Are we choosing the correct antibiotic to treat male urinary tract infection in primary care? - A cross-sectional study

Kai-lim Chow 周啟廉， Pang-fai Chan 陳鵬飛， Loretta Kit-ping Lai 黎潔萍， David Vai-kiong Chao 周偉強

HK Pract 2015;37:51-57

Summary

Objectives:

Keywords: Urinary tract infection, Male, Primary care, Amoxicillin-Clavulanate, Nitrofurantoin

摘要

目的：

1. 敘述基層診所之急性下尿道病徵男性患者小便樣本含細菌的流行率。
2. 評估兩種被廣泛使用之抗生素：阿莫西林克拉維酸鉀片(Amoxicillin-Clavulanate)和呋喃妥因(Nitrofurantoin)的受藥性。

設計：橫切面比較性研究。

研究對象：於2013年，在本港九龍東聯網被挑選的三間公立基層診所內患急性下尿道病徵的男性病人。

主要測量內容：中段小便樣本含各樣細菌的流行率，及該等細菌對阿莫西林克拉維酸鉀片和呋喃妥因的受藥性。

結果：在基層醫療環境，小便中的細菌種類比在醫院的更多樣化，而大腸杆菌的流行率比在醫院中發現的則少許多。整體上，細菌對阿莫西林克拉維酸鉀片的受藥性比對呋喃妥因的顯著地高(p=0.033)。

結論：在醫院制訂的抗生素圖譜或許未能為基層醫療提供準確參考。在基層醫療，按經驗地以阿莫西林克拉維酸鉀片為患有尿道炎的男性病人治療，可能會有較高的細菌學上治癒機會。

關鍵字：尿道炎、男性、基層醫療、阿莫西林克拉維酸鉀片，呋喃妥因

Introduction

Antibiotic resistance

Urinary tract infection is one of the common clinical indications for an empirical antibiotic treatment (treatment based on clinical symptoms or signs unconfirmed by urine culture) in primary care. Treatment failure may be the result due to increasing antibiotic resistance, with local hospital data demonstrating 73%, 99% and 97% of Escherichia coli (E.coli), Klebsiella and Enterobactors specimens were resistant to Ampicillin respectively.¹ Indeed, resistance to all classes of antibiotics has developed among other common and important nosocomial pathogens.² Antibiotic resistance not only increases health costs but also adversely affects patient treatment outcome.^3-4 Therefore treating patients with the right antibiotic is essential in reducing antibiotic resistance rate.

Differences in disease epidemiology in different countries

Urinary tract infections are usually treated with empirical antibiotics according to the data on the prevalence of the organisms causing the infections and their antibiotics susceptibility pattern, which varies between different countries even in primary care settings.^5-8 This highlights the need for local prevalence and antibiotic susceptibility data for general practitioners who commonly treat urinary tract infections with empirical antibiotics in primary care.⁹ However, most existing local and overseas data were based on hospitalised patients, the majority of whom were female.^6,10

Gender difference in disease epidemiology

Urinary tract infection in male is much less common than that in female, and was considered as complicated urinary tract infection.^11-12 However studies found that overall lifetime prevalence of urinary tract infection amongst men was estimated to be 13,689/100,000 and was rising with increasing age.¹³ Apart from the difference in prevalence of organisms, studies found that E.coli susceptibility to Ampicillin and to Amoxicillin-Clavulanate was less in specimens from male than that in female.^14-16 Most management guidelines were developed from studies involving female patients.^17-20 Management on urinary tract infection in men was currently underrepresented in medical literature and called for novel strategies in managing male urinary tract infection due to increasing antibiotic resistance.^6,21,22

Problems in our locality

There is currently no unified local primary care guideline on empirical antibiotic usage for patients with urinary tract infection. Previous studies showed variations in clinical approaches among physicians.²³ Physicians in the primary care were also over-prescribing empirical antibiotics which increased the risk of antibiotic resistance.²⁴ Since rates of resistance have undergone considerable variations, data on organisms prevalence and antibiotics sensitivity for different gender are needed and being updated constantly in order to determine the most appropriate empirical treatment for urinary tract infection.²⁵

As there is a knowledge gap on the prevalence of the organisms in urine specimens and their antibiotic susceptibility in male patients in the primary care, this research aimed to describe the prevalence of organisms in urine specimens in male patients presented with lower urinary tract symptoms and to find out the common antibiotic susceptibility among different organisms. Hence we can obtain an updated local data as reference for choosing the best empirical antibiotic to treat male patients with urinary tract infection in primary care.

There is no agreement at this time on what empirical antibiotic to treat male patients with urinary tract infection in the primary care setting. According to different studies, recommended first-line therapy usually included Nitrofurantoin, Quinolone, Trimethoprim and Amoxicillin-Clavulanate.^8,26-29 The Health Protection Association and the Association of Medical Microbiologists recommended Trimethoprim and Nitrofurantoin as first-line empirical treatment for urinary tract infection in men because they are narrow-spectrum antibiotics that cover the most prevalent pathogens.³⁰ In Hong Kong, it was found that the resistant rates of E.coli from all kinds of hospital specimens to Quinolone (37%) and Trimethoprim (46%) were high.³¹ For this reason, it was recommended that Nitrofurantoin or Amoxicillin-Clavulanate were the preferred choice of regimen in Hong Kong and in some other countries, too.^1,32-33 However, there is no strong evidence on which one is better between Nitrofurantoin and Amoxicillin-Clavulanate in treating male patients with urinary tract infection and therefore this study will mainly focus on the susceptibility to Nitrofurantoin and to Amoxicillin-Clavulanate.

Method

Study design

This is a cross-sectional comparative study using secondary data analysis.

Subjects

In the period from 1 Jan 2013 to 31 Dec 2013, all male patients aged 18 years old or older attending three selected regional public primary care clinics with any one of the classic acute lower urinary tract symptoms (i.e. dysuria, frequency of urination, suprapubic pain, urgency and haematuria) were identified by International Classification of Primary Care (ICPC) code U71 and U07.³⁴ The three public primary care clinics were under the Hospital Authority of Hong Kong and were located in the Sai Kung district, serving a population of over 300,000. Patients with known urinary tract structural abnormalities, had urinary tract instrumentation within one week of onset of symptoms, received oral antibiotic within the previous one week, other upper urinary tract symptoms (i.e. loin pain, flank tenderness, fever, rigors and other manifestations of systemic inflammatory response) or urine culture showing more than one organism identified in the urine sample indicating contamination were excluded.

Laboratory test

All eligible patients had saved their mid-stream urine specimen in a proper way taught by the clinic nurses with instructions such as retracting the foreskin before micturition and collecting the midstream portion of urine into the given sterile specimen bottle. The specimens were then sent to the microbiology laboratory. Significant bacteriuria in male is defined as the presence of a single organism with 10³ or more colony forming units per 1 ml urine. ³⁴

Data collection

Patient data were collected from the computerised Clinical Management System, which is being used by all physicians working in Hong Kong’s public primary care clinics. Collected data included patients’ demographics, past medical history, symptoms on the day of consultation and the microbiology result of the urine cultures. Approval for this study was obtained from the Research Ethics Committee (Kowloon Central/ Kowloon East) of Hospital Authority.

Statistical method

Organism prevalence and antibiotic susceptibility pattern to Amoxicillin-Clavulanate and Nitrofurantoin were described. Comparisons on prevalence and susceptibility with the antibiogram in 2013 from a regional hospital of the same district were performed. ¹⁰ Pearson Chi-Square test and Fisher’s exact test were used to test the difference between categorical data. A p-value of < 0.05 was considered to be statistically significant. All data analysis was performed using the International Business Machines Corporation (IBM) Statistical Package for the Social Sciences (SPSS) Statistics version 21.0.0.0 for Windows.

Results

Study sample

During the study period, 90 male patients were identified. Eleven were excluded based on our criteria (1 had recent urinary tract instrumentation, 4 with antibiotic administration within the prior 1 week, 4 with upper urinary tract symptoms, 2 had more than one organisms identified in the urine sample) leaving 79 cases eligible for the study. The age of patients Prevalence of organisms ranged from 27 to 95 with a mean of 65 years. Table 1 describes the demographics, co-morbidity and clinical symptoms of these patients.

Prevalence of organisms

E.coli, Enterococcus, Proteus and klebsiella accounted for about 70% of the organisms found. E.coli was the most prevalent (32.9%) among our patients but was significantly less prevalent than that in the hospital setting (32.9% vs 58.8%, p < 0.001) (Table 2). On the other hand, Enterococcus species were less prevalent in the hospital setting when compared to primary care setting (16.5% in primary care vs 7.2% in hospital, p = 0.002).

Antibiotics susceptibility

Overall there was a significant difference in susceptibility to Amoxicillin-Clavulanate and to Nitrofurantoin (70.9% vs 54.4%, p = 0.033), which was not observed in the hospital setting (Table 3). No significant differences in susceptibilities were observed for E.coli and Enterococcus species within the primary care setting. However, similar to the hospital setting, Proteus isolates were mostly resistant to Nitrofurantoin.

E.coli isolates in primary care were significantly more susceptible to Amoxicillin-Clavulanate than hospital isolates (96.2% vs 75.0%, p = 0.013) (Table 4). Overall susceptibility to Nitrofurantoin in the primary clinics was 20% less than that in the hospital setting (54.4% vs 74.1%, p < 0.001).

Discussion

Our results demonstrated there was a lower prevalence of E.coli, but higher prevalence of other causative organisms including Enterococcus species in male urinary tract infection in the primary care setting compared with that in secondary care. This is comparable with previous community-based urinary tract infection studies which also demonstrated differences in antibiotic susceptibility between settings in primary and secondary care.^35-37 This confirms the need for an antibiogram that is unique for primary care setting, especially for male patients.

In our study, the overall susceptibility to Amoxicillin-Clavulanate was significantly higher than to Nitrofurantoin in the primary care setting, which was not observed in the hospital setting. This implies that if male patients with lower urinary tract infection are empirically treated with Amoxicillin-Clavulanate, more bacteriological cure can be achieved.

Clinical implication

From this study, it was demonstrated that treating male patients presenting with acute lower urinary tract symptoms in the primary care setting in Hong Kong with Amoxicillin-Clavulanate had a better bacteriological cure rate than Nitrofurantoin. Early treatment with the more susceptible empirical antibiotic can avoid “delayed” treatment which causes more distress symptoms and even complications. Nevertheless, urine culture should be saved preferably before starting antibiotic to identify those organisms resistant to Amoxicillin-Clavulanate.

Limitations

This study was limited by its subject selection, where only three out of 73 public primary care clinics in Hong Kong were involved. However all samples from patients within that district attending the public primary care clinics were used. Further studies involving more centres should be considered in order to produce more generalisable results. Hospital data for individual patient characteristics and isolates were not available, and comparison could only be made through the hospital antibiogram. Sensitivity tests were only routinely performed for the two studied antibiotics, therefore susceptibility patterns for other antibiotics were unavailable. Collaboration with hospital microbiology departments should be considered in the future so that a more comprehensive analysis can be performed.

Conclusion

1. Ho PL, Wong SY. Reducing bacterial resistance with (Interhospital Multi-disciplinary Programme on Antimicrobial Chemotherapy) IMPACT 4th edition. Hong Kong; 2012.20p.
2. Recommendations of the Hospital Infection Control Practices Advisory Committee (HICPAC).Recommendations for preventing the spread of vancomycin resistance. MMWR Recomm Rep 1995;22;44(RR-12):1-13.
3. Ho PL, Yuen KY, Yam WC et al. Changing patterns of susceptibilities of blood, urinary and respiratory pathogens in Hong Kong. J Hosp Infect 1995;31(4):305-317.
4. Butler CC, Hillier S, Roberts Z et al. Antibiotic-resistant infections in primary care are symptomatic for longer and increase workload: Outcomes for patients with E. coli UTIs. Br J Gen Pract 2006;56(530):686-692.
5. Tandogdu Z, Cek M, Wagenlehner F et al. Resistance patterns of nosocomial urinary tract infections in urology departments: 8-year results of the global prevalence of infections in urology study. World J Urol 2014;32(3):791-801.
6. Tryfinopoulou K, Polemis M, Avramidi T et al. Community-acquired urinary tract infections: Isolation frequency and antimicrobial resistance rates of the commonest pathogens. Acta Microbiologica Hellenica. 2014;59(1):39-46.
7. A R, Kalpana S. Prevalence and antimicrobial susceptibility pattern of Escherichia Coli causing urinary tract infection. Int J Pharma Bio Sci 2013;4:(4):927-936.
8. Den Heijer CDJ, Donker GA, Maes J et al. Optimal empirical therapy for male urinary tract infections in Dutch general practices. 22nd European Congress of Clinical Microbiology and Infectious Diseases London United Kingdom. 2012 Mar 31-Apr 3. Clin Microbiol Infect 2012;18:740.
9. Zalmanovici Trestioreanu A, Green H, Paul M et al. Antimicrobial agents for treating uncomplicated urinary tract infection in women. Cochrane Database Syst Rev 2010;Oct 6;(10).
10. Tseung Kwan O Hospital. Antibiogram of top 10 isolates for urine in all units. Hong Kong 2014.
11. Hooton TM. Uncomplicated urinary tract infection. N Engl J Med 2012 15;366(11):1028-1037.
12. Lipsky BA. Urinary tract infections in men. Epidemiology, pathophysiology, diagnosis, and treatment. Ann Intern Med 1989;110(2):138-150.
13. Griebling TL. Urologic diseases in America project: trends in resource use for urinary tract infections in men. J Urol 2005;173(4):1288-1294.
14. Ulleryd P, Zackrisson B, Aus G et al. Selective urological evaluation in men with febrile urinary tract infection. BJU Int 2001;88(1):15-20.
15. McGregor JC1, Elman MR, Bearden DT et al. Sex- and age-specific trends in antibiotic resistance patterns of Escherichia coli urinary isolates from outpatients. BMC Fam Pract 2013;14:25.
16. Weber P, Scotto M, Plaisance JJ et al. In vitro activities of amoxycillin and co-amoxyclav against general practice isolates of Escherichia coli. Med Mal Infect 1995;25(4):593-598.
17. Gossius G, Vorland L. The treatment of acute dysuria-frequency syndrome in adult women: Double-blind, randomized comparison of three-day vs ten-day trimethoprim therapy. Curr Ther Res Clin Exp 1985;37:34-42.
18. Christiaens TCM, De Meyere M, Verschcragen G et al. Randomised controlled trial of nitrofurantoin versus placebo in the treatment of uncomplicated urinary tract infection in adult women. Brit J Gen Pract 2002;52:729-734.
19. Naber KG, Schito G, Botto H et al. Surveillance study in Europe and Brazil on clinical aspects and Antimicrobial Resistance Epidemiology in Females with Cystitis (ARESC): implications for empiric therapy. Eur Urol 2008;54:1164-1175.
20. Gupta K1, Hooton TM, Naber KG 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. Clin Infect Dis 2011;1;52(5):e103-120.
21. Wagenlehner FM1, Weidner W, Pilatz A et al. Urinary tract infections and bacterial prostatitis in men. Curr Opin Infect Dis 2014;27(1):97-101.
22. Hummers-Pradier E1, Kochen MM. Urinary tract infections in adult general practice patients. Br J Gen Pract 2002;52(482):752-761.
23. Flach SD, Longenecker JC, Tape TG et al. The relationship between treatment objectives and practice patterns in the management of urinary tract infections. Med Decis Making 2003;23(2):131-139.
24. Canbaz S, Peksen Y, Sunter AT et al. Antibiotic prescribing and urinary tract infection. Int J Antimicrob Agents 2002;20(6)407-411.
25. Alós JI. Epidemiology and etiology of urinary tract infections in thecommunity. Antimicrobial susceptibility of the main pathogens and clinical significance of resistance. Enferm Infecc Microbiol Clin 2005;23Suppl4:3-8.
26. Lipsky BA. Prostatitis and urinary tract infection in men: what's new; what's true? Am J Med 1999;106(3):327-334.
27. Grabe M, Bartoletti R, Bjerklund-Johansen TE et al. Guidelines on urological infections. European Association of Urology 2014.
28. Drekonja DM, Rector TS, Cutting A et al. Urinary tract infection in male veterans: treatment patterns and outcomes. JAMA Intern Med 2013 14;173(1):62-68.
29. Hooton TM1, Scholes D, Gupta K et al. Amoxicillin-clavulanate vs ciprofloxacin for the treatment of uncomplicated cystitis in women: a randomized trial. JAMA 2005;23;293(8):949-955.
30. Health Protection Agency UK. Management of infection guidance for primary care for consultation & local adaptation. 2012.
31. Ho PL, Lo WU, Lai EL et al. Escherichia coli O25b-ST131 is an important cause of antimicrobial-resistant infections in women with uncomplicated cystitis. J Antimicrob Chemother 2012;67(10):2534-2535.
32. DTB. Risks of extended-spectrum beta-lactamases. Drug Ther Bull 2008;46(3):21-24.
33. Naber KG, Schito G, Botto H et al. Surveillance study in Europe and Brazil on clinical aspects and Antimicrobial Resistance epidemiology in Females with Cystitis (ARESC): implications for empiric therapy. Eur Urol 2008;54:1164-1175.
34. Scottish Intercollegiate Guidelines Network (SIGN). Management of suspected bacterial urinary tract infection in adults. Edinburgh: SIGN; 2012 July. SIGN publication no. 88.
35. Farrell DJ, Morrissey I, De Rubeis D et al. A UK multicentre study of the antimicrobial susceptibility of bacterial pathogens causing urinary tract infection. J Infect 2003;46(2):94-100.
36. Koeijers JJ, Verbon A, Kessels AG et al. Urinary tract infection in male general practice patients: uropathogens and antibiotic susceptibility. Urology. 2010;76(2):336-340.
37. Hummers-Pradier E, Ohse AM, Koch M et al. Urinary tract infection in men. Int J Clin Pharmacol Ther 2004;42(7):360-366.