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1
SIGN. Management of suspected bacterial urinary tract infection in adults: a national clinical guideline. Scottish Intercollegiate Guidelines Network. 2006 http://www.sign.ac.uk/guidelines/fulltext/88/index.html Accessed 23.09.14. RATIONALE: Diagnosis in women: expert consensus is that it is reasonable to start empirical antibiotics in women with symptoms of UTI without urine dipstick or urine culture. Diagnosis in men: a urine sample is recommended because UTI in men is generally regarded as complicated (it results from an anatomic or functional abnormality) and there are no studies on the predictive values of dipstick testing in men. Duration of treatment for men: there is no evidence to guide duration of treatment; expert consensus is that 7 days of antibiotics should be used because men are likely to have a complicating factor. Second line treatment: resistance is increasing to all antibiotics used to treat UTI, if possible antibiotic choice should be based on microbiology results.

2
Lutters M, Vogt-Ferrier NB. Antibiotic duration for treating uncomplicated, symptomatic lower urinary tract infections in elderly women. Cochrane Database of Systematic Reviews. 2002(3):CD001535.
RATIONALE: In this Cochrane Review Lutters and Vogt-Ferrier examined 4 studies comparing 3 days to 7 days treatment of ciprofloxacin or norfloxacin and 1 study comparing 3 days to 5 days treatment of trimethoprim in uncomplicated UTI in elderly women (age 60 or more). There was no significant difference in persistent UTI, clinical failure or re-infection rates but side-effects were higher in those given 7 days treatment.

3
American College of Obstetricians and Gynecologists. ACOG Practice Bulletin no. 91: Treatment of urinary tract infections in non-pregnant women. Obstetrics and Gynecology 2008;111(3):785-794.
RATIONALE: Diagnosis in women: expert consensus is that it is reasonable to start empirical antibiotics in women with symptoms of UTI without urine culture.
4
Little P, Turner S, Rumsby K., Warner G, Moore M, Lowes JA, Smith H, Hawke C, Turner D, Leydon GM, Arscott A, Mullee M. Dipsticks and diagnostic algorithms in urinary tract infection: development and validation, randomised trial, economic analysis, observational cohort and qualitative study. Health Technology Assessment 2009;13(19):1-96. RATIONALE: In women with uncomplicated UTI, the negative predictive value when nitrite, leucocytes, and blood are ALL negative was 76%. The positive predictive value for having nitrite and EITHER blood or leucocytes was 92%.

5
Grabe M, Bishop MC, Bjerkland-Johansen TE, Botto H, Cek M, Lobel B, Naber KG, Palou, J, Tenke, P, Wagenlehner F. Guidelines on Urological Infections. European Association of Urology 2009: 1-110. RATIONALE: Diagnosis in men: a urine sample is recommended because UTI in men is generally regarded as complicated (it results from an anatomic or functional abnormality) and there are no studies on the predictive values of dipstick testing in men. Duration of treatment for men: there is no evidence to guide duration of treatment; expert consensus is that 7 days of antibiotics should be used because men are likely to have a complicating factor.

6
Although use of dipstick testing has not been well studied in men, it seems reasonable to extrapolate results from studies of dipstick testing in women with suspected UTI to men with only mild symptoms of UTI as contamination is likely to be lower.

7
Gossius G and Vorland L. The treatment of acute dysuria-frequency syndrome in adult women: Double-blind, randomised comparison of three-day vs ten-day trimethoprim therapy. Current Therapeutic Research, Clinical & Experimental 1985;37:34-42. RATIONALE: Two-weeks after completion of treatment, 94% of women using a 3-day course of trimethoprim achieved bacteriological cure compared with 97% of those using a 10-day course of trimethoprim (n =135).

8
Christiaens TCM, De Meyere M, Verschcragen G, Peersman W, Heytens S, De Maeseneer JM. Randomised controlled trial of nitrofurantoin versus placebo in the treatment of uncomplicated urinary tract infection in adult women. Brit J Gen Pract 2002;52:729-34.RATIONALE: This small (n = 78) double-blind RCT found that nitrofurantoin 100mg qds for 3 days was more effective than placebo (NNT = 4.4, 95% CI 2.3 to 79).

9
Public Health England and the British Infection Association recommends nitrofurantoin as first-line empirical treatment and trimethoprim as an alternative if GFR is under 45 mL/min for uncomplicated UTI in women and men because they are narrow-spectrum antibiotics that cover the most prevalent pathogens. Broad spectrum antibiotics (e.g. co-amoxiclav, pivmecillinam, quinolones and cephalosporins) should be avoided when narrow spectrum antibiotics remain effective, as they increase risk of Clostridium difficile, MRSA and resistant UTIs.
The choice of trimethoprim or nitrofurantoin as first line varies by locality and is dependent on resistance rates to the two agents.
Resistance to nitrofurantoin is generally lower however nitrofurantoin should not routinely be used if upper UTI suspected or in patients with eGFR less than 45mL/minute/1.73m2. Several guidelines recommend that nitrofurantoin should not be used to treat UTI in men. This is on the grounds that it can be difficult to exclude the possibility of prostatitis, and that nitrofurantoin is not present in therapeutic concentrations in prostatic secretions. However, these recommendations refer to UTI with fever or other signs of acute prostatitis, and neither guideline expressed concern that acute prostatitis would be likely in men with symptoms of lower UTI and without fever and other symptoms of prostatitis.

10
MeReC Bulletin. Modified-release preparations. 2000; 11(4). RATIONALE: Modified-release preparations can be used to reduce dosing frequency. Reduced dosing frequency (e.g. from four times a day to twice a day) improves compliance.

11
Spencer RC, Moseley DJ, Greensmith MJ. Nitrofurantoin modified release versus trimethoprim or co-trimoxazole in the treatment of uncomplicated urinary tract infection in general practice. J Antimicrob Chemother 1994;33(Suppl A):121-9. RATIONALE: This non-blinded RCT (n = 538) found that nitrofurantoin MR had equivalent clinical cure rates to co-trimoxazole, and trimethoprim. The rate of gastrointestinal adverse effects was similar between groups (7-8%). This study used 7 days of treatment with each antibiotic; no shorter durations were trialled.
12
Falagas, M.E., Kotsantis, I.K., Vouloumanou, E.K. and Rafailidis, P.I. Antibiotics versus placebo in the treatment of women with uncomplicated cystitis: a meta-analysis of randomized controlled trials. Journal of Infection 2009;58(2):91-102. RATIONALE: Clinical cure for antibiotics compared with placebo: OR 4.67 (95% CI 2.34 to 9.35; four RCTs, n = 1062).

13
Milo G, Katchman EA, Paul M, Christiaens T, Baerheim A, Leibovici L. Duration of antibacterial treatment for uncomplicated urinary tract infection in women. Cochrane Database Review. The Cochrane Library 2006, Issue 2. http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD004682/pdf_fs.html Accessed 23.09.14. RATIONALE: No difference in outcome between 3 day, 5 day or 10 day antibiotic treatment course for uncomplicated UTI in women (RR 1.06; 95% CI 0.88 to 1.28; 32 trials, n = 9605).

14
Newell A, Bunting P, Anson K, Fox E. Multicentre audit of the treatment of uncomplicated urinary tract infection in South Thames. International Journal of STD & AIDS 2005;16:74-77.RATIONALE: This audit of urine samples taken at presentation found that 43.3% of isolates were resistant to amoxicillin, 22.6% were resistant to trimethoprim, and 10.3% were resistant to nitrofurantoin

15
DTB. Risks of extended-spectrum beta-lactamases. Drug and Therapeutics Bulletin 2008;46(3):21-24. RATIONALE: Extended spectrum beta-lactamases (ESBLs) are able to hydrolyse antibiotics that were designed to resist the action of older beta-lactamases. These organisms may be resistant to most antibiotics commonly used to treat UTI, such as trimethoprim, ciprofloxacin, co-amoxiclav, and all cephalosporins. Many ESBL-producing E. coli are sensitive to nitrofurantoin.

16
Naber KG, Schito G, Botto H, Palou J, Mazzei T. Surveillance study in Europe and Brazil on clinical aspects and Antimicrobial Resistance epidemiology in Females with Cystitis (ARESC): implications for empiric therapy. European Urology 2008;54:1164-1175. RATIONALE: In all countries, susceptibility rate to E. coli above 90% (p < 0.0001) was found only for fosfomycin, mecillinam, and nitrofurantoin.

17
Falagas ME, Kastoris AC, Kapaskelis AM, Karageorgopoulos DE. Fosfomycin for the treatment of multidrug-resistant, including extended-spectrum beta-lactamase producing, Enterobacteriaceae infections: a systematic review. Lancet Infect Dis 2010;10:43-50. RATIONALE: Ninety seven per cent of ESBL-producing E. coli isolates and 81% of Klebsiella pneumonia ESBL-producing isolates were susceptible to fosfomycin. Fosfomycin is now available commercially as a intravenous licensed product in the UK.
Nutritional interactions: Food intake can slow down the absorption of fosfomycin with, as a result, lower concentrations in the urine. Fosfomycin should, therefore, be administered while fasting or 2 or 3 hours before meals.

18
Martindale 30th (The Extra Pharmacopeia) and 36th Editions (The Complete Drug Reference). RATIONALE: Concentrations of fosfomycin are maintained in the urine for 2 days. A single dose is therefore sufficient in uncomplicated UTI in women. A second dose is required at 3 days in men to maintain inhibitory concentrations to ESBLs in the urine for the 6-7 days recommended for treatment of UTI in men.

19
Ben-Ami R, Rodriguez-Bano J, Arslan H, Pitout JD, Quentin C, Calbo ES, Azap OK, Arpin C, Pascual A, Livermore DM, Carau J, Carmeli Y. A multinational survey of risk factors for infection with extended-spectrum beta-lactamase-producing enterobacteriaceae in nonhospitalized patients. Clin Infect Dis. 2009 Sep 1;49(5);682-90.

20
Scottish Antimicrobial Prescribing Group, SAPG 2014. Alternative management of lower urinary tract infection in non-pregnant women. http://www.scottishmedicines.org.uk/files/sapg/Alternative_management_of_lower_UTI_in_non-pregnant_women.pdf Accessed 23.09.14. RATIONALE: This evidence based guidance has reviewed, and now recommends that clinicians consider the use of delayed / back-up antibiotics for the management of women with less severe or limited urinary symptoms. The guidance is based on two randomised controlled trials in English and Dutch general practice. 51 of 137 (37%) of Dutch women were willing to delay their antibiotics, 55% (28/51) did not use the antibiotics and 71% of these patients (20/28) reported clinical cure.

21
Thomas K, Weinbren MJ, Warner M, Woodford N, Livermore D. Activity of mecillinam against ESBL producers in vitro. J Antimicrob Chemother. 2006 Feb;57(2):367-8. RATIONALE: This laboratory work indicates that mecillinam is active against the majority of enterobacteriaceae causing UTI, including many ESBL: producing organisms.

22
Damsgaard T, Jacobsen J, Korner B, Tybring L. Pivmecillinam and trimethoprim/sulfamethoxazole in the treatment of bacteriuria. A bacteriological and pharmacokinetic study. J Antimicrob Chemother 1979 May; 5(3): 267-74. RATIONALE: In this study pivmecillinam was used for lower urinary tract infection, where it had similar short term symptomatic efficacy to co-trimoxazole.

23
Titelman E, Iversen A, Kalin M, Giske CG. Efficacy of pivmecillinam for treatment of lower urinary tract infection caused by extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae. Microb Drug Resist. 2012 Apr;18(2):189-92.

24
Oplinger M, Andrews CO. Nitrofurantoin Contraindication in Patients with a Creatinine Clearance Below 60 mL/min: Looking for the Evidence. Ann Pharmacother 2013;47:106-11.Published Online, 22 Jan 2013, theannals.com, doi: 10.1345/aph.1R352 MHRA – advice August 2014.

25
Bains A, Buna D, Hoag NA (2009). "A retrospective review assessing the efficacy and safety of nitrofurantoin in renal impairment". Canadian Pharmacists Journal 142(5): 248–252. doi:10.3821/1913-701X-142.5.248. RATIONALE: These recent reviews of the literature, Oplinger considered patients with reduced renal function, and suggested that nitrofurantoin could be used down to a eGFR of 40mL.min.The MHRA has reviewed this literature and 2014 recommendations from the MHRA will advise that nitrofurantoin may be used down to a GFR of 45mL/min, and can be used for short courses when the GFR is 30 to 45 mL/min in cases where benefits outweigh the risks because resistance testing indicates there is no other practical antibiotic alternative.

26
Livermore DM, Mushtaq S, Nguyen T, Warner M.Strategies to overcome extended-spectrum β-lactamases (ESBLs) and AmpC β-lactamases in shigellae. Int J Antimicrob Agents. 2011; 37:405-9. doi: 10.1016/j.ijantimicag.2010.11.028. Epub 2011 Jan 26. RATIONALE: Mecillinam is a ß-lactam antibiotic that resists hydrolysis by many common ß lactamases. However, innate resistance occurs in proteus and some other enterobacteriaceae including some ESBL producing organisms. Co-amoxiclav can be added to prevent hydrolysis by those ESBLs that can attack the molecule. Pivmecillinam is the oral preparation of mecillinam.

27
Baines SD, O’Connor R, Huscroft G et al. Mecillinam: a low-risk antimicrobial agent for induction of Clostridium difficile infection in an in vitro human gut model. J Antimicrob Chemother 2009; 63: 838–9. RATIONALE: Pivmecillinam is the oral preparation of mecillinam. Pivmecillinam is a prodrug that is very well absorbed intestinally and as such has minimal effect on the normal intestinal microflora thus there is a lower rate of Clostridium difficile.

28
Dewar S, Lee C. Reed LC, Koerner RJ. Emerging clinical role of pivmecillinam in the treatment of urinary tract infection in the context of multidrug-resistant bacteria. J Antimicrob Chemother 2013 doi:10.1093/jac/dkt368. RATIONALE: Pivmecillinam is an oral drug with minimal effect on the normal intestinal or vaginal microflora and is associated with a lower rate of Clostridium difficile infection and vaginal candidiasis.

The POCAST project is funded by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at Imperial College London and by the Imperial College Healthcare Charity (Grant Ref No:7006/P36U).