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Sulfonamides: Clinical Evaluation in Infectious Diseases of the Colon
Medical Climcs of North America January, 194J. Chicago Number
SULFONAMIDES: CLINICAL EVALUATION IN INFECTIOUS DISEASES OF THE COLON M. H. STREICHER, M.D.-
THE therapeutic value of the sulfonamides in certain bacterial diseases is established. Specific activities exhibited by certain sulfonamide derivatives. against various bacteria have also become well known t.o the profession. The action of the sulfonamide compounds is primary; it produces a reduction in bacterial rate of growth. It is important to understand that the activity of these drugs depends on bacteriostatic action and on the defense mechanism of the patient. Failures or successes in the control of infections by these derivatives often parallel the degree of blood and tissue concentration. While specificity in antibacterial action against many organisms has been established, it is nevertheless true that derivatives of the sulfonamide group are being prescribed even in the absence of a specific etiologic diagnosis based on bacteriologic correlation. In this clinic a report· will be made of clinical experiences. in the use of sulfonamide derivatives in infectious diseases of the colon. The literature presents reports of the use of sulfanilamide, sulfapyridine, sulfathiazole, sulfadiazine, sulfaguanidine and succinylsulfathiazole in these diseases. Succinylsulfathiazole (sulfasuxidine, 2 [N4-succinyl-sulfanilamido]-thiazole) is already conjugated and cannot be acetylated. Its absorption from the gastro-intestinal tract is slight and therefore the dose excreted by the kidneys is very small (recorded about 5 per cent). One of the superlative features of this derivative is the fact that its activity is confined to the gastro-intestinal tract. Bacterial specificity has been re• From Grant Hospital, Chicago.
1119
190
M. H. STREICHER
. corded against Shigella dysenteriae, the Bacillus coli group and some anaerobic bacteria. The dosage suggested for sulfasuxidine is 0.25 gm. per kilogram of body weight per day, divided into five parts and administered every four hours until the temperature is normal or stool cultures are negative. Sulfasuxidine is practically free of all toxic manifestations. It has been my impression that, among the sulfonamide drugs given in gastro-intestinal tract disease, the worst offender is sulfanilamide, .that sulfathiazole is less toxic and that sulfasuxidine is least toxic. It is true, however, that some of the compounds have not been given sufficient clinical trial to permit their final evaluation from the standpoint of toxicity. One should be familiar with certain difficulties encountered in the treatment of infectious diseases of the colon with one of the sulfonamide derivatives. A specific example may be the . application of sulfanilamide in the treatment of an infectious process of the colon where several organisms are etiologic factors, as in chronic ulcerative colitis. Sulfanilamide may inhibit the growth of some types of Streptococcus viridans, but is of no aid against Streptococcus faecalis. Again, in an infec-: tious process of the colon where Streptococcus haemolyticus and Bacillus coli are the two predominant invaders, sulfanilamide may well curtail the growth of the hemolytic streptococci but will have little or no effect on the Bacillus coli group. This line of thought applies to the evaluation of each of the sulfa derivatives as used in various infectious processes of the colon. Table 1 shows the bacterial specificity, or lack of it, of the various compounds in colonic infections. It is important to appreciate the fact, as demonstrated in Table 1, that practically all sulfonamides may be used as bacteriostatic agents against Streptococcus viridans, beta hemolytic streptococci and staphylococci, but only sulfathiazole and sulfasuxidine are effective against Streptococcus faecalis and only sulfasuxidine against nonhemolytic streptococci, beta hemolytic streptococci, staphylococci, Streptococcus faecalis and enterococci combined. It is evident from the voluminous literature on the sul-
0
0 0 0 0
Streptococcusfaecalis ..............
Bacillus pyocyaneus .... '...........
Bacillus coli. . . . . . . . . . . . . . . . . . . . . .
Enterococci .•....................
Nonhemolytic gamma group ........
Shigella dysenteriae ...............
Paratyphoid bacilli. ...............
Eberthella typhi ..................
Coliform group ...................
Gas gangrene group ...............
Staphylococci .....................
0
0
0
0
.
0
0
0
0
0
0
+ + + + + + + + + +
+ + + + + +
+ + + + + + + +
Streptococcus viridans .............
Beta hemolytic streptococci ........
Sulfathiazole
Sulfapyridine
Sulfanilamide
Bacteria
0 0 0
0 0 0
-
0
0
0
0
0
0
0
+ 0
+ + +
+ 0
0
0
0
+
0
0
0
0
+ + + 0
0
+
0
Sulfaquanidine Sulfasuxidine
------
0
+ + +
Sulfadiazine
BACTERIAL SPECIFICITY OF Till; SULFONAMIDES IN INFECTIONS OF THE COWN
TABLE 1
~
' -0
~
00
..,o
~
~
Z
00
~ ~
~
"'l
00
192
M. H. STREICHER
fonamides that the investigators are still struggling in search of a derivative that will merit general use in infections of the colon; a derivative that will prove to be an excellent intestinal antiseptic and yet maintain a low toxicity quotient. While the investigators do not claim specific action by these drugs in typhoid fever, paratyphoid fever and bacillary dysentery, the fact remains that sulfanilamide, sulfapyridine and sulfathiazole have been used in these conditions to good advantage. It is logical to assume that the improvement is due to the fact that the drugs are bacteriostatic against the secondary invaders, and that, as the secondary bacterial invaders are checked, the defense mechanism of the patient is increased against the primary infestation. As mentioned previously, it has been our experience that sulfasuxidine elicits less toxic manifestations than any other derivative and is seemingly most applicable in infectious processes of the colon. To prove that our impression is correct, let use examine some of the reports in the use of this drug in one of the most dreaded infections in the colon, chronic ulcerative colitis. Any derivative that would prove of definite benefit in chronic ulcerative colitis would in our opinion very probably be efficacious in infectious diseases of the colon in general, inasmuch as all principles of bacterial specificity are incorporated in one entity in chronic ulcerative colitis. Table 2 illustrates the results obtained in the management of chronic ulcerative colitis with some of the derivatives of the sulfonamide group. Generally speaking, it will be noted in the table that the poorest results were obtained in the acute cases. Sulfaguanidine gave better than average results in the acutely ill patient, but by far the best results in these cases were obtained with sulfasuxidine. Of eighteen patients treated with sulfasuxidine, eight had the acute type of colitis and ten the chronic (remission) variety. Seven patients with the acute disease improved remarkably and eight with chronic disease showed good results. Furthermore, these results were obtained within a comparatively short period of time. These results are really more encouraging than any obtained in the past with any of the sulfa derivatives.
193
SULFONAMIDES IN DISEASES OF COLON
In the interpretation of clinical data on the efficacy of sulfa drugs reponed in the literature, the general practitioner should examine carefully the circumstances under which the drugs were administered, noting particularly whether the mugs were administered per se or in conjunction with other therapy. In the present study supportive therapy only was given in addition to the sulfa drugs. The value of these derivatives in remissions of chronic ulcerative colitis has not yet been determined. TABLE 2 COMPARATIVE STUDY OF THE EFFICACY OF VARIOUS SULFONAMIDES IN CHRONIC ULCERATIVE COLITIS
Type of Colitis Acute
Chronic
12
Azosulfamirle ..................................
22
14
Sodium sulfathiazole ...........................
9
6
Sulfaguanidine .................................
13
10
Sulfasuxidine ..................................
8
10
Total numher of patients .................... '." .
64
Good
Fair
2 C·
IC
- -- -- -
Sulfanilamide ..................................
Patients in each group ..........................
Results
5
--45 109
{4 A 2C 3A QC fA 7A SC ~-
{18 A 21 C
eA I C 4C {8 A IC IC
-{9 ASC
-39- -17-
Poor 12 At 2C
r
HC 6AA 2C lA
eA I C {37 A 16 C 53
• C = Chronic ulcerative colitis. - Acute ulcerative colitis.
tA
It should be emphasized that the administration of a sulfonamide drug over a prolonged period with no interval of rest is not advocated, inasmuch as some patients do not tolerate the drug well and become nauseated or lose their appetite for several days. When sulfasuxidine is given for a period of two to four weeks, the patient with ulcerative colitis exhibits almost a miraculous improvement: the cramping in the abdomen subsides, the blood and pus in the stool decrease in amount or disappear entirely, the stools are decreased in frequency to one or two daily and gradully become formed. Careful study of these patients by proctoscopic examina-
194
M. H. STREICHER
tion to compare and correlate the findings with the clinical improvement will be essential and will provide a basic contribution to the literature of the future. The few cases that we have had examined by proctoscopy after treatment with sulfasuxidine demonstrated a decrease in the degree of edema of the rectal and colonic mucosa and showed a decrease in tissue pus. It is difficult in a brief period to determine accurately whether actual healing of ulcerations or scar tissue replacement has taken place, but from the fact that there is less blood and pus in the stool one can properly assume that healing is apparently in progress. The bacteriologic studies made on some of the stools of these patients showed a remarkable change in the intestinal flora. In one instance the total bacterial count of a 0.5 -gm. specimen dropped from 35,600,000 to 19,500,000, the Bacillus coli count decreased from 600,000 to 30,000 and the nonhemolytic streptococcus count from 3,000,000 to 250,000. This change in the flora occurred after the daily administration of sulfasuxidine to an acutely ill patient for four days. Another stool presented the following changes in intestinal flora after four weeks of treatment; the total bacteri'1! count decreased from 388,000,000 to 3,100,000, the Bacillus coli count from 89,000,000 to 100,000 and the nonhemolytic streptococcus count from 200,000 to 15,000. The observations so far made are very encouraging, but more correlated data are required and more time is needed for careful analysis of similar cases before a final estimate of the value of the sulfonamide drugs in infectious diseases of the colon is made. CONCLUSIONS
1. Sulfasuxidine is a distinct addition to the therapy of infectious diseases of the colon. 2. Sulfasuxidine as an intestinal antiseptic is superior to any of the previously discovered derivatives of the sulfonamide group. 3. More time is needed for clinical evaluation of sulfasuxidine in infectious diseases of the colon.
SULFONAMIDES: CLINICAL EVALUATION IN INFECTIOUS DISEASES OF THE COLON M. H. STREICHER, M.D.-
THE therapeutic value of the sulfonamides in certain bacterial diseases is established. Specific activities exhibited by certain sulfonamide derivatives. against various bacteria have also become well known t.o the profession. The action of the sulfonamide compounds is primary; it produces a reduction in bacterial rate of growth. It is important to understand that the activity of these drugs depends on bacteriostatic action and on the defense mechanism of the patient. Failures or successes in the control of infections by these derivatives often parallel the degree of blood and tissue concentration. While specificity in antibacterial action against many organisms has been established, it is nevertheless true that derivatives of the sulfonamide group are being prescribed even in the absence of a specific etiologic diagnosis based on bacteriologic correlation. In this clinic a report· will be made of clinical experiences. in the use of sulfonamide derivatives in infectious diseases of the colon. The literature presents reports of the use of sulfanilamide, sulfapyridine, sulfathiazole, sulfadiazine, sulfaguanidine and succinylsulfathiazole in these diseases. Succinylsulfathiazole (sulfasuxidine, 2 [N4-succinyl-sulfanilamido]-thiazole) is already conjugated and cannot be acetylated. Its absorption from the gastro-intestinal tract is slight and therefore the dose excreted by the kidneys is very small (recorded about 5 per cent). One of the superlative features of this derivative is the fact that its activity is confined to the gastro-intestinal tract. Bacterial specificity has been re• From Grant Hospital, Chicago.
1119
190
M. H. STREICHER
. corded against Shigella dysenteriae, the Bacillus coli group and some anaerobic bacteria. The dosage suggested for sulfasuxidine is 0.25 gm. per kilogram of body weight per day, divided into five parts and administered every four hours until the temperature is normal or stool cultures are negative. Sulfasuxidine is practically free of all toxic manifestations. It has been my impression that, among the sulfonamide drugs given in gastro-intestinal tract disease, the worst offender is sulfanilamide, .that sulfathiazole is less toxic and that sulfasuxidine is least toxic. It is true, however, that some of the compounds have not been given sufficient clinical trial to permit their final evaluation from the standpoint of toxicity. One should be familiar with certain difficulties encountered in the treatment of infectious diseases of the colon with one of the sulfonamide derivatives. A specific example may be the . application of sulfanilamide in the treatment of an infectious process of the colon where several organisms are etiologic factors, as in chronic ulcerative colitis. Sulfanilamide may inhibit the growth of some types of Streptococcus viridans, but is of no aid against Streptococcus faecalis. Again, in an infec-: tious process of the colon where Streptococcus haemolyticus and Bacillus coli are the two predominant invaders, sulfanilamide may well curtail the growth of the hemolytic streptococci but will have little or no effect on the Bacillus coli group. This line of thought applies to the evaluation of each of the sulfa derivatives as used in various infectious processes of the colon. Table 1 shows the bacterial specificity, or lack of it, of the various compounds in colonic infections. It is important to appreciate the fact, as demonstrated in Table 1, that practically all sulfonamides may be used as bacteriostatic agents against Streptococcus viridans, beta hemolytic streptococci and staphylococci, but only sulfathiazole and sulfasuxidine are effective against Streptococcus faecalis and only sulfasuxidine against nonhemolytic streptococci, beta hemolytic streptococci, staphylococci, Streptococcus faecalis and enterococci combined. It is evident from the voluminous literature on the sul-
0
0 0 0 0
Streptococcusfaecalis ..............
Bacillus pyocyaneus .... '...........
Bacillus coli. . . . . . . . . . . . . . . . . . . . . .
Enterococci .•....................
Nonhemolytic gamma group ........
Shigella dysenteriae ...............
Paratyphoid bacilli. ...............
Eberthella typhi ..................
Coliform group ...................
Gas gangrene group ...............
Staphylococci .....................
0
0
0
0
.
0
0
0
0
0
0
+ + + + + + + + + +
+ + + + + +
+ + + + + + + +
Streptococcus viridans .............
Beta hemolytic streptococci ........
Sulfathiazole
Sulfapyridine
Sulfanilamide
Bacteria
0 0 0
0 0 0
-
0
0
0
0
0
0
0
+ 0
+ + +
+ 0
0
0
0
+
0
0
0
0
+ + + 0
0
+
0
Sulfaquanidine Sulfasuxidine
------
0
+ + +
Sulfadiazine
BACTERIAL SPECIFICITY OF Till; SULFONAMIDES IN INFECTIONS OF THE COWN
TABLE 1
~
' -0
~
00
..,o
~
~
Z
00
~ ~
~
"'l
00
192
M. H. STREICHER
fonamides that the investigators are still struggling in search of a derivative that will merit general use in infections of the colon; a derivative that will prove to be an excellent intestinal antiseptic and yet maintain a low toxicity quotient. While the investigators do not claim specific action by these drugs in typhoid fever, paratyphoid fever and bacillary dysentery, the fact remains that sulfanilamide, sulfapyridine and sulfathiazole have been used in these conditions to good advantage. It is logical to assume that the improvement is due to the fact that the drugs are bacteriostatic against the secondary invaders, and that, as the secondary bacterial invaders are checked, the defense mechanism of the patient is increased against the primary infestation. As mentioned previously, it has been our experience that sulfasuxidine elicits less toxic manifestations than any other derivative and is seemingly most applicable in infectious processes of the colon. To prove that our impression is correct, let use examine some of the reports in the use of this drug in one of the most dreaded infections in the colon, chronic ulcerative colitis. Any derivative that would prove of definite benefit in chronic ulcerative colitis would in our opinion very probably be efficacious in infectious diseases of the colon in general, inasmuch as all principles of bacterial specificity are incorporated in one entity in chronic ulcerative colitis. Table 2 illustrates the results obtained in the management of chronic ulcerative colitis with some of the derivatives of the sulfonamide group. Generally speaking, it will be noted in the table that the poorest results were obtained in the acute cases. Sulfaguanidine gave better than average results in the acutely ill patient, but by far the best results in these cases were obtained with sulfasuxidine. Of eighteen patients treated with sulfasuxidine, eight had the acute type of colitis and ten the chronic (remission) variety. Seven patients with the acute disease improved remarkably and eight with chronic disease showed good results. Furthermore, these results were obtained within a comparatively short period of time. These results are really more encouraging than any obtained in the past with any of the sulfa derivatives.
193
SULFONAMIDES IN DISEASES OF COLON
In the interpretation of clinical data on the efficacy of sulfa drugs reponed in the literature, the general practitioner should examine carefully the circumstances under which the drugs were administered, noting particularly whether the mugs were administered per se or in conjunction with other therapy. In the present study supportive therapy only was given in addition to the sulfa drugs. The value of these derivatives in remissions of chronic ulcerative colitis has not yet been determined. TABLE 2 COMPARATIVE STUDY OF THE EFFICACY OF VARIOUS SULFONAMIDES IN CHRONIC ULCERATIVE COLITIS
Type of Colitis Acute
Chronic
12
Azosulfamirle ..................................
22
14
Sodium sulfathiazole ...........................
9
6
Sulfaguanidine .................................
13
10
Sulfasuxidine ..................................
8
10
Total numher of patients .................... '." .
64
Good
Fair
2 C·
IC
- -- -- -
Sulfanilamide ..................................
Patients in each group ..........................
Results
5
--45 109
{4 A 2C 3A QC fA 7A SC ~-
{18 A 21 C
eA I C 4C {8 A IC IC
-{9 ASC
-39- -17-
Poor 12 At 2C
r
HC 6AA 2C lA
eA I C {37 A 16 C 53
• C = Chronic ulcerative colitis. - Acute ulcerative colitis.
tA
It should be emphasized that the administration of a sulfonamide drug over a prolonged period with no interval of rest is not advocated, inasmuch as some patients do not tolerate the drug well and become nauseated or lose their appetite for several days. When sulfasuxidine is given for a period of two to four weeks, the patient with ulcerative colitis exhibits almost a miraculous improvement: the cramping in the abdomen subsides, the blood and pus in the stool decrease in amount or disappear entirely, the stools are decreased in frequency to one or two daily and gradully become formed. Careful study of these patients by proctoscopic examina-
194
M. H. STREICHER
tion to compare and correlate the findings with the clinical improvement will be essential and will provide a basic contribution to the literature of the future. The few cases that we have had examined by proctoscopy after treatment with sulfasuxidine demonstrated a decrease in the degree of edema of the rectal and colonic mucosa and showed a decrease in tissue pus. It is difficult in a brief period to determine accurately whether actual healing of ulcerations or scar tissue replacement has taken place, but from the fact that there is less blood and pus in the stool one can properly assume that healing is apparently in progress. The bacteriologic studies made on some of the stools of these patients showed a remarkable change in the intestinal flora. In one instance the total bacterial count of a 0.5 -gm. specimen dropped from 35,600,000 to 19,500,000, the Bacillus coli count decreased from 600,000 to 30,000 and the nonhemolytic streptococcus count from 3,000,000 to 250,000. This change in the flora occurred after the daily administration of sulfasuxidine to an acutely ill patient for four days. Another stool presented the following changes in intestinal flora after four weeks of treatment; the total bacteri'1! count decreased from 388,000,000 to 3,100,000, the Bacillus coli count from 89,000,000 to 100,000 and the nonhemolytic streptococcus count from 200,000 to 15,000. The observations so far made are very encouraging, but more correlated data are required and more time is needed for careful analysis of similar cases before a final estimate of the value of the sulfonamide drugs in infectious diseases of the colon is made. CONCLUSIONS
1. Sulfasuxidine is a distinct addition to the therapy of infectious diseases of the colon. 2. Sulfasuxidine as an intestinal antiseptic is superior to any of the previously discovered derivatives of the sulfonamide group. 3. More time is needed for clinical evaluation of sulfasuxidine in infectious diseases of the colon.