Clinical Report Chemotherapy 19: 314-321 (1973) Efficacy of Trimethoprim, Sulfamethoxazole and the Combination of Both in Acute Urinary Tract Infection Clinical and Pharmacokinetical Studies U. J. Koch, K. P. Schumann, R. Küchler and H. Kewitz Frauenklinik und -poliklinik, Institut für Klinische Chemie und Klinische Biochemie, Institut für Hygiene und Medizinische Mikrobiologie und Institut für Klinische Pharmakologie im Klinikum Steglitz der Freien Universität Berlin Abstract. The effectiveness of sulfamethoxazole Key Words (SMZ; 13 patients), trimethoprim (TMP; 23 patients), Trimethoprim and the combination of both (39 patients) in therapy Sulfamethoxazole for acute urinary tract infections after major gynecol Combination ogical operations has been studied. Plasma concentra Pharmacokinetics tions of TMP and SMZ were measured on the 1st Urinary tract infections and 5th days of treatment before as well as 4, 7 and 12 h after administering the drugs. No difference was found between TMP and TMP/SMZ, although there are minor differences in the antibacterial spectrum. Treatment with TMP alone is superior to the combined regimen due to a smaller in cidence of side effects; thus, in addition to the combination with SMZ, introduction of TMP alone on the market is recommended. In a previous paper  we reported on comparative studies on the antibacterial action of trimethoprim (TMP), sulfamethoxazole (SMZ), and their combination (TMP/SMZ) in vitro. We concluded that TMP alone is often as effective as its combination with SMZ. Other investiga tors found that the efficacy of TMP was equal to the combination of TMP/SMZ in acute urinary tract infections [26, 27]. The combined administration of two chemotherapeutics is only recom mended for a few specified reasons: for example, to enlarge the antibac terial spectrum, to intensify antibacterial activity, or to prevent chemoresistance. But the combination may at the same time increase the frequency Downloaded by: Vanderbilt University Library 188.8.131.52 - 10/27/2017 12:35:16 PM Introduction Koch/Schumann/K uchler/Kewitz 315 of adverse reactions. Therefore, it has to be shown under what conditions the combination is superior to the single components. This paper reports on the results of the treatment with TMP, SMZ, and their combination in acute urinary tract infections occurring after ma jor gynecological operations. The plasma concentrations of the two com pounds were estimated routinely in all patients in order to make sure that the drugs were present at effective levels. Material and Methods 1 The tablets were kindly supplied by Hoffmann-La Roche, Grenzach. Downloaded by: Vanderbilt University Library 184.108.40.206 - 10/27/2017 12:35:16 PM Patients. 75 women, ranging from 32 to 77 years, who suffered from acute uri nary tract infection after gynecological surgery were treated. Table I gives the types of operation preceding investigation of urinary tract infection treatment. No patient had a history of former urinary tract infection. Diagnosis of acute urinary tract infection. Diagnosis was based on history (uri nary frequency, burning on urination, and continual urge to void), leukocyte count of noncentrifuged urine in counting chamber, and bacteriological examination. Pa tients were catheterized routinely on the day before and 5 days after surgery. If there were major complaints, postoperative catheterization was performed earlier. Bacteriological cultures from the urine samples were inoculated within 4 h after catheterization. The bacterial count was determined semiquantitatively by spreading 0.01 ml urine evenly on a sheep-blood agar plate and by counting the colonies after 18 h of incubation at 37 °C . Therapy and clinical observation. Therapy was initiated only after the results of bacteriological, chemical (i.e. total protein content of serum, electrophoresis, and creatinine) and microscopic data (e.g. leukocytes and erythrocytes in urine) were ob tained. Depending on the results of the bacteriological tests, either TMP or SMZ alone or TMP/SMZ were given. The individual doses of the compounds were as follows: SMZ: 2 X 3 tablets daily, each tablet containing 400 mg SMZ; TMP: 2 X 3 tablets daily, each tablet containing 80 mg TMP; TMP/SMZ: 2 X 3 tablets daily, each tab let containing 400 mg SMZ and 80 mg TMP. The tablets were administered at 8 a.m. and 8 p.m.; 13 patients were treated with SMZ, 23 with TMP, and 39 with TMP/SMZ.1 To check treatment, urine samples were studied microscopically and bacteriologically before onset of the antibacterial treatment. This occurred on the 5th day of treatment and 2-4 weeks after the end of treatment. On the 1st and 5th days of treatment, urine was collected during a 24-hour period to determine the excretion of TMP and SMZ. Serum protein, electrophoresis, and serum creatinine were checked once between the 1st and 5th days of treatment. Blood examinations for leukocytes, erythrocytes and thrombocytes were performed before, during, and after the course of treatment. To measure TMP and SMZ concentrations in plasma, 10 ml of blood were col lected on the 1st and 5th days of treatment at 8 a.m., 11 a.m., 3 p.m., and 8 p.m. 316 Koch et al. Efficacy of Trimethoprim, Sulfamethoxazole and the Table /. Type of gynecological operation preceding investigation of acute urinary tract infection treatment Chemotherapeutic drug Number of patients Type of operation SMZ 13 TMP 23 TMP/SMZ 39 vaginal hysterectomy/colporrhaphy (6) abdominal hysterectomy/adnexectomy (6) abdominal radical operation (Wertheim) (1) abdominal hysterectomy (1) abdominal hysterectomy/adnexectomy (12) vaginal hysterectomy/colporrhaphy (9) vulvectomy (1) abdominal hysterectomy (1) abdominal hysterectomy/adnexectomy (18) vaginal hysterectomy/colporrhaphy (19) antefixatior. (Baldy)/adhesiotomy (1) sectio parva/sterilization (1) Immediately after collection, the samples were centrifuged. In the morning and at night the samples were obtained directly before applying the drugs. The treatment was withdrawn if the bacteriological examination on the 5th day resulted in ‘no growth’ and the patients were free of complaints. In no case did the period of medication last longer than 10 days. Determination of TMP and SMZ concentrations in plasma and urine. TMP con centrations were quantitated according to Schwartz et al. . Total sulfonamide was analyzed by the Bratton-Marshall reaction as suggested by R ieder . All de terminations were done in triplicate. Statistical analysis followed standard proce dures (Student test) . Success of therapy was assumed if the examination was negative 2-4 weeks after the end of antibacterial treatment. Results Downloaded by: Vanderbilt University Library 220.127.116.11 - 10/27/2017 12:35:16 PM The clinical results after treatment with TMP, SMZ, or TMP/SMZ are presented in table II. The side effects that were observed in the course of treatment are reported in table III. Additional side effects were observed in only one patient of the TMP group, who suffered from an acute, re versible leukopenia. The concentrations of TMP and SMZ, as observed at various times on days 1 and 5 of treatment, are presented in table IV. The average sulfon amide concentrations on the 1st day of treatment were significantly higher with SMZ alone than with TMP/SMZ (11a.m.: p<0.1; 3 and 8 p.m.: p<0.0125). Combination of Both in Acute Urinary Tract Infection 317 Table II. Treatment and results in infections with various species of bacteria Course of treatment Number of patients Species of bacteria E. coli Enterococcus Proteus Staph, aureus Klebsiella SMZ Total 13 Successful 12 12 11 1 1 - 1 1 14 14 6 5 3 3 4 4 24 23 23 23 5 4 7 7 - - - TMP Total 23 Successful 22 - - TMP/SMZ Total 39 Successful 37 4 4 Course of treatment Gastrointestinal irritations Exanthema SMZ (n = 15) TMP (n = 23) TMP/SMZ (n = 39) 7 6 16 1 3 On the 5th day of treatment, total sulfonamide concentrations after combined therapy with TMP were significantly higher than after applica tion of SMZ alone (8 a.m. and 8 p.m.: p<0.0125; 11a.m. and 3 p.m.: 0.0125<p<0.025). The highest levels of total sulfonamide were observed at 3 p.m. on day 1 of treatment and at 11 a.m. on day 5. The highest levels of TMP were found at 11 a.m. on both days 1 and 5 of therapy. The TMP concentra tions on the 1st day of medication were almost identical in patients treat ed with TMP alone or with TMP/SMZ. On the 5th day of treatment TMP levels after administration of TMP alone were significantly higher than after combined therapy with SMZ (8 a.m.: p<0.05; 11 a.m.: 0.0005<p<0.0025; 3 p.m.: 0.0125<p<0.025; 8 p.m.: 0.025<p<0.05). The levels of TMP and SMZ in urine were even higher than in plasma. Downloaded by: Vanderbilt University Library 18.104.22.168 - 10/27/2017 12:35:16 PM Table III. Most frequent side effects during the course of treatment with TMP, SMZ, or TMP/SMZ 318 K och et al. Efficacy of Trimethoprim, Sulfamethoxazole and the Table IV. Concentrations (//g/ml) of TMP and SMZ in plasma Time SMZ X TMP s minimal maximal n After administration o f the single compounds 1st day 8 a.m. 0 12 11 a.m. 87.3 40.9 19-159 12 3 p.m. 99.1 38.2 47-174 10 8 p.m. 75.9 35.3 34-141 10 5th day 8 a.m. 75.1 17.7 52-103 11 11 a.m. 119.4 25.3 66-152 11 3 p.m. 99.5 18.1 75-128 11 8 p.m. 74.7 13.7 56-97 11 After combined administration o f TMP and SM Z 1st day 8 a.m. 0 22 11 a.m. 66.5 32.9 22-136 22 3 p.m. 72.8 23.4 32-130 22 8 p.m. 51.5 19.4 20-94 19 5th day 8 a.m. 96.7 26.8 56-149 20 11 a.m. 140.3 25.6 117-194 19 3 p.m. 117.6 24.8 66-168 20 8 p.m. 98.7 34.0 56-168 18 X s minimal maximal 0 2.51 1.97 1.35 0.86 0.57 0.41 1.10-4.40 1.30-3.10 0.50-1.90 17 17 17 16 2.30 4.52 3.49 2.28 0.90 1.02 1.05 0.74 0.90-3.72 2.38-6.10 1.51-5.18 1.25-3.56 12 13 13 13 0 2.63 1.99 1.43 0.60 0.44 0.39 1.86-3.42 1.10-2.84 0.70-2.08 21 17 20 18 1.84 3.46 2.79 1.84 0.67 0.81 0.84 0.62 1.04-3.91 1.70-5.00 1.92-5.70 1.22-3.53 20 17 18 16 n Discussion Downloaded by: Vanderbilt University Library 22.214.171.124 - 10/27/2017 12:35:16 PM Based on the results of bacteriological examination and sensitivity tests, no difference in the therapeutical effectiveness of the three treat ments was observed in our study. Similar results have been reported by other investigators [26, 27J. The one failure in the SMZ group was due to an error in interpretation of isolated bacteria in the agar diffusion test. In the TMP group there was one case of chronical pyelonephritis which had not been recognized prior to surgery; this patient was not treated long enough to allow a final judgement on effectiveness. In the TMP/SMZ group there were two therapeutical failures. One was due to a re-infection with a different bacterium; the other patient was suffering from subchronical pyelonephritis which was not treated sufficiently. Further treatment of this case also proved to be rather difficult. Combination of Both in Acute Urinary Tract Infection 319 According to our measurements, the recommended standard doses lead to fully effective plasma concentrations of the single compounds: the lowest plasma concentration of TMP observed in the course of this study was 0.9 jUg/ml with a mean value of 2.3 ±0.9 .«g/ml 12 h after repeated administration. The lowest plasma concentration of total sulfonamide was 52 /rg/ml with a mean value of 75.1 ± 17.7 ;tg/ml 12 h after repeated administration. Sensitivity of bacteria towards TMP and SMZ was as sumed if the minimal inhibiting concentration was less than 0.75 and 12.5 /tg/ml, respectively. Concentrations of the two compounds are even higher in urine [8, 32-34], According to our results, the biological half-life of SMZ is 13.2 h, that of TMP 9.2 h. Schwartz and R ieder  reported a mean biological TMP half-life of 8.6 h. The difference in mean plasma concen trations of SMZ after single and combined administrations are obscure. Patients receiving TMP alone had considerably less complaints than patients taking SMZ or TMP/SMZ. These include gastrointestinal dis turbances as well as allergic exanthemas. The frequency of gastrointestin al distress was high in all groups, because patients were few after surgery, and the drugs were given before meals. One additional adverse reaction after treatment with TMP alone was found in one patient, i.e. a reversi ble, acute leukopenia. Allergic exanthemas, as appearing in the SMZ groups, were reported with similar frequency by other investigators [27, 35], Exanthemas have not yet been observed after administration of TMP alone. According to the results reported here and elsewhere in the literature [26, 27], TMP is equally effective alone as in combination with SMZ when treating acute urinary tract infection, although a synergism has been reported in treating chronic pyelonephritis, gonorrhea, and in animal ex periments [4-7, 9-16, 20, 22, 26]. Considering the frequency of adverse reactions, therapy of acute uri nary tract infections with TMP alone is superior to the combined regi men. Introduction on the market of a TMP preparation for treatment of acute urinary tract infections is therefore desirable. 1 Beck, H. and P echere, J. C.: Pharmacodynamic activity of Bactrim Roche in man, a combination of trimethoprim with sulfamethoxazole. 6th Int. Congr. Chemotherapy, Tokyo 1969. Downloaded by: Vanderbilt University Library 126.96.36.199 - 10/27/2017 12:35:16 PM References 320 Koch et al. Efficacy of Trimethoprim, Sulfamethoxazole and the 2 Bergan, T. and Brodwall, E. K.: Renal excretion of sulfamethoxazole and tri methoprim. 7th Int. Congr. Chemotherapy, Prague 1971. 3 Biro, L.; Ivan, E.; Perenyi, T., and M agdolna, A.: Clinicopharmacological and experimental investigations with trimethoprim and sulfonamide combinations. 7th Int. Congr. Chemotherapy, Prague 1971. 4 Böhm, E.: Über antibakterielle Eigenschaften der Kombination Trimethoprim/ Sulfamethoxazol im Vergleich mit Antibiotika. Schweiz, med. Wschr. 99: 1505 (1969). 5 Böhni, E.: Sensitivity testing and outcome of therapy with the combination trimethoprim/sulfamethoxazole in patients with urinary tract infections. Proc. 6th Int. Congr. Chemotherapy 1: 975 (1969). 6 Böhni, E.: Vergleichende bakteriologische Untersuchungen mit der Kombination Trimethoprim/Sulfamethoxazol in vitro und in vivo. Chemotherapy 14: suppl., p. 1 (1969). 7 Böhni, E.: Chemotherapeutic activity of the combination trimethoprim and sul famethoxazole in infections of mice. Postgrad, med. J. 45: suppl., p. 18 (1969). 8 Brumfitt, W.; F aiers, M. C.; P ursell, R. E.; R eeves, D. S., and T urnbull, A. R.: Bacteriological, pharmacological and clinical studies with trimethoprimsulphonamide combinations. Postgrad, med. J. 45: suppl., p. 56 (1969). 9 Bushby, S. R. M.: Trimethoprim and sulphonamides. Laboratory studies. Sth afr. med. J., suppl., p. 1 (1970). 10 Bushby, S. R. M.: Combined antibacterial action in vitro of trimethoprim and sulphonamides. The in vitro nature of synergy. Postgrad, med. J. 45: suppl., p. 10 (1969). 11 Bushby, S. R. M. and H itchings, G. H.: Trimethoprim, a sulphonamide poten tiator. Brit. J. Pharmacol. 33: 72 (1968). 12 Cox, C. E. and M ontgomery, W. G.: Combined trimethoprim-sulfisoxazole therapy of urinary infections. Postgrad, med. J. 45: suppl., p. 65 (1969). 13 C sonka, G. W.: Therapeutic trial of some genital infections with trimethoprimsulphamethoxazole. Postgrad, med. J. 45: suppl., p. 77 (1969). 14 Csonka, G. W. and Knight, G. J.: Therapeutic trial of trimethoprim as poten tiator of sulphonamides in gonorrhoea. Brit. J. vener. Dis. 43: 161 (1967). 15 D arrell, J. H.; G arrod, L. P., and Waterworth, P. M.: Trimethoprim: labora tory and clinical studies. J. clin. Path. 21: 202 (1968). 16 D ornbusch, K.: Regression line analysis of the synergistic effect for the combi nation of trimethoprim/sulphamethoxazole. Chemotherapy 16: 229 (1971). 17 G allien, R. und Schönfeld, H.: Antibakterielle Wirksamkeit sulphonamidhaltiger Kombinationspräparate. Diagnostik 5: 427 (1972). 18 G allien, R. and Schönfeld, H.: Untersuchungen zur Frage der Resistenz Downloaded by: Vanderbilt University Library 188.8.131.52 - 10/27/2017 12:35:16 PM prüfung von Bakterien gegen Wirkstoffkombinationen am Beispiel der Kombina tion Trimethoprim und Sulfamethoxazol. Arzneimittelforsch. 21: 577 (1971). 19 G arrod, L. P.: The possible scope of trimethoprim-sulphonamide treatment. Postgrad, med. J. 45: suppl., p. 52 (1969). 20 G runberg, E. and D e Lorenzo, W. F.: Potentiation of sulfonamides and anti biotics by trimethoprim. Proc. 6th Int. Intersci. Conf. on Antimicrobial Agents and Chemotherapy, Philadelphia 1966, p. 430. 21 G rüneberg, R. N. and K olbe, R.: Trimethoprim in the treatment of urinary infections in hospital. Brit. med. J. i: 545 (1969). Combination of Both in Acute Urinary Tract Infection 321 Request reprints from: Dr. U. J. Koch (Ass. Prof.), Frauenklinik und -poliklinik, Klinikum Steglitz der Freien Universität Berlin, Hindenburgdamm 30, D-l Berlin 45 (FRG) Downloaded by: Vanderbilt University Library 184.108.40.206 - 10/27/2017 12:35:16 PM 22 H itchings, G. H.: Species differences among dihydrofolate reductases as basis for chemotherapy. Postgrad, med. J. 45: suppl., p. 7 (1969). 23 H oignL, R.; Bartholome-Pat6, J. und M üller, U.: Die Beurteilung des Be handlungserfolgs bei Harnwegsinfektionen auf Grund quantitativer Bestimmung von Bakteriurie und Leukozyturie. Schweiz, med. Wschr. 98: 1939 (1968). 24 H oigne, R. und K eller, M. F.: Bewährtes und Neues in der Chemotherapie der Infektionskrankheiten. Schweiz, med. Wschr. 102: 933 (1972). 25 H oignL, R.; M üller, U. und E lmiger, J.: Trimethoprim, Sulfamethoxazol und die Kombination beider Präparate bei Infektionen der Harnwege. Proc. 5th Int. Congr. Infect. Dis., Vienna 1970, p. 6. 26 H oigne, R.; M üller, U., and Schneider, H. R.: A comparison of chemothera py in patients with urinary tract infections using trimethoprim alone and in com bination with sulfamethoxazole. Proc. 6th Int. Congr. Chemotherapy, Tokyo 1969, p. 971. 27 HoiGNfe, R.; Müller, U. und Schneider, H. R.: Bactrim Roche, ein Kombinationspräparat von Sulfamethoxazol und Trimethoprim. Schweiz, med. Wschr. 99: 1511 (1969). 28 K üchler, R. and K och, U. J.: The in vitro demonstration of the efficacy of tri methoprim as an antibacterial agent in a comparative bacteriological study on the effects of trimethoprim, sulfamethoxazole and the combination trimethoprim/sulfamethoxazole. Chemotherapy 18: 242 (1973). 29 Reeves, D. S.; F aiers, M. C.; Pursell, R. E., and Brumfitt, W.: Trimethoprimsulfamethoxazole: comparative study in urinary infection in hospital. Brit. med. J. i: 541 (1969). 30 R ieder, J.; F ernex, M.; Schwartz, D. E.; Brodwall, E. K.; Bergan, T.; Blumberg, A.; C ottiert, P.; Locher, G., and Scheitlin, W.: Pharmacokinetic data of the combination of sulfamethoxazole plus trimethoprim in patients with renal impairment. 7th Int. Congr. Chemotherapy, Prague 1971. 31 Schwartz, D. E.; Koechlin, B. A., and Weinfeld, R. E.: Spectrofluorimetric method for the determination of trimethoprim in body fluids. Chemotherapy 14: suppl., p. 22 (1969). 32 Schwartz, D. E. and R ieder, J.: Pharmacokinetics of sulfamethoxazole and tri methoprim in man and their distribution in the rat. Chemotherapy 15: 337 (1970). 33 Schwartz, D. E. and Z iegler, W. H.: Assay and pharmacokinetics of trimetho prim in man and animals. Postgrad, med. J. 45: suppl., p. 32 (1969). 34 Sharpstone, P.: The renal handling of trimethoprim and sulfamethoxazole in man. Postgrad, med. J. 45: suppl., p. 38 (1969). 35 Stockhausen, G. und F elbier, R.: Erfahrungen (Feldstudie) mit einem neuen Breitband-Bakterizidum. Z. allg. Med. 49: 691 (1973). 36 R ieder, J.: Quantitative determination of the bacteriostatically active fraction of sulfonamides and the sum of their inactive metabolites in the body fluids. Commun. Depart. Exp. Med., Hoffmann-La Roche, Basel. 37 Sachs, L.: Statistische Auswertungsmethoden (Springer, Berlin 1969).