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The Treatment of Bacillus Coli and Bacillus Proteus Infections of the Urinary Tract with a New Sulfonamide (Nu-445)1
THE TREATMENT OF BACILLUS COLI AND BACILLUS PROTEUS INFECTIONS OF THE URINARY TRACT WITH A NEW SULFONAMIDE (NU-445) 1 LESTER NARINS
From the Genito-Urinary Surgical Service, Beth Israel Hospital, New York, N. Y.
The management of chronic urinary tract infections, especially those caused by Bacillus coli and Bacillus proteus often poses a difficult problem. In an effort to sterilize the urine, urologists have used a variety of chemotherapeutic agents including acidifiers, the sulfonamides, penicillin, and finally what appeared to be the long sought for panacea, streptomycin. 2 , 3 , 4 Not one of these agents has been found to be universally or even consistently e:fficacious. 5 The acidifiers, including mandelic acid, sodium acid phosphate, etc., are the least toxic as evidenced by a minimum of by-effects, and occasionally, they are fairly effective. The sulfonamides, including sulfanilamide, sulfathiazole, sulfadiazine, etc., are very frequently without value in combating Proteus or the colon bacillus and may be potentially dangerous by eliciting serious sidereactions such as agranulocytosis, hemolysis, rash, or crystallization with urinary tract obstruction. Penicillin is almost completely ineffectual against infections in which gram-negative bacilli are the offending organisms. 5 While streptomycin appears to be immediately bacteriostatic in chronic urinary tract infections due to Bacillus coli or Bacillus proteus, it soon loses its activity since these organisms tend to develop a strong resistance to it. 6 , 7 , 8 Furthermore, streptomycin has the disadvantage of requiring frequent and often painful intramuscular injections and it may cause such reactions as deafness, vestibular symptoms and rashes. Hence, the search for a non-toxic agent which is effective against these types of urinary tract infection still continues. With this in mind, it was decided to investigate the therapeutic value of a new sulfonamide, namely, 3 ,4-dimethyl-5-sulfanilamido-isoxazole, which was supplied under the designation NU-445. 1 This drug has proved to be effective against Bacillus coli and Bacillus proteus both in vitro and in vivo (animal ex1 The NU-445 was generously supplied by Dr. Leo A. Pirk of Hoffmann-La Roche Inc., Nutley, New Jersey. 2 SCHATZ, A., BuGrn, E. AND WAKSMAN, S. A.: Streptomycin, a substance exhibiting antibiotic activity against gram-positive and gram-negative bacteria. Proc. Soc. Exper. Biol. and Med., 65: 66-69, 1944. • 3 PULASKI, E. J.: Streptomycin in surgical infections; infections of the genito-urinary tract. Ann. Surg., 124: 392-401, 1946. ~ HELMHOLZ, H.F.: The effect of streptomycin on bacteria commonly found in urinary tract infections, Proc. Staff Meet. Mayo Olin., 20: 357-362, 1945. 6 PooL, T. L. AND OooK, E. N.: Present concepts of treatment of infectiollB of the urinary tract. J. A. M.A., 133: 584-587, 1947. 6 ADCOCK, J. D. AND PLUMB, R. T.: Streptomycin for urinary tract infectioM. J. A. M.A., 133: 579-584, 1947. 7 KNOP, 0. Q.: Experimental study of the development of resistance to streptomycin by some bacteria commonly found in urinary tract infections. Proc. Staff Meet. Mayo Olin., 21: 273-276, 1946. 8 FINLAND, M., MURRAY, R., HARRIS, H. W., KILHAM, L. AND MEADS, M.: Development of streptomycin resistance during treatment. J. A. M.A., 132: 16-21, 1946. 92
93
TREATMENT OF INFECTIONS OF URINARY TRACT
periments) and is distinguished by extremely low toxicity. Another outstanding property of NU-445 is its solubility which is strikingly greater than that of other commonly used sulfonamides in the pH range 5.5-6.5. 9 , 10 The experimental compound was administered to 50 consecutive patients with urinary tract infections due to Bacillus coli and/ or Bacillus proteus. The patients were taken from the Genito-Urinary Surgical Service of the Beth Israel Hospital in New York and partly from private practice. The types and numbers of cases treated are shown in table 1. TABLE 1 RESULTS TYPE OF CASES
NUMBER
Perineal prostatectomy Suprapubic prostatectomy
7 7
Transurethral prostatectomy Vesical calculi Permanent nephrostomy Pyelonephritis Nephrectomy Pyelolithotomy Chronic cystitis Periurethral phlegmon Carcinoma of bladder Perinea! fistula Carcinoma of kidney Prostatic abscess Nephropexy Chronic prostatitis
7 5 1 5 1 2
1 1 1 1
Total .............. ........
50
6
1 3 1
FORM OF DRAINAGE
Foley's catheter Indwelling suprapubic tube or urethral catheter Foley's catheter Suprapubic tube N ephrostomy tube None None None None None Suprapubic tube Urethral catheter None Suprapubic tube None None
Cures
Failures
1 1
6
2 1 0 4 0 1 3 0 2
6
5 4 1 1 1 1 3 1 1
0 1 0 1 1
l 0 1
18
32
0 0
The dosage plan was as follows: The first 24 patients received 1.5 gm. q.i.d., a total daily dose of 6 gm. With the exception of 4 cases in which medication had to be discontinued because of toxic symptoms (dermatitis in 2 and nausea in 2), NU-445 was given over periods of time ranging from 6 to 60 days, depending on the response of the patient. Since clinical results in this group fell short of expectations, the total daily dose for the subsequent 26 patients was increased to 8 gm., given in 4 equally divided doses. In this group, NU-445 was administered for from 5 to 57 days. In the majority of cases, however, the period of treatment was 12 days or less. Generally, treatment was continued until a bacteriological reversal occurred or until clinical ineffectiveness of the drug became apparent. For all patients routine urine analyses, complete blood counts and determinaPersonal communication from the Medical Department of Hoffmann-La Roche. SARNOFF, S. J., FREEDMAN, M. A. AND HYMAN, A. A.: The treatment of Bacillus proteus infections with NU-445. J. Urol., 66: 417---427, 1946. 9
10
94
LESTER NARINS
tions of blood levels of NU-445 were carried out semi-weekly. Smears of the urinary sediment were examined at frequent intervals. Similarly, urinary sediments were transferred to blood agar and Endo's medium and inoculated in broth with subsequent study of the bacteriological cultures thus obtained. The appraisal of clinical results was solely on the basis of bacteriological findings. Cures were assumed if urine cultures remained negative for at least 2 weeks following cessation of therapy. Many patients in whom there was no bacteriological cure were greatly improved clinically, but these were not counted as positive results. Table 2 shows the number of unmixed infections due to Bacillus coli and Bacillus proteus and the number of mixed infections treated at the 2 dosage levels. TABLE
2 NtJMBER Oll' CASES
TYPE Oll' INFECTION
6 gm. NU-445 daily
8 gm. NU-445 daily
9
9
5
7
6
10
Bacillus coli .............................. . Bacillus proteus ........................... . Mixed infections due to Bacillus proteus and Bacillus coli ............................. .
26
20
46*
Total ................................... .
* The 4 cases in which therapy wa.s stopped early because of side reactions are excluded from this table. The results attained appear in table 3. In tabulating the results, each of the two offending organisms of the mixed infections was counted separately and therefore, the number of results listed is seemingly gTeater than the number of patients. It is obvious that Bacillus coli infections responded more readily to NU-445 than Bacillus proteus infections and that the increase of dosage to 8 gm. was attended by an increase in good results with regard to both types of infections. TABLE 3 RESULTS TYPE Oll' lNll'ECTION
Bacillus coli Bacillus proteus
6 gm. NU-445 daily Cures
8 gm. NU-445 daily
Failures
Cures
Failures
7 (46.6%)
8 (53.4%)
11
(57.9%)
8 (12.1%)
2 (18.2%)
9 (81.8%)
8 (47.1%)
9 (52.9%)
(The percentages refer to the number of infections with a given organism treated at that particular dosage level.)
TREATMENT OF INFECTIONS OF URINARY TRACT
95
Thus, :in the patients affected with Bacillus coli, there were 46.6 per cent cures on a daily dosage level of 6 gm. as compared with 57.9 per cent when the daily :intake was raised to 8 gm. The :incidence of cures was even more strikingly :increased with the heighten:ing of the dose :in the Bacillus proteus infections (18.2 per cent cures on 6 gm., as against 47.l per cent on 8 gm). As has been noted previously with the use of other ur:inary tract dis:infectants, 11 • 12 the incidence of bacteriological reversals was greater in those cases :in which no form of prolonged dra:inage, involving a foreign body, was used. In the series presented the percentage of failures was 39 in patients :in whom no dra:inage was employed, whereas it was 78 in those in whom a catheter or a tube was used. Thus, best results were obtained in uncomplicated cases of acute and chronic cystitis or pyelonephritis. Save for the 2 cases each of dermatitis and nausea mentioned, the large doses of NU-445 used were tolerated without any ill effects. There was no instance of leukopenia nor evidence of deposition of crystals with:in the urinary tract. In fact, no :instance of crystalluria was observed. This is all the more remarkable s:ince no concomitant alkali medication was given and fluid intake was not forced. SUMMARY AND CONCLUSIONS
3 ,4-dimethyl-5-sulfanilamido-isoxazole (NU-445) was used in the treatment of 50 consecutive cases of urinary tract :infections due to Bacillus coli and/ or Bacillus proteus. Twenty-four patients received a total daily dose of 6 gm. and 26 subjects were given 8 gm. a day. In most instances the period of treatment was 12 days or less. To satisfy the criteria for cure, negative cultures were required for at least 2 weeks following cessation of treatment. Cases of clinical improvement without bacteriological cure were not counted as positive responses. The results are presented in tabulated form. Bacillus coli infections responded more readily to NU-445 than Bacillus proteus infections. The larger dose proved to be more effective. Best results were obtained in uncomplicated cases of acute or chronic cystitis or pyelonephritis not requiring prolonged drainage involving a foreign body. The new drug is distinguished by good tolerability characterized by freedom from crystalluria and from consequent damage to the urinary tract. In view of this and because of its apparent effectiveness :in Bacillus coli and Bacillus proteus infections, J'fU-445 represents a useful addition to the various chemotherapeutic agents available for the treatment of these urinary tract infections. Grateful acknowledgment is made to Dr. S. F. Wilhelm, attending genitourinary surgeon at the Beth Israel Hospital, for organization and direction of this study, and for his k:ind permission to include cases from his private practice in the series. 11 KEEFER, C. S., WEINSTEIN, L. AND HEWITT, W. L.: Clinical experience with streptomycin; a study of 50 cases. M. Olin. North Amer., 30: 985-997, 1946. 12 WILHELM, S. F. AND LEVINE, B.: Solution of incrustations and calculi in alkaline cystitis. J. Urol., 47: 270-273, 1942.
From the Genito-Urinary Surgical Service, Beth Israel Hospital, New York, N. Y.
The management of chronic urinary tract infections, especially those caused by Bacillus coli and Bacillus proteus often poses a difficult problem. In an effort to sterilize the urine, urologists have used a variety of chemotherapeutic agents including acidifiers, the sulfonamides, penicillin, and finally what appeared to be the long sought for panacea, streptomycin. 2 , 3 , 4 Not one of these agents has been found to be universally or even consistently e:fficacious. 5 The acidifiers, including mandelic acid, sodium acid phosphate, etc., are the least toxic as evidenced by a minimum of by-effects, and occasionally, they are fairly effective. The sulfonamides, including sulfanilamide, sulfathiazole, sulfadiazine, etc., are very frequently without value in combating Proteus or the colon bacillus and may be potentially dangerous by eliciting serious sidereactions such as agranulocytosis, hemolysis, rash, or crystallization with urinary tract obstruction. Penicillin is almost completely ineffectual against infections in which gram-negative bacilli are the offending organisms. 5 While streptomycin appears to be immediately bacteriostatic in chronic urinary tract infections due to Bacillus coli or Bacillus proteus, it soon loses its activity since these organisms tend to develop a strong resistance to it. 6 , 7 , 8 Furthermore, streptomycin has the disadvantage of requiring frequent and often painful intramuscular injections and it may cause such reactions as deafness, vestibular symptoms and rashes. Hence, the search for a non-toxic agent which is effective against these types of urinary tract infection still continues. With this in mind, it was decided to investigate the therapeutic value of a new sulfonamide, namely, 3 ,4-dimethyl-5-sulfanilamido-isoxazole, which was supplied under the designation NU-445. 1 This drug has proved to be effective against Bacillus coli and Bacillus proteus both in vitro and in vivo (animal ex1 The NU-445 was generously supplied by Dr. Leo A. Pirk of Hoffmann-La Roche Inc., Nutley, New Jersey. 2 SCHATZ, A., BuGrn, E. AND WAKSMAN, S. A.: Streptomycin, a substance exhibiting antibiotic activity against gram-positive and gram-negative bacteria. Proc. Soc. Exper. Biol. and Med., 65: 66-69, 1944. • 3 PULASKI, E. J.: Streptomycin in surgical infections; infections of the genito-urinary tract. Ann. Surg., 124: 392-401, 1946. ~ HELMHOLZ, H.F.: The effect of streptomycin on bacteria commonly found in urinary tract infections, Proc. Staff Meet. Mayo Olin., 20: 357-362, 1945. 6 PooL, T. L. AND OooK, E. N.: Present concepts of treatment of infectiollB of the urinary tract. J. A. M.A., 133: 584-587, 1947. 6 ADCOCK, J. D. AND PLUMB, R. T.: Streptomycin for urinary tract infectioM. J. A. M.A., 133: 579-584, 1947. 7 KNOP, 0. Q.: Experimental study of the development of resistance to streptomycin by some bacteria commonly found in urinary tract infections. Proc. Staff Meet. Mayo Olin., 21: 273-276, 1946. 8 FINLAND, M., MURRAY, R., HARRIS, H. W., KILHAM, L. AND MEADS, M.: Development of streptomycin resistance during treatment. J. A. M.A., 132: 16-21, 1946. 92
93
TREATMENT OF INFECTIONS OF URINARY TRACT
periments) and is distinguished by extremely low toxicity. Another outstanding property of NU-445 is its solubility which is strikingly greater than that of other commonly used sulfonamides in the pH range 5.5-6.5. 9 , 10 The experimental compound was administered to 50 consecutive patients with urinary tract infections due to Bacillus coli and/ or Bacillus proteus. The patients were taken from the Genito-Urinary Surgical Service of the Beth Israel Hospital in New York and partly from private practice. The types and numbers of cases treated are shown in table 1. TABLE 1 RESULTS TYPE OF CASES
NUMBER
Perineal prostatectomy Suprapubic prostatectomy
7 7
Transurethral prostatectomy Vesical calculi Permanent nephrostomy Pyelonephritis Nephrectomy Pyelolithotomy Chronic cystitis Periurethral phlegmon Carcinoma of bladder Perinea! fistula Carcinoma of kidney Prostatic abscess Nephropexy Chronic prostatitis
7 5 1 5 1 2
1 1 1 1
Total .............. ........
50
6
1 3 1
FORM OF DRAINAGE
Foley's catheter Indwelling suprapubic tube or urethral catheter Foley's catheter Suprapubic tube N ephrostomy tube None None None None None Suprapubic tube Urethral catheter None Suprapubic tube None None
Cures
Failures
1 1
6
2 1 0 4 0 1 3 0 2
6
5 4 1 1 1 1 3 1 1
0 1 0 1 1
l 0 1
18
32
0 0
The dosage plan was as follows: The first 24 patients received 1.5 gm. q.i.d., a total daily dose of 6 gm. With the exception of 4 cases in which medication had to be discontinued because of toxic symptoms (dermatitis in 2 and nausea in 2), NU-445 was given over periods of time ranging from 6 to 60 days, depending on the response of the patient. Since clinical results in this group fell short of expectations, the total daily dose for the subsequent 26 patients was increased to 8 gm., given in 4 equally divided doses. In this group, NU-445 was administered for from 5 to 57 days. In the majority of cases, however, the period of treatment was 12 days or less. Generally, treatment was continued until a bacteriological reversal occurred or until clinical ineffectiveness of the drug became apparent. For all patients routine urine analyses, complete blood counts and determinaPersonal communication from the Medical Department of Hoffmann-La Roche. SARNOFF, S. J., FREEDMAN, M. A. AND HYMAN, A. A.: The treatment of Bacillus proteus infections with NU-445. J. Urol., 66: 417---427, 1946. 9
10
94
LESTER NARINS
tions of blood levels of NU-445 were carried out semi-weekly. Smears of the urinary sediment were examined at frequent intervals. Similarly, urinary sediments were transferred to blood agar and Endo's medium and inoculated in broth with subsequent study of the bacteriological cultures thus obtained. The appraisal of clinical results was solely on the basis of bacteriological findings. Cures were assumed if urine cultures remained negative for at least 2 weeks following cessation of therapy. Many patients in whom there was no bacteriological cure were greatly improved clinically, but these were not counted as positive results. Table 2 shows the number of unmixed infections due to Bacillus coli and Bacillus proteus and the number of mixed infections treated at the 2 dosage levels. TABLE
2 NtJMBER Oll' CASES
TYPE Oll' INFECTION
6 gm. NU-445 daily
8 gm. NU-445 daily
9
9
5
7
6
10
Bacillus coli .............................. . Bacillus proteus ........................... . Mixed infections due to Bacillus proteus and Bacillus coli ............................. .
26
20
46*
Total ................................... .
* The 4 cases in which therapy wa.s stopped early because of side reactions are excluded from this table. The results attained appear in table 3. In tabulating the results, each of the two offending organisms of the mixed infections was counted separately and therefore, the number of results listed is seemingly gTeater than the number of patients. It is obvious that Bacillus coli infections responded more readily to NU-445 than Bacillus proteus infections and that the increase of dosage to 8 gm. was attended by an increase in good results with regard to both types of infections. TABLE 3 RESULTS TYPE Oll' lNll'ECTION
Bacillus coli Bacillus proteus
6 gm. NU-445 daily Cures
8 gm. NU-445 daily
Failures
Cures
Failures
7 (46.6%)
8 (53.4%)
11
(57.9%)
8 (12.1%)
2 (18.2%)
9 (81.8%)
8 (47.1%)
9 (52.9%)
(The percentages refer to the number of infections with a given organism treated at that particular dosage level.)
TREATMENT OF INFECTIONS OF URINARY TRACT
95
Thus, :in the patients affected with Bacillus coli, there were 46.6 per cent cures on a daily dosage level of 6 gm. as compared with 57.9 per cent when the daily :intake was raised to 8 gm. The :incidence of cures was even more strikingly :increased with the heighten:ing of the dose :in the Bacillus proteus infections (18.2 per cent cures on 6 gm., as against 47.l per cent on 8 gm). As has been noted previously with the use of other ur:inary tract dis:infectants, 11 • 12 the incidence of bacteriological reversals was greater in those cases :in which no form of prolonged dra:inage, involving a foreign body, was used. In the series presented the percentage of failures was 39 in patients :in whom no dra:inage was employed, whereas it was 78 in those in whom a catheter or a tube was used. Thus, best results were obtained in uncomplicated cases of acute and chronic cystitis or pyelonephritis. Save for the 2 cases each of dermatitis and nausea mentioned, the large doses of NU-445 used were tolerated without any ill effects. There was no instance of leukopenia nor evidence of deposition of crystals with:in the urinary tract. In fact, no :instance of crystalluria was observed. This is all the more remarkable s:ince no concomitant alkali medication was given and fluid intake was not forced. SUMMARY AND CONCLUSIONS
3 ,4-dimethyl-5-sulfanilamido-isoxazole (NU-445) was used in the treatment of 50 consecutive cases of urinary tract :infections due to Bacillus coli and/ or Bacillus proteus. Twenty-four patients received a total daily dose of 6 gm. and 26 subjects were given 8 gm. a day. In most instances the period of treatment was 12 days or less. To satisfy the criteria for cure, negative cultures were required for at least 2 weeks following cessation of treatment. Cases of clinical improvement without bacteriological cure were not counted as positive responses. The results are presented in tabulated form. Bacillus coli infections responded more readily to NU-445 than Bacillus proteus infections. The larger dose proved to be more effective. Best results were obtained in uncomplicated cases of acute or chronic cystitis or pyelonephritis not requiring prolonged drainage involving a foreign body. The new drug is distinguished by good tolerability characterized by freedom from crystalluria and from consequent damage to the urinary tract. In view of this and because of its apparent effectiveness :in Bacillus coli and Bacillus proteus infections, J'fU-445 represents a useful addition to the various chemotherapeutic agents available for the treatment of these urinary tract infections. Grateful acknowledgment is made to Dr. S. F. Wilhelm, attending genitourinary surgeon at the Beth Israel Hospital, for organization and direction of this study, and for his k:ind permission to include cases from his private practice in the series. 11 KEEFER, C. S., WEINSTEIN, L. AND HEWITT, W. L.: Clinical experience with streptomycin; a study of 50 cases. M. Olin. North Amer., 30: 985-997, 1946. 12 WILHELM, S. F. AND LEVINE, B.: Solution of incrustations and calculi in alkaline cystitis. J. Urol., 47: 270-273, 1942.