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The Use of Sulfonamides in Urinary Tract Infection
The Use of Sulfonarnides in Urinary Tract Infection CHARLES V. PRYLES, M.D., F.A.A.P.*
Overall indications for the use of sulfonamides are few. They are used for prophylaxis against group A streptococcal infections in patients with rheumatic cardiovascular disease who are sensitive to penicillin. Combinations of sulfonamides and other antimicrobials are effective against Nocardia infections, trachoma, toxoplasmosis, pneumocystis carinii infections, and some other infrequent or minor infections. Their greatest. use is in the treatment of uncomplicated, nonrecurrent, acute urinary tract infections caused by a variety of microorganisms. Their low cost, ease of administration, safety, and high order of efficacy against a broad spectrum of urinary pathogens are special recommendations for this class of drugs. The sulfonamides represent drugs of first choice in the treatment of initial acute uncomplicated urinary tract infection. Whether or not bactericidal agents (such as ampicillin) may be more useful than the bacteriostatic sulfonamides is not known. It is difficult enough to determine which member of the sulfonamide group of drugs is the most effective, and the literature is controversial and replete with conflicting claims. Suffice it to state that sulfadiazine, sulfamerazine, and sulfamethazine, alone or as mixtures of two or more, and sulfisoxazole have all been used with effectiveness. The use of the newer derivatives of sulfonamides presently available under various trade names is not recommended on the ground that they do not have.a long and clearly proved history of clinical use and effectiveness. As experience and confidence in the less toxic sulfas have grown, their use is no longer accompanied by meticulous and frequent examinations of urine and blood to detect hematuria, cylindruria, or anemia. Nonetheless, it is important that care be exercised in their administration, and that their use not be indiscriminate or lacking in close surveillance by the physician. In any contemplation of the use of sulfonamides in the treatment of urinary tract infection, due consideration must be given to the fact *Professor ofPediatrics, State University of New York, Downstate Medical Center; Chairman, Department of Pediatrics, The Jewish Hospital and Medical Center of Brooklyn, New York Medical Clinics of North America- Vol. 54, No. 5, September, 1970
1077
1078
CHARLES
V.
PRYLES
that the most serious and frequent complications from the systemic administration of sulfonamides are related to the urinary tract. 1 Urinary tract complications caused by sulfonamides are of three major types: (1) crystalluria (most common type), (2) toxic nephrosis (less common, more serious), and (3) hypersensitivity reactions (rare, often serious, may be fatal). Nissen and his associates 3 have carefully examined the frequency of injury to the urinary tract by various commonly used sulfonamides and have found it to be approximately the same (gross or microscopic hematuria in less than 2 per cent of cases). We use a mixture of sulfonamides~~ in our clinic 4 for the following reasons: (1) chemical and clinical studies of sulfadiazine, sulfamerazine, and sulfamethazine in combination have demonstrated that the total amount of sulfonamide that can be held in solution in urine is substantially increased when two or more of these substances are administered simultaneously; (2) this is accomplished without sacrificing therapeutic activity; (3) it has also been demonstrated that such a mixture is more soluble at pH 5.5 and below than any single soluble sulfonamide. Finally, it may be pointed out that milligram for milligram the sulfonamides contained in the mixture are more active than the dimethyl sulfonamides such as sulfisoxazole or sulfadimetine. Nonetheless, in view of the lack of data pointing to an unmistakable clinical superiority of the mixture or sulfisoxazole, it would seem wise for the clinician to choose one or the other in his management of renal infections and to learn to use it well. In our own experience gross hematuria has not been encountered, although microscopic hematuria is occasionally observed. Sulfonamides have had to be discontinued in about 2 per cent of our child patients; in one group of children treated during a particularly hot and prolonged summer, skin rashes occurred in about 6 per cent. It was at this time that we became acutely aware of the element of heliosensitivity in the rashes of certain patients, and undue exposure to sunlight was interdicted. Because there is some evidence that the incidence of drug rash and fever increases in direct proportion to the dose of sulfonamide, we have also decreased the amount administered during the height of summer. The use of these agents has been gratifyingly free of toxicity in our hands, but we are exquisitely sensitive to their potential for producing serious and even fatal consequences. Warning signals, most commonly hematuria and skin rash, but also chills, fever, weakness, vomiting, jaundice, headache, and sore throat, must not be ignored. It is useful to know that acute hemolytic anemia, if it is to occur, will most likely do so during the first week of administration, and that leukopenia or agranulocytosis tends to occur during the third or fourth week of therapy.1 Absolute contraindications to the use of sulfonamides are few. The main one is hypersensitivity to the drug as indicated by a previous toxic reaction to it, such as a severe dermatitis, acute hemolytic anemia, purpura, fever, or jaundice. ;;'Trisulfapyrimidines uSP (Sulfose, Wyeth)
THE USE OF SULFONAMIDES IN URINARY TRACT INFECTION
1079
The long-acting sulfonamides, sulfadimethoxine (Madribon) and sulfamethoxypyridazine (Kynex, Midicel), are not recommended for either therapy or prophylaxis because of serious toxic reactions which have been disturbing in their number; several deaths from hypersensitivity have been reported. 5 It is our practice to use the mixture of sulfadiazine, sulfamerazine, and sulfamethazine in all initial acute infections of the kidney and urinary tract and in a dosage of 100 to 150 mg. per kg. of body weight per day in 3 or 4 divided doses by mouth; the dosage is the same for sulfisoxazole.~:~ In vitro sensitivity tests with sulfonamides, as usually performed, are unreliable; in vivo results often do not agree with such sensitivity tests. This is probably related to the fact that while blood levels of sulfonamide easily attainable following the usual therapeutic doses may reach 50 micrograms per m!. (5 mg. per 100 m!.), urine levels may be 10 times higher. 2 Under these circumstances it is felt that the best sensitivity test is the patient himself; we will culture a clean-voided sample of the patient's urine 24 to 48 hours after administration of the drug to make sure the bacteria have been eliminated. If they have not been eliminated, a comprehensive urologic examination is required. One should not change to another drug without carrying out such an examination with an appropriate consultant in urology. Rarely will failure to eradicate a first infection be due to resistance of the organism to the chemotherapeutic agent. Rather, it will be due to some impairment of urine flow secondary to a structural or functional abnormality, or both, in the urinary system. If the bacteria have been eliminated, treatment is continued for 10 days to 2 weeks, after which time the patient is followed at monthly intervals for 3 months, and then every 3 months thereafter. At each visit, a careful interim history should be obtained, physical examination should be carried out as required, and urinalysis and a quantitative urine culture should be obtained. If the patient has no further infections after a year of follow-up, he should be seen at 6 month intervals for another year, and then discharged. Examination of the urine should always be carried out thereafter whenever a febrile illness occurs - regardless of symptoms. Most of the recurrences of infection, if they are to occur, will take place within 18 to 24 months following the initial infection, and this is the period during which careful follow-up is essential. The operative word here is follow-up. With diligent follow-up assured, one may wait until infection recurs before seeking urographic examination. In dealing with a clinic population, we obtain an intravenous pyelogram during the second week of treatment of the initial acute infection, or shortly thereafter, in order to provide an opportunity for the inflammatory changes to subside. In this way, erroneous over-interpretation of the disease processes may be avoided. Bacteriologic control can be effected by use of the sulfonamides in the great majority of infections caused by the coliform organisms *Sulfisoxazole uSP (Gantrisin, Roche)
1080
CHARLES
V.
PRYLES
(Escherichia coli, Paracolobactrum) and some gram-positive bacteria (staphylococci and streptococci, other than enterococci). Proteus species, Aerobacter aerogenes, and Pseudomonas are usually resistant, but on occasion can be controlled by the sulfonamides. In general, these latter microorganisms are encountered in chronic, recurrent, usually complicated (i.e., with some functional or structural defect) infections, and one is guided in these circumstances by the results of in vitro susceptibility tests. Since strains resistant to the sulfonamides are more likely to be encountered in such recurrent infections, the use of these drugs will not be as satisfactory as in initial acute infections. The use of sulfonamides in long-term maintenance therapy for the suppression of bacteriuria in children with chronic infections is sometimes undertaken in children who, in the absence of a correctable structural or functional defect, nonetheless continue to have recurrent infections. The dose is reduced to one-half or one-third the recommended dosage, and the frequency of administration may often be reduced to twice daily or to a single dose given at bedtime. By careful trial and error, titrating the dose against the patient's requirements, one may arrive at the minimal effective dose for "long-term" (months to years) prophylactic maintenance therapy. The sulfonamides are effective when used in this way, but the emergence of resistant variants of the pathogens in chronic recurrent disease diminishes their utility.
REFERENCES 1. Goodman, L. S., and Gilman, A.: The Pharmacological Basis of Therapeutics. 2nd ed.,
New York, The Macmillan Company, 1958. 2. Kass, E. H.: Chemotherapeutic and antibiotic drugs in the management of infections of the urinary tract. Amer. J. Med., 17:764,1955. 3. Nissen, N. I., Aagard, K., and Flindt-Hansen, E.: Sulfonamide hematuria. Frequency of injury to urinary tract as estimated on the basis of 6,084 cases treated with different sulfonamide preparations. Acta Med. Scandinav., 138:301, 1950. 4. Pryles, C. V., Wherrett, B. A., and McCarthy, J. M.: Urinary tract infections in infants and children. Amer. J. Dis. Child., 108: 1, 1964. 5. Rollison, M. L., O'Brien, J., and Good, R. A.: Severe reactions to long-acting sulfonamides. Pediatrics, 28:908,1961. The Jewish Hospital and Medical Center of Brooklyn 555 Prospect Place Brooklyn, New York 11238
Overall indications for the use of sulfonamides are few. They are used for prophylaxis against group A streptococcal infections in patients with rheumatic cardiovascular disease who are sensitive to penicillin. Combinations of sulfonamides and other antimicrobials are effective against Nocardia infections, trachoma, toxoplasmosis, pneumocystis carinii infections, and some other infrequent or minor infections. Their greatest. use is in the treatment of uncomplicated, nonrecurrent, acute urinary tract infections caused by a variety of microorganisms. Their low cost, ease of administration, safety, and high order of efficacy against a broad spectrum of urinary pathogens are special recommendations for this class of drugs. The sulfonamides represent drugs of first choice in the treatment of initial acute uncomplicated urinary tract infection. Whether or not bactericidal agents (such as ampicillin) may be more useful than the bacteriostatic sulfonamides is not known. It is difficult enough to determine which member of the sulfonamide group of drugs is the most effective, and the literature is controversial and replete with conflicting claims. Suffice it to state that sulfadiazine, sulfamerazine, and sulfamethazine, alone or as mixtures of two or more, and sulfisoxazole have all been used with effectiveness. The use of the newer derivatives of sulfonamides presently available under various trade names is not recommended on the ground that they do not have.a long and clearly proved history of clinical use and effectiveness. As experience and confidence in the less toxic sulfas have grown, their use is no longer accompanied by meticulous and frequent examinations of urine and blood to detect hematuria, cylindruria, or anemia. Nonetheless, it is important that care be exercised in their administration, and that their use not be indiscriminate or lacking in close surveillance by the physician. In any contemplation of the use of sulfonamides in the treatment of urinary tract infection, due consideration must be given to the fact *Professor ofPediatrics, State University of New York, Downstate Medical Center; Chairman, Department of Pediatrics, The Jewish Hospital and Medical Center of Brooklyn, New York Medical Clinics of North America- Vol. 54, No. 5, September, 1970
1077
1078
CHARLES
V.
PRYLES
that the most serious and frequent complications from the systemic administration of sulfonamides are related to the urinary tract. 1 Urinary tract complications caused by sulfonamides are of three major types: (1) crystalluria (most common type), (2) toxic nephrosis (less common, more serious), and (3) hypersensitivity reactions (rare, often serious, may be fatal). Nissen and his associates 3 have carefully examined the frequency of injury to the urinary tract by various commonly used sulfonamides and have found it to be approximately the same (gross or microscopic hematuria in less than 2 per cent of cases). We use a mixture of sulfonamides~~ in our clinic 4 for the following reasons: (1) chemical and clinical studies of sulfadiazine, sulfamerazine, and sulfamethazine in combination have demonstrated that the total amount of sulfonamide that can be held in solution in urine is substantially increased when two or more of these substances are administered simultaneously; (2) this is accomplished without sacrificing therapeutic activity; (3) it has also been demonstrated that such a mixture is more soluble at pH 5.5 and below than any single soluble sulfonamide. Finally, it may be pointed out that milligram for milligram the sulfonamides contained in the mixture are more active than the dimethyl sulfonamides such as sulfisoxazole or sulfadimetine. Nonetheless, in view of the lack of data pointing to an unmistakable clinical superiority of the mixture or sulfisoxazole, it would seem wise for the clinician to choose one or the other in his management of renal infections and to learn to use it well. In our own experience gross hematuria has not been encountered, although microscopic hematuria is occasionally observed. Sulfonamides have had to be discontinued in about 2 per cent of our child patients; in one group of children treated during a particularly hot and prolonged summer, skin rashes occurred in about 6 per cent. It was at this time that we became acutely aware of the element of heliosensitivity in the rashes of certain patients, and undue exposure to sunlight was interdicted. Because there is some evidence that the incidence of drug rash and fever increases in direct proportion to the dose of sulfonamide, we have also decreased the amount administered during the height of summer. The use of these agents has been gratifyingly free of toxicity in our hands, but we are exquisitely sensitive to their potential for producing serious and even fatal consequences. Warning signals, most commonly hematuria and skin rash, but also chills, fever, weakness, vomiting, jaundice, headache, and sore throat, must not be ignored. It is useful to know that acute hemolytic anemia, if it is to occur, will most likely do so during the first week of administration, and that leukopenia or agranulocytosis tends to occur during the third or fourth week of therapy.1 Absolute contraindications to the use of sulfonamides are few. The main one is hypersensitivity to the drug as indicated by a previous toxic reaction to it, such as a severe dermatitis, acute hemolytic anemia, purpura, fever, or jaundice. ;;'Trisulfapyrimidines uSP (Sulfose, Wyeth)
THE USE OF SULFONAMIDES IN URINARY TRACT INFECTION
1079
The long-acting sulfonamides, sulfadimethoxine (Madribon) and sulfamethoxypyridazine (Kynex, Midicel), are not recommended for either therapy or prophylaxis because of serious toxic reactions which have been disturbing in their number; several deaths from hypersensitivity have been reported. 5 It is our practice to use the mixture of sulfadiazine, sulfamerazine, and sulfamethazine in all initial acute infections of the kidney and urinary tract and in a dosage of 100 to 150 mg. per kg. of body weight per day in 3 or 4 divided doses by mouth; the dosage is the same for sulfisoxazole.~:~ In vitro sensitivity tests with sulfonamides, as usually performed, are unreliable; in vivo results often do not agree with such sensitivity tests. This is probably related to the fact that while blood levels of sulfonamide easily attainable following the usual therapeutic doses may reach 50 micrograms per m!. (5 mg. per 100 m!.), urine levels may be 10 times higher. 2 Under these circumstances it is felt that the best sensitivity test is the patient himself; we will culture a clean-voided sample of the patient's urine 24 to 48 hours after administration of the drug to make sure the bacteria have been eliminated. If they have not been eliminated, a comprehensive urologic examination is required. One should not change to another drug without carrying out such an examination with an appropriate consultant in urology. Rarely will failure to eradicate a first infection be due to resistance of the organism to the chemotherapeutic agent. Rather, it will be due to some impairment of urine flow secondary to a structural or functional abnormality, or both, in the urinary system. If the bacteria have been eliminated, treatment is continued for 10 days to 2 weeks, after which time the patient is followed at monthly intervals for 3 months, and then every 3 months thereafter. At each visit, a careful interim history should be obtained, physical examination should be carried out as required, and urinalysis and a quantitative urine culture should be obtained. If the patient has no further infections after a year of follow-up, he should be seen at 6 month intervals for another year, and then discharged. Examination of the urine should always be carried out thereafter whenever a febrile illness occurs - regardless of symptoms. Most of the recurrences of infection, if they are to occur, will take place within 18 to 24 months following the initial infection, and this is the period during which careful follow-up is essential. The operative word here is follow-up. With diligent follow-up assured, one may wait until infection recurs before seeking urographic examination. In dealing with a clinic population, we obtain an intravenous pyelogram during the second week of treatment of the initial acute infection, or shortly thereafter, in order to provide an opportunity for the inflammatory changes to subside. In this way, erroneous over-interpretation of the disease processes may be avoided. Bacteriologic control can be effected by use of the sulfonamides in the great majority of infections caused by the coliform organisms *Sulfisoxazole uSP (Gantrisin, Roche)
1080
CHARLES
V.
PRYLES
(Escherichia coli, Paracolobactrum) and some gram-positive bacteria (staphylococci and streptococci, other than enterococci). Proteus species, Aerobacter aerogenes, and Pseudomonas are usually resistant, but on occasion can be controlled by the sulfonamides. In general, these latter microorganisms are encountered in chronic, recurrent, usually complicated (i.e., with some functional or structural defect) infections, and one is guided in these circumstances by the results of in vitro susceptibility tests. Since strains resistant to the sulfonamides are more likely to be encountered in such recurrent infections, the use of these drugs will not be as satisfactory as in initial acute infections. The use of sulfonamides in long-term maintenance therapy for the suppression of bacteriuria in children with chronic infections is sometimes undertaken in children who, in the absence of a correctable structural or functional defect, nonetheless continue to have recurrent infections. The dose is reduced to one-half or one-third the recommended dosage, and the frequency of administration may often be reduced to twice daily or to a single dose given at bedtime. By careful trial and error, titrating the dose against the patient's requirements, one may arrive at the minimal effective dose for "long-term" (months to years) prophylactic maintenance therapy. The sulfonamides are effective when used in this way, but the emergence of resistant variants of the pathogens in chronic recurrent disease diminishes their utility.
REFERENCES 1. Goodman, L. S., and Gilman, A.: The Pharmacological Basis of Therapeutics. 2nd ed.,
New York, The Macmillan Company, 1958. 2. Kass, E. H.: Chemotherapeutic and antibiotic drugs in the management of infections of the urinary tract. Amer. J. Med., 17:764,1955. 3. Nissen, N. I., Aagard, K., and Flindt-Hansen, E.: Sulfonamide hematuria. Frequency of injury to urinary tract as estimated on the basis of 6,084 cases treated with different sulfonamide preparations. Acta Med. Scandinav., 138:301, 1950. 4. Pryles, C. V., Wherrett, B. A., and McCarthy, J. M.: Urinary tract infections in infants and children. Amer. J. Dis. Child., 108: 1, 1964. 5. Rollison, M. L., O'Brien, J., and Good, R. A.: Severe reactions to long-acting sulfonamides. Pediatrics, 28:908,1961. The Jewish Hospital and Medical Center of Brooklyn 555 Prospect Place Brooklyn, New York 11238