Originalia J. Cooper, A. Raeburn, W. Brumfitt, J. M. T. Hamilton-Miller
Single Dose and Conventional Treatment for Acute Bacterial and Non-Bacterial Dysuria and Frequency in General Practice Summary: A five day course of clavulanate-potentiated amoxicillin (Augmentin®) has been compared with a single oral dose of fosfomycin trometamol in the treatment of patients complaining of symptoms suggesting urinary tract infection. The study took place in a single urban general practice of 15,000 patients in Cheshire. The microbiology was performed at a London Teaching Hospital. 141 patients entered the trial. 65 had a significant bacteriuria, 62 of which were assessable for the ability of the trial drugs to eradicate bacteriuria: 29 patients received clavulanate-potentiated amoxicillin and 33 fosfomycin trometarnol. The cure rates, assessed at five to ten days and at four to six weeks post treatment, were 72% and 65%, respectively for clavulanate-potentiated amoxicillin and 85% and 81%, respectively for fosfomycin trometamol. Side effects, assessed in all 141 patients, oc-
cured in 11.6% receiving clavulanate-potentiated amoxicillin and in 8.3% receiving fosfomycin. Statistically there is no difference between any of these findings and the effect of sample size is discussed. 69 patients were symptomatic but did not have a significant bacteriuria ("urethral syndrome"). These patients were assessed for the effect of treatment in relieving symptoms: 33 received fosfomycin trometamol and 36 clavulanate-potentiated amoxicillin. The success and speed of relieving the symptoms were very similar in the two groups. The finding that both groups responded equally well appears to refute an aetiological role for lactobaciUi and diphtheroids in the "urethral syndrome", since these organisms are resistant to fosfomycin but sensitive to clavulanate-potentiated amoxiciUin.
Zusammenfassung: Behandlung der akuten bakteriellen und nicht bakteriellen Dysurie mit Harndrang in der Allgemeinpraxis - Vergleich einer Einmaldosis mit einer konventionellen Behandlung. Patienten, die Beschwerden einer Harnwegsinfektion hatten, wurden entweder ftinf Tage lang mit AmoxiciUin-Clavulansgure (Augmentan®) oder mit einer oralen Einzeldosis von Fosfomycin Trometamot behandelt. Die Studie wurde in einer Allgemeinpraxis in Cheshire durchgeftihrt, die 15 000 Patienten versorgt. 141 Patienten wurden in die Studie aufgenommen. 65 hatten eine signifikante Bakteriurie, davon konnten 62 in die Auswertung beztiglich Eradikation der Bakteriurie durch alas Prtifmedikament einbezogen werden; 29 Patienten erhielten Amoxicillin-Clavulans~iure und 33 Fosfomycin Trometamol. In der ersten Gmppe waren am 5.-10. Tag und vier bis sechs Wochen nach Therapieende 72% beziehungsweise 65% geheilt, die entsprechenden Zahlen ftir Fosfornycin Trometamol waxen 85% und 81%.
Bei 11,6% der insgesamt ausgewerteten 141 Patienten traten Nebenwirkungen unter Amoxicillin-Clavulans~iure und bei 8,3% unter Fosfomycin Trometamol auf. Ein statistischer Unterschied zwischen diesen Befunden besteht nicht, die Bedeutung der Probengrrl3e hierftir wird diskutiert. 69 Patienten klagten iJber Beschwerden, hatten jedoch keine signifikante Bakteriurie (urethrales Syndrom). Sie wurden im Hinblick auf eine Linderung ihrer Beschwerden durch Fosfomycin Trometamol (n= 33) oder Amoxicillin-Clavulans~iure (n=36) geprtift. In beiden Gruppen war der Einflug auf die Beschwerden nach Grad und Geschwindigkeit sehr ~ihnlich. Das vergleichbar gute Ansprechen der beiden Gruppen scheint gegen eine ~itiologische Bedeutung yon Laktobazillen und Diphtheroiden beim ,,urethralen Syndrom" zu sprechen, denn diese Bakterien sind gegen Fosfomycin Trometamol resistent, gegen Amoxicillin-Clavulans~iure hingegen empfindlich.
Introduction In general practice symptoms suggestive of urinary tract infection, such as dysuria and frequency (often refei-red to by patients as "cystitis"), commonly cause patients to visit their general practitioner. According to various estimates, visits from women who suffer from dysuria amount to 50 to 200 per 1000 per annum [1-3]. Many of the patients are women aged 18-50 years, and they are often treated with antibiotics for five to seven days. However, a trial with amoxicillin in uncomplicated urinary infections treated in general practice showed an equally good response to a three-day or a ten-day course of treatment [4].
More than 20 years ago a controlled trial [5] showed that single dose treatment with a long-acting sulphonmnide was as effective as ampicillin for seven days. Since then a number of antimicrobial agents including amoxicillin, co-trimoxazole or nitrofurantoin, given in single doses have been shown to result in clinical and bacteriological cure rates not Received: 3 July 1989/Revision accepted: 17 January 1990 J. Cooper, MB BCh., A. Raeburn, MB BCh., Eamswood Medical Centre, Crewe CW 2JR; Prof. W. Brumfitt, M.D., Prof. J. M. T. Hamilton-Miller, DSc., Department of Medical Microbiology, The Royal Free Hospital School of Medicine, Pond Street, London NW 3 2QG, UK.
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significantly different from those obtained using longer courses of treatment [6, 7]. However, such studies only apply to those patients suffering from initial or isolated attacks of acute bacterial cystitis. In spite of these findings most general practitioners do not use single dose therapy, and no single dose regimens are recommended by pharmaceutical companies in the United Kingdom [8]. We have compared a single dose of fosfomycin trometamot with a five-day course of treatment with clavulanate-potentiated amoxicillin in general practice. The careful documentation, follow-up and the high standard of bacteriology necessary was achieved by collaboration between a multipartner group practice and the urine research laboratory in the Department of Medical Microbiology at The Royal Free Hospital, Fosfomycin is a broad-spectrum antibiotic which is bactericidal, non-toxic, penetrates into leucocytes and because of its unique chemical structure shows no cross-resistance with other antibiotics. The trometamol (mono tris[hydroxymethyl] aminomethane) salt is a more recently developed water-soluble derivative which is well absorbed by mouth
[9, 10]. In this study we achieved three objectives. First, we compared the efficacy of the single dose treatment and conventional therapy in proven infections. Second, we assessed tolerance of the two regimens in all patients, whether or not they had significant bacteriuria. Third, we investigated the aetiology of tile "urethral syndrome", by observing the effect of antibiotic treatment on patients who were symptomatic but had no significant bacteriuria. Fosfomycin is not active against lactobacilli and diphtheroids, which have been suggested [11] to be causative agents of the "urethral syndrome", whereasclavulanate-potentiated amoxicillin is active against these organisms. Thus, a less favourable response would be expected in those patients given fosfomycin if this suggestion is correct.
Patients and Methods Patients: Every patient (of either sex) who attended his or her general practitioner's surgery complaining of dysttria and/or frequency was eligible for the study. Patients were excluded if they had suffered more than three infections in the previous 12 months, were below t6 years of age, were pregnant or lactating, or had a penicillin allergy. 141 eligible patients agreed to enter the study and 65 of these were found subsequently to have a significant bacteriuria (>_ 105 bacteria/ml). Clinical procedure : All 141 patients were documented and examined, the results being recorded on special forms, and a properly taken midstream urine (MSU) obtained. They were then allotted by means of a randomization chart to receive a single dose of fosfomycin trometamol or a five-day course of clavulanate-potentiated amoxicillin. Patients received sachets containing fosfomycin trometamol, equivalent to 3 g fosfomycin, in an orange flavoured tbrmulation (supplied by Zambon Pharmaceuticals, Bresso, Italy). The contents of one sachet were dissolved in water, and drunk in the presence of the practice nursing sister. Alternatively, t h e y w e r e given clavulanate-potentiated amoxicillin 8 / 66
375 mg (250 mg amoxicillin + 125 mg clavulanate), and asked to take one tablet 8 hourly for five days. All patients were requested to return to the medical centre five to ten days after the end of treatment, and again a month later. At follow-up a further MSU was taken and the patients questioned about symptoms or adverse effects. At the medical centre, MSUs were tested with N-Labstix, a dipslide (Uricult, Orion) was inoculated and 20 ml of urine put into a bottle containing 380 mg boric acid (supplied by Steritin, UK). The dipslides and borated urine were sent in a special container by first class mail to the Department of Medical Microbiology at The Royal Free Hospital. Laboratory procedures: On arrival the dipslide was incubated at 37 °C overnight and was read by comparison with the standard chart. Pathogens present in significant numbers were identified and tested for antibiotic sensitivity by Stokes' method on IsoSen-" sitest agar (Oxoid). Strains showing zones of inhibition around disks containing either 200 gg fosfomycin plus 50 gg glucose-6phosphate or 20 gg amoxicillin plus 10 gg clavulanic acid with diameters similar to that shown by a fully sensitive control strain (Escherichia coli NCTC 10418) were considered sensitive. The borated urine was examined by microscopy and counts of white cells and red cells were made. Results were reported by telephone and confirmed in writing.
Results Infected Patients - Comparison of Patient Groups A total of 62 patients had significant bacteriuria due to organisms sensitive to the allotted drugs and were assessed for efficacy of treatment. One patient in each group was infected with an organism resistant to the allocated antibiotic, and these were excluded from the analysis. 29 of the assessable patients were given clavulanate-potentiated amoxicillin (27 female, two male) and 33 fosfomycin trometamol (31 female, two male). The two groups were similar in terms of age, weight, previous history of dysuria and/or frequency (Table ] ), infecting organisms (Table 2) and results of urine microscopy (Table 3). The presenting symptoms were very similar in the two groups, the most common complaints being of frequency (89%), dysuria (83%) and urgency (59%). Table 1: Characteristics of patients with bacteriuria.
No. of patients Mean.age (range) No. (%) of females of child-bearing age Mean weight (range) No. (%) with previous history suggestiveof urinary infection No. (%) with an attack during previous 12 months
33 (31F, 2M) 45.4 y (17-78)
29 (27F, 2M) 50 y (18-75)
16 (52%) 65 kg (41.8-I00)
16 (59%) 62.1kg (45.%100.7)
28 (85%)
24 (83%)
15 (45%)
9 (31%)
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J. Cooper et al.: Single Dose Therapy in UTI Table 2: Infecting organisms.
coli I] Escherichia Proteus mirabilis ] Kiebsiellapneumoniae ] Enterobacteraerogenex ] Staphylocoecussaprophyticus I Enterococcusfaeealis
23 (70%)
4 2 1 3 0
24 (85%)
1 0 1 2 1
Table 3: Results of microscopy on initial midstream urines.
No. of patients % with -> 10 wbc/rnm 3 Median no. of wbc/mm3 (range) % with >_10 rbc/mm3 Median no. of rbc/mm3 (range)
33 91% 300 (0-4000) 24% 0 (0-4000)
29 93% 300 (0-6600) 38% 0 (0-7500)
Clinical and Bacteriological Efficacy 85% of those receiving fosfomycin trometamol and 79% given clavulanate-potentiated amoxiciUin reported at follow-up that their symptoms had either disappeared or were greatly improved following treatment. White cell counts per ~tl of urine had fallen to median values of 2 (range 0->1000) in the fosfomycin trometamol group, and 1 (range 0-600) in the clavulanate-potentiated amoxicillin group, Bacteriological cure rates - the eradication of the original infecting organisms from the urine - are shown in Table 4. No statistically significant differences were detected by the Chi-square test. Infecting strains that were not eradicated were: in the fosfomycin trometamol group, four E. coli and one Staphylococcus saprophyticus; in the group given clavulanate-potentiated amoxicillin seven E. coli and one Enterobacter aerogenes. In all cases, these strains remained sensitive to the antibiotic used to treat the infection. There were seven reinfections in the group given fosfomycin trometamol (five E. coli, one Staphylococcus Table 4: Results of treatment in patients with significant bacteriuda.
Fosfornycin trometamol Amoxicillin-clavulanicacid
28/33 = 85% (97-73%) 21/29 = 72% (85-59%)
26/32 = 81% (95-67%) 17/26 = 65% (83--47%)
epidermidis, one group B streptococcus). There were four reinfections among patients who had taken clavulanateaugmented amoxiciUin (three E. coli and one Proteus mirabilis). All the reinfecting strains were sensitive to the antibiotic that had been prescribed. Patients with "Urethral Syndrome" 69 of the abacteriuric patients (all female) attended for follow-up seven to ten days after the end of treatment and so were assessable for the effect of antibiotic treatment on their symptoms. 33 had taken fosfomycin trometamol and 36 clavulanate-potentiated amoxicillin and the two groups were similar in terms of age distribution and previous history of urinary symptoms. At follow-up 76% of those who had taken fosfomycin trometamol and 75% of those given clavulanate-potentiated amoxicillin reported that their initial symptoms had either disappeared or were substantially improved. Thus, both treatments were of equal efficacy in removing symptoms.
Adverse Events All 141 patients given a course of treatment were questioned about side effects. Details of these are shown in Table 5. Only one patient had an adverse event serious enough to require cessation of treatment: this was a 75year-old man who developed a typical penicillin rash on the second day of clavulanate-potentiated amoxicillin treatment.
Discussion Several possible advantages and disadvantages' have been suggested for short course (including single dose) therapy compared with conventional courses [t2]. Advantages include a decreased likelihood of side effects, possibly lower costs and perhaps selection of fewer resistant organisms. However, these remain to be proven under clinical trial conditions [13]. An outstanding practical advantage of single dose therapy with fosfomycin trometamol as used in the present study was that total compliance was assured, the entire course of antibiotic (3 g sachet) being given in the presence of the practice sister. However, under normal circumstances in the United Kingdom this would not occur since the patient would be given a prescription and therefore would be relied Table 5: Side effects reported by patients taking fosfomyein trometamol or amoxicillin plus clavutanic acid.
No. patients reporting a side effect Nature of side effect Gastro-intestinal Vaginal irri~ation Rash
Infection 18 (1990) No. 2 © MMV Medizin Verlag GmbH Miinchen, Miinchen 1990
6/72 (8.3%)
7/69 (10.1%)
5 (nausea 1 diarrhoea 4) 0 1
3 (indigestion l diarrhoea 2) 3 1
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J. Cooper et al.: Single Dose Therapy in UTI upon to take the treatment without supervision. Fosfomycin is active against virtually all recognized urinary pathogens and the only resistance found was in two S. saprophyticus strains, a species in which intrinsic resistance to fosfomycin is not uncommon [14]. The lack of resistance in most organisms may be because fosfomycin has not previously been used in Great Britain. Our results show that a single dose of fosfomycin trometamol is as effective clinically as a conventional dose of clavulanate-potentiated amoxicillin. The cure rate obtained with the latter compound (72%) appears to be somewhat lower than that found in other trials in similar infections, in which cure rates ranging from 100% to 84% have been reported [t5-19]. By protocol we excluded patients who had had more than three infections in the preceding year, who are known to be more likely to fail treatment [20]. Another reason for our apparently lower cure rate is probably a statistical one resulting from a relatively small sample size. For instance, in order to obtain a statistically significantly different cure rate with 90% confidence between apparent cure rates of 70% (as obtained here for clavulanate-potentiated amoxicillin) and 85% (as obtained here for fosfomycin trometamol) at a probability (o0 of 0.05, one would need to study two groups each of 158 subjects. Most other trials on single dose treatment have involved small numbers of patients. Multicentre trials in which large numbers of patients are studied suffer from a number of inherent disadvantages, including varying results from different participating centres and the use of different laboratories which provide a microbiology service of an inconsistent quality. Recently, a comparative trial involving 886 patients was considered to be too small to give a statistically significant result, since both the trial drugs gave excellent results [21]. The latter study has given rise to a discussion [22] of the problems of reaching an appropriate level of statistical significance in clinical trials. The results obtained in patients suffering from the "urethral
References t. Waters, W. E.: Prevalence of symptoms of urinary tract infection in women. Br. J. Prevent. Soc. Med. 23 (1969) 263-266. 2. Brooks, D.: A general practitioner's view of the laboratory examination of urine. In: Meers, P. D. (ed.): The bacteriological examination of urine: report of a workshop on needs and methods. HMSO-London 1978, pp. 39--40. 3. Walker, M., Heady, J. A., Shaper, A. G.: The prevalence of dysuria in women in London. J. R. Coll. Gen. Practit. 33 (1983) 411-415. 4. Charlton, C. A. C., Crowther, A., Davies, J. G., Dynes, J., Howard, M. R. A., Mann, P. G., Rye, S.: Three day and ten day chemotherapy for urinary tract infections in general practice. Br. Med. L i (1976) 124-126. 5. Grnneberg, R.N., Brumfitt, W.: Single dose treatment of acute urinary tract infection: a controlledtrial. Br. Med. J. iii (1967) 649-651. 6. Bailey, R. R. (ed.): Single dose therapy o'f urinary tract infection. Adis Press, Sydney 1983. 7, Brumfitt, W., Hamilton-Miller,J. M. T.: Single dose antibiotic therapy in urinary tract infections. In: Andreucci, V. E. (ed.): International 10 / 68
syndrome" are instructive in terms of its aetiology. The fact that treatment with fosfomycin, which is inactive against lactobacilli and diphtheroids, gave the same clear-up rate of symptoms as did clavulanate-potentiated amoxicillin (to which these pathogens are sensitive), strongly suggests that these "fastidious" species do not play an aetiological role in the condition [ 11]. Further studies are needed to determine whether the "urethral syndrome" is caused by other microorganisms [23] or by psychological factors [24]. Such studies can only be done in a general practice setting, where the selection of special groups of patients is avoided. In the present study carried out by several general practitioners in a single practice excellent cooperation was obtained from the participat-. ing patients. Only one infected patient was lost to the study because of failure to attend both the five to ten day and four to six week post treatment follow-up. The four to six week follow-up is important, since where apparent cure occurs at seven days after treatment, this may not be not maintained at the six week follow-up [20, 25]. The six week follow-up is particularly important when assessing single dose treatment [7], in order to detect relapse. Our results are encouraging and merit further studies. A single dose of fosfomycin trometamol may prove to be valuable in the treatment of uncomplicated symptomatic urinary infections.
Acknowledgments We thank Drs. Lockwood, Vickers, Booth, Calderhead and the late Dr. I.R. Kerr of the Earnswood Medical Centre who collaborated in this study. We are grateful to Mr. C. Maple and Mrs. A. Dekker for help in the organisation of the study. Dr. V. Cicchetti and Dr. G. DeI Bono of Zambon Laboratories kindly supplied the trial drugs and helped to meet the costs of the study. Financial support was also given by the Special Trustees of The Royal Free Hospital.
Yearbook of Nephrology 1989. Kluwer, Massachusetts 1989, pp. 49-63. 8. ABPI Data Sheet Compendium 1988-89: Datapharm Publications, London 1988. 9. Ferrari, V., Bonanomi, L , Boreia, M., Lodola, E., Marea, G.: A new fosfomycin derivative with much improved bioavailabitity by oral route. Chemother. Antimicrob. iv (1981 ) 59-63. I0. Gallego, A., Rodriguez, A., Mata, J. M.: Fosfomycin: pharmacological studies. Drugs &Today 10 (1974) 161-t68. 11. Maskell, R.: Are fastidious organisim an important cause of dysuria and frequency? - the case for. In: Asscher, A. W., Brumfitt, W. (eds.): Microbial diseases in nephrology. Wiley, Chichester 1986, pp. 1-18. 12. Kunin, C. M.: Foreword. In: Bailey, R. R. (ed.): Single dose therapy of urinary tract infection. Adis Press, Sydney 1983, pp. viii-x. 13. Brumfitt, W., Hamilton-Miller, J. M. T.: The optimal duration of antibiotic treatment of urinary infections. In: Neu, H. C., Williams, J. D. (eds.): New trends in urinary tract infections. Karger, Basel 1988, pp. 62-77. 14. Loulerque, J., Pinon, G., Laudat, P., Audurier, A.: La rtsistance a la fosfomycine chez Staphylococcus saprophyticus et chez les autres
Infection 18 (1990) No, 2 © MMV Medizin Verlag GmbH Mtinchen, Mttnchen 1990
J. Cooper et al.: Single Dose Therapy in UTI esp~ces de stapylococcuscoagulase negative. Ann. Microbiol. (lnstitut Pasteur) 135A (1984) 239-247. 15. Stamboulian, D., Sarachian, B., Arguelllo, E., Beiforte, B.: Evaluation of amoxiciUin with and without BRL 14151 in the treatment of urinary tract infections. In: Nelson. J. D., Grassi, C, (eds.): Current Chemotherapy and Infectious Disee~ses. American Society of Medicine-Washington 1980, pp. 338-340. 16. Nishiura, T.: Efficacy of Augmentin (BRL 25 000) in urinary tract infections. In: Leigh, D.A., Robinson, O. P. W. (eds.): Augmeaatin: clavulanate-potentiated amoxicillin. Excerpta Medica, Amsterdam 1982, pp. 65-77. 17. Gurwith, NL J., Stein, G. E., Gurwith, D.: Prospective comparison of amoxicillin-cLavulanic acid and cefaclor in treatment of uncomplicated urinary tract infections. Antimicrob. Agents Chemother. 24 (1983) 716-719. 18. Karachalios, G. N., Georgiopouios, A. N.: Treatment of acute urinary tract infections with amoxicillinand clavulanic acid combination. IRCS Med. Sci. 12 (t984) 1042-1043. 19. lravani, A., Richard, G. A.: Treatment of urinary infections with a combination of amoxicillin mad clavulanic acid. Antimicrob. Agents
Chemother. 22 (1982) 672-677. 20. Cooper, J., Brumfitt, W., Hamilton-Miller, J. M. T.: A comparative trial ofco-trimoxazoleand cephradine in patients with recurrent urinary infections. J. Antimicrob. Chemother. 6 (1980) 231-239. 21. The Urinary Tract Infection Study Group: Coordinaredmulticenter study of norfloxacin versus trimethoprim-sulphamethoxazole treatment of symptomatic urinary tract infections. J. Infect. Dis. 155 (1987) 170-177. 22. Silverblatt, F. J.: Clinical trials and statistical rigor - are the benefits necessarily worth the cost? J. Infect. Dis. 155 (1987) 168-169. 23. Stamm, W. E., Wagner, K, F., Amsel, R., Alexander, E. R., Turek, M., Counts, G.W., Holmes, K, K.: Causes of the acute urethral syndrome in women. New Engl. J, Med. 303 (1980) 409-415. 24. O'Dowd, T. C., Pill, R., Small, J. E., Davis, R. H.: Irritable urethral syndrome: follow-up study ha general practice. Br. Med. J. 292 (1986) 30-32. 25. Brumfitt, W., Hamilton-Miller, J.M.T., Smith, G.W.: Comparative trial of cefuroxime axetiI in recurrent urinary tract infections, illustrating importance of 6-week follow-up. Antimicrob. Agents Chemother. 31 (1987) 1442-1443.
16-19 May 1990 7th Annual Meeting of the Europaen Society for Paediatric Infectious Diseases (ESPID) Grteborg, Sweden. Theme of the Meeting: Prevention of Infections in Children. It includes all aspects of prevention of infections, in particular active immunization, immunoglobulin prophylaxis and prophylaxis with antimicrobial agents. ~ e r e are also a free paper session and poster presentations, to which all presentations dealing with infections in children are welcome. Correspondence to: Dr. Birger Trollfors, Dept. of Paediattics, Ostra sjukhuset, S-416 85 G6teborg, Sweden.
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Single Dose and Conventional Treatment for Acute Bacterial and Non-Bacterial Dysuria and Frequency in General Practice Summary: A five day course of clavulanate-potentiated amoxicillin (Augmentin®) has been compared with a single oral dose of fosfomycin trometamol in the treatment of patients complaining of symptoms suggesting urinary tract infection. The study took place in a single urban general practice of 15,000 patients in Cheshire. The microbiology was performed at a London Teaching Hospital. 141 patients entered the trial. 65 had a significant bacteriuria, 62 of which were assessable for the ability of the trial drugs to eradicate bacteriuria: 29 patients received clavulanate-potentiated amoxicillin and 33 fosfomycin trometarnol. The cure rates, assessed at five to ten days and at four to six weeks post treatment, were 72% and 65%, respectively for clavulanate-potentiated amoxicillin and 85% and 81%, respectively for fosfomycin trometamol. Side effects, assessed in all 141 patients, oc-
cured in 11.6% receiving clavulanate-potentiated amoxicillin and in 8.3% receiving fosfomycin. Statistically there is no difference between any of these findings and the effect of sample size is discussed. 69 patients were symptomatic but did not have a significant bacteriuria ("urethral syndrome"). These patients were assessed for the effect of treatment in relieving symptoms: 33 received fosfomycin trometamol and 36 clavulanate-potentiated amoxicillin. The success and speed of relieving the symptoms were very similar in the two groups. The finding that both groups responded equally well appears to refute an aetiological role for lactobaciUi and diphtheroids in the "urethral syndrome", since these organisms are resistant to fosfomycin but sensitive to clavulanate-potentiated amoxiciUin.
Zusammenfassung: Behandlung der akuten bakteriellen und nicht bakteriellen Dysurie mit Harndrang in der Allgemeinpraxis - Vergleich einer Einmaldosis mit einer konventionellen Behandlung. Patienten, die Beschwerden einer Harnwegsinfektion hatten, wurden entweder ftinf Tage lang mit AmoxiciUin-Clavulansgure (Augmentan®) oder mit einer oralen Einzeldosis von Fosfomycin Trometamot behandelt. Die Studie wurde in einer Allgemeinpraxis in Cheshire durchgeftihrt, die 15 000 Patienten versorgt. 141 Patienten wurden in die Studie aufgenommen. 65 hatten eine signifikante Bakteriurie, davon konnten 62 in die Auswertung beztiglich Eradikation der Bakteriurie durch alas Prtifmedikament einbezogen werden; 29 Patienten erhielten Amoxicillin-Clavulans~iure und 33 Fosfomycin Trometamol. In der ersten Gmppe waren am 5.-10. Tag und vier bis sechs Wochen nach Therapieende 72% beziehungsweise 65% geheilt, die entsprechenden Zahlen ftir Fosfornycin Trometamol waxen 85% und 81%.
Bei 11,6% der insgesamt ausgewerteten 141 Patienten traten Nebenwirkungen unter Amoxicillin-Clavulans~iure und bei 8,3% unter Fosfomycin Trometamol auf. Ein statistischer Unterschied zwischen diesen Befunden besteht nicht, die Bedeutung der Probengrrl3e hierftir wird diskutiert. 69 Patienten klagten iJber Beschwerden, hatten jedoch keine signifikante Bakteriurie (urethrales Syndrom). Sie wurden im Hinblick auf eine Linderung ihrer Beschwerden durch Fosfomycin Trometamol (n= 33) oder Amoxicillin-Clavulans~iure (n=36) geprtift. In beiden Gruppen war der Einflug auf die Beschwerden nach Grad und Geschwindigkeit sehr ~ihnlich. Das vergleichbar gute Ansprechen der beiden Gruppen scheint gegen eine ~itiologische Bedeutung yon Laktobazillen und Diphtheroiden beim ,,urethralen Syndrom" zu sprechen, denn diese Bakterien sind gegen Fosfomycin Trometamol resistent, gegen Amoxicillin-Clavulans~iure hingegen empfindlich.
Introduction In general practice symptoms suggestive of urinary tract infection, such as dysuria and frequency (often refei-red to by patients as "cystitis"), commonly cause patients to visit their general practitioner. According to various estimates, visits from women who suffer from dysuria amount to 50 to 200 per 1000 per annum [1-3]. Many of the patients are women aged 18-50 years, and they are often treated with antibiotics for five to seven days. However, a trial with amoxicillin in uncomplicated urinary infections treated in general practice showed an equally good response to a three-day or a ten-day course of treatment [4].
More than 20 years ago a controlled trial [5] showed that single dose treatment with a long-acting sulphonmnide was as effective as ampicillin for seven days. Since then a number of antimicrobial agents including amoxicillin, co-trimoxazole or nitrofurantoin, given in single doses have been shown to result in clinical and bacteriological cure rates not Received: 3 July 1989/Revision accepted: 17 January 1990 J. Cooper, MB BCh., A. Raeburn, MB BCh., Eamswood Medical Centre, Crewe CW 2JR; Prof. W. Brumfitt, M.D., Prof. J. M. T. Hamilton-Miller, DSc., Department of Medical Microbiology, The Royal Free Hospital School of Medicine, Pond Street, London NW 3 2QG, UK.
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J. Cooper et al.: Single DoseTherapy in UTI
significantly different from those obtained using longer courses of treatment [6, 7]. However, such studies only apply to those patients suffering from initial or isolated attacks of acute bacterial cystitis. In spite of these findings most general practitioners do not use single dose therapy, and no single dose regimens are recommended by pharmaceutical companies in the United Kingdom [8]. We have compared a single dose of fosfomycin trometamot with a five-day course of treatment with clavulanate-potentiated amoxicillin in general practice. The careful documentation, follow-up and the high standard of bacteriology necessary was achieved by collaboration between a multipartner group practice and the urine research laboratory in the Department of Medical Microbiology at The Royal Free Hospital, Fosfomycin is a broad-spectrum antibiotic which is bactericidal, non-toxic, penetrates into leucocytes and because of its unique chemical structure shows no cross-resistance with other antibiotics. The trometamol (mono tris[hydroxymethyl] aminomethane) salt is a more recently developed water-soluble derivative which is well absorbed by mouth
[9, 10]. In this study we achieved three objectives. First, we compared the efficacy of the single dose treatment and conventional therapy in proven infections. Second, we assessed tolerance of the two regimens in all patients, whether or not they had significant bacteriuria. Third, we investigated the aetiology of tile "urethral syndrome", by observing the effect of antibiotic treatment on patients who were symptomatic but had no significant bacteriuria. Fosfomycin is not active against lactobacilli and diphtheroids, which have been suggested [11] to be causative agents of the "urethral syndrome", whereasclavulanate-potentiated amoxicillin is active against these organisms. Thus, a less favourable response would be expected in those patients given fosfomycin if this suggestion is correct.
Patients and Methods Patients: Every patient (of either sex) who attended his or her general practitioner's surgery complaining of dysttria and/or frequency was eligible for the study. Patients were excluded if they had suffered more than three infections in the previous 12 months, were below t6 years of age, were pregnant or lactating, or had a penicillin allergy. 141 eligible patients agreed to enter the study and 65 of these were found subsequently to have a significant bacteriuria (>_ 105 bacteria/ml). Clinical procedure : All 141 patients were documented and examined, the results being recorded on special forms, and a properly taken midstream urine (MSU) obtained. They were then allotted by means of a randomization chart to receive a single dose of fosfomycin trometamol or a five-day course of clavulanate-potentiated amoxicillin. Patients received sachets containing fosfomycin trometamol, equivalent to 3 g fosfomycin, in an orange flavoured tbrmulation (supplied by Zambon Pharmaceuticals, Bresso, Italy). The contents of one sachet were dissolved in water, and drunk in the presence of the practice nursing sister. Alternatively, t h e y w e r e given clavulanate-potentiated amoxicillin 8 / 66
375 mg (250 mg amoxicillin + 125 mg clavulanate), and asked to take one tablet 8 hourly for five days. All patients were requested to return to the medical centre five to ten days after the end of treatment, and again a month later. At follow-up a further MSU was taken and the patients questioned about symptoms or adverse effects. At the medical centre, MSUs were tested with N-Labstix, a dipslide (Uricult, Orion) was inoculated and 20 ml of urine put into a bottle containing 380 mg boric acid (supplied by Steritin, UK). The dipslides and borated urine were sent in a special container by first class mail to the Department of Medical Microbiology at The Royal Free Hospital. Laboratory procedures: On arrival the dipslide was incubated at 37 °C overnight and was read by comparison with the standard chart. Pathogens present in significant numbers were identified and tested for antibiotic sensitivity by Stokes' method on IsoSen-" sitest agar (Oxoid). Strains showing zones of inhibition around disks containing either 200 gg fosfomycin plus 50 gg glucose-6phosphate or 20 gg amoxicillin plus 10 gg clavulanic acid with diameters similar to that shown by a fully sensitive control strain (Escherichia coli NCTC 10418) were considered sensitive. The borated urine was examined by microscopy and counts of white cells and red cells were made. Results were reported by telephone and confirmed in writing.
Results Infected Patients - Comparison of Patient Groups A total of 62 patients had significant bacteriuria due to organisms sensitive to the allotted drugs and were assessed for efficacy of treatment. One patient in each group was infected with an organism resistant to the allocated antibiotic, and these were excluded from the analysis. 29 of the assessable patients were given clavulanate-potentiated amoxicillin (27 female, two male) and 33 fosfomycin trometamol (31 female, two male). The two groups were similar in terms of age, weight, previous history of dysuria and/or frequency (Table ] ), infecting organisms (Table 2) and results of urine microscopy (Table 3). The presenting symptoms were very similar in the two groups, the most common complaints being of frequency (89%), dysuria (83%) and urgency (59%). Table 1: Characteristics of patients with bacteriuria.
No. of patients Mean.age (range) No. (%) of females of child-bearing age Mean weight (range) No. (%) with previous history suggestiveof urinary infection No. (%) with an attack during previous 12 months
33 (31F, 2M) 45.4 y (17-78)
29 (27F, 2M) 50 y (18-75)
16 (52%) 65 kg (41.8-I00)
16 (59%) 62.1kg (45.%100.7)
28 (85%)
24 (83%)
15 (45%)
9 (31%)
Infection 18 (1990) No. 2 © MMV MedizinVerlag GmbH Mtinchen,Mtinchen 1990
J. Cooper et al.: Single Dose Therapy in UTI Table 2: Infecting organisms.
coli I] Escherichia Proteus mirabilis ] Kiebsiellapneumoniae ] Enterobacteraerogenex ] Staphylocoecussaprophyticus I Enterococcusfaeealis
23 (70%)
4 2 1 3 0
24 (85%)
1 0 1 2 1
Table 3: Results of microscopy on initial midstream urines.
No. of patients % with -> 10 wbc/rnm 3 Median no. of wbc/mm3 (range) % with >_10 rbc/mm3 Median no. of rbc/mm3 (range)
33 91% 300 (0-4000) 24% 0 (0-4000)
29 93% 300 (0-6600) 38% 0 (0-7500)
Clinical and Bacteriological Efficacy 85% of those receiving fosfomycin trometamol and 79% given clavulanate-potentiated amoxiciUin reported at follow-up that their symptoms had either disappeared or were greatly improved following treatment. White cell counts per ~tl of urine had fallen to median values of 2 (range 0->1000) in the fosfomycin trometamol group, and 1 (range 0-600) in the clavulanate-potentiated amoxicillin group, Bacteriological cure rates - the eradication of the original infecting organisms from the urine - are shown in Table 4. No statistically significant differences were detected by the Chi-square test. Infecting strains that were not eradicated were: in the fosfomycin trometamol group, four E. coli and one Staphylococcus saprophyticus; in the group given clavulanate-potentiated amoxicillin seven E. coli and one Enterobacter aerogenes. In all cases, these strains remained sensitive to the antibiotic used to treat the infection. There were seven reinfections in the group given fosfomycin trometamol (five E. coli, one Staphylococcus Table 4: Results of treatment in patients with significant bacteriuda.
Fosfornycin trometamol Amoxicillin-clavulanicacid
28/33 = 85% (97-73%) 21/29 = 72% (85-59%)
26/32 = 81% (95-67%) 17/26 = 65% (83--47%)
epidermidis, one group B streptococcus). There were four reinfections among patients who had taken clavulanateaugmented amoxiciUin (three E. coli and one Proteus mirabilis). All the reinfecting strains were sensitive to the antibiotic that had been prescribed. Patients with "Urethral Syndrome" 69 of the abacteriuric patients (all female) attended for follow-up seven to ten days after the end of treatment and so were assessable for the effect of antibiotic treatment on their symptoms. 33 had taken fosfomycin trometamol and 36 clavulanate-potentiated amoxicillin and the two groups were similar in terms of age distribution and previous history of urinary symptoms. At follow-up 76% of those who had taken fosfomycin trometamol and 75% of those given clavulanate-potentiated amoxicillin reported that their initial symptoms had either disappeared or were substantially improved. Thus, both treatments were of equal efficacy in removing symptoms.
Adverse Events All 141 patients given a course of treatment were questioned about side effects. Details of these are shown in Table 5. Only one patient had an adverse event serious enough to require cessation of treatment: this was a 75year-old man who developed a typical penicillin rash on the second day of clavulanate-potentiated amoxicillin treatment.
Discussion Several possible advantages and disadvantages' have been suggested for short course (including single dose) therapy compared with conventional courses [t2]. Advantages include a decreased likelihood of side effects, possibly lower costs and perhaps selection of fewer resistant organisms. However, these remain to be proven under clinical trial conditions [13]. An outstanding practical advantage of single dose therapy with fosfomycin trometamol as used in the present study was that total compliance was assured, the entire course of antibiotic (3 g sachet) being given in the presence of the practice sister. However, under normal circumstances in the United Kingdom this would not occur since the patient would be given a prescription and therefore would be relied Table 5: Side effects reported by patients taking fosfomyein trometamol or amoxicillin plus clavutanic acid.
No. patients reporting a side effect Nature of side effect Gastro-intestinal Vaginal irri~ation Rash
Infection 18 (1990) No. 2 © MMV Medizin Verlag GmbH Miinchen, Miinchen 1990
6/72 (8.3%)
7/69 (10.1%)
5 (nausea 1 diarrhoea 4) 0 1
3 (indigestion l diarrhoea 2) 3 1
67 / 9
J. Cooper et al.: Single Dose Therapy in UTI upon to take the treatment without supervision. Fosfomycin is active against virtually all recognized urinary pathogens and the only resistance found was in two S. saprophyticus strains, a species in which intrinsic resistance to fosfomycin is not uncommon [14]. The lack of resistance in most organisms may be because fosfomycin has not previously been used in Great Britain. Our results show that a single dose of fosfomycin trometamol is as effective clinically as a conventional dose of clavulanate-potentiated amoxicillin. The cure rate obtained with the latter compound (72%) appears to be somewhat lower than that found in other trials in similar infections, in which cure rates ranging from 100% to 84% have been reported [t5-19]. By protocol we excluded patients who had had more than three infections in the preceding year, who are known to be more likely to fail treatment [20]. Another reason for our apparently lower cure rate is probably a statistical one resulting from a relatively small sample size. For instance, in order to obtain a statistically significantly different cure rate with 90% confidence between apparent cure rates of 70% (as obtained here for clavulanate-potentiated amoxicillin) and 85% (as obtained here for fosfomycin trometamol) at a probability (o0 of 0.05, one would need to study two groups each of 158 subjects. Most other trials on single dose treatment have involved small numbers of patients. Multicentre trials in which large numbers of patients are studied suffer from a number of inherent disadvantages, including varying results from different participating centres and the use of different laboratories which provide a microbiology service of an inconsistent quality. Recently, a comparative trial involving 886 patients was considered to be too small to give a statistically significant result, since both the trial drugs gave excellent results [21]. The latter study has given rise to a discussion [22] of the problems of reaching an appropriate level of statistical significance in clinical trials. The results obtained in patients suffering from the "urethral
References t. Waters, W. E.: Prevalence of symptoms of urinary tract infection in women. Br. J. Prevent. Soc. Med. 23 (1969) 263-266. 2. Brooks, D.: A general practitioner's view of the laboratory examination of urine. In: Meers, P. D. (ed.): The bacteriological examination of urine: report of a workshop on needs and methods. HMSO-London 1978, pp. 39--40. 3. Walker, M., Heady, J. A., Shaper, A. G.: The prevalence of dysuria in women in London. J. R. Coll. Gen. Practit. 33 (1983) 411-415. 4. Charlton, C. A. C., Crowther, A., Davies, J. G., Dynes, J., Howard, M. R. A., Mann, P. G., Rye, S.: Three day and ten day chemotherapy for urinary tract infections in general practice. Br. Med. L i (1976) 124-126. 5. Grnneberg, R.N., Brumfitt, W.: Single dose treatment of acute urinary tract infection: a controlledtrial. Br. Med. J. iii (1967) 649-651. 6. Bailey, R. R. (ed.): Single dose therapy o'f urinary tract infection. Adis Press, Sydney 1983. 7, Brumfitt, W., Hamilton-Miller,J. M. T.: Single dose antibiotic therapy in urinary tract infections. In: Andreucci, V. E. (ed.): International 10 / 68
syndrome" are instructive in terms of its aetiology. The fact that treatment with fosfomycin, which is inactive against lactobacilli and diphtheroids, gave the same clear-up rate of symptoms as did clavulanate-potentiated amoxicillin (to which these pathogens are sensitive), strongly suggests that these "fastidious" species do not play an aetiological role in the condition [ 11]. Further studies are needed to determine whether the "urethral syndrome" is caused by other microorganisms [23] or by psychological factors [24]. Such studies can only be done in a general practice setting, where the selection of special groups of patients is avoided. In the present study carried out by several general practitioners in a single practice excellent cooperation was obtained from the participat-. ing patients. Only one infected patient was lost to the study because of failure to attend both the five to ten day and four to six week post treatment follow-up. The four to six week follow-up is important, since where apparent cure occurs at seven days after treatment, this may not be not maintained at the six week follow-up [20, 25]. The six week follow-up is particularly important when assessing single dose treatment [7], in order to detect relapse. Our results are encouraging and merit further studies. A single dose of fosfomycin trometamol may prove to be valuable in the treatment of uncomplicated symptomatic urinary infections.
Acknowledgments We thank Drs. Lockwood, Vickers, Booth, Calderhead and the late Dr. I.R. Kerr of the Earnswood Medical Centre who collaborated in this study. We are grateful to Mr. C. Maple and Mrs. A. Dekker for help in the organisation of the study. Dr. V. Cicchetti and Dr. G. DeI Bono of Zambon Laboratories kindly supplied the trial drugs and helped to meet the costs of the study. Financial support was also given by the Special Trustees of The Royal Free Hospital.
Yearbook of Nephrology 1989. Kluwer, Massachusetts 1989, pp. 49-63. 8. ABPI Data Sheet Compendium 1988-89: Datapharm Publications, London 1988. 9. Ferrari, V., Bonanomi, L , Boreia, M., Lodola, E., Marea, G.: A new fosfomycin derivative with much improved bioavailabitity by oral route. Chemother. Antimicrob. iv (1981 ) 59-63. I0. Gallego, A., Rodriguez, A., Mata, J. M.: Fosfomycin: pharmacological studies. Drugs &Today 10 (1974) 161-t68. 11. Maskell, R.: Are fastidious organisim an important cause of dysuria and frequency? - the case for. In: Asscher, A. W., Brumfitt, W. (eds.): Microbial diseases in nephrology. Wiley, Chichester 1986, pp. 1-18. 12. Kunin, C. M.: Foreword. In: Bailey, R. R. (ed.): Single dose therapy of urinary tract infection. Adis Press, Sydney 1983, pp. viii-x. 13. Brumfitt, W., Hamilton-Miller, J. M. T.: The optimal duration of antibiotic treatment of urinary infections. In: Neu, H. C., Williams, J. D. (eds.): New trends in urinary tract infections. Karger, Basel 1988, pp. 62-77. 14. Loulerque, J., Pinon, G., Laudat, P., Audurier, A.: La rtsistance a la fosfomycine chez Staphylococcus saprophyticus et chez les autres
Infection 18 (1990) No, 2 © MMV Medizin Verlag GmbH Mtinchen, Mttnchen 1990
J. Cooper et al.: Single Dose Therapy in UTI esp~ces de stapylococcuscoagulase negative. Ann. Microbiol. (lnstitut Pasteur) 135A (1984) 239-247. 15. Stamboulian, D., Sarachian, B., Arguelllo, E., Beiforte, B.: Evaluation of amoxiciUin with and without BRL 14151 in the treatment of urinary tract infections. In: Nelson. J. D., Grassi, C, (eds.): Current Chemotherapy and Infectious Disee~ses. American Society of Medicine-Washington 1980, pp. 338-340. 16. Nishiura, T.: Efficacy of Augmentin (BRL 25 000) in urinary tract infections. In: Leigh, D.A., Robinson, O. P. W. (eds.): Augmeaatin: clavulanate-potentiated amoxicillin. Excerpta Medica, Amsterdam 1982, pp. 65-77. 17. Gurwith, NL J., Stein, G. E., Gurwith, D.: Prospective comparison of amoxicillin-cLavulanic acid and cefaclor in treatment of uncomplicated urinary tract infections. Antimicrob. Agents Chemother. 24 (1983) 716-719. 18. Karachalios, G. N., Georgiopouios, A. N.: Treatment of acute urinary tract infections with amoxicillinand clavulanic acid combination. IRCS Med. Sci. 12 (t984) 1042-1043. 19. lravani, A., Richard, G. A.: Treatment of urinary infections with a combination of amoxicillin mad clavulanic acid. Antimicrob. Agents
Chemother. 22 (1982) 672-677. 20. Cooper, J., Brumfitt, W., Hamilton-Miller, J. M. T.: A comparative trial ofco-trimoxazoleand cephradine in patients with recurrent urinary infections. J. Antimicrob. Chemother. 6 (1980) 231-239. 21. The Urinary Tract Infection Study Group: Coordinaredmulticenter study of norfloxacin versus trimethoprim-sulphamethoxazole treatment of symptomatic urinary tract infections. J. Infect. Dis. 155 (1987) 170-177. 22. Silverblatt, F. J.: Clinical trials and statistical rigor - are the benefits necessarily worth the cost? J. Infect. Dis. 155 (1987) 168-169. 23. Stamm, W. E., Wagner, K, F., Amsel, R., Alexander, E. R., Turek, M., Counts, G.W., Holmes, K, K.: Causes of the acute urethral syndrome in women. New Engl. J, Med. 303 (1980) 409-415. 24. O'Dowd, T. C., Pill, R., Small, J. E., Davis, R. H.: Irritable urethral syndrome: follow-up study ha general practice. Br. Med. J. 292 (1986) 30-32. 25. Brumfitt, W., Hamilton-Miller, J.M.T., Smith, G.W.: Comparative trial of cefuroxime axetiI in recurrent urinary tract infections, illustrating importance of 6-week follow-up. Antimicrob. Agents Chemother. 31 (1987) 1442-1443.
16-19 May 1990 7th Annual Meeting of the Europaen Society for Paediatric Infectious Diseases (ESPID) Grteborg, Sweden. Theme of the Meeting: Prevention of Infections in Children. It includes all aspects of prevention of infections, in particular active immunization, immunoglobulin prophylaxis and prophylaxis with antimicrobial agents. ~ e r e are also a free paper session and poster presentations, to which all presentations dealing with infections in children are welcome. Correspondence to: Dr. Birger Trollfors, Dept. of Paediattics, Ostra sjukhuset, S-416 85 G6teborg, Sweden.
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