Biography - Sean Egan is currently the Antimicrobial Pharmacist at Tallaght Hospital in Dublin and has been in this position for five years. In his role, he aims to drive quality improvement in antimicrobial usage. He first registered as a pharmacist in 2003, and has worked as a Clinical Pharmacist in the hospital setting in Ireland and the UK since registration. He graduated from the University of Nottingham School of Pharmacy. Egan also has an MSc from Trinity College Dublin and, has completed Green-Belt certification in Six Sigma process improvement methodology.

CPD 16: URINARY TRACT INFECTION

Urinary Tract Infection

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60 Second SummaryUrinary tract infections (UTIs) are among the most common infections encountered in primary care.

UTIs are more common in women, with the lifetime risk of UTI among women being reported as 60% [1-3].

UTIs are usually caused by transfer and invasion of patient bowel flora such as enterobacteriaceae (for example E.coli, Klebsiella pneumoniae or Proteus mirabilis) or enterococci (Enterococcus faecium or Enterococcus faecalis) translocating into the urinary system via the ascending transurethral route (most commonly), the bloodstream, the lymphatics or by direct extension. Typically E. coli is identified in 80-90% of positive urine samples processed in Irish microbiology laboratories.

Urinary tract infection may be classified as either uncomplicated, complicated or urosepsis. Risk factors for UTIs include pregnancy, poorly controlled diabetes mellitus, urological surgery, ureteral obstruction, increasing age and transient short-term catheterisation.

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DefinitionsUncomplicated UTIsUncomplicated UTIs include simple cystitis and acute pyelonephritis.

Cystitis is defined as inflammation of the urinary bladder and associated symptoms include frequency, dysuria, urgency, haematuria, suprapubic pain and change in the smell of the urine. This accounts for the vast majority of patients with UTI, and is usually treated successfully in the community setting.

Pyelonephritis is defined as bacterial infection of the kidney substance. Acute pyelonephritis is distinguished from simple cystitis by symptoms including fever, rigors, nausea, vomiting and flank pain. The symptoms of cystitis may or may not occur in patients with acute pyelonephritis. While these symptoms are characteristic, confusion and other non-specific signs and symptoms can make diagnosis difficult, particularly in elderly patients. The risk of mortality is increased in pyelonephritis, and some patients may require hospitalisation for treatment. Both of these types of infection should be distinguished from asymptomatic bacteriuria which is the presence of bacteria in urine without signs or symptoms of infection. This may be common in some cohorts of the population, including nursing home patients and does not typically require treatment (however pregnant women with asymptomatic bacteriuria should be treated with antibiotics as they are at much higher risk of complications).

Complicated UTIsComplicated UTIs are associated with a structural or functional urological abnormality, or immunosuppression, which alters the natural defence system and exposes the patient to an increased risk of infection. Patients with indwelling catheters, men, diabetics and pregnant women are also classified as complicated as their treatment requires an alternative and more cautious approach compared to uncomplicated cystitis. Typically, urine culture in patients with indwelling urinary

catheters will reveal the presence of a potential Gram-negative urinary pathogen. However, this commonly reflects catheter colonisation rather than infection, and positive microbiological identification should not generally be treated without other signs of infection. On the other hand, bacteriuria is commonly associated with both short-term and long-term catheterisation and the duration of catheterisation is an important risk factor for the development of catheter associated bacteriuria.

Urinary tract infection is less common in men, and may be associated with diabetes mellitus. UTI in men requires a longer duration of treatment as there is a higher risk of progression to pyelonephritis or associated prostatitis. Likewise, all diabetic patients are at higher risk of progression to urosepsis and need a longer treatment course.

Urosepsis is a systemic infection of the bloodstream with an associated inflammatory response to infection caused by UTI. This is more common with complicated UTIs and pyelonephritis, and is associated with a mortality rate of 13-30%. Early diagnosis and initial broad-spectrum antibiotic treatment of urosepsis is vital.

The treatment of complicated UTI, pyelonephritis and UTI in pregnancy and children is usually undertaken under specialist supervision or in the hospital setting. The remainder of this article with therefore largely focus upon the general principles of diagnosis and treatment of urinary tract infection, with a particular focus on the rationale for antibiotic agent choice in the treatment of uncomplicated UTI.

Risk Factors for a UTIPhysiologically, the urinary tract and kidney are designed to flush away any bacterial overgrowth which might cause infection. In principle, anything which increases the chance of urinary bacterial colonisation or reduces the urinary system's ability to void properly may increase the risk of infection. Moreover, factors

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CPD 16: URINARY TRACT INFECTION

which affect the body’s immune function will also increase infection risk. Risk factors for UTI include;

• Catheterisation

• Pregnancy

• Urinary tract procedures

• Diabetes mellitus

• Immunocompromised state

• Structural or functional urological abnormalities

• Sexual activity

DiagnosisDiagnosis of a urinary tract infection may be made by the presence of clinical signs of infection, and urinary microbiological testing. This may be challenging in some patient groups, such as elderly patients with dementia as a good clinical history may be difficult, and bacteriuria will be common. Urine dipstick testing in the medical centre can help to differentiate patients who have urinary tract infection from those without UTI, including those with asymptomatic bacteriuria. Testing for urinary nitrites and leukocytes can act as a useful negative screen, as inability to detect both together suggests a UTI is unlikely 95% of the time. However dipstick testing is unreliable in pregnancy, children under three years and patients with complicated UTIs – these patients need urine culture in the laboratory.

Laboratory DetectionLaboratory detection can take the form of direct microscopy or culture. Microscopy measures the amount of red and white blood cells in urine, which can indicate infection. In addition it may be possible to quantify the number of bacteria present. The presence of both blood cells and bacteria in urine is highly suggestive of infection.

More commonly, semi-quantitative culture of urine to identify bacteria is used to aid UTI diagnosis. This technique counts the number of colony forming units of bacteria per ml of urine. The bottom third of the urethra is likely to be colonised with bacteria in most patients, which is why a mid-stream urine sample should be used. There will, therefore likely be bacteria in any urine sample, but this may just correspond to urethral colonisation rather than UTI. Semi-quantitative culture aims to differentiate between colonisation and infection by using a cut-off point of 100,000 colony forming units per ml. Samples which yield the presence of below this concentration for one or more species of bacteria per urine sample may indicate bacterial colonisation. With the exception of catheter colonisation, a sample with more than 100,000 colony forming units per ml is indicative of infection. The infecting species is also identified at this point and, where a significant result is found antibiotic susceptibility testing is performed.

Urinary Pathogen Antibiotic Susceptibility in IrelandUTI is usually caused by bacterial translocation from the patients bowel and the potential infecting pathogen may range from enterobacteriacea to enterococci, staphylococci or candida. However, the vast majority of infections are caused by the enterobacteriaceae – Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis, and the enterococci -

Enterococcus faecium or Enterococcus faecalis. When devising empiric antibiotic guidelines, an awareness of changes in the resistance patterns of these key species is paramount.

Currently, national data on the resistance patterns to these pathogens in urinary samples is, unfortunately lacking, and we have to rely on data extrapolated from patterns derived from blood culture isolates. These are not directly applicable to UTI treatment in the community because they often reflect resistance patterns in sicker, largely hospitalised patients, who will be more likely to have received antibiotics and exhibit infection with more resistant organisms. Nevertheless, this data provides us with useful directly comparable data with which to benchmark trends both nationally and internationally. A number of important trends have emerged.

New trends in Enterobacteriaceae ResistanceFully sensitive enterobacteriaceae will usually be successfully treated with penicillins, cephalosporins, trimethoprim, co-trimoxazole, nitrofurantoin or the fluoroquinolones, such as ofloxacin or ciprofloxacin. Unfortunately, amoxicillin resistance levels have rendered this agent redundant for empiric therapy across Ireland. However the remaining agents still have a potential place in therapy.

Historically, enterobacteriaceae have overcome amoxicillin treatment through the evolution and spread of the beta-lactamase class of enzymes, which hydrolyse this drug. Mankind fought back with the discovery of beta-lactamase inhibitors, such as clavulanic acid, which prevented penicillin hydrolysis. Co-amoxiclav remains a useful option for the treatment of most UTIs. However, the enterobacteriaceae have continued to evolve new resistance mechanisms, such as cephalosporinases or extended-spectrum beta-lactamases (ESBLs), which allow them to overcome antibiotics, such as co-amoxiclav and cephalosporins. This has begun to manifest itself in Ireland over the past 5 years. An examination of resistance trends amongst E. coli bloodstream isolates nationally

over the past decade reveals in increase in the incidence of ESBL-producing organisms and, currently just over 1 in 20 isolates identified in blood-cultures in hospitalised patients produce ESBL and may be resistant to cephalosporins and co-amoxiclav [4]. This new form of resistance has also been accompanied by co-resistance to fluoroquinolones and trimethoprim in some bacterial strains, meaning that conventional agents may not be as universally efficacious as in previous decades.

Whilst data on resistance to bloodstream isolates provides us with a useful picture of underlying trends in our sicker patients, good practice in the formulation of an evidence based empiric policy needs to be informed by resistance patterns in urinary isolates. Unfortunately, national data on resistance patterns amongst urinary bacterial isolates is not available. However, a recent survey published by five hospital microbiology laboratories in the Cork and Kerry regions (Cork University Hospital, Mercy University Hospital, Kerry General Hospital, Bons Secours Hospital Cork and Bons Secours Hospital Tralee) provides a useful insight into more regional data [5].

Data on positive urine samples, which originated in general practice were compared on the same month each year from 2004-2010, and trends in infecting pathogen and resistance rates were analysed. Enterobacteriaceae accounted for 88% of positive samples and enterococci accounted for a further 5%. Antimicrobial resistance patterns were analysed for these two groups of organisms. Ampicillin was tested in place of amoxicillin and the sensitivity result for ampicillin may be regarded as comparable.

Table 1. (Below) Percent of Enterobacteriaceae and Enterococcus sp sensitive (%S) to 1st line antibiotics by month and year of sample (N=5152, not all samples were tested for all antibiotics)Similar analysis of laboratory testing of GP urine samples at Tallaght hospital demonstrates a comparable pattern of resistance [6]. National empiric guidelines for the treatment of infection

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Antibiotic Feb 04 Feb 05 Feb 06 Feb07 Feb 08 Feb 09 Feb 10 Total χ2 p-value

First line antibiotics

Trimethoprim %S 69.5% 72.0% 69.9% 69.5% 69.5% 72.5% 71.2% 70.6% 0.726

N 518 578 658 717 868 848 889 5076

Nitrofurantoin %S 92.8% 87.0% 88.4% 89.5% 89.3% 87.8% 91.1% 89.4% 0.319

N 97 123 155 687 853 838 888 3641

Ampicillin %S 50.1% 53.2% 47.6% 47.9% 48.1% 50.2% 50.3% 49.5% 0.408

N 525 588 660 728 877 838 890 5106

Second line antibiotics

Cephalexin %S 94.0% 93.3% 89.9% 92.5% 89.9% 92.9% - 91.9% 0.759

N 83 104 138 146 159 162 - 812

Cephradine %S 88.4% 89.6% 85.8% 85.1% 87.8% 86.5% 84.7% 86.6% 0.137

N 432 471 513 565 704 666 885 4236

Ciprofloxacin %S 95.7% 95.0% 93.8% 92.4% 88.2% 90.0% 85.2% 90.8% <0.05

N 510 575 645 706 861 842 881 5020

Co-amoxyclav %S 87.6% 87.8% 81.6% 82.9% 89.2% 82.1% 88.0% 85.2% <0.05

N 525 588 662 730 879 862 899 5145

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CPD 16: URINARY TRACT INFECTION

in general practice were produced by a working group of the Health Protection Surveillance Centre/Strategy for the Control of Antimicrobial Resistance in Ireland (SARI) in November 2011. These guidelines recommend that nitrofurantoin and trimethoprim be used empirically as first-line agents for the treatment of UTI. Data from the Cork/Kerry study reveal that sensitivity to these two agents remained high in 2010 at 89% for nitrofurantoin and 71% for trimethoprim.

Trimethoprim resistance has increased in the period since 2004. Traditionally, a cut-off point of 80% sensitivity has been used to guide the utility of an agent for empiric UTI efficacy in the hospital setting. In this study, trimethoprim fell below this cut-off point – however the authors point out that these results will be biased towards patients with persistent UTI post-antibiotics, as urine culture is usually only utilised in the minority of patients treated in primary care. Trimethoprim sensitivity rates are likely to be much higher in the general community population, and they suggested that empiric trimethoprim should continue to be used in their region as per national guidelines [7].

Figure 2. (Below) National Empiric Antibiotic Treatment Guidelines for UTI. [7]Low sensitivity rates to ampicillin support the view that amoxicillin should not be used empirically for UTIs.

These guidelines also include a separate section on the diagnosis and treatment of UTI in long-term care residents over the age of 65 years, and include recommendations for the treatment of patients with catheter associated UTIs.

Use of Broader-Spectrum Agents Empirically for Uncomplicated UTIIt is possible that individual pockets of trimethoprim resistance may exist in other regions of Ireland, and the existence of such data may preclude the application of national guidelines to local use. However it is unlikely that a similar co-resistance pattern to nitrofurantoin will also be found. Empiric therapy with one or both drugs should be possible in most patients who are not contra-indicated to nitrofurantoin or trimethoprim.

The oral cephalosporins cefalexin and cefradine remain useful second-line agents, but it should be noted that they do not have activity against enterococci. Co-amoxiclav and ciprofloxacin are much more broad-spectrum than agents discussed to date. Whilst both will likely be effective against most UTIs, usage also exposes patients to additional and arguably unnecessary ecological collateral damage. Co-amoxiclav, quinolones and cephalosporins have been implicated as agents which are more likely to encourage the emergence of antimicrobial resistance or Clostridium difficile-associated diarrhoea than trimethoprim or nitrofurantoin. They should therefore be considered as second-line agents on the basis of their risk-benefit profile in this setting.

Treatment Options for More Resistant Enterobacteriacea in Primary CareWhilst national empiric guidelines will work for the majority of patients, the treatment of infection caused by more resistant infecting pathogens may increasingly require the use of less conventional therapy. Enterobacteriaceae

which produce cephalosporinases or extended-spectrum beta-lactamases may not be treatable with cephalosporins or co-amoxiclav. Amongst the samples processed in the laboratory at Tallaght Hospital, activity appears to be retained to nitrofurantoin in the majority of patients, and this remains a useful therapeutic option. In a small number of patients, nitrofurantoin may be contraindicated or co-resistance to this drug may be present. In these circumstances, alternative oral agents are limited and clinicians are beginning to rediscover antibiotic choices which were formally used in Ireland but have fallen out of favour until recent times.

Fosfomycin tromethamine is a phosphonic acid antimicrobial agent which retains activity against a wide range ofenterobacteriaceae, including those that produce extended-spectrum beta-lactamases (ESBLs) [8]. This drug is unlicensed in Ireland and the UK but has been used extensively across Europe and North America for some time. A German brand of the product called Monuril is currently available from the specialist wholesaler Medisource, and this comes in a 3000mg (3g) sachet format. It is licensed in Germany for the treatment of acute uncomplicated UTI in women aged from 12 to 65 years. The drug is given as a 3g one off “mega-dose”, and patients should be advised to mix this in a glass of water before swallowing. They should also be advised that although this drug only requires a one-off dose, it may take a number of days for symptomatic relief to emerge as the drug is excreted via the urinary system over time. The side-effect profile of this drug is comparable to other antibiotics, with diarrhoea occurring in 2.4-9%

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CPD 16: URINARY TRACT INFECTION

of cases. Serious adverse events are rare and are isolated to limited case-reports. These include angioedema, aplastic anaemia, asthma exacerbations, cholestatic jaundice, hepatic necrosis and toxic megacolon.

Pivmecillinam hydrochloride may also be used as an agent to treat UTI in an era of increasing beta-lactam and cephalosporin resistance [9]. This drug is licensed in the UK and has been used in some centres to fill the clinical need for an oral agent used to treat multidrug-resistant enterobacteriaceae. There is less experience of using the drug against isolates which produce ESBLs, and some authors have suggested that it should be used in combination with co-amoxiclav as it displays synergy when given with clavulanic acid. Currently, pivmecillinam susceptibility testing is not widely available in Irish microbiology laboratories.

There is a significant clinical need for more oral agents which retain activity against enterobacteriaceae. In the absence of activity against drugs such as nitrofurantoin, fosfomycin or pivmecillinam, clinicians increasingly need to fall back on intravenous antibiotic options which require much greater healthcare utilisation and are far from ideal from a patient perspective. Without further drug discovery in this field, it is likely that the treatment of UTI may increasingly require intravenous therapy in some patients.

Usual Duration of Antibiotic TreatmentUncomplicated cystitis in women should respond to three days therapy of an antibiotic which retains activity to the infection organism, although some guidelines recommend up to 5 days of nitrofurantoin. UTI antibiotic treatment courses in diabetics, pregnant women and men are longer with seven to 14 days being required. Pyelonephritis may require 14 days therapy, although a seven day treatment course may be possible with ciprofloxacin.

Treatment Options for Patients who Present to the PharmacyWho Can Be Treated Symptomatically?Balakrishnan et al [10] recommend that for non-pregnant female patients with mild dysuria and no underlying risk factors, referral to the general practitioner for antibiotic therapy may not be necessary. In such patients, it is likely that antibiotic therapy will only shorten the duration of UTI symptoms by up to one day. In this cohort of patients ensuring adequate hydration should result in resolution of symptoms. Use of urine alkalinising agents may also be of benefit for these patients, however a robust evidence base to support their use is not present. Where use of these agents could be recommended, care should be taken to avoid use in conjunction with interacting agents such as ACE-inhibitors, potassium-sparing diuretics, or lithium. If symptoms persist or worsen following presentation to the Pharmacy, patients should be advised to consult with their GP. Patients with a history of persistent UTI may benefit from drinking cranberry juice, as it inhibits bacterial adhesion to the urinary tract epithelium and can prevent infection [10]. Heterogeneity between studies has meant that the optimal dose and duration of cranberry juice consumption is yet to be fully determined. Cranberry juice interacts with warfarin and should be avoided in patients taking this medicine.

Who Needs to be Automatically Referred to their GP?Balakrishnan et al recommend that all pregnant women, diabetics, men, children under 16 or patients with underlying heart or renal disease should be referred to their GP for treatment. They also recommend that patients with cloudy or smelly urine, haematuria, thirst and unexplained weight-loss should also be referred. This is not an extensive list for referral however, nor is it possible to outline every scenario where GP referral should occur. Careful clinical judgement on a case-by-case basis should also occur in the pharmacy, with consideration of the possibility of other differential diagnoses. In addition to the factors outlined by Balakrishnan et al, referral of patients to their GP if there is the possibility of progression to upper urinary tract infection should also occur. This would include the immunocompromised, any patient with flank pain, increased temperature, nausea and vomiting or flu like symptoms, patients with indwelling urinary catheters, those who have had recent urological procedures, or patients with underlying structural urological abnormalities. All patients with persistent urinary symptoms should also be referred.

Overall ConclusionsUrinary tract infection is one of the most common infection types encountered in primary care. Antibiotic choice has become more complicated in recent times with the evolution of greater Gram-negative resistance, and it is likely that unless new licensed oral treatment options come to market in Ireland, we will increasingly need to rely on older unlicensed agents or intravenous options. This has implications for patients, community pharmacists, GPs and secondary/tertiary healthcare providers.

The way we use antibiotics for the treatment of UTI in primary care also has important implications for preventing the emergence of resistance to these agents, especially those which have activity against Gram-negative pathogens. Good practice both in the diagnosis and prescription of antibiotics, with a special emphasis on ensuring optimal agent choice, dose and duration are vital in helping to preserve antibiotic utility into the future.

References1. Grabe M, Bjerklund-Johansen TE, Botto H, Wullt B, Cek M, Naber, K.G et al.. Guidelines on Urological Infections. The Netherlands: European Association of Urology, 2011. ISBN 978-90-79754-96-0.

2. Kumar, P. and Clark, M (Eds). 2008. Clinical Medicine. 6th Edition. London: Elsevier Saunders Limited

3. Kalpana, G., Hooten, T.M., Naber, K.G., Wullt, B., Colgan, R., Miller, L.G., Moran, G.J et al.. International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clinical Practice Guidelines, 2011;52: e103-e118.

4. The Health Protection Surveillance Centre/ Health Service Executive. EARS-Net Report Quarter 3 2011. Available at http://www.hpsc.ie/hpsc/A-Z/MicrobiologyAntimicrobialResistance/EuropeanAntimicrobialResistanceSurveillanceSystem EARSS/EARSSSurveillanceReports/2011Reports

5. A Brennan, A Sheahan, O Murphy, L Cronin, M Kelly, M Coughlan, B O’Reilly, L Barry, S O’Connell. Cork and Kerry study looks at antibiotic susceptibility in urine samples - Epi-Insight – Disease Surveillance Report of

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the HPSC Vol 13 Issue 2. Feb 2012. Available at http://ndsc.newsweaver.ie/epiinsight/1mn862vqdrs?a=1&p=20966705&t=17517774

6. Cullen IM, Manecksha RP, McCullagh E, Ahmad S, O’Kelly F, Flynn RJ, McDermott T et al. The changing pattern of antimicrobial resistance within 42,033 Eschericia coli isolates from nosocomial, community and urology patient-specific urinary tract infections, Dublin 1999-2009. BJU Int. 2011 Aug 24. doi: 10.1111/j.1464-410X.2011.10528.x. [Epub ahead of print]

7. Bradley CP, Carey B, Murphy M, O’Connor N, Cunney R, Byrne S Sheehan A, on Behalf of SARI/HSE. Guidelines for Antimicrobial Prescribing in Primary Care in Ireland, November 2011. Available at http://www.hpsc.ie/hpsc/A-Z/MicrobiologyAntimicrobialResistance/InfectionControlandHAI/Guidelines/#d.en.3334

8. Falagas ME, Kastoris AC, Kapaskelis AM, Karageorgeopolis DE. Fosfomycin for the treatment of multidrug resistant, including extended-spectrum beta-lactamase producing, Enterobacteriaceae infections: a systematic review. Lancet Infectious Diseases. 2010;10:43-50

9. Pallett, A. and Hand, K.. Complicated urinary tract infections: practical solutions for the treatment of multi-resistant Gram-negative bacteria. Journal of Antimicrobial Chemotherapy, 2010;65:iii25-iii33

10. Balakrishnan I, Hill V. Dealing with Urinary Tract Infections. The Pharmaceutical Journal. 2012 pages 687-690

11. Jepson RG, Craig JC. Cranberries for preventing urinary tract infections. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD001321. DOI: 10.1002/14651858.CD001321.pub4.