- Email: [email protected]
Sulfacetimide or Sulamyd (Schering): Clinical Study of Efficiency and Toxicity in Urinary Tract Infections and Comparison with Sulfanilamide Therapy1
SULFACETIMIDE OR SULAMYD (SCHERING): CLINICAL STUDY OF EFFICIENCY AND TOXICITY IN URINARY TRACT INFECTION'S AND COMPARISON WITH SULFANILAMIDE THERAPY1 ROBERT J. PRENTISS
AND
JOHN F. KANEALY
From the Department of Urology, College of Medicine, State University of Iowa, Iowa City
Since the advent of the sulfonamide drugs there has been a constant search for the ideal compound characterized by highest potency with least toxicity. Chemists have long been aware of the biological detoxification, with consequent loss of potency, of the sulfonamides by acetylization. In this biological detoxification, the acetylization occurs at the amino group directly attached to the benzene ring. This fact led to the hope of finding a non-toxic, but potent, compound by acetylating sulfanilamide at another point than that usual for biological detoxification. Paraamino-benzene-sulfonyl-acetyl-imide, also known as albucid, sulfacetimide, compound 338A (Schering), and sulamyd (Schering), is such a compound; the structural formula is given elsewhere. It is the purpose of this paper to report clinical experience in the use of this drug, and to compare it, so far as possible, with experience gained in the sulfanilamide therapy of a similar group. Subjects and methods. The subjects of this study were 135 patients, the first of a group of approximately 400 which has been treated with sulfacetimide within the past 2 years. All but one were hospitalized, but many were ambulatory. The distribution concerning age, sex and types of infection is listed in tables 1 and 2, and is similar to a previously reported group of patients treated with sulfanilamide. Of note is the preponderance of males, the advanced age groups, the number of complicated infections, and infections subsequent to vesical and prostatic operations. Of the latter, all but 2 were transurethral procedures. The organisms found in the patients subjected to culture were felt to be representative of the whole group. All medication was given orally without attempting to alter fluid consumption. The daily adult dose ranged from 2 to 10 gm., the average 1 We wish to thank Dr. Max Gilbert of the Schering Corporation for bis kindness in giving financial aid and in supplying all of the sulfacetimide or Sulamyd (Schering) used in this study. 11
12
ROBERT J. PRENTISS AND JOHN F. KANEALY
being 4.89 gm. The daily dosage rarely exceeded 6 gm., and larger amounts were not continued more than a day or two. Doses for children were reduced according to age and weight. Length of treatment varied TABLE
1
SEX
NUMBER OF PATIENTS
Males. . .. . .. . . . . . . .. . . . . .. . .. . . .. ... . . . . . .. . . . ..... . .. ... . . . ... Females. ... . . . . .. . ... .. . .. ... . .... .. .. . .. . . . ... ... .. ..... . .. . . .
110 25
AGE
1-9 years .. . .. .. ....... .. . . . .. .. . . .. . .. . . . . . . . . .. .. . .. . ... . . .. . 10-19 years . . ... ..... . . . . . . .. ... . . .. ... . . . . . . . .. . . . .. . . . . . .... . . 20-39 years ...... .. .. . ... . . . . .... . . ... .. . . . . .. .. . . . . . ... . . .. . .. . 40-59 years ...... . ... . . . ....... . . .. ... .. . . .. . . . . . ... . . .... .. . . . . 60-79 years . .. . . . . . .. . .. . . . . .. ..... . .... . . . . .. . .... . . . . . .. . . . . . . 80-85 years . . . .. .... ..... .. . .. . . .. .. ... . . . . . .. . . . . . . . . . . . . .. .. . .
3
7 24 23
77 1
TYPE OF INFECTION
Sepsis after prostatic and bladder operations . . . . . . . .. . . . . . .... . . . . . . Complicated urinary tract infections* . .. . . .. . .. .. .... . ........... . . Uncomplicated urinary tract infections . .... . . ... . . .. ... . . . . . .. .. .. . Gonorrhea . ..... . .... . ... . .. .. .. . . . .. . . . . . . . .. . . .. . . . . . . . . . . . . . . Pyelitis of pregnancy . .. . . ... . .... ... . ..... . . . ... . . . .. . . . .. . . . .. . .
42 59 28 3
3
* Abscess, cancer, uremia, stone, obstructions, etc. TABLE
2.- Bacteria cultured from 62 patients' blood and/or urine: 19 mixed; 43 pure cultures NUMBER OF PATIENTS
Escherichia coli ..... .. . . . . .... .. . . . . ...... . .... . . . . . ... . . .. . . . . . Staphylococcus aureus . . . ... . .. . . . .... .. . .. . . .. ... ... . .. .. . . . . ... . Staphylococcus albus . .. . .... . .... . ....... . . . .. . . . . . . . . .. . . .. ... . . Alpha Streptococcus hemolyticus ..... ... . ..... . . ..... . . .. . .. .. .. . . Aerobacter aerogenes .. ..... . . . . . ..... . . .. . . .... . . . .............. . Bacillus proteus .. . . . ... . . .. . . ... . .... . . .. .. . . . . . . .. .. ....... . . . . Streptococcus non-hemolyticus .. . . . . . ... . .. . . .... . .... .. . .. ..... . . . Diphtheroid . . .. . .... . .. .. . ..... ... ... . . .... . . .... .. . . . . . ..... . . . Pseudomonas pyocyaneus . . . . . ... . . . . . . . . . . .. . . . .. . . . . .. . . . . .. . . . . Fecalis alkaligenes .... . . .. . . . . .. . . . .. . . . . . . . .. . . . ... . . . . . .. . . .. . .
27 15 11
7 6
5 4 2 2 1
from 2 to 23 days; the average was approximately 7 days. The amount of the drug administered in the course of treatment varied from 10 to 103 gm., but the average patient received 32.3 gm. The most common method of administration was in the amounts of 1.5 gm. 4 times daily, but the same amount given 3 times daily was nearly as frequently em-
SULFACETIMIDE OR SULAMYD
13
ployed. Ten to 15 gr. of sodium bicarbonate were given with each dose of sulfacetimide. Blood levels of sulfacetimide obtained with this method of administration were satisfactory. The average of 70 determinations made on the fourth or :fifth day of treatment was 6.5 mg. of free sulfacetimide per 100 cc of blood, while the range was 2.0 to 15.4 mg. per cent. Patients with impaired renal function exhibited the higher levels. Patients receiving 1.5 gm. of the drug 3 times a day exhibited an average blood level of 5.1 mg. per cent on the fourth or fifth day of therapy, while in those receiving the same amount 4 times daily the average blood level was 7.5 mg. per cent. The urine concentrations of the drug were not determined as this had been surveyed adequately previously. Toxic reactions. There were no severe and relatively few mild toxic reactions. In 5 patients cyanosis developed and, of these, 1 was severe although he exhibited only a trace of methemoglobin. Mild decreases in hemoglobin and erythrocyte values were noted in 4 patients, but in no instance did anemia develop requiring specific treatment or cessation of medication. Moderate leucopenia developed in 2 patients, but prompt recovery followed discontinuance of sulfacetimide therapy. No clinical acidosis occurred and in 11 unselected patients results of determining plasma carbon dioxide combining power varied between 36 and 57 volume per cent. Few patients suffered from severe gastrointestinal symptoms. Cerebral manifestations were minor, but did appear in 4 patients with severe infection, advanced age or both. No instances occurred of dermatitis, neuritis, episcleritis, conjunctivitis, urinary suppression, sulfacetimide urolithiasis, hematuria due to sulfacetimide, or late complications such as jaundice. In 1 patient simple fever developed, 2 others suffered from appreciable malaise, and 1 was incapacitated generally, but not specifically, and, as such, was classed as "toxic." Clinical jaundice, immediate or late, did not occur although the 39 Van den Bergh reactions of 33 patients selected at random revealed slight increases in plasma bilirubin. One reached a value of 3.2 mg. per cent, but only 3 were of the direct variety indicating hepatic damage. There was no material difference in toxic manifestations in those patients receiving 6 gm. of sulfacetimide as compared to those receiving 4½ gm. daily. In every respect fewer and less severe toxic reactions have occurred in patients treated with sulfacetimide in this clinic than have occurred in those treated with either sulfathiazol or sulfanilamide.
14
ROBERT J. PRENTISS AND JOHN F. KANEALY
Results. The results of this study are tabulated in tables 3, 4, 5 and 6. In considering the results in reference to the invading organism it should be stated that most failures occurred in patients suffering from chronic and/or complicated conditions. Without this in mind, table 3 would TABLE
3.-Results according to infecting organism
ORGANISMS
Escherichia coli .............................. . Staphylococcus aureus ........................ . Staphylococcus albus ......................... . a-Streptococcus hemolyticus .................. . Mixed infections ............................. . TABLE
GOOD
FAILURE
per cenl
per cent
per cent
68.4 14.3 50.0 25.0 57.8
15.8 0.0 0.0 25.0 21.1
15.8 85.7 50.0 50.0 21.1
4.-Results in uncomplicated injections
Excellent .................................... . Good ....................................... . Failure ...................................... .
TABLE
ACUTE
CHRONIC
per cent
per cent
78.5 14.4 7.1
50.0 14.8 35.2
5.-Results in complicated infections
Excellent .................................... . Good ....................................... . Failure ...................................... .
TABLE
EXCELLENT
ACUTE
CHRONIC
per cent
per cent.
71.8 21.3 6.9
14.9 22.2 62.9
6.-Results in sepsis after bladder and prostatic operations PER CENT
Excellent ...................................................... . Good .......................................................... . No benefit ..................................................... .
76.2 11.9 11.9
seem to indicate very poor results with Staphylococcus aureus and Staphylococcus albus. Also, it should be noted that results with mixed infections were good. Eighty per cent excellent or good results obtained when the combination included Staphylococcus aureus or albus indicates that sulfacetimide is effective against cocci despite the poor results shown in the tabulation of invasions by single strains of cocci. In 6 patients
15
SULFACETIMIDE OR SULAMYD
with Aerobacter aerogenes and in 5 with Bacillus proteus infections, sulfacetimide failed in 2 cases with the former and in 1 with the latter, but in each instance of failure the infection was of the mixed variety. Thus it would seem that, as with sulfanilamide, the character of the invading organism will not alter significantly the expected good result. In fact, inspection of tables 4 and 5 indicate that the 2 factors of (1) the acuity or chronicity of the disease, and (2) the presence or absence of coincidental complications play much the larger part in determining the ultimate efficacy of the drug in urinary infections than the nature of the invading organisms. In general, better results were obtained in patients in the younger than in the older age groups. The use of sulfacetimide in the urinary tract infections of children produced uniformly good results without toxic effects. Not tabulated are the results of sulfacetimide therapy in gonorrhea and in pyelitis of pregnancy. In the latter, the 3 patients treated achieved excellent results. Of the 3 patients with gonorrhea, the first with acute anterior urethritis achieved definitive cure, while the other 2, with chronic urethritis, prostatitis, and subacute arthritis were benefited but not cured by sulfacetimide therapy. SUMMARY
A report of a clinical study of the use of a relatively new sulfonamide compound, sulfacetimide, in the therapy of urinary tract infections in 135 patients is presented. The nature of the subjects, methods of administration of the drug, toxic manifestations exhibited by the patients, and the results of therapy are listed and discussed. It is concluded from this study and from two previous reports on sulfanilamide therapy in a similar group of patients that sulfacetimide is less toxic and more efficient than sulfanilamide in the treatment of urinary tract infections. REFERENCES
J.: J.
FLOCKS, R.H., AND PRENTISS, R. Ia. State Med. Soc., April, KARBE, P.: Arch. f. Dermat. u. Syph., 178: 742, 1939. PRENTISS, R. AND FLOCKS, R. H.: Urol., 44: 377-380, 1940. YOUNG, I-L H., ET AL.: Urol., 46: 903-928, 1941.
J.,
J.
J.
1940.
AND
JOHN F. KANEALY
From the Department of Urology, College of Medicine, State University of Iowa, Iowa City
Since the advent of the sulfonamide drugs there has been a constant search for the ideal compound characterized by highest potency with least toxicity. Chemists have long been aware of the biological detoxification, with consequent loss of potency, of the sulfonamides by acetylization. In this biological detoxification, the acetylization occurs at the amino group directly attached to the benzene ring. This fact led to the hope of finding a non-toxic, but potent, compound by acetylating sulfanilamide at another point than that usual for biological detoxification. Paraamino-benzene-sulfonyl-acetyl-imide, also known as albucid, sulfacetimide, compound 338A (Schering), and sulamyd (Schering), is such a compound; the structural formula is given elsewhere. It is the purpose of this paper to report clinical experience in the use of this drug, and to compare it, so far as possible, with experience gained in the sulfanilamide therapy of a similar group. Subjects and methods. The subjects of this study were 135 patients, the first of a group of approximately 400 which has been treated with sulfacetimide within the past 2 years. All but one were hospitalized, but many were ambulatory. The distribution concerning age, sex and types of infection is listed in tables 1 and 2, and is similar to a previously reported group of patients treated with sulfanilamide. Of note is the preponderance of males, the advanced age groups, the number of complicated infections, and infections subsequent to vesical and prostatic operations. Of the latter, all but 2 were transurethral procedures. The organisms found in the patients subjected to culture were felt to be representative of the whole group. All medication was given orally without attempting to alter fluid consumption. The daily adult dose ranged from 2 to 10 gm., the average 1 We wish to thank Dr. Max Gilbert of the Schering Corporation for bis kindness in giving financial aid and in supplying all of the sulfacetimide or Sulamyd (Schering) used in this study. 11
12
ROBERT J. PRENTISS AND JOHN F. KANEALY
being 4.89 gm. The daily dosage rarely exceeded 6 gm., and larger amounts were not continued more than a day or two. Doses for children were reduced according to age and weight. Length of treatment varied TABLE
1
SEX
NUMBER OF PATIENTS
Males. . .. . .. . . . . . . .. . . . . .. . .. . . .. ... . . . . . .. . . . ..... . .. ... . . . ... Females. ... . . . . .. . ... .. . .. ... . .... .. .. . .. . . . ... ... .. ..... . .. . . .
110 25
AGE
1-9 years .. . .. .. ....... .. . . . .. .. . . .. . .. . . . . . . . . .. .. . .. . ... . . .. . 10-19 years . . ... ..... . . . . . . .. ... . . .. ... . . . . . . . .. . . . .. . . . . . .... . . 20-39 years ...... .. .. . ... . . . . .... . . ... .. . . . . .. .. . . . . . ... . . .. . .. . 40-59 years ...... . ... . . . ....... . . .. ... .. . . .. . . . . . ... . . .... .. . . . . 60-79 years . .. . . . . . .. . .. . . . . .. ..... . .... . . . . .. . .... . . . . . .. . . . . . . 80-85 years . . . .. .... ..... .. . .. . . .. .. ... . . . . . .. . . . . . . . . . . . . .. .. . .
3
7 24 23
77 1
TYPE OF INFECTION
Sepsis after prostatic and bladder operations . . . . . . . .. . . . . . .... . . . . . . Complicated urinary tract infections* . .. . . .. . .. .. .... . ........... . . Uncomplicated urinary tract infections . .... . . ... . . .. ... . . . . . .. .. .. . Gonorrhea . ..... . .... . ... . .. .. .. . . . .. . . . . . . . .. . . .. . . . . . . . . . . . . . . Pyelitis of pregnancy . .. . . ... . .... ... . ..... . . . ... . . . .. . . . .. . . . .. . .
42 59 28 3
3
* Abscess, cancer, uremia, stone, obstructions, etc. TABLE
2.- Bacteria cultured from 62 patients' blood and/or urine: 19 mixed; 43 pure cultures NUMBER OF PATIENTS
Escherichia coli ..... .. . . . . .... .. . . . . ...... . .... . . . . . ... . . .. . . . . . Staphylococcus aureus . . . ... . .. . . . .... .. . .. . . .. ... ... . .. .. . . . . ... . Staphylococcus albus . .. . .... . .... . ....... . . . .. . . . . . . . . .. . . .. ... . . Alpha Streptococcus hemolyticus ..... ... . ..... . . ..... . . .. . .. .. .. . . Aerobacter aerogenes .. ..... . . . . . ..... . . .. . . .... . . . .............. . Bacillus proteus .. . . . ... . . .. . . ... . .... . . .. .. . . . . . . .. .. ....... . . . . Streptococcus non-hemolyticus .. . . . . . ... . .. . . .... . .... .. . .. ..... . . . Diphtheroid . . .. . .... . .. .. . ..... ... ... . . .... . . .... .. . . . . . ..... . . . Pseudomonas pyocyaneus . . . . . ... . . . . . . . . . . .. . . . .. . . . . .. . . . . .. . . . . Fecalis alkaligenes .... . . .. . . . . .. . . . .. . . . . . . . .. . . . ... . . . . . .. . . .. . .
27 15 11
7 6
5 4 2 2 1
from 2 to 23 days; the average was approximately 7 days. The amount of the drug administered in the course of treatment varied from 10 to 103 gm., but the average patient received 32.3 gm. The most common method of administration was in the amounts of 1.5 gm. 4 times daily, but the same amount given 3 times daily was nearly as frequently em-
SULFACETIMIDE OR SULAMYD
13
ployed. Ten to 15 gr. of sodium bicarbonate were given with each dose of sulfacetimide. Blood levels of sulfacetimide obtained with this method of administration were satisfactory. The average of 70 determinations made on the fourth or :fifth day of treatment was 6.5 mg. of free sulfacetimide per 100 cc of blood, while the range was 2.0 to 15.4 mg. per cent. Patients with impaired renal function exhibited the higher levels. Patients receiving 1.5 gm. of the drug 3 times a day exhibited an average blood level of 5.1 mg. per cent on the fourth or fifth day of therapy, while in those receiving the same amount 4 times daily the average blood level was 7.5 mg. per cent. The urine concentrations of the drug were not determined as this had been surveyed adequately previously. Toxic reactions. There were no severe and relatively few mild toxic reactions. In 5 patients cyanosis developed and, of these, 1 was severe although he exhibited only a trace of methemoglobin. Mild decreases in hemoglobin and erythrocyte values were noted in 4 patients, but in no instance did anemia develop requiring specific treatment or cessation of medication. Moderate leucopenia developed in 2 patients, but prompt recovery followed discontinuance of sulfacetimide therapy. No clinical acidosis occurred and in 11 unselected patients results of determining plasma carbon dioxide combining power varied between 36 and 57 volume per cent. Few patients suffered from severe gastrointestinal symptoms. Cerebral manifestations were minor, but did appear in 4 patients with severe infection, advanced age or both. No instances occurred of dermatitis, neuritis, episcleritis, conjunctivitis, urinary suppression, sulfacetimide urolithiasis, hematuria due to sulfacetimide, or late complications such as jaundice. In 1 patient simple fever developed, 2 others suffered from appreciable malaise, and 1 was incapacitated generally, but not specifically, and, as such, was classed as "toxic." Clinical jaundice, immediate or late, did not occur although the 39 Van den Bergh reactions of 33 patients selected at random revealed slight increases in plasma bilirubin. One reached a value of 3.2 mg. per cent, but only 3 were of the direct variety indicating hepatic damage. There was no material difference in toxic manifestations in those patients receiving 6 gm. of sulfacetimide as compared to those receiving 4½ gm. daily. In every respect fewer and less severe toxic reactions have occurred in patients treated with sulfacetimide in this clinic than have occurred in those treated with either sulfathiazol or sulfanilamide.
14
ROBERT J. PRENTISS AND JOHN F. KANEALY
Results. The results of this study are tabulated in tables 3, 4, 5 and 6. In considering the results in reference to the invading organism it should be stated that most failures occurred in patients suffering from chronic and/or complicated conditions. Without this in mind, table 3 would TABLE
3.-Results according to infecting organism
ORGANISMS
Escherichia coli .............................. . Staphylococcus aureus ........................ . Staphylococcus albus ......................... . a-Streptococcus hemolyticus .................. . Mixed infections ............................. . TABLE
GOOD
FAILURE
per cenl
per cent
per cent
68.4 14.3 50.0 25.0 57.8
15.8 0.0 0.0 25.0 21.1
15.8 85.7 50.0 50.0 21.1
4.-Results in uncomplicated injections
Excellent .................................... . Good ....................................... . Failure ...................................... .
TABLE
ACUTE
CHRONIC
per cent
per cent
78.5 14.4 7.1
50.0 14.8 35.2
5.-Results in complicated infections
Excellent .................................... . Good ....................................... . Failure ...................................... .
TABLE
EXCELLENT
ACUTE
CHRONIC
per cent
per cent.
71.8 21.3 6.9
14.9 22.2 62.9
6.-Results in sepsis after bladder and prostatic operations PER CENT
Excellent ...................................................... . Good .......................................................... . No benefit ..................................................... .
76.2 11.9 11.9
seem to indicate very poor results with Staphylococcus aureus and Staphylococcus albus. Also, it should be noted that results with mixed infections were good. Eighty per cent excellent or good results obtained when the combination included Staphylococcus aureus or albus indicates that sulfacetimide is effective against cocci despite the poor results shown in the tabulation of invasions by single strains of cocci. In 6 patients
15
SULFACETIMIDE OR SULAMYD
with Aerobacter aerogenes and in 5 with Bacillus proteus infections, sulfacetimide failed in 2 cases with the former and in 1 with the latter, but in each instance of failure the infection was of the mixed variety. Thus it would seem that, as with sulfanilamide, the character of the invading organism will not alter significantly the expected good result. In fact, inspection of tables 4 and 5 indicate that the 2 factors of (1) the acuity or chronicity of the disease, and (2) the presence or absence of coincidental complications play much the larger part in determining the ultimate efficacy of the drug in urinary infections than the nature of the invading organisms. In general, better results were obtained in patients in the younger than in the older age groups. The use of sulfacetimide in the urinary tract infections of children produced uniformly good results without toxic effects. Not tabulated are the results of sulfacetimide therapy in gonorrhea and in pyelitis of pregnancy. In the latter, the 3 patients treated achieved excellent results. Of the 3 patients with gonorrhea, the first with acute anterior urethritis achieved definitive cure, while the other 2, with chronic urethritis, prostatitis, and subacute arthritis were benefited but not cured by sulfacetimide therapy. SUMMARY
A report of a clinical study of the use of a relatively new sulfonamide compound, sulfacetimide, in the therapy of urinary tract infections in 135 patients is presented. The nature of the subjects, methods of administration of the drug, toxic manifestations exhibited by the patients, and the results of therapy are listed and discussed. It is concluded from this study and from two previous reports on sulfanilamide therapy in a similar group of patients that sulfacetimide is less toxic and more efficient than sulfanilamide in the treatment of urinary tract infections. REFERENCES
J.: J.
FLOCKS, R.H., AND PRENTISS, R. Ia. State Med. Soc., April, KARBE, P.: Arch. f. Dermat. u. Syph., 178: 742, 1939. PRENTISS, R. AND FLOCKS, R. H.: Urol., 44: 377-380, 1940. YOUNG, I-L H., ET AL.: Urol., 46: 903-928, 1941.
J.,
J.
J.
1940.