uncommon: nausea, vomiting, diarrhoea, dyspepsia, headache, dizziness, tiredness, dyspnoea, hypernatraemia, hypokalaemia, transient rise in liver enzymes Rare/Very rare: hypersensitivity reactions, anaphylaxis, bronchospasm, aplastic anaemia, visual disturbances Drug interactions Metoclopramide reduces serum and urine levels of fosfomycin (separate administration times by at least 2 hours) Dosage and administration Patients are eligible for treatment with fosfomycin if the following criteria are fulfilled: They must be suffering from a symptomatic lower UTI, without fever, loin pain, or other signs of an upper UTI or pyelopnephritis. There must be a significant growth of a fosfomycin-sensitive organism in the urine sample. There must be no other suitable oral treatment alternative, either because of bacterial resistance, or patient allergy or intolerance to suitable antimicrobials. 3

Prescribing information Dose egfr 60ml/min egfr 20-60ml/min egfr <20ml/min Uncomplicated cystitis 3g oral x 1 dose 3g oral x 1 dose Complicated cystitis a 3g oral every 2 days for 3 doses 3g oral every 3 days for 2 doses a definition of complicated = anything which increases the risk of treatment failure e.g. male patient, diabetes, urinary catheter, immunocompromised, functional or anatomical abnormality of the urinary tract Inadequate concentrations may be reached in the urine. Do not use The contents of ONE sachet should be taken in half a glass of water as a single dose at least two - three hours before food on an empty stomach. Meals may delay the absorption of the active ingredient causing a slight decrease in peak blood and urine levels. The ideal time to take it is in the evening before going to bed. Guidance: NICE Guidance published No Cochrane No British Infection Association 1 Yes The management of infection guidance gives treatment options for urinary tract infections in different populations: In adults with uncomplicated urinary tract infection (without fever or flank pain, which may indicate pyelonephritis), urine culture and sensitivity testing should be performed after first-line treatment failure. If the organism is susceptible, amoxicillin is a treatment option. Nitrofurantoin or fosfomycin should be considered on the advice of a microbiologist if the infection is due to multidrug-resistant extended-spectrum beta-lactamase-producing E. coli. If fosfomycin is used, the management of infection guidance recommends a single 3 g dose in women. In men, a second 3 g dose should be taken after 3 days. 4

Efficacy: NICE Evidence Summary 2 Yes Fosfomycin trometamol compared with other antibiotic treatments The evidence summary is based on 4 small observational studies. Treatment with fosfomycin was associated with clinical success rate (defined as the resolution of symptoms after treatment) of between 77.8% and 94.2% in the 3 studies that reported this outcome. There were no randomised controlled trials that assessed the clinical efficacy of oral fosfomycin for treating UTI caused by multidrug resistant bacteria. The study by Senol et al. 3 was a small prospective cohort study of 47 people with complicated lower urinary tract infections caused by extended-spectrum beta-lactamase-producing E. coli who attended a hospital and outpatient clinic in Turkey between March 2005 and January 2006. The study compared the efficacy of fosfomycin trometamol (n=27; 3 g orally every other night for 3 doses) with the carbapenems (n=20), meropenem (n=12; 1 g intravenously 3 times daily for 14 days) and imipenem cilastatin (n=8; 500 mg intravenously 4 times daily for 14 days). Allocation to treatment was not randomised and how treatment was decided was not reported. Reported outcomes were clinical success (defined as resolution of symptoms), microbiological success (defined as sterile urine culture performed 7 to 9 days after the end of treatment), relapse (defined as isolation of ESBL E. coli in urine cultures performed 28 to 31 days after the start of treatment), and reinfection (defined as isolation of any pathogen in urine cultures performed 28 to 31 days after the start of treatment). Clinical and microbiological success rates in the carbapenem and fosfomycin trometamol groups were similar. In the carbapenem group, 19 out of 20 (95.0%) people had clinical success compared with 21 out of 27 (77.8%) in the fosfomycin trometamol group (p>0.05). In the carbapenem group, 16 out of 20 (80.0%) people had microbiological success compared with 16 out of 27 (59.3%) in the fosfomycin trometamol group (p>0.05). The number of people who experienced relapse or reinfection was the same in both groups (each occurred in 1 person receiving fosfomycin trometamol and 1 person receiving a carbapenem). Both reinfections were due to Klebsiella pneumonia. Rodríguez-Baño et al 4 was a case-control study of people with community-acquired infections due to (cases), or not due to (controls), extended-spectrum beta-lactamase-producing E. coli in 11 Spanish hospitals from February 2002 to May 2003. It investigated the risk factors for all types of communityacquired infections caused by ESBL producing E. coli. Information on clinical outcomes was reported for 65 people with cystitis due to ESBL producing E. coli which was treated with either a single 3 g dose of fosfomycin trometamol (n=28) or co-amoxiclav 500 mg/125 mg 3 times daily for 5 to 7 days (n=37). Patients were considered to be clinically cured if they showed no persistent symptoms after completion of treatment and did not experience a recurrence of their urinary tract infection. Of the people who received fosfomycin trometamol, 26 out of 28 (92.9%) were clinically cured (all isolates were susceptible to fosfomycin). Persistent or recurrent urinary tract infection was microbiologically confirmed in the 2 people in whom treatment failed. Of the people who received co-amoxiclav, 31 out of 37 (83.8%) were clinically cured. In those with susceptible infections (defined as isolates with a minimum inhibitory concentration of 5

8 micrograms/ml or less), 26 out of 28 (92.9%) were clinically cured. Clinical cure was seen in 92.9% of people taking fosfomycin trometamol and 83.8% of people taking co-amoxiclav. The study did not report whether the difference between the treatments was statistically significant. Fosfomycin assessed retrospectively in case series The study by Neuner et al. 6 was a retrospective chart review of 41 adults who were in hospital and had a UTI (abnormal urinalysis and/or symptoms of urinary tract infection) and who had a urine culture for a multidrug-resistant pathogen (defined as resistance to at least 1 agent in 3 or more antimicrobial classes) that was susceptible to, and subsequently treated with, fosfomycin trometamol at a single US centre between January 2006 and December 2010. This study was uncontrolled and reported a single-centre experience of a small number of people. The decision to treat the infection with fosfomycin trometamol was at the discretion of the treating physician. The timing of follow-up cultures to assess relapse and reinfection was not standard, although 90% of people had follow-up cultures within 21 days of starting treatment with fosfomycin. 33 people had complicated UTI and the most common complicating factors were use of urinary Foley catheters (63.4%) and history of recurrent UTIs (24.4%). Urine culture identified 44 multidrug-resistant urinary isolates of 8 different pathogens with only 3 isolates resistant to fosfomycin. 2.9 fosfomycin doses were given on average to treat the UTI. Eleven people had combination of fosfomycin with another antibiotic (tigecycline, aminoglycosides, colistin, pipracillin/tazobactam, imipenem or daptomycin). The primary outcome of this study was overall microbiological cure, defined as the presence of a documented negative urine culture at the end of treatment and/or the absence of relapse or reinfection. Microbiological cure occurred in 24 people (58.5%) with 41.5% failure (17 people). Failure was because of either relapse (defined as the development of a urinary tract infection with the same pathogen within 30 days, n=10 [24.4%]) or reinfection (defined as the development of a urinary tract infection with a different organism within 30 days, n=7 [17.1%]). Clinical success was not reported. The study by Pullukcu et al. 7 was a retrospective case series of 52 people with lower urinary tract infections due to extended-spectrum beta-lactamase-producing E. coli treated with fosfomycin trometamol between September 2004 and July 2006 in an outpatient clinic and hospital in Turkey. This study was uncontrolled, and reported a single-centre experience of a small number of people. Everyone was treated empirically with fosfomycin trometamol (3 g every other night for 3 doses) and had a urine culture performed 7 to 9 days after the end of treatment. The main outcomes were clinical success (defined as resolution of symptoms on a follow-up visit 7 to 9 days after the end of treatment) and microbiological success (defined as a sterile urine culture on follow-up). 36 people has complicated UTIs; with complicating factors including indwelling urinary catheterisation (13.5%), recent urological intervention (11.5%), diabetes mellitus (9.6%) and renal transplantation (9.6%). Clinical success occurred in 49 people (94.2%) and microbiological success occurred in 41 people (78.8%). Follow-up urine culture was performed 28 days after the end of treatment in 28 of the 41 people with microbiological success. No one experienced a relapse of their infection (defined as isolation of ESBL producing E. coli in the urine cultures performed 28 days after the end of treatment). The rate of 6

This cost analysis has taken into account of the fact that fosfomycin will be used only in patients who are not suitable to be treated with any other oral antibiotics. The only option currently for these patients is to be admitted to the acute hospital of IV antibiotics. A database of these patients will be maintained and audited. reinfection (defined as isolation of any pathogen in the urine cultures performed 28 days after the end of treatment) was 10.7% (3/28). Safety Of the 4 observational studies of fosfomycin trometamol for treating UTI caused by multidrug-resistant organisms, 2 (Senol et al. 3 and Pullukcu et al. 7 ) stated that there were no adverse effects while Neuner et al. 6 and Rodriguez-Banu et al. 4 did not report adverse events. The summary of product characteristics for the 3g sachets states that gastrointestinal disturbances (e.g. nausea, diarrhoea and heartburn) and skin rashes have been reported. NOTE: 3 doses of fosfomycin trometamol were taken by most of the people in 3 of the 4 studies and most people had complicated UTI and were treated in hospital. On the contrary, management of infection guidance recommends a single 3g dose of fosfomycin in women and a second 3g dose taken after 3 days in men for uncomplicated UTI in adults due to multidrug-resistant ESBL producing E. coli in the community. Cost (Primary Care): Women Men Drug Dose 1 Cost Dose 1 Cost Fosfomycin trometamol (Monuril ) 3 g single dose 40.70-81.20 3 g every 3 days for 2 doses 81.14-162.40 Nitrofurantoin* 100 mg twice daily 1.32 100 mg twice daily 3.08 for 3 days for 7 days *Prices from July 2014 online Drug Tariff References 1 Health Protection Agency Management of infection guidance for primary care for consultation and local adaptation 2013. Available from http://www.hpa.org.uk/topics/infectiousdiseases/infectionsaz/primarycareguidance/#uti <accessed 09/06/14> 2 The National Institute for Health and Care Excellence. Evidence Summary: Unlicensed or off-label medicine Multidrug resistant urinary tract infections: fosfomycin trometamol. July 2013. Available from http://www.nice.org.uk/ <accessed 05/06/14> 7

3 Senol S, Tasbakan M, Pullukcu H et al. Carbapenem versus fosfomycin trometamol in the treatment of extendedspectrum beta-lactamase-producing Escherichia coli-related complicated lower urinary tract infection. Journal of Chemotherapy 2010; 22:355-357. 4 Rodríguez-Baño J, Alcala JC, Cisneros JM et al. Community infections caused by extended-spectrum beta-lactamaseproducing Escherichia coli. Archives of Internal Medicine 2008; 168: 1897 902 5 Medicines and Healthcare products Regulatory Agency Summary of product characteristics Monuril sachets 3 g. available from http://www.mhra.gov.uk/safetyinformation/medicinesinformation/spcandpils/index.htm?prodname=monuril%2 0SACHETS%203G&subsName=FOSFOMYCIN%20TROMETAMOL&pageID=SecondLevel <accessed 09/06/14> 6 Neuner EA, Sekeres J, Hall GS et al. Experience with fosfomycin for treatment of urinary tract infections due to multidrug-resistant organisms. Antimicrobial Agents & Chemotherapy 2012; 56: 5744-5748. 7 Pullukcu H, Tasbakan M, Sipahi OR et al. Fosfomycin in the treatment of extended spectrum beta-lactamaseproducing Escherichia coli-related lower urinary tract infections. International Journal of Antimicrobial Agents 2007; 29: 62 5. Produced by Sr. Maria Chidiamara Njoku Primary Care/Secondary Care Interface Pharmacist University Hospital of North Staffordshire Telephone: 01782 674541 e-mail: Maria.Njoku@uhns.nhs.uk Produced for use within the NHS. Not to be reproduced for commercial purposes. 8