Comparison of trimethoprim in combination with sulfadiazine or sulfamethoxazole in the treatment of urinary tract infections.
In recent years high degree of resistance of urinary pathogens to antibacterial agents has led to the search for newer drugs. These drugs have been used singly or in combination of two drugs with action at different sites on the microbes. Co-trimoxazole, which is a combination of antifolic acid agents, trimethoprim (TMP) and sulfamethoxazole (SMZ) was developed as an example of such a strategy. Trimethoprim and sulfamethoxazole act at different stages in the synthesis of folic acid in the formation of DNA. Trimethoprim alone, in adequate doses, has been reported to be effective in the treatment of urinary tract infections. The present study was carried out to evaluate the efficacy of a new combination of trimethoprim (TMP) and sulfadiazine (SD) as compared to TMP and SMZ.
Patients suffering from uncomplicated urinary tract infection confirmed by urine culture from the sample obtained either by suprapubic bladder puncture or 3 mid-stream urine (M.S.U.) samples, were chosen for the trial. The urine samples were studied for significant bacteriuria (colony count of more than 105 organisms/ml) by dip-slide inoculum method, whenever M.S.U. sample was obtained. The sensitivity test was performed by impregnated disc method as described by Bauer et ale using sensitivity disc of TMP (1.25 µg) + SD (23.75 µg) and TMP (1.25 µg) + SMZ (23.75 µg). Of the 37 patients taken for the randomized double blind trial, 19 patients received TMP 75 mg with SD 225 mg (drug A) and 18 patients were given TMP 80 mg with SMZ 400 mg (drug B). Ten out of the total of 19 patients on drug A were hospitalized and the remaining were treated in the out-patient department (O.P.D.). For drug B trial, there were 9 patients in each group of the hospitalized and O.P.D. patients.
Since the correlation between in vitro and in vivo test is lacking on many occasions, we have also included in the trial in vitro resistant cases [Table - 1]. Out of the 19 patients on drug A group and 18 patients on drug B group treatment, 5 and 7 patients respectively were found to be resistant in in vitro test. The rest of the patients in both treatment groups were categorised as sensitive.
Dysuria burning micturition, pain in the abdomen and fever were the major symptoms which were equally distributed in both groups.
Clinical, biochemical, haematological and microbiological evaluations were carried out before starting the drug therapy. Microbiological investigations were repeated on the 3rd, 7th and 14th day of the trial.
Biochemical (urea nitrogen, plasma bicarbonate, electrolytes, creatinine, bilirubin, SCOT, SGPT, alkaline phosphatase and blood sugar) and haematological (complete blood count and erythrocyte sedimentation rate) examinations were repeated on the 14th day of the trial.
Clinical evaluation was conducted daily but for recording and analysis it was considered on weekly basis. Both groups received 2 tablets of each drug twice a day for 14 days.
The patients on drug A were between 11 and 66 years of age. There were 4 males in the age group of 22 to 58 and 15 females between 11 and 66 years. The age group of patients on drug B was between 15 and 65 of which 7 males were between the range of 46 to 65 years and 11 females were between 15 and 65 years of age. Thirty-six out of the total 37 patients completed the trial. One 30 year old female patient who was receiving TMP with SD expired on the 15th day of the trial due to a cause not related to the drug therapy. Her urine culture and sensitivity response on the 3rd day of the trial was classified as 'good'.
Out of 367 strains isolated from urine and screened for in vitro sensitivity tests, 20.5% were sensitive to TMP with SD combination as compared to 23.9% found sensitive to TMP with SMZ combination. The difference was statistically not significant however, there was a high degree of in vitro resistance to both combinations.
The response was considered as `good' when there was symptomatic improvement and the urine culture became sterile on the 3rd day and remained so thereafter during the course of the trial. Symptomatic improvement and initial recovery from the infection on the 3rd and 7th days but relapse or reinfection due to other organisms on the 14th day was considered as `partial' response. `Poor' response was recorded when there was no symptomatic improvement and the urinary tract infection persisted throughout the trial period. [Table - 2] shows respective grades of response in both the drugs A and B. E. coli was the commonest organism, isolated in 14 patients on drug A and 8 patients on drug B. The next common organism in drug B group was Klebsiella (7 cases).
Out of 19 patients on TMP with SD, 14 were categorised as good responders whereas one patient gave partial response. Remaining 4 patients responded poorly. In TMP with SMZ group, 11 showed good, 3 partial and 4 poor responses. Sensitivity and resistance of organisms in in vitro urine culture and sensitivity and the corresponding response in vivo to drug A or B are shown in [Table - 1].
Dysuria, burning micturition, abdominal pain, fever, haematuria, puffiness of the face, weakness and itching were present in both groups of patients. Of these, the first four symptoms were the commonest in both groups. There were patients with mixed symptoms also.
Seven out of 19 patients on TMP and SD were asymptomatic on the first day of the trial but showed significant bacteriuria. One patient had fever which disappeared in one week. Seven out of the 8 patients who had burning and frequency of micturition and loin tenderness improved in one week. The remaining patients did not improve at the end of the trial. Two out of 3 patients with fever; burning micturition along with frequency and loin tenderness improved symptomatically in the first week. In the 3rd patient, fever came down at the end of the 2nd week. Eight. out of the 18 patients on TA/1P with SMZ (drug B) were asymptomatic clinically. One patient who had fever responded in the first week. Four out of the 6 patients with burning micturition with frequency and loin tenderness improved in one week. The remaining two patients responded after two weeks. Three patients who complained of dysuria, burning micturition, abdominal pairs and fever were asymptomatic at the end of the first week.
One patient on TMP with SD developed generalised, mild, macular rash on the second day of the therapy but the trial was not discontinued and the skin rash disappeared in due course. One patient complained of nausea and vomiting on the third day. He vomited only once and tolerated the drug later. There was no significant difference in biochemical, haematological and liver function tests on the 1st and 14th day of the trial in both the groups. Two patients who, had mild azotemia showed good response clinically.
Investigations have shown that TMP used in combination with sulfamethoxazole (SMZ) invariably enhanced the response to SMZ, when bacteria were sensitive to both the drugs.,  Thus, the combination of TMP with SMZ was proved to be highly effective in urinary tract infection. On the other hand, when bacteria were resistant to SMZ, the synergistic activity of TMP-SMZ was not constantly observed in vitro. Hence a search was deemed essential to find out another variety of sulfonamide which may still be effective along with TMP even in cases that were resistant to SMZ. Statistical analysis of our data in confirmation with others revealed that TMP with SD combination is as effective as TMP with SMZ combination in urinary tract infections and both combinations were equally well tolerated. Thus it appears that a combination of any one form of sulfonamide with TMP is probably equally effective as compared to any other form. It must be noted here that the resistance against the combinations of various forms of sulfonamides with trimethoprim is increasing rapidly day by day. Our own experience over the past 8 years has shown increasing resistance to TMP with SAM and TMP with sulfamoxole (Supristol) combinations from 72% to 82% and 70% to 78% respectively. The increasing resistance to various combinations may be due to the development of resistance to various forms of sulfonamides which was about 97%.6 Several clinical studies, ,  suggest that TMP given alone may be as effective as TMP + SMZ in patients with chronic urinary tract infections without underlying gross anatomic changes. The potential advantage of single drug therapy is in its utility in patients who are allergic to sulfonamides, but there is a possible disadvantage of producing TMP resistant bacteria. The superiority of TMP alone over the combination is not established and needs further studies. Because of such concern about the upsurge of resistant organisms to TMP alone or the combination, indiscriminate use of these valuable drugs should be avoided.
We thank the Dean, Seth G.S. Medical College and K.E.M. Hospital, Bombay, for permitting us to use the hospital data. We also thank M/s. Anglo French Drug Co. (Eastern) India for supplying the drugs.