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Urogenital Tuberculosis
Vol. 104, Aug. Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1970 by The Williams & Wilkins Co.
UROGENITAL TUBERCULOSIS N. L. MANGELSON, J. C. SAUNDERS ANDS. A. BROSMAN From the Department of Urology, Harbor General Hospital, Torrance and the University of California School of Medicine, Los Angeles, California
Tuberculosis, with its complications, is the most common infection causing death not only in the United States but in the entire world. 1 Last year this disease was responsible for more deaths than the war in Vietnam. 2 Geographically, tuberculosis is concentrated in the older and poorer sections of urban areas where minority groups and immigrants cluster and live in overcrowded and substandard housing. Newly-reported cases occur in 45.5 per cent of patients more than 25 years old. Of these 52 per cent of patients are more than 45 years old. 2 The incidence of renal tuberculosis has remained constant over the past decade despite widely used and effective chemotherapy. The clinical impression that urologists are seeing fewer cases is probably reflected by the fact that these patients are being cured medically more often than surgically. Although the new-case rate is constant, there are fewer far-advanced cases and most of the new cases consist primarily of moderately advanced disease. 3 The insidious nature of this disease was dramatized by Lattimer when he reported that 72 per cent of 25 physicians working for the urinary tuberculosis research unit of Kingsbridge Veterans Hospital demonstrated advanced cavitary tuberculosis of the kidneys. 4 The advanced disease had developed without significant symptoms. Diagnosis of urogenital tuberculosis depends upon finding the organism in the urinary tract by culture or biopsy. Cultures of 3 morning specimens of urine are considered as good as a 24-hour collection. Symptoms of chronic urinary tract infection are an indication of the possibility of urogenital tuberculosis. The diagnosis should Accepted for publication July 25, 1969. 1 Murray, J.: Tuberculosis. Calif. Med., 109: 390, 1968. 2 Curry, F. J.: The tuberculosis problem today. Calif. Med., 109: 418, 1968. 3 Siegel, J. and Lattimer, J. K.: Renal tuberculosis: has the incidence of advanced lesions decreased in the past two decades? J. Urol., 91: 330, 1964. 4 Lattimer, J. K.: Renal tuberculosis. New Engl. J. Med., 273: 208, 1965.
be considered in patients with chronic epididymoorchitis. Tuberculosis of the prostate, epididymis and testicle has been diagnosed by needle biopsy. Treatment should not be started until a positive diagnosis has been made. Kurosaka reported that the history alone suggested the presence of tuberculosis in 60 per cent of 240 patients.' Of these, the largest proportion of primary symptoms was related to bladder involvement. Renal involvement occurred in approximately one-third of these patients. Pulmonary tuberculosis is present in approximately 15 per cent of those patients with urinary tract tuberculosis. The reproductive organs are involved in 13 per cent and the skeletal system in 10 per cent of cases. 6 CASE REPORTS
Case 1. L. S., a 74-year-old woman, had dysuria and had been treated by a physician for pyuria for 6 months without resolution of the infection. She had noted occasional right costovertebral angle aching pain but few other symptoms. An excretory urogram (IVP) revealed bilateral hydronephrosis (fig. 1, A). Cystoscopy revealed generalized inflammation of the bladder. A left bulb retrograde pyelogram revealed numerous strictures of the ureter (fig. 1, B). A right bulb retrograde pyelogram was unsuccessful. An antegrade pyelogram performed by injecting contrast material directly into the right renal pelvis confirmed a distal ureteral stricture with hydronephrosis and hydroureter. Intermediate purified protein derivative (PPD) intradermal induration was 12 mm. in diameter at 72 hours. Concentrated urine smear was 2-plus positive for acid-fast bacillus (AFB). Repeated chest x-rays and sputum culture were negative. Triple-drug therapy was instituted. Urine cultures subse6 Kurosaka, M.: Studies on tuberculosis of the urinary tract. I. Clinical observations. Acta Urol. Jap., 12: 107, 1966. 6 Scheinin, T. M. and Kontturi, M.: Incidence and fate of renal tuberculosis in patients with bone and joint tuberculosis. Ann. Chir. Gynaec. Fenn., 66: 36, 1966.
309
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MANGELSON, SAUNDERS AND BROSMAN
FrG. 1. Case 1. A, IVP prior to therapy reveals bilateral hydronephrosis. B, left retrograde pyelogram prior to therapy reveals tuberculous ureteral strictures. C, retrograde pyelogram drainage film after 8 months of therapy. No improvement of right hydroureteronephrosis. D, IVP following excision of right ureterovesical stricture and ureteroneocystostomy shows marked improvement in right hydroureteronephrosis.
quently were positive. The patient had an intolerance to para-aminosalicylate (PAS) which necessitated its discontinuance. Resistance to streptomycin developed after 3 months. Cycloserine and ethionamide were substituted in the regimen. Cycloserine was discontinued after 1 month because of psychic depression. Urine cultures became negative 4 months after beginning therapy. Ethionamide, pyrazinamide and isoniazid (INH) were continued for 20 months and INH continuously for 4½ years with negative cultures. ln the first 8 months of therapy the right
ureteral stricture responded poorly to ureteral dilations, necessitating excision of the stricture and right ureteroneocystostomy (fig. 1, C). This procedure improved the right kidney function (fig. 1, D). The patient suffered organic psychotic depression postoperatively, necessitating electroshock therapy to which she responded well. The left ureteral obstruction has gradually progressed resulting in diminished left renal function presently but the patient is asymptomatic and has a serum creatinine of 1.0. This case demonstrates the problem of resistance developing to antituberculous drugs and the need for periodic
UROGENITAL TUBERCULOSIS
reculturing for sensitivity. It also demonstrates the need for operative intervention when chemotherapy fails to adequately manage the disease. Case 2. G. L., a 48-year-old Caucasian man, had painful swelling of the right testicle and scrotum 3 months in duration. Four years previously he had gross hematuria which recurred approximately each 6 months. Two yearn prior to seeking medical help he had frequency of urination every 2 hours which progressed to frequency of urination each hour 1 year prior to admission to the hospital and every 15 to 30 minutes in the last 6 months. He had a 10-pound weight loss over 1½ years. Physical examination showed a 5 by 7 cm. translucent right hydrocele with an adjacent indurated tender epididymis adherent to the scrotum. The left epididymis was indurated at the globus minor. The right seminal vesicle was palpable and indurated. A first strength PPD developed 18 mm. induration in 72 hours. Urinalysis revealed numerous red and white blood cells. An IVP revealed bilateral ureteropelvic junction obstruction, ureterovesical junction obstruction and hydroureteronephrosis (fig. 2, A). A cystourethrogram revealed a markedly contracted bladder with diverticula and right vesicoureteral reflux (fig. 2, B). Right orchiectomy and partial vasectomy were performed. The pathological report described caseating granulomatous epididymoorchitis. Triple-drug therapy was instituted.
311
Three urine cultures were subsequently reported positive for AFB. After 6 months of therapy with PAS, INH and streptomycin, progressive ureteral stricture and bilateral hydroureteronephrosis were noted. Operative intervention will be necessary. This case demonstrates the severity of lower urinary tract symptoms due to the contracted inflamed bladder. Periodic radiographic evaluation while on therapy is most essential. The case also indicates that chronic indolent epididymoorchitis should suggest tuberculosis. Case 3. I. T., a 39-year-old Negress, had had recurrent gross hematuria and dysuria 2 years in duration. Symptoms progressed to crampy lower abdominal pains, frequency and strangury. Significant in the history was an accidental gunshot wound 20 years previously necessitating a cesarean section for removal of a 7,l,Ji-month dead fetus. The bullet was retained anterior to the left acroiliac joint. Physical examination was unremarkable. Urinalysis revealed numerous red and white blood cells. Urine culture yielded Escherichia intermedium. An IVP showed a double left collecting system with hydroureteronephrosis of the inferior system, the point of obstruction being apparent at the level of the foreign object adjacent to the ureter (figs. 3, A and B). A retrograde ureterogram confirmed the level of obstruction. Cystoscopy revealed severe erythema and bullous edema of the bladder mucosa. The preoperative diagnosis was ureteral
Fm. 2. Case 2. A, IVP shows bilateral hydroureteronephrosis. B, voiding cystourethrogram reveals contracted bladder with diverticula and right vesicoureteral reflux.
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MANGELSON, SAUNDERS AND BROSMAN
Fm. 3. Case 3. A, IVP, anteroposterior view, reveals hydroureter and hydronephrosis of lower left double collecting system. B, left posterior oblique view shows point of ureteral obstruction at level of foreign object. stricture with hydroureteronephrosis secondary to foreign object reaction. The patient underwent left partial nephroureterectomy and excision of the bullet. However, the pathology report revealed tuberculosis of the kidney. The preoperative chest x-ray which had been reported as normal was reviewed and showed pleural thickening in the apices consistent with old tuberculosis. Postoperatively, an intermediate PPD showed 20 mm. induration at 72 hours and urine culture was positive for AFB. The sputum culture was also positive for AFB. The patient was given INH and PAS therapy but these were temporarily discontinued after 6 weeks because of evidence of hepatic decompensation. Subsequently, INH was resumed. This case demonstrates how tuberculosis of the urogenital system may masquerade when a different etiology for the malady seems more likely. DISCUSSION'
The primary drugs used in the management of urogenital tuberculosis are para-aminosalicylate (PAS), isoniazid (INH) and streptomycin. To reduce the high incidence of gastrointestinal side effects from the use of PAS, buffered varieties of this drug are available. Resistance to PAS is usually not detected until the drug has been taken for approximately 4 months. By the end
of 1 year, 75 per cent of the bacterial strains show evidence of resistance, even in patients on triple-drug therapy. 7 INH has been considered the most consistently effective drug in the management of tuberculosis. Toxicity primarily involves the central nervous system and these symptoms are seen most commonly in elderly patients. Drug resistance to this medication is high. Primary drug resistance occurs in 1 to 5 per cent of patients. Miyake and associates reported 33 per cent of their patients with urogenital tuberculosis showed primary resistance to INH. 8 Primary resistance is defined as the recovery of a resistant organism in a patient who has never received any therapy with that particular drug. Acquired resistance is the development of resistant strains in patients who have had prior therapy. Acquired resistance to INH is 25 per cent when used alone and 13 per cent when used in combination with other drugs. 8 Streptomycin is given in doses of 1 gm. daily for 4 weeks and then 1 gm. twice weekly until resistance to this medication develops. This drug is 500 times more effective at a pH ot 7 .8 7 Gould, R. S.: Current concepts of renal tuberculosis. J. Urol., 100: 124, 1968. 8 Miyake, K., Smith, M. J. V. and Lattimer, J. K.: Drug resistance of acid fast bacilli in the urine. J. Urol., 98: 263, 1967.
UROGENITAL TUBERCULOSIS
than at a pH of 6. 7 Therefore, alkalinization of the urine is necessary when administering this agent. The primary toxicity of this drug is generally confined to eighth nerve damage. Resistance occurs more rapidly with this drug than the others. After 4 months, 80 per cent of bacterial strains begin to show evidence of resistance. 8 A variety of secondary drugs is useful in the management of tuberculosis in patients who have primary or acquired resistance. Many or these drugs have not been investigated extensively in this country and their effectiveness is not well established. These secondary drugs have a high incidence of toxic manifestations and acquired resistance. Ethambutol is given in a single daily dose of 15 to 25 mg. per kg. 9 A significant incidence of optic neuritis (6 to 10 per cent) occurs with this agent and it is not recommended in children. The drug is generally given in combination with INH and/or streptomycin. Ethionamide, chemically related to INH, is prescribed at 250 mg., 3 times a day. 10 The toxic effects are primarily in the central nervous system and liver. This drug is not excreted by the kidney and, therefore, has a low urine concentration. A high tissue concentration may account for its effectiveness in the urogenital tract. This drug develops resistance rapidly when used alone. Like most antituberculosis agents, it should be used in combination. Ethionamide is 8 times more effective than streptomycin and exerts about the same degree of antituberculous activity as INH. 9 Cycloserine (seromycin) is given 250 mg. every 12 hours and is used as an agent in combination therapy. 9 This drug has central nervous system toxicity similar to but greater than INH. Pyridoxine is used to control these toxic manifestations.7 This drug is useful in those patients who show resistance to the primary drugs. Because of its high urine concentration, it is effective against E. coli, Enterococcus, paracolon and Staphylococcus aureus. 7 Pyrazinamide is administered in a divided dose of 20 to 35 mg. per kg. per day. 7 This drug 9 Goodman, L. S. and Gilman, A.: The Pharmacological Basis of Therapeutics. New York: The MacMillan Co., 1965. 10 Lattimer, J. K., Reilly, R. J., Segawa, A., Wechsler, H., Siegel, J., Girgis, A. and Gleason, D.: Injections are no longer necessary in the treatment of renal tuberculosis. J. Urol., 93: 735, 1965.
313
causes a high incidence of liver dysfunction when used in high dosage. The development of jaundice is common. This drug is primarily used for seriously ill, hospitalized patients who have been unresponsive to other drugs or who show resistance to the primary group of drugs. Viomycin is used in doses of 1 gm. intramuscularly twice a day. Viomycin, like streptomycin and kanamycin, causes eighth nerve damage. Electrocardiogram changes may also appear. This drug is less toxic than kanamycin to the liver and kidney. It has greater toxicity than streptomycin. Viomycin has no cross resistance to kanamycin or streptomycin. This drug is useful in the patient who is being prepared for operation or is being covered postoperatively and is resistant to streptomycin. The thiosemicarbazones are given in doses of 50 mg. per day for 1 to 2 weeks. The dose is increased gradually to 200 mg. per day. 9 This drug has a high incidence of gastrointestinal symptoms and jaundice. Bone marrow depression has also been seen with this agent. Its effectiveness in urogenital tuberculosis has not been ascertained. Operative therapy of urogenital tuberculosis prior to the advent of effective chemotherapy consisted primarily of extirpation of the affected organ. In recent years the incidence and need for nephrectomy have been greatly reduced and an effort is made to preserve functioning renal tissue. 4 • 11 • 12 Judicious operative intervention may be indispensible, both as an adjunct to systemic chemotherapy and in eliminating cicatricial lesions which are often a frequent aftermath of unsuccessful medical therapy. The primary operative indications for nephrectomy are intractable pain, a ureteral stricture, hypertension secondary to a tuberculous kidney and failure of medical therapy to eradicate tuberculous infection due to drug resistance, drug intolerance, rapid drug inactivation or sealed-off or obstructive lesions. 11-14 Partial nephrectomy, is being 11 Beck, A. D. and Marshall, V. F.: Is nephrectomy obsolete for unilateral renal tuberculosis? J. Urol., 98: 65, 1967. 12 Gow, J. G.: The surgery of genito-urinary tuberculosis. Brit. J. Surg., 53: 210, 1966. 13 Malament, M., Auerbach, 0. and Harris, J. T.: Limitation of chemotherapy in advanced cavitary tuberculosis of the kidney. J. Urol., 99:
700, 1968.
14 Kaufman, J. J. and Goodwin, W. E.: Renal hypertension secondary to renal tuberculosis. Report of cure in four patients treated by nephrectomy. Amer. ,J. Med., 38: 337, 1965.
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MANGELSON, SAUNDERS AND BROSMAN
utilized with good results in an effort to save renal tissue. 15 SUMMARY
The diagnosis of urogenital tuberculosis may be elusive but should be clearly established before drug therapy is initiated. Diagnosis is obtained by urine cultures and biopsy. When chemotherapy is used it is important to be cognizant of the high incidence of primary resistance and the rapidity with which acquired drug resistance 15 Puigvert, A. and Gittes, R. F.: Partial nep~rectomy in the solitary kidney. II. Experience with 20 cases of renal tuberculosis. J. Urol., 100:
243, 1968.
develops. Frequent drug sensitivity studies should be obtained in these patients in order that effective chemotherapy may be used. Two years is considered to be an adequate period of time for drug therapy. Operative treatment of urogenital tuberculosis is generally confined to the complications or the failures of drug therapy. The incidence of nephrectomy has rapidly decreased whereas operative procedures designed to preserve renal tissue have increased. An operation is a useful and perhaps indispensable adjunct to systemic drug therapy in eradicating the disease and in eliminating the dangerous cicatricial lesions which often form following drug therapy.
THE JOURNAL OF UROLOGY
Copyright © 1970 by The Williams & Wilkins Co.
UROGENITAL TUBERCULOSIS N. L. MANGELSON, J. C. SAUNDERS ANDS. A. BROSMAN From the Department of Urology, Harbor General Hospital, Torrance and the University of California School of Medicine, Los Angeles, California
Tuberculosis, with its complications, is the most common infection causing death not only in the United States but in the entire world. 1 Last year this disease was responsible for more deaths than the war in Vietnam. 2 Geographically, tuberculosis is concentrated in the older and poorer sections of urban areas where minority groups and immigrants cluster and live in overcrowded and substandard housing. Newly-reported cases occur in 45.5 per cent of patients more than 25 years old. Of these 52 per cent of patients are more than 45 years old. 2 The incidence of renal tuberculosis has remained constant over the past decade despite widely used and effective chemotherapy. The clinical impression that urologists are seeing fewer cases is probably reflected by the fact that these patients are being cured medically more often than surgically. Although the new-case rate is constant, there are fewer far-advanced cases and most of the new cases consist primarily of moderately advanced disease. 3 The insidious nature of this disease was dramatized by Lattimer when he reported that 72 per cent of 25 physicians working for the urinary tuberculosis research unit of Kingsbridge Veterans Hospital demonstrated advanced cavitary tuberculosis of the kidneys. 4 The advanced disease had developed without significant symptoms. Diagnosis of urogenital tuberculosis depends upon finding the organism in the urinary tract by culture or biopsy. Cultures of 3 morning specimens of urine are considered as good as a 24-hour collection. Symptoms of chronic urinary tract infection are an indication of the possibility of urogenital tuberculosis. The diagnosis should Accepted for publication July 25, 1969. 1 Murray, J.: Tuberculosis. Calif. Med., 109: 390, 1968. 2 Curry, F. J.: The tuberculosis problem today. Calif. Med., 109: 418, 1968. 3 Siegel, J. and Lattimer, J. K.: Renal tuberculosis: has the incidence of advanced lesions decreased in the past two decades? J. Urol., 91: 330, 1964. 4 Lattimer, J. K.: Renal tuberculosis. New Engl. J. Med., 273: 208, 1965.
be considered in patients with chronic epididymoorchitis. Tuberculosis of the prostate, epididymis and testicle has been diagnosed by needle biopsy. Treatment should not be started until a positive diagnosis has been made. Kurosaka reported that the history alone suggested the presence of tuberculosis in 60 per cent of 240 patients.' Of these, the largest proportion of primary symptoms was related to bladder involvement. Renal involvement occurred in approximately one-third of these patients. Pulmonary tuberculosis is present in approximately 15 per cent of those patients with urinary tract tuberculosis. The reproductive organs are involved in 13 per cent and the skeletal system in 10 per cent of cases. 6 CASE REPORTS
Case 1. L. S., a 74-year-old woman, had dysuria and had been treated by a physician for pyuria for 6 months without resolution of the infection. She had noted occasional right costovertebral angle aching pain but few other symptoms. An excretory urogram (IVP) revealed bilateral hydronephrosis (fig. 1, A). Cystoscopy revealed generalized inflammation of the bladder. A left bulb retrograde pyelogram revealed numerous strictures of the ureter (fig. 1, B). A right bulb retrograde pyelogram was unsuccessful. An antegrade pyelogram performed by injecting contrast material directly into the right renal pelvis confirmed a distal ureteral stricture with hydronephrosis and hydroureter. Intermediate purified protein derivative (PPD) intradermal induration was 12 mm. in diameter at 72 hours. Concentrated urine smear was 2-plus positive for acid-fast bacillus (AFB). Repeated chest x-rays and sputum culture were negative. Triple-drug therapy was instituted. Urine cultures subse6 Kurosaka, M.: Studies on tuberculosis of the urinary tract. I. Clinical observations. Acta Urol. Jap., 12: 107, 1966. 6 Scheinin, T. M. and Kontturi, M.: Incidence and fate of renal tuberculosis in patients with bone and joint tuberculosis. Ann. Chir. Gynaec. Fenn., 66: 36, 1966.
309
310
MANGELSON, SAUNDERS AND BROSMAN
FrG. 1. Case 1. A, IVP prior to therapy reveals bilateral hydronephrosis. B, left retrograde pyelogram prior to therapy reveals tuberculous ureteral strictures. C, retrograde pyelogram drainage film after 8 months of therapy. No improvement of right hydroureteronephrosis. D, IVP following excision of right ureterovesical stricture and ureteroneocystostomy shows marked improvement in right hydroureteronephrosis.
quently were positive. The patient had an intolerance to para-aminosalicylate (PAS) which necessitated its discontinuance. Resistance to streptomycin developed after 3 months. Cycloserine and ethionamide were substituted in the regimen. Cycloserine was discontinued after 1 month because of psychic depression. Urine cultures became negative 4 months after beginning therapy. Ethionamide, pyrazinamide and isoniazid (INH) were continued for 20 months and INH continuously for 4½ years with negative cultures. ln the first 8 months of therapy the right
ureteral stricture responded poorly to ureteral dilations, necessitating excision of the stricture and right ureteroneocystostomy (fig. 1, C). This procedure improved the right kidney function (fig. 1, D). The patient suffered organic psychotic depression postoperatively, necessitating electroshock therapy to which she responded well. The left ureteral obstruction has gradually progressed resulting in diminished left renal function presently but the patient is asymptomatic and has a serum creatinine of 1.0. This case demonstrates the problem of resistance developing to antituberculous drugs and the need for periodic
UROGENITAL TUBERCULOSIS
reculturing for sensitivity. It also demonstrates the need for operative intervention when chemotherapy fails to adequately manage the disease. Case 2. G. L., a 48-year-old Caucasian man, had painful swelling of the right testicle and scrotum 3 months in duration. Four years previously he had gross hematuria which recurred approximately each 6 months. Two yearn prior to seeking medical help he had frequency of urination every 2 hours which progressed to frequency of urination each hour 1 year prior to admission to the hospital and every 15 to 30 minutes in the last 6 months. He had a 10-pound weight loss over 1½ years. Physical examination showed a 5 by 7 cm. translucent right hydrocele with an adjacent indurated tender epididymis adherent to the scrotum. The left epididymis was indurated at the globus minor. The right seminal vesicle was palpable and indurated. A first strength PPD developed 18 mm. induration in 72 hours. Urinalysis revealed numerous red and white blood cells. An IVP revealed bilateral ureteropelvic junction obstruction, ureterovesical junction obstruction and hydroureteronephrosis (fig. 2, A). A cystourethrogram revealed a markedly contracted bladder with diverticula and right vesicoureteral reflux (fig. 2, B). Right orchiectomy and partial vasectomy were performed. The pathological report described caseating granulomatous epididymoorchitis. Triple-drug therapy was instituted.
311
Three urine cultures were subsequently reported positive for AFB. After 6 months of therapy with PAS, INH and streptomycin, progressive ureteral stricture and bilateral hydroureteronephrosis were noted. Operative intervention will be necessary. This case demonstrates the severity of lower urinary tract symptoms due to the contracted inflamed bladder. Periodic radiographic evaluation while on therapy is most essential. The case also indicates that chronic indolent epididymoorchitis should suggest tuberculosis. Case 3. I. T., a 39-year-old Negress, had had recurrent gross hematuria and dysuria 2 years in duration. Symptoms progressed to crampy lower abdominal pains, frequency and strangury. Significant in the history was an accidental gunshot wound 20 years previously necessitating a cesarean section for removal of a 7,l,Ji-month dead fetus. The bullet was retained anterior to the left acroiliac joint. Physical examination was unremarkable. Urinalysis revealed numerous red and white blood cells. Urine culture yielded Escherichia intermedium. An IVP showed a double left collecting system with hydroureteronephrosis of the inferior system, the point of obstruction being apparent at the level of the foreign object adjacent to the ureter (figs. 3, A and B). A retrograde ureterogram confirmed the level of obstruction. Cystoscopy revealed severe erythema and bullous edema of the bladder mucosa. The preoperative diagnosis was ureteral
Fm. 2. Case 2. A, IVP shows bilateral hydroureteronephrosis. B, voiding cystourethrogram reveals contracted bladder with diverticula and right vesicoureteral reflux.
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MANGELSON, SAUNDERS AND BROSMAN
Fm. 3. Case 3. A, IVP, anteroposterior view, reveals hydroureter and hydronephrosis of lower left double collecting system. B, left posterior oblique view shows point of ureteral obstruction at level of foreign object. stricture with hydroureteronephrosis secondary to foreign object reaction. The patient underwent left partial nephroureterectomy and excision of the bullet. However, the pathology report revealed tuberculosis of the kidney. The preoperative chest x-ray which had been reported as normal was reviewed and showed pleural thickening in the apices consistent with old tuberculosis. Postoperatively, an intermediate PPD showed 20 mm. induration at 72 hours and urine culture was positive for AFB. The sputum culture was also positive for AFB. The patient was given INH and PAS therapy but these were temporarily discontinued after 6 weeks because of evidence of hepatic decompensation. Subsequently, INH was resumed. This case demonstrates how tuberculosis of the urogenital system may masquerade when a different etiology for the malady seems more likely. DISCUSSION'
The primary drugs used in the management of urogenital tuberculosis are para-aminosalicylate (PAS), isoniazid (INH) and streptomycin. To reduce the high incidence of gastrointestinal side effects from the use of PAS, buffered varieties of this drug are available. Resistance to PAS is usually not detected until the drug has been taken for approximately 4 months. By the end
of 1 year, 75 per cent of the bacterial strains show evidence of resistance, even in patients on triple-drug therapy. 7 INH has been considered the most consistently effective drug in the management of tuberculosis. Toxicity primarily involves the central nervous system and these symptoms are seen most commonly in elderly patients. Drug resistance to this medication is high. Primary drug resistance occurs in 1 to 5 per cent of patients. Miyake and associates reported 33 per cent of their patients with urogenital tuberculosis showed primary resistance to INH. 8 Primary resistance is defined as the recovery of a resistant organism in a patient who has never received any therapy with that particular drug. Acquired resistance is the development of resistant strains in patients who have had prior therapy. Acquired resistance to INH is 25 per cent when used alone and 13 per cent when used in combination with other drugs. 8 Streptomycin is given in doses of 1 gm. daily for 4 weeks and then 1 gm. twice weekly until resistance to this medication develops. This drug is 500 times more effective at a pH ot 7 .8 7 Gould, R. S.: Current concepts of renal tuberculosis. J. Urol., 100: 124, 1968. 8 Miyake, K., Smith, M. J. V. and Lattimer, J. K.: Drug resistance of acid fast bacilli in the urine. J. Urol., 98: 263, 1967.
UROGENITAL TUBERCULOSIS
than at a pH of 6. 7 Therefore, alkalinization of the urine is necessary when administering this agent. The primary toxicity of this drug is generally confined to eighth nerve damage. Resistance occurs more rapidly with this drug than the others. After 4 months, 80 per cent of bacterial strains begin to show evidence of resistance. 8 A variety of secondary drugs is useful in the management of tuberculosis in patients who have primary or acquired resistance. Many or these drugs have not been investigated extensively in this country and their effectiveness is not well established. These secondary drugs have a high incidence of toxic manifestations and acquired resistance. Ethambutol is given in a single daily dose of 15 to 25 mg. per kg. 9 A significant incidence of optic neuritis (6 to 10 per cent) occurs with this agent and it is not recommended in children. The drug is generally given in combination with INH and/or streptomycin. Ethionamide, chemically related to INH, is prescribed at 250 mg., 3 times a day. 10 The toxic effects are primarily in the central nervous system and liver. This drug is not excreted by the kidney and, therefore, has a low urine concentration. A high tissue concentration may account for its effectiveness in the urogenital tract. This drug develops resistance rapidly when used alone. Like most antituberculosis agents, it should be used in combination. Ethionamide is 8 times more effective than streptomycin and exerts about the same degree of antituberculous activity as INH. 9 Cycloserine (seromycin) is given 250 mg. every 12 hours and is used as an agent in combination therapy. 9 This drug has central nervous system toxicity similar to but greater than INH. Pyridoxine is used to control these toxic manifestations.7 This drug is useful in those patients who show resistance to the primary drugs. Because of its high urine concentration, it is effective against E. coli, Enterococcus, paracolon and Staphylococcus aureus. 7 Pyrazinamide is administered in a divided dose of 20 to 35 mg. per kg. per day. 7 This drug 9 Goodman, L. S. and Gilman, A.: The Pharmacological Basis of Therapeutics. New York: The MacMillan Co., 1965. 10 Lattimer, J. K., Reilly, R. J., Segawa, A., Wechsler, H., Siegel, J., Girgis, A. and Gleason, D.: Injections are no longer necessary in the treatment of renal tuberculosis. J. Urol., 93: 735, 1965.
313
causes a high incidence of liver dysfunction when used in high dosage. The development of jaundice is common. This drug is primarily used for seriously ill, hospitalized patients who have been unresponsive to other drugs or who show resistance to the primary group of drugs. Viomycin is used in doses of 1 gm. intramuscularly twice a day. Viomycin, like streptomycin and kanamycin, causes eighth nerve damage. Electrocardiogram changes may also appear. This drug is less toxic than kanamycin to the liver and kidney. It has greater toxicity than streptomycin. Viomycin has no cross resistance to kanamycin or streptomycin. This drug is useful in the patient who is being prepared for operation or is being covered postoperatively and is resistant to streptomycin. The thiosemicarbazones are given in doses of 50 mg. per day for 1 to 2 weeks. The dose is increased gradually to 200 mg. per day. 9 This drug has a high incidence of gastrointestinal symptoms and jaundice. Bone marrow depression has also been seen with this agent. Its effectiveness in urogenital tuberculosis has not been ascertained. Operative therapy of urogenital tuberculosis prior to the advent of effective chemotherapy consisted primarily of extirpation of the affected organ. In recent years the incidence and need for nephrectomy have been greatly reduced and an effort is made to preserve functioning renal tissue. 4 • 11 • 12 Judicious operative intervention may be indispensible, both as an adjunct to systemic chemotherapy and in eliminating cicatricial lesions which are often a frequent aftermath of unsuccessful medical therapy. The primary operative indications for nephrectomy are intractable pain, a ureteral stricture, hypertension secondary to a tuberculous kidney and failure of medical therapy to eradicate tuberculous infection due to drug resistance, drug intolerance, rapid drug inactivation or sealed-off or obstructive lesions. 11-14 Partial nephrectomy, is being 11 Beck, A. D. and Marshall, V. F.: Is nephrectomy obsolete for unilateral renal tuberculosis? J. Urol., 98: 65, 1967. 12 Gow, J. G.: The surgery of genito-urinary tuberculosis. Brit. J. Surg., 53: 210, 1966. 13 Malament, M., Auerbach, 0. and Harris, J. T.: Limitation of chemotherapy in advanced cavitary tuberculosis of the kidney. J. Urol., 99:
700, 1968.
14 Kaufman, J. J. and Goodwin, W. E.: Renal hypertension secondary to renal tuberculosis. Report of cure in four patients treated by nephrectomy. Amer. ,J. Med., 38: 337, 1965.
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MANGELSON, SAUNDERS AND BROSMAN
utilized with good results in an effort to save renal tissue. 15 SUMMARY
The diagnosis of urogenital tuberculosis may be elusive but should be clearly established before drug therapy is initiated. Diagnosis is obtained by urine cultures and biopsy. When chemotherapy is used it is important to be cognizant of the high incidence of primary resistance and the rapidity with which acquired drug resistance 15 Puigvert, A. and Gittes, R. F.: Partial nep~rectomy in the solitary kidney. II. Experience with 20 cases of renal tuberculosis. J. Urol., 100:
243, 1968.
develops. Frequent drug sensitivity studies should be obtained in these patients in order that effective chemotherapy may be used. Two years is considered to be an adequate period of time for drug therapy. Operative treatment of urogenital tuberculosis is generally confined to the complications or the failures of drug therapy. The incidence of nephrectomy has rapidly decreased whereas operative procedures designed to preserve renal tissue have increased. An operation is a useful and perhaps indispensable adjunct to systemic drug therapy in eradicating the disease and in eliminating the dangerous cicatricial lesions which often form following drug therapy.