plicated infections respond well to long-term antimicrobial therapy. We believe our results can be explained by the circumstances that all the patients were supervised by the same individual and were clearly taught the prophylaxis of reinfection. It is our experience that recurrence, either in complicated or uncomplicated infections, does not depend altogether on the type of antibiotics employed but, to a great degree, on general hygiene and prophylactic measures, in which all patients should be instructed. Out of respect for the double-blind study we administered the medications as one pill 4 times daily instead of two pills twice daily as recommended for trimethoprim-sulfamethoxazole. This dosage schedule did not seem to affect the general results. Important side effects were observed in three patients. Two had a rash on the 9th day of therapy but the whole course was completed. One patient had to stop her treatment on the 4th day because of severe digestive intolerance that receded when

the drug was withdrawn; she is considered as an unsuccessful result. We did not observe any hematologic or biochemical changes in our patients. In conclusion, trimethoprim-sulfamethoxazole on a short-term basis of 10 days is quite comparable with ampicillin in the treatment of urinary tract infection. This has already been reported by others.2'3 The urine became sterile and remained so for at least 3 months in patients who had had multiple attacks and complicated urinary tract infections after short-term therapy. References 1. Sulfamethoxazole-trimethoprim (co-trimoxazole). Med Left Drugs Ther 15:65, 1973 2. KINCAID-SMITH P. KALOWSKI S. NANRA RS: Co-trimoxazoic in urinary tract infection. Med J Aust 2 (suppl): 49, 1973 3. BRUMFITT W, PURSELL R: Trimethoprim-sulfamethoxazole in the treatment of urinary infection. Ibid. p 44

A comparison of trimethoprimsulfamethoxazole with sulfamethoxazole alone in infections localized to the kidneys G.K.M. HARDING, MD, FRCP[G]; AR. RONALD, MD, FRCP[C]; P. BOUTROS, MD, FRCS[C]; B. LANK, RN

Summary: Ninety patients with urinary tract infections were treated in a randomized double-blind study with either a combination of trimethoprim and sulfamethoxazole (TMP-SMX) or sulfamethoxazole alone (SMX). Thirty of 42 patients treated with TMP-SMX were cured by the time of follow-up compared with 26 of 48 treated with SMX alone. Of the 29 patients infected with SMX-resistant organisms, the combination TMP-SMX cured 12 of 17, whereas SMX alone cured 2 of 12. Of the 61 patients infected with SMX-sensitive organisme, TMP-SMX cured 18 of 25; SMX alone cured 24 of 36. In 50 women the infection was found localized to the upper urinary tract by the use of the Fairley bladder washout technique. TMP-SMX cured 16 of 24 of these patients with proved upper tract infections and SMX alone cured 11 of 26. Although none of these differences were significant, TMP-SMX appears to be an effective drug combination for the therapy of proved upper tract infection and is also effective in eradicating sulfonamide-resistant organisms. R.sum6: Comparaison entre le trim.thoprime-suIfam6thoxazoIe et le sulfam6thoxazole seul dans des infections Iocalis6es aux reins

vojes urinairos au moyon do Ia methodo A double anonymat. Cos malados ont ro.u au hasard, soit uno association do trimhthoprimo ot do sulfamAthoxazolo (TMP-SMX) soit I. sulfamAthoxazolo soul (SMX). Tronto dos 42 malados traitbs au TMP-SMX Atalont gubris au tomps do Ia postobsorvation. par comparaison avoc 26 dos 48 malados traitAs par lo soul SMX. Dos 29 malados dont l'infoction rolovait do microorganismos rAsistants au SMX, l'association TMP-SMX guerissait 12 malados sur 17, tandis quo lo SMX soul n'on guArissait quo 2 sur 12. Dos 61 malados dont l'organismo pathogAno Atait sonsiblo au SMX. lo TMP-SMX on guArissait 18 sur 25 ot lo SMX soul 24 sur 36. Choz 50 fommos on a decouvort quo l'infoction Atait localisho dans los voios urinairos supbriouros, d'aprAs Ia tochniquo do Fairloy do lavago do Ia vossie. Lo TMP-SMX a guAri 16 malados sur los 24 dont l'infoction siAgoalt dans los voios urinairos supAriouros ot lo SMX soul on guArissait 11 sur 26. Bion qu'aucuno do cos diffAroncos no soit vraimont significanto. lo TMP-SMX constituo uno association mAdicamontouso officaco pour traitor los infoctions dOmont confirm4os dos voios urinairos supAriouros ot ost Agalomont officaco pour l'Alimination dos organismos sulfonamido-rAsistants.

Nous avons traits 90 malades souffrant d'infections des From the departments of medical microbiology, medicine, and obstetrics and gynecology, University of Manitoba and the Health Sciences Centre, Winnipeg This study was supported by the Medical Research Council of Canada grant MA 3065 and by a grant-in.aid from Hoffmann-La Roche Ltd. Reprint requests to: Dr. Godfrey K. Harding, Department of medical microbiology, Basic Sciences Building, 730 William Ave., Winnipeg, Man. R3E 0Z3

The combination of trimethoprim (TMP) and sulfamethoxazole (SMX) has been shown to be very effective in the prophylaxis as well as in the therapy of urinary tract infections in a number of clinical studies.1 -16 Few studies have been double-blind randomized comparisons of trimethoprim-sulfamethoxazole (TMP-SMX) with either of its components. Moreover, in none of these studies had the site of infection been determined prior to therapy. CMA JOURNAL/JUNE 14, 1975/VOL. 112

9S

We treated 90 patients with urinary tract infection with either sulfamethoxazole alone or trimethoprim-sulfamethox¬ azole in a randomized double-blind fashion. Since the site of infection within the urinary tract is a most important determinant of successful therapy, we tried to determine its location prior to therapy in as many patients as possible. Materials and methods

Selection of patients The majority of patients treated were selected from a group followed up in the urinary infection clinic at the Health Sciences Centre. Most had had previous urinary tract infections and had undergone complete urologic and radiologic investiga¬ tion. Many patients had had the site of their infection within the urinary tract identified prior to the institution of therapy. Patients

attending

the

gynecology

clinic with

infections were also included in the series.

urinary

tract

Dosage and duration of treatment Sixty-three patients received a tablet containing 500 mg of SMX, or else one containing 80 mg of TMP with 400 mg of SMX, four times daily for 15 days. The last 27 patients entered in the study received two tablets of either medication twice daily for 15 days. Side effects and toxicity

patients were questioned regarding undesirable reactions they returned for cultures of urine during and after completion of therapy. Values for serial hemoglobin, hemato¬ crit, leukocyte count and platelet count were determined on most of the patients treated. Criteria for diagnosis The diagnosis of urinary tract infection depended on the isolation of more than 100 000 organisms of the same bacterial species from two consecutive cleanly voided midstream urine specimens. In 50 women the site of infection was localized in the upper tract as shown by means of the modified Fairley technique of bladder washout.17»18 Criteria of cure All when

and in most patients also at 6 weeks. A bacteriologic relapse was defined as the recurrence of the same species of bacteria or the same serotype of Escherichia coli within 2 weeks of completion of therapy.

Bacteriologic techniques Gram-negative organisms were identified by standard me¬ thods.19*20 E. coli was serotyped with 0 antisera.19 Sensitivities were initially determined with a single disc diffusion method with the use of a standard inoculum of 5 x 107 organisms on Mueller-Hinton agar. Content of the trimetho¬ prim disc was 1.25 ng and the sulfonamide disc 250 ng. Agar dilution sensitivities to trimethoprim and sulfamethoxazole were studied with an inoculum of 106 organisms/ml using the Steers inoculating apparatus.21 After incubation overnight at 35°C, the lowest concentration showing marked inhibition of growth was read as the minimal inhibitory concentration (MIC). Resistance to sulfonamide was defined as an MIC of sulfame¬ thoxazole greater than or equal to 400 ng/m\. All organisms that persisted during treatment or recurred after therapy was discontinued were tested for resistance to trimethoprim. Results

Ninety-six patients were investigated. Six who had been scheduled to receive TMP-SMX had to be excluded, five of these because of side effects. Hence a total of 90 patients were evaluated; 48 received SMX and 42 received TMP-SMX. Table I sets forth the characteristics of the group. The sex and age distribution was similar in both treatment groups. Both groups included patients with underlying renal disease^ with specific radiographic evidence of chronic pyelonephritis. No patient had a urinary calculus. In all, the serum creatinine concentration was 1.5 mg/dl or less. Table II.The bacterial

study group Variable

etiology and sulfonamide susceptibility in the SMX

TMP-SMX

obtained during the 2nd week of after completion of treatment. A follow-up urine culture after 6 weeks was obtained from most patients. An immediate failure was defined as a positive urine culture during therapy; that is, there was persistence of the pathogen. A long-term cure was defined as the finding of a negative urine culture at 2 weeks after completion of therapy Urine cultures

were

treatment and at 2 weeks

Table I.Characteristics of the 90 patients treated with either sulfamethoxazole alone or trimethoprim-sulfamethoxazole Variable

SMX

TMP-SMX

*

SMX-resistant

=

MIC

>

400 ng of SMX/ml

Table III.Location of urinary tract infection and / or symptoms in the

study group Population Location

10S CMA JOURNAL/JUNE 14,

1975/VOL. 112

SMX

TMP-SMX

Table II lists the bacteria identified and their susceptibility to sulfonamide. Infecting organisms were similar in both treatment groups. It should be noted that the three patients who had Pseudomonas aeruginosa infection were in the TMPSMX-treated group. Also, there were more patients with sulfamethoxazole-resistant organisms in the TMP-SMX-treated group. Table III summarizes the results of localization studies and symptoms before treatment. The majority of patients in both groups had their infection localized to the upper urinary tract. In respect of the location of infection and the symptoms, both treatment groups were similar. Table IV shows the immediate response to treatment and long-term results. In 8 of the 12 patients infected with sulfonamide-resistant organisms the pathogen persisted during the treatment with SMX. In only 1 of 17 patients infected with sulfonamide-resistant organisms did the pathogen persist during treatment with TMP-SMX. This was a 70-year-old man who had chronic Streptococcus faecalis prostatitis. Of 36 patients with an immediate response who were followed up, 10 relapsed after completing 15 days of treatment with SMX. Nine of the 29 who were initially treated successfully with the combination had a recurrence of the same pathogen as determined by follow-up cultures. Overall, SMX cured 54% of patients treated, whereas TMP-SMX cured 72%. In patients infected with sulfonamide-resistant pathogens, 12 of the 17 treated with TMP-SMX were cured, whereas only 2 of 12 such patients were cured with SMX alone. This difference is not significant (P =

0.1).

Fifty women with infection restricted to the upper urinary treated. These patients offered a more homogeneous population for careful comparison of the two therapeutic regimens. Table V shows the long-term results of treatment. Eleven of the 26 treated with SMX alone were cured; these included only 1 of the 8 infected with SMX-resistant pathogens. TMP-SMX was given to 24 women and brought about cure in 5 of 9 infected with SMX-resistant pathogens and in 16 of the 24 who had bacteriuria originating in the upper tract. Analysis of these results by the chi-square test showed no significant difference between these treatment groups. The antimicrobial agents used in this study were accepted well by most patients. Two patients who received SMX alone developed nausea and vomiting and one of these had to be dropped from the study. Of those who received TMP-SMX, four developed nausea and vomiting and four others had such side effects as a maculopapular rash, a sore tongue and buccal mucosa, diarrhea and increased muscular weakness in one patient with pre-existing myotonic muscular dystrophy. No patient developed leukopenia, thrombocytopenia or anemia. tract were

Discussion

with potentially toxic antimicrobial agents. It is well known that bladder infections may resolve spontaneously. As a result the efficacy of an antimicrobial agent must be judged in patients with proved infection of the upper urinary tract. In addition, when the infection is in the kidney, patients may be at greater risk from their disease. In patients who have recurrent urinary tract infections, localization studies should be perform¬ ed to exclude renal involvement even in those who are asymp¬ tomatic or who have symptoms only referable to the lower urinary tract. Such investigation is also useful to prove the presence of upjDer tract infection in patients with upper tract treatment

symptoms.17"^ The combination of TMP and SMX has been shown

by many urinary infections. However, in no study to date has an attempt been made to determine precisely the site of infection prior to therapy. This may explain the varying rates of cure for TMP-SMX (67 to 92%) reported in hospitalized patients.6'7*15 Previously we noted that TMP-SMX cured 91% of 21 women with asymptomatic infection or infection of the lower urinary tract.22 In 50 women with proved infection of the upper urinary tract studied in a randomized double-blind manner, two tablets of TMP-SMX taken twice daily for 15 days cured 16 of 24 (67%), whereas SMX alone cured 12 of 26 (42%). We know of no report of a similar homogeneous group whose results may be compared with our own. TMP-SMX was extremely effective in eradicating pathogens from the urinary tract. This outcome was shown by 39 of 42 patients (93%) treated with TMP-SMX as compared with 36 of 48 (75%) who were given SMX alone. These results are similar to those obtained by Lemieux, who noted eradication of infecting organisms in 14 of 17 patients (82%) and in 13 of 22 (59%) patients treated with TMP-SMX and SMX alone He employed the same dosage as ourselves and respectively.4 studied his patients in a randomized double-blind fashion. In this population 24 of 36 patients (67%) infected with sulfonamide-sensitive organisms and treated with SMX alone were cured. This is comparable with 18 of 25 (72%) similar patients cured with TMP-SMX. These data do not suggest that the combination is more effective than SMX alone in treating

investigators

to be very

therapy

of

Table V.Long-term results of therapy in 50 women with proved infection of the upper urinary tract treated with SMX or TMP-SMX TMP-SMX

SMX

1/8(13%)t

SMX-resistant* SMX-sensitive

10/18(56%) 11/26(42%)

Total

5/9(56%) 11/15(73%) 16/24(67%)

important

determinant of successful treatment of urinary tract infection is the actual site of infection. Women with infection confined to the bladder have been cured with very short courses of treatment and do not require prolonged A most

effective in the

.SMX-resistant

tCured/treated

=

MIC > 400 M9 SMX/ml

Table IV.Immediate and long-term results of therapy

Numbers in parentheses indicate number of patients treated. SMX-resistant MIC > 400 Mg/ml of SMX/ml

.

=

CMA JOURNAL/JUNE

14, 1975/VOL.

112

1 IS

infections with sulfonamide-sensitive organisms. However, Gleckman, in a multicentre cooperative study of patients with chronic urinary tract infections noted that TMP-SMX was significantly better than sulfamethoxazole alone in treating patients with sulfonamide-susceptible organisms.3 Overall, TMP-SMX cured 30 of 42 patients (72%), compared with 26 of 48 (54%) treated with SMX alone. The reason for the superiority of the former seemed to be the greater efficacy of TMP-SMX in curing infections caused by sulfonamide-resistant organisms; it cured 12 of 17 patients (71%) infected with sulfonamide-resistant pathogens as opposed to only 2 of 12 patients (17%) in whom the organism was sulfonamide-resistant. This difference is not significant when analysed by the chi-square test employing the Yates's correction. These results are similar to those obtained by Sourander, Saarimaa and Arvilommi,9 who used three regimens in patients with recurrent infections due to organisms resistant to sulfonamides; the duration of therapy and the dosage used were similar to those we employed. They noted that sulfamethoxazole alone cured only 1 of 12 patients, trimethoprim alone cured 8 of 13 (44%) and the combination cured 21 of 24 (84%).. Gruneberg and Kolbe also reported a cure rate of 81% in hospitalized patients infected with sulfonamide-resistant organisms and treated with TMP-SMX.6 Both antimicrobial agents were accepted well by most patients in our series. In 8 of the 47 who were to have received TMP-SMX undesirable side effects developed, and in 4 these necessitated discontinuance of the drug. This incidence of side effects in patients treated with TMP-SMX is less than that reported by Brumfitt and Pursell, who reported a figure of 15% in a group of 64 domiciliary patients.11 Darrell, Garrod and Waterworth have pointed out that when an organism is initially resistant to sulfonamides, resistance to TMP may emerge on treatment with TMP-SMX.23 In only one instance in this study did an initially susceptible organism become resistant to TMP. A patient with a sulfonamide-resistant E. coil, type 075, originating in the upper urinary tract, relapsed after 15 days of treatment with TMP-SMX. The MIC to TMP increased from 0.39 .g/ml before treatment to 3.1 .g/m1 during relapse. A subsequent 6-week course of treatment with TMP-SMX cured the infection and there has been no subsequent recurrence.

12S CMA JOURNAL/JUNE 14, 1975/VOL. 112

References 1. HARDING GKM, RONALD AR: A controlled study of antimicrobial prophylaxis of recurrent urinary infection in women. N Engi J Med 291: 597, 1974 2. KINCAID-SMITH P. KALOWSKI 5, NANRA RS: Co-trimoxazole in urinary tract infection. Med J Aust (suppl) 1: 49, 1973 3. GLECKMAN RA: A cooperative controlled study of the use of trimethoprim-sulfamethoxazole in chronic urinary tract infections. J Infect Dis 128 (suppi): 647, 1973 4. LEMIEUX G: Trimethoprim-sulfamethoxazole compared with sulfamethoxazole in urinary tract infection. Can Med Assoc J 110: 910, 1974 5. CRICHTON EP, MCDONNELL CE: The combination of trimethoprim and sulfamethoxazole in the treatment of urinary tract infection. Can

MedAssocJ 107: 292, 1972 6. GRUNEBERO RN, KOLBE R: Trimethoprim in the treatment of urinary infections in hospital. Br Med J 1: 545, 1967 7. REEVES DS, FAIERS MC, PURSELL RE, et al: Trimethoprim-sulfamethoxazole: comparative study in urinary infection in hospital. Br Med J 1: 541, 1969 8. BRUMFITT W, PURSELL R: Double-blind trial to compare ampicillin, cephalexin, co-trimoxazole, and trimethoprim in treatment of urinary infection. BrMedJ2: 673, 1972 9. SOURANDER L, SAARIMAA H, ARVILOMMI H: Treatment of

sulfonamide-resistant urinary tract infections with a combination of sulfonamide and trimethoprim. Ada Med Scand 191: 1, 1972 10. DARGIE Hi, ALLISON MEM, MCGEACHIE J, et al: Long-term trimethoprim-sulfamethoxazole in the management of recurrent urinary infection. Scot: Med J 16: 504, 1971 11. BRUMFITT W, PURSELL R: Trimethoprim-sulfamethoxazole in the treatment of bacteriuria in women. J Infect Dis 128(suppl): 657, 1973 12. GAYRAS H, LAWSON DH, LINTON AL: Extended therapy with a trimethoprim-sulfonamide for the treatment of established urinary tract infection. Scott MedJ 16: 506, 1971 13. CATELL WR, CHAMBERLAIN DA, FRY 1K, et al: Long-term control of bacteriuria with trimethoprim-sulfonamide. Br Med J 1: 377, 1971 14. WILLIAMS JD, BRUMFITT W, CONDIE AP, et al: The treatment of bacteriuria in pregnant women with sulfamethoxazole and trimethoprim.

PostgradMedJ45 (suppl): 71, 1969 15. WREN BG: Double-blind trial comparing trimethoprim-sulfamethoxazole (Bactrim) with ampicillin in treating urinary infections. Med J Aust 1: 261, 1972 16. STRATFORD BC, DIXoN 5: Results of treatment of 108 patients using

trimethoprim plus sulfamethoxazole. Med J Aust 1: 526, 1971 17. FAIRLEY KF, BOND AG, BROWN RB, et al: Simple test to determine the site of urinary tract infection. Lancet 2: 427, 1967 18. BOUTROS P, MOURTADA H, RONALD AR: Urinary infection

localization. Am J Obstet Gynecol 112: 379, 1972 19. THOMAS T, SHELoKov A, FORLAND M: Antibody-coated bacteria in the urine and the site of urinary tract infection. N Engi J Med 290: 588, 1974 20. EDWARDS PR, EWING WH: Identification of enterobacteriaceae.

third ed. Minneapolis, Burgess, 1972 21. STEERS E, FOLTZ EL, GRAVES BS: Inocula replicating apparatus for routine testing of bacterial susceptibility to antibiotics. Antibiot Chemoth-

er9: 307, 1959 22. HARDING GKM, RONALD AR: Efficacy of trimethoprim-sulfame-

thoxazole in bacteriuria. J Infect Dis 1 28(suppl): 641, 1973

23. DARRELL JH, GARROD LP, WATERWORTH PM: Trimethoprim:

laboratory and clinical studies. J Clin Pathol 21: 202, 1968