Recommended antibiotics for uncomplicated UTI in women

Drug review UTI Recommended antibiotics for uncomplicated UTI in women SPL Sarah Thompson BSc, MB ChB and Robert Townsend MSc, MRCPath, DTM&H Short courses of oral antibiotics in uncomplicated UTI remain highly effective, improve adherence, reduce costs and cause fewer adverse reactions. Our Drug review describes the properties and side-effects of the recommended antibiotics, followed by sources of further information. E very year, around 5 per cent of women present to their GP with symptoms of dysuria and frequency, and approximately half of this number have confirmed urinary tract infection (UTI) upon laboratory investigation. This makes UTI one of the most common reasons for both presentation to primary care (especially in otherwise well women) and for antibiotic prescription.1 Acute uncomplicated UTI is defined as an infection of the lower urinary tract in a person with a structurally and functionally normal urinary tract. In contrast, a UTI can be considered complicated if there are functional or anatomical abnormalities within the urinary tract or underlying diseases that predispose to UTI, eg diabetes mellitus.2 Acute uncomplicated UTI is predominantly obser ved in women, and recurrent cystitis is seen mostly in young, healthy women with normal urinary www.prescriber.co.uk tracts (though the shorter female urethra is a predisposing factor to UTI). Complicated UTI may occur in anyone with predisposing illness or underlying abnormalities and treatment options may be more problematic, having to take into account the underlying condition. We will therefore restrict our discussion to the management of uncomplicated UTI. Bacterial spectrum The majority of UTIs are caused by Escherichia coli (over 70 per cent generally), with approximately 10-15 per cent caused by other enterobacteriaceae (such as Proteus spp. and Klebsiella spp.) and faecal streptococci (Enterococcus spp.). Faecal flora account for most of the uropathogens encountered, probably utilising a mechanism of initial Prescriber 5 June 2012 21

colonisation of the perineum followed by passage up the female urethra (a process often aided by sexual intercourse). The skin commensal Staphylococcus saprophyticus accounts for around 5-10 per cent of UTI cases in young women. Treatment options There is evidence that untreated, uncomplicated cystitis in nonpregnant women appears not to be associated with any long-term sequelae, ie impaired renal function or increased mortality, and that untreated recurrent cystitis rarely progresses to an upper UTI. 3 The treatment of uncomplicated UTI is therefore aimed at the morbidity associated with potentially distressing (and disrupting) symptoms. A substantial proportion of women will spontaneously recover without any effective antimicrobial treatment. 4 Empirical therapeutic decisions should be guided by local knowledge of resistance patterns of the likely uropathogens. The trend away from sending urine samples for culture and sensitivity in uncomplicated UTI means that these data may be lacking or incomplete. So, for example, if only urine from treatment failures is examined, then a skewed population of more resistant organisms may be seen (the more sensitive organisms would be less likely to fail treatment). One approach is to send urine for culture and at the same time prescribe a first-line urinary antibiotic: this not only provides good sensitivity data on which to base future resistance trends, but also a prepared result if the patient fails treatment. Short courses of antibiotic appear to be highly effective in the treatment of uncomplicated UTI and are desirable as they improve adherence, cost less and are associated with fewer adverse reactions. 5 A study of 75 clinical trials by the Infectious Diseases Society of America produced guidelines that were later reviewed by the American Urological Association and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID)6 In summary, they concluded: Antibiotic Contraindications Common side-effects Rare but serious side-effects Trimethoprim trimethoprim hypersensitivity, nausea, vomiting, hypersensitivity, severe skin rash, blood dyscrasias, severe renal pruritus, rash blood dyscrasias impairment, porphyria Nitrofurantoin nitrofurantoin hypersensitivity, anorexia, nausea hypersensitivity, acute and chronic renal impairment, G6PD pulmonary reactions, hepatitis, deficiency, <3 months of age, peripheral neuropathy, severe skin porphyria rashes, pancreatitis, blood dyscrasias, neurological disturbance Amoxicillin and penicillin hypersensitivity, nausea, vomiting, hypersensitivity, severe skin rash, co-amoxiclav penicillin-associated hepatic diarrhoea, rash pseudomembranous colitis, dysfunction hepatitis, blood dyscrasias Cephalosporins cephalosporin hypersensitivity, nausea, vomiting, hypersensitivity, severe skin rash, porphyria diarrhoea, rash pseudomembranous colitis, blood dyscrasias Quinolones quinolone hypersensitivity, nausea, diarrhoea, neurological disturbance children, pregnant or vomiting, abdominal (including hallucinations and lactating women pain, headache, rest- psychosis), hypersensitivity, photolessness, rash, pruritus sensitivity, tendon inflammation and damage, hepatic necrosis, severe skin rash, blood dyscrasias Fosfomycin fosfomycin hypersensitivity diarrhoea, nausea hypersensitivity Table 1. Contraindications and common and rare side-effects of antibiotics prescribed in UTIs 22 Prescriber 5 June 2012 www.prescriber.co.uk

Antibiotic Trimethoprim Nitrofurantoin Amoxicillin and co-amoxiclav Quinolones Cefalexin Interactions warfarin, phenytoin, digoxin, antimalarials, ciclosporin, cytotoxics antacids warfarin, oral contraceptives NSAIDs, antacids, warfarin, phenytoin, ciclosporin, iron, theophylline warfarin, oral contraceptives UTIs untreatable with currently available oral antibiotics are encountered with increasing frequency across the UK. Such infections clearly cause significant management difficulties and intravenous antibiotics may be necessary. IV antibiotics may be administered as an inpatient or through an outpatient parenteral antibiotic therapy service (OPAT), if available locally. OPAT services deliver antibiotics during a brief, daily hospital visit or in the patient s home. While offering clear patient and economic benefits over an inpatient stay, OPAT ser vices are nonetheless costly in comparison to a short course of oral antibiotics. The increasing problems with resistant organisms highlights the importance of vigilance regarding antimicrobial prescribing, and also of knowing your local resistance patterns. Fosfomycin limited data Table 2. Drug interactions with antibiotics used to treat UTIs trimethoprim, co-trimoxazole and quinolones given for three days was as effective as treatment for a longer duration single-dose regimens appear to be less effective than the same antibiotic given for longer and should not be recommended longer duration of treatment usually causes higher rates of adverse events although co-trimoxazole was the most commonly studied drug, it was found that trimethoprim alone was equivalent to co-trimoxazole in eradication and, given the side-effect profile of sulphonamides, trimethoprim alone may be considered the preferred drug fluoroquinolones showed a similar three-day efficacy to co-trimoxazole/ trimethoprim; however, given the greater expense and possibility of higher incidence of adverse events, they are not recommended as first-line agents for empirical therapy. 2 Resistance There is a trend towards increasing rates of resistance in uropathogens. Extended-spectrum beta-lactamase (ESBL)-producing Gram-negatives are a particular problem, usually conferring resistance to all penicillins and cephalosporins. In the community setting, prior antibiotic exposure is the single largest risk factor for acquisition of an ESBL-producing organism. Such resistance can be spread between different Gram-negative bacteria on a mobile section of RNA (a plasmid). Plasmids can also carry mutations giving rise to resistance to other classes of antibiotics, eg fluoroquinolones. Supportive treatments General measures shown to be of benefit include increased fluid intake (to increase urinary output) and an analgesic (to control pain and/or fever). Oral agents that alkalinise the urine may also be of benefit and may help to alleviate symptoms. Antibiotics Antibiotics commonly used in uncomplicated UTI include trimethoprim, nitrofurantoin, beta-lactam antibiotics and quinolones. Fosfomycin is an unlicensed agent increasingly used against otherwise resistant isolates. Their contraindications and side-effects are shown in Table 1, and their drug interactions in Table 2. Trimethoprim Trimethoprim is a dihydrofolate reductase inhibitor first introduced to augment the activity of sulphon - amides by sequential inhibition of folic acid synthesis, and is the commonest first-line therapy. Sensitivity of enterobacteriaceae to this antibiotic varies according to location and whether primary- or secondary-care populations are examined. Trimethoprim has no activity against Pseudomonas aeruginosa and variable activity against enterococci. Enterococci will often test sensitive to trimethoprim in vitro, but this does not always correlate with an in vivo clinical response. This observation reflects the ability of enterococci to use exogenous folates, reversing the effect of the trimethoprim. Clinically, the most important method of resistance is by the use of plasmidmediated dihydrofolate reductases that are resistant to the effects of this antibiotic. Antibiotic resistance to trimethoprim is increasing among uropathogens, with one recent study showing 24 Prescriber 5 June 2012 www.prescriber.co.uk

that approximately 39 per cent of isolates of E. coli are now resistant. 7 Trimethoprim is absorbed readily from the GI tract and reaches peak serum levels one to four hours after ingestion. About 60-80 per cent of the dose is excreted in the urine, achieving an excess of the minimum inhibitory concentration (MIC) for most of the urinary pathogens. Trimethoprim monotherapy at a dose of 100-200mg twice daily is effective first-line therapy for uncomplicated UTI in women. Trimethoprim s antifolate mode of action has led to concerns about its use in pregnancy, particularly during the first trimester. However, the evidence of teratogenicity is not strong, and any risk will be small in a woman taking a folic acid supplement. In such women, trimethoprim may be considered if there are no preferable alternatives available (see Table 1). Figure 1. Dipstick urinalysis showing positive for leukocytes and nitrites is suggestive of infection; a short (three-day) course of empirical treatment is recommended in uncomplicated UTI SPL Nitrofurantoin Another commonly used first-line agent, nitrofurantoin has a poorly understood mode of action but appears to require intracellular reduction via nitrofuran reductase. The active components are capable of blocking inducible enzymes and also damaging bacterial DNA. Susceptible organisms vary somewhat, with E. coli, Citrobacter spp., enterococci and Staph. saprophyticus being generally sensitive, but members of the Proteus, Providencia, Morganella and Pseudomonas groups being resistant. GI absorption is enhanced when the drug is taken with food. Although serum concentrations are low with a serum half-life estimated at only about 30 minutes, the drug concentration in the urine is substantial and easily able to exceed the MIC of susceptible organisms. Alkalinising agents adversely affect the activity of nitrofurantoin and concurrent use should be avoided. Nitrofurantoin is very poorly distributed to tissues, but well concentrated into the urine. It is therefore for use exclusively in infections of the lower urinary tract. Careful consideration is required in renal insufficiency since such patients may not achieve therapeutic urinary levels of nitrofurantoin. Guidance is variable regarding the degree of renal compromise necessary to render nitrofurantoin ineffective. Patients with a glomerular filtration rate (GFR) <20ml per minute are unlikely to excrete sufficient antibiotic into their urine to be effective, and nitrofurantoin should not be used in these patients. 8 Nitrofurantoin may cause neonatal haemo - lysis and should therefore be used with caution in pregnancies at term. Beta-lactam antibiotics Beta-lactams are a large group of broad-spectrum antibiotics that target cell wall synthesis in a range of Gram-positive and Gram-negative organisms. They act by attaching to penicillin-binding proteins that, aside from binding to beta-lactam antibiotics, are responsible for the final cross-linking of the bacterial cell wall, thus conferring strength, rigidity and the ability to withstand osmotic pressures. This large group of antibiotics is comprised of penicillins, aminopenicillins, cephalosporins, monobactams and carbapenems. Although many beta-lactams are used in the treatment of UTI, we shall restrict ourselves to the oral agents commonly used in primary care for simple uncomplicated UTI. The principal ones are therefore amoxicillin, co-amoxiclav and cefalexin. As always, before commencing on a course of betalactam antibiotics, penicillin allergy should be enquired about and borne in mind. Amoxicillin Initially introduced as a development of penicillin that demonstrated a broader spectrum of activity both for Gram positives and negatives, its usefulness is, however, now limited by bacterial resistance. Amoxicillin is thus no longer recommended as empirical therapy for uncomplicated UTI given the level of beta-lactamase-mediated resistance, which is around 50 per cent. 7 It may be used as a second-line agent when the results of culture and sensitivities are known. Amoxicillin is safe to use in pregnancy but only when antibiotic sensitivities are known (as discussed above). It demonstrates good bioavailability from oral dosing and is excreted in the urine. Co-amoxiclav Co-amoxiclav is a combination drug comprising amoxicillin and clavulanic acid. Clavulanic acid is an inhibitor of a range of bacterial beta-lactamase enzymes and thus restores some of the lost spectrum of activity to amoxicillin. It is thus suitable for empirical therapy. Co-amoxiclav may cause clinical resolution of symptoms caused by ESBL-producing organisms, but www.prescriber.co.uk Prescriber 5 June 2012 27

should not be relied upon to treat systemic or complicated infection. This combination drug is often expressed as a ratio of amoxicillin:clavulanate and demonstrates absorption and bioavailability similar to that of amoxicillin. Co-amoxiclav can be used during pregnancy, and in lactating mothers. Cefalexin This is a first-generation cephalosporin anti - biotic that is stable to some of the beta-lactamase enzymes that have so limited the use of amoxicillin. ESBL-producing bacteria may limit the use of cefalexin in the future. Levels of resistance are currently under 10 per cent. 7 Caution must be exercised in patients with known penicillin allergy, especially since the reported crosshypersensitivity between penicillins and cephalo sporins is around the 10 per cent mark. Cefalexin is the most commonly used oral cephalosporin for the management of UTI, showing reasonable bioavailability and excretion into the urinary tract. Cephalosporins have no activity against the uropathogen Enterococcus and variable activity against Staph. saprophyticus, with sensitivity usually correlating with that of flucloxacillin. history and examination suggest a urinary tract infection positive result (presence of leukocytes and nitrites) 3-day course of empirical treatment dipstick urinalysis negative result reassure, consider alternative diagnosis, eg STIs, candidosis, pelvic pathology (treat and investigate as appropriate) failure of treatment or recurrence of symptoms send urine to laboratory for culture and sensitivity no resolution or recurrence of symptoms positive result negative result treatment course as per sensitivity report failure of treatment or recurrence of symptoms, if more than 3 episodes of recurrence, refer for investigation and consider prophylaxis consider alternative diagnosis, eg STIs, candidosis, pelvic pathology (treat and investigate as appropriate) Figure 2. Recommended management of women with an uncomplicated UTI; the management of a patient with a complicated UTI should routinely include an MSU sample see Resources, European Association of Urology guidelines 28 Prescriber 5 June 2012 www.prescriber.co.uk

Quinolones These are a large family of synthetic bactericidal agents that do not act on the cell wall as beta-lactams do, but instead at the level of the bacterial chromosome. They inhibit the activity of DNA gyrase and topoisomerase, enzymes essential for the correct packaging and managing of cellular DNA. These enzymes have no effect on their mammalian counterparts. Quinolones can be divided into generations like cephalosporins. The use of nalidixic acid, the firstgeneration quinolone, has largely been superseded by second-generation fluoroquinolones such as ciprofloxacin. This antibiotic class has good Gram-negative action but very limited Gram-positive action, especially against Gram-positive uropathogens. Quinolone antibiotics should be avoided in pregnancy and breastfeeding due to concerns regarding arthropathy in animal studies. Caution should also be exercised when considering quinolone use in patients with G6PD deficiency or epilepsy. Resistance of uropathogens in the community to ciprofloxacin is currently less than 10 per cent, 7 which is a good reason for this important antibiotic not to be a first-line choice. 9 Quinolone antibiotics are known to select for and encourage MRSA (meticillin-resistant Staph. aureus) colonisation and should be used cautiously in patients known (or suspected) to be MRSA positive. 10 Likewise, in numerous recent publications quinolone usage has also been implicated in Clostridium difficile infection, particularly with reference to the recently described O27 hypervirulent strain. 11 13 Quinolone antibiotics are not recommended for first-line management of uncomplicated UTI partly for the reasons already expressed: to attempt to limit resistance occurring to this potent group of antibiotics, because they are more expensive than some of the alternatives already mentioned, and because of some of the issues concerning MRSA and C. difficile. Fosfomycin Fosfomycin is a broad-spectrum, bactericidal, oral antibiotic currently unlicensed in the UK. It inhibits the first step of cell wall synthesis via inhibition of UDP- N-acetylglucosamine enolpyruvyl transferase, a novel mechanism of action. A compound discovered decades ago, fosfomycin is generating new interest due to activity against organisms otherwise untreatable with oral agents. Studies have demonstrated sensitivity to fosfomycin in 90 per cent of ESBL-producing Gram negatives. 14 Fosfomycin is generally administered as a single 3g megadose, resulting in adequate urinary concentrations for 48 hours. It is generally well tolerated. Adverse Key points uncomplicated UTI is a very common complaint and one of the most common reasons for GP referral one of the commonest reasons for the prescribing of antibiotics the majority (>70 per cent) are caused by E. coli, with coliforms, enterococci and staphylococci making up most of the remainder three days of a first-line empirical antibiotic is usually sufficient treatment ideally, urine samples should be sent for analysis to provide local epidemiology and antibiotic resistance data and to guide subsequent management should first-line treatment fail; this may, however, be impractical and expensive events primarily constitute mild and self-limiting gastro - intestinal symptoms. Taking MSUs While nearly all primary-care physicians would request an MSU be sent in more complex cases such as UTI in children, pregnancy and in diabetic men, it has been shown that in otherwise well women there can a wide variation in sample requesting. 15 The optimum management of uncomplicated UTIs should ideally include the taking of an MSU just prior to starting the course of antibiotics for several reasons: this would reassure the physician that the empirical choice was correct when the report is duly available it would provide accurate epidemiological and anti - biotic resistance data essential for guiding future strategy (rather than just sending in complex, relapse or recurrent cases) if the empirical therapy fails due to resistance, then a second antibiotic with known sensitivity can be selected without having to wait for an MSU to be sent in for someone who has now been symptomatic for at least three days. A urine sample is easily contaminated with perineal flora, and the interpretation of both the microscopy and culture result can be difficult in this scenario. It is important that patients are advised on the correct method for obtaining their urine for culture. Sending an MSU will also be useful if it demonstrates pyuria, ie white cells but no growth, in which case it may point to another pathology/diagnosis. However, in the majority of otherwise well women, the cost of routinely sending MSUs to the lab for culture and sensitivity may be the most expensive part of the treatment. A recent study demonstrated that sending an 30 Prescriber 5 June 2012 www.prescriber.co.uk

MSU in a patient with an uncomplicated UTI did not significantly improve symptom duration and outcome. 16 Separate study data suggest that 23 urine cultures would need to be performed to predict one infection in which resistance would cause clinical failure. 7 Requesting an MSU in all straightforward cases may therefore be impractical and expensive, in which case restricting sample sending for only complex cases, treatment failures and those at risk of resistant isolates (previous antibiotics, hospitalisation or known resistant organisms) may represent the most optimal use of resources, while acknowledging that this may skew local resistance data. Structured surveillance of local resistance patterns will provide essential data for drawing up local guidelines. For example, knowing the resistance to agents such as amoxicillin and cefalexin may change the firstand second-line agents. As such, microbiological input should be sought for drawing up and altering such guidelines, and will be essential in the forward monitoring of antibiotic resistance patterns. Resources Further reading Clinical Knowledge Summaries. www.cks.nhs.uk/ urinary_tract_infection_lower_women. Diagnosis of UTI. Quick reference guide for primary care. Health Protection Agency. 2011. www.hpa.org. uk/webc/hpawebfile/hpaweb_c/1194947404720. Guidelines on urological infections. European Association of Urology, 2012. www.uroweb.org/professionalresources/guidelines. Medical microbiology: a guide to microbial infections: pathogenesis, immunity, laboratory diagnosis and control. 17th ed. Greenwood D, et al. Edinburgh, New York: Churchill Livingstone/Elsevier, 2007. Conclusions Uncomplicated UTI in an otherwise well woman is a common problem for primary care and accounts for a considerable amount of morbidity, antibiotic prescribing, laboratory time and NHS cost. It has been demonstrated that, generally speaking, the majority of well women should need no more than three days antibiotic therapy with a first-line agent. Short courses, where possible, to minimise antibiotic exposure are essential if we are to maintain the effectiveness of the currently available antibiotic classes in an era of increasing resistance (including ESBL-producing E. coli and Klebsiella species) while still providing effective treatment. References 1. Hamilton-Miller JM. J Antimicrob Chemother 1994;33:63 73. 2. Naber KG. J Antimicrob Chemother 2000;46(S1):23 7. 3. Hooton TM, et al. Infect Dis Clin North Am 1997;11(3): 551 81. 4. Ferry SA, et al. Scand J Infect Dis 2004;36:296 301. 5. Naber KG. Current Opinion in Urology 1999;9:57 64. 6. Warren JW, et al. Clin Infect Dis 1999;29(4):745 58. 7. Bean DC. Ann Clin Microbiol Antimicrob 2008;7:13. 8. Gilbert D, et al. Clin J Am Soc Nephrol 2006;1:327 31. 9. Drug & Therapeutics Bulletin 1998;36(4). 10. Weber SG, et al. Emerg Infect Dis 2003;9(11):1415 22. 11. Kazakova SV, et al. Arch Intern Med 2006;166(22):2518 24. 12. Cookson B. Postgrad Med J 2007;83(979):291 5. 13. Delaney JA. Emerg Infect Dis 2007;13(5):761 3. 14. Falagas ME. Lancet Infectious Diseases 2010;10:43 50. 15. Hillier S, et al. J Antimicrob Chemother 2006;58:1303 6. 16. Little P, et al. BMJ 2010;340:c199 doi:10.1136/bmj.c199. 17. McNulty CA, et al. J Antimicrob Chemother 2006;58:1000 8. Declaration of interests None to declare. Dr Thompson is a microbiology registrar at Sheffield Teaching Hospitals and Dr Townsend is a consultant microbiologist at Sheffield Teaching Hospitals, an honorary clinical lecturer at the University of Sheffield and honorary clinical fellow at Sheffield Hallam University Mims medical microbiology. 5th ed. Goering R, et al. Saunders, 2012. SIGN guidance no. 88. Management of suspected bacterial urinary tract infection in adults. 2006. www.sign.ac.uk/ pdf/sign88.pdf. Websites EdRenINFO. Information provided by the Royal Infirmary of Edinburgh Renal Unit, including urinary tract infections. http://renux.dmed.ed.ac.uk/ EdREN/EdRenINFOhome.html. Information and support for people with any kind of cystitis: www.cobfoundation.org/. 32 Prescriber 5 June 2012 www.prescriber.co.uk