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The Responsibility of an Internist in the Treatment of Pyelonephritis
THE JOURNAL OF UROLOGY
Vol. 68, No. 5, November 1952
Printed in U.S.A.
THE RESPONSIBILITY OF AN INTERNIST IN THE TREATMENT OF PYELONEPHRITIS ROBERT BIRCHALL From the Departments of Medicine, Tulane University and Ochsner Clinic, New Orleans, La.
The privilege of addressing the members of another specialty on a subject which is one of their problems is stimulating. True, it imposes certain limitations, for it would obviously be fruitless to discuss the pathology of pyelonephritis or the differential diagnosis of its various phases, or even the indications for use of the various antibiotics. These are accepted as the urologist's domain, and he should be completely familiar with them. However, it does offer the opportunity of discussing the reasons for the difference in our therapeutic approach and yours. First, let me explain why we internists should have a definite therapeutic approach to a disease which is most often treated by the urologist. We are, of necessity, interested in the manner in which the kidney, as a highly specialized organ, maintains a constant internal environment for every cell in the body. Therefore, we must be just as interested in the manner in which each renal disease alters the integrity of that organ and so upsets the delicately maintained equilibrium. Of all renal diseases acute pyelonephritis is the commonest, 1 - 4 a contention Mansfield, Mallory and Ellis 5 proved by finding the scars of healed pyelonephritis in nearly 15 per cent of 1000 consecutive autopsies. The chronic stage, as demonstrated by Weiss and Parker,1 not only is commoner than chronic glomerulonephritis but also is responsible for the smallest kidneys of chronic Bright's disease and for 15 to 20 per cent of all examples of necrotizing arteriolitis.2 This is further documented by the experience of every internist of having been asked to see in consultation a patient who has both hypertension and renal insufficiency. Relatives and the referring physician are anxious to know the treatment and prognosis, and, of course, both of these, depend, to a considerable extent, upon an accurate diagnosis. Physical examination helps little, since the fundi, heart and blood pressure may all be affected to varying degrees by almost any type of renal disease. Laboratory studies, with the exception of a careful examination of the urinary sediment, an excretory urogram, and a urine culture provide only a cross sectional view of renal function at the time the patient is examined, but help little in establishing the correct clinical diagnosis. We are therefore forced to rely primarily on what the patient tells us about his disease. With extraordinary frequency we find the patient's history to be compatible Presented before annual meeting of Clinical Society of Genito-Urinary Surgeons, New Orleans, February 7, 1952. 1 Weiss, S. and Parker, F., Jr.: Medicine, 18: 221-315, 1939. 2 Weiss, S. and Parker, F., Jr.: New Eng. J. Med., 223: 959-967, 1940. 3 Nesbit, R. M. and Conger, K. B.: New York State J. Med., 42: 225-232, 1942. 4 Braasch, W. F. and Cathcart, E. P.: J. A. M. A., 88: 1630-1633, 1927. 0 Mansfield, J. S., Mallory, G. K. and Ellis, L. B.: New Eng. J. Med., 229: 387-395, 1943. 798
INTERNIST RESPONSIBILITY IN PYELONEPHRITIS
799
with the natural history of pyelonephritis, as delineated by Longcope and Winkenwerder, 6 and to be totally unlike the natural history of any other form of Bright's disease. Thus, from our point of view, pyelonephritis is indeed an important disease. Another reason for our interest in pyelonephritis is that it seems to us to be, in general, a poorly managed disease. This rather dogmatic statement is made for two reasons : First, if we let figure 1 represent the life span of a patient with typical pyelonephritis, it is evident that there has been no continuity in treatment. The chills and fever which first appeared in childhood were, of course, treated by a pediatrician. The patient was then relatively free of symptoms until she married at the age of 18 years, when the so-typical "honeymoon pyelitis" developed. She consulted a gynecologist, who probably forced fluids and administered small doses of sulfonamides and, again, she apparently recovered. Shortly afterward I
I
I
I
PEDlATRICIA~: GY~!ECOW615T\ OB5TRETICIAl-l! UROUJGIST: INTERWIST
I
I
I I
/,GE-Yes.
I
1
15
1
20 1
I
30 1
chills.Fever :t-bneymoon iroxemi.dof : llii.nary \ 1.Jremia Pyu.ria. : 'Pya.hb..s" : Prepno.ncy i Trad i 1 / I lnfczcbon i
Fm. 1. Schematic representation of natural history of pyelonephritis
she became pregnant and once again symptoms of pyelonephritis, with or without toxemia of pregnancy,7 · 8 developed. At that time, of course, she was treated by her obstetrician. Finally, at about the age of 30 years the chills, fever, back pain and dysuria returned. Since symptoms were referable to the urinary tract, she consulted a urologist, who made the necessary examinations and treated her with mandelic acid, or possibly 0.5 gm. of gantrisin 4 times a day. Under this regimen the acute episode subsided, and she never again complained of chills, fever or even dysuria. However, she soon began to tire easily, looked pale, and had to force herself to complete her routine daily chores. Finally, she returned to the urologist, who discovered that she was anemic, the blood urea nitrogen was elevated, phenolsulfonphthalein excretion was depressed, erythrocyte sedi6 Longcope, W. T. and Winkenwerder, W. L.: Bull. Johns Hopkins Hosp., 63: 255-287, 1933. 7 Peters, J.P.: New Eng. J. Med., 213: 653-659, 1935. 8 Peters, J. P., Lavietes, P. H. and Zimmerman, H. M.: Am. J. Obst. & Gynec., 32: 911-927, 1936.
800
ROBERT BIRCHALL
mentation rate was greatly elevated and an excretory urogram showed minimal concentration of the dye. She was considered to have bilateral renal disease and therefore transferred to the medical service. This history, and it is fairly typical of pyelonephritis, suggests that the early stages of the disease are too often treated as entities by the pediatrician, obstetrician and even urologist, and not until terminal renal insufficiency appears is the internist consulted. This lack of continuity in observation and management has tended to absolve each from the responsibility of devising better means of eradicating the initial infection and so helping to prevent recurrence and chronicity. Secondly, it seems clearly established, both from the natural history and from the pathology, that pyelonephritis is simply a bacterial infection in the interstitial tissue of the kidney. If that be true, the judicious use of antibiotics should completely eradicate the disease and terminal chronic pyelonephritis should be rare. Unfortunately, it is still a much too common cause of death. With these as introductory remarks, the therapeutic problem posed by pyelonephritis may now be considered. If we define the disease as an infection in the interstitial tissue of the kidney which, if not eradicated or if permitted to recur repeatedly, will progressively and inexorably destroy an ever increasing area of contiguous nephrons until too few remain to maintain life, we actually arrive at the crux of the problem, that is, the difference between the therapeutic approach of the internist and the urologist. It is almost as if, to borrow from Robert Frost, "Two roads diverged in a wood and I-I took the one less traveled by." The congested road, as followed I believe by most urologists, leads directly to sterilization of the urine. In order to achieve this, the optimum dosage of any antibiotic is the one which will, by virtue of the concentrating ability of the cells of the distal convoluted tubules, provide a bacteriostatic concentration of antibiotic in the urine. It is almost possible to calcu,late this mathematically. To use the sulfonamides as an example, it was soon established that a urinary sulfonamide concentration of 50 to 200 mg. per 100 cc is adequate to sterilize the urine against almost all organisms.9 - 15 Therefore, if a urinary output of 1000 cc in 24 hours is anticipated, and it is assumed that 100 per cent of the total amount of drug ingested is absorbed, 90 per cent is excreted in the urine, and approximately 30 per cent of this is converted to the ineffective acetylated form, it is clear that a dosage of 4 gm. a day will produce an effective urinary concentration of approximately 250 mg. per 100 cc: 4000 X 1.0 X 0.9 X 0.7 = 250 mg. per l00 cc 10 Since a urinary concentration of 50 mg. per cent is adequate for the majority of infections, it seemed rational to recommend a dosage of 0.5 gm. three or four Alyea, E. P. and Roberts, L. C.: J. A. M.A., 115: 1345-1350, 1940. Helmholz, H. F.: J. Urol., 45: 135-145, 1941. Borst, R. C.: New York State J. Med.: 42: 217-224, 1942. 12 Rammelkamp, C.H. and Stoneburner, L. T., III: New Eng. J. Med., 224: 45-52, ,1941. 13 Alyea, E. P.: J. Urol., 47: 219-223, :1942. 14 Long, P.H. and Bliss, E. A.: South .Med. J., 31: 308-315, 1938. 16 Peterson, 0. L. and Finland, M.: Am. J. M. Sc., 202: 757-772, 1941. 9
10
11
INTERNIST RESPONSIBILITY IN PYELONEPHRITIS
801
times a day. Such a scheme of therapy can be expected to inhibit multiplication of organisms in the pelvis, ureter and bladder, decrease the likelihood of re-infection by sterilizing the urine and reduce the superficial inflammation of the mucosa by direct perfusion and absorption of the drug. In turn, this will alleviate the symptoms of associated or secondary cystitis and urethritis. Although
Fw. 2. Diagrammatic sketch showing calculated concentration of sulfadiazine in interstitial tissue of kidney when plasma concentration of sulfadiazine is 4 mg. %- A, plasma concentration of sulfadiazine = 4 mg. %- Tissue concentration of diffusable sulfadiazine = 3.4 mg.%; pH = 7.4. B, amount of fluid reabsorbed per minute= 119 cc. Amount of sulfadiazine reabsorbed per minute = 2.7 mg. Concentration of sulfadiazine in tubular reabsorbate = 2.4 mg.%; pH = 7.4. C, amount of fluid filtered per minute = 120 cc. Amount of sulfadiazine filtered per minute = 4.1 mg. Concentration of sulfadiazine in glomerular filtrate = 3.4 mg.%; pH = 7.4. D, amount of urine formed per minute = 1 cc. Amount of sulfadiazine excreted per minute = 1.4 mg. Concentration of sulfadiazine in urine = 140 mg. %; pH = 5.5.
this regimen is apparently successful in the majority of patients with acute pyelonephritis, the formidable number of patients in whom terminal chronic pyelonephritis ultimately develops casts considerable doubt on its actual efficacy and calls into question the wisdom of directing our efforts toward sterilization of the urine. On the other hand, if one actually considers pyelonephritis to be an infection
802
ROBERT BIRCHALL
of the interstitial tissue of the kidney, he cannot be content with simple sterilization of the exudate that appears in the urine. Comparison with the obvious futility of treating a patient with empyema by simply sterilizing the fluid in the intrapleural space seems valid. Instead, he must "take the road less traveled by" and devise a scheme of therapy aimed at eradicating the infection in the interstitial tissue of the kidney by maintaining an effective antibiotic level at the actual site of the infection. As is illustrated in figure 2, glomerular filtrate is neither concentrated nor acidified until it reaches the distal tubular segment. Therefore, the concentration of any antibiotic in the interstitial fluid of the kidney is entirely independent of its subsequently attained concentration in the urine, and can at no time exceed its concentration in the plasma. Furthermore, it should be remembered that mandelic acid and mandelamine are effective only at a pH of 5.5 or less. Since the pH of the interstitial tissue of the kidney ranges from 7.2 to 7.4, it is clear that these two drugs have no place in the treatment of pyelonephritis, and should be reserved for those rare patients who present evidence of uncomplicated cystitis or infection of the lower urinary conduit. Therefore, with this concept in mind, a few general principles to be applied to the treatment of acute, recurrent and chronic pyelonephritis may now be presented. 1. Acute and recurrent pyelonephritis a) The appropriate sulfonamide or combination of sulfonamides is usually, but of course not always, the drug of choice. Adequate urinary output and alkalinity of the urine should be assured. b) Dosage of the sulfonamides should be that which will maintain a plasma level of 8 to 10 mg. per 100 cc. The dosage of other antibiotics should be proportionate. c) Duration of therapy should be arbitrarily fixed at 7 to 10 days. d) Cure should be established only by the demonstration of 2 or 3 negative urinary cultures obtained after all traces of antibiotics have disappeared from the urine. This probably seems drastic, but it must be remembered that acute pyelonephritis may be a formidable and rapidly progressing disease. Necrotizing arteriolitis secondary to pyelonephritis has been demonstrated at the autopsy of a baby 6 months old. 1 Recently, with the Department of Urology, we saw a physician's wife in whom severe renal insufficiency developed within one year of her first recognizable attack of acute pyelonephritis. Still more recently, with the Department of Urology, we observed a young girl in whom the excretory urogram was normal but urine culture yielded a positive result. She received a full course of chloramphenicol but failed to return for follow-up cultures. She was seen again just 5 months later with not only a positive urine culture but also easily demonstrable hydronephrosis and obstruction at the ureteropelvic junction. It is for such reasons that, regardless of the antibiotics selected or the dosage employed, several follow-up urinary cultures must be negative before cure can be established. 2. Chronic pyelonephritis a) The antibiotic should be selected according to combined urinary culture
INTERNIST RESPONSIBILITY IN PYELONEPHRITIS
803
and sensitivity studies, coupled with a consideration of the spectra covered by each antibiotic. b) Duration of treatment should be at least 7 to 10 days. c) Intensity of treatment should be as much antibiotic as the patient can or will tolerate. d) Urine should be cultured after treatment has been discontinued and, if still positive, a dillerent and more intensive regimen, vvith consideration of combination of antibiotics, should be devised. The problem of treating a patient with chronic pyelonephritis is difficult. Usually a prolonged and expensive investment, in many ways it is similar to that of treating a patient with subacute bacterial endocarditis. Despite the greatly reduced renal blood flow and the prevalence of avascular scar tissue, we are faced with the problem of delivering as much antibiotic as possible to the infected area. Since the renal blood flow cannot be effectively increased, the only recourse is to increase, to the upper limits of tolerance, the concentration of antibiotic in what little blood actually reaches the infected area. Most antibiotics in extremely high dosage produce almost intolerable reactions; it is this which, in most cases, limits the duration of therapy and tests one's ability to cajole, to sedate and, if necessary, almost to force the patient to accept a treatment which soon becomes repulsive. Moreover, neither should the physician nor the patient be unduly disturbed if the first course of therapy is unsuccessful. There are always other antibiotics and other combinations of them, and perserverance together with designing and redesigning the therapeutic regimen will almost certainly succeed in overcoming the infection. Repeated short courses of intensive antibiotic therapy would appear to be more efficacious than a single prolonged course administered in doses so low that at no time is the infection in the interstitial tissue of the kidney exposed to an adequate concentration of the drug. Destroyed nephrons cannot be replaced, but hypertrophy of others and subsidence of the inflammatory reaction will probably result in some degree of permanent improvement in renal function. In conclusion, let me say that in no other field should close cooperation between the internist and the urologist be so fruitful. Infection in itself, regardless of the organ where it lodges, is the domain of the internist. An infection which does not drain cannot be effectively treated. Evaluation of the drainage and actual construction of adequate drainage of an infected kidney, if it does not initially exist, is the domain of the urologist. It would thus seem appropriate for both specialties to combine their efforts in an attempt to eradicate at the onset this potentially fatal disease.
Vol. 68, No. 5, November 1952
Printed in U.S.A.
THE RESPONSIBILITY OF AN INTERNIST IN THE TREATMENT OF PYELONEPHRITIS ROBERT BIRCHALL From the Departments of Medicine, Tulane University and Ochsner Clinic, New Orleans, La.
The privilege of addressing the members of another specialty on a subject which is one of their problems is stimulating. True, it imposes certain limitations, for it would obviously be fruitless to discuss the pathology of pyelonephritis or the differential diagnosis of its various phases, or even the indications for use of the various antibiotics. These are accepted as the urologist's domain, and he should be completely familiar with them. However, it does offer the opportunity of discussing the reasons for the difference in our therapeutic approach and yours. First, let me explain why we internists should have a definite therapeutic approach to a disease which is most often treated by the urologist. We are, of necessity, interested in the manner in which the kidney, as a highly specialized organ, maintains a constant internal environment for every cell in the body. Therefore, we must be just as interested in the manner in which each renal disease alters the integrity of that organ and so upsets the delicately maintained equilibrium. Of all renal diseases acute pyelonephritis is the commonest, 1 - 4 a contention Mansfield, Mallory and Ellis 5 proved by finding the scars of healed pyelonephritis in nearly 15 per cent of 1000 consecutive autopsies. The chronic stage, as demonstrated by Weiss and Parker,1 not only is commoner than chronic glomerulonephritis but also is responsible for the smallest kidneys of chronic Bright's disease and for 15 to 20 per cent of all examples of necrotizing arteriolitis.2 This is further documented by the experience of every internist of having been asked to see in consultation a patient who has both hypertension and renal insufficiency. Relatives and the referring physician are anxious to know the treatment and prognosis, and, of course, both of these, depend, to a considerable extent, upon an accurate diagnosis. Physical examination helps little, since the fundi, heart and blood pressure may all be affected to varying degrees by almost any type of renal disease. Laboratory studies, with the exception of a careful examination of the urinary sediment, an excretory urogram, and a urine culture provide only a cross sectional view of renal function at the time the patient is examined, but help little in establishing the correct clinical diagnosis. We are therefore forced to rely primarily on what the patient tells us about his disease. With extraordinary frequency we find the patient's history to be compatible Presented before annual meeting of Clinical Society of Genito-Urinary Surgeons, New Orleans, February 7, 1952. 1 Weiss, S. and Parker, F., Jr.: Medicine, 18: 221-315, 1939. 2 Weiss, S. and Parker, F., Jr.: New Eng. J. Med., 223: 959-967, 1940. 3 Nesbit, R. M. and Conger, K. B.: New York State J. Med., 42: 225-232, 1942. 4 Braasch, W. F. and Cathcart, E. P.: J. A. M. A., 88: 1630-1633, 1927. 0 Mansfield, J. S., Mallory, G. K. and Ellis, L. B.: New Eng. J. Med., 229: 387-395, 1943. 798
INTERNIST RESPONSIBILITY IN PYELONEPHRITIS
799
with the natural history of pyelonephritis, as delineated by Longcope and Winkenwerder, 6 and to be totally unlike the natural history of any other form of Bright's disease. Thus, from our point of view, pyelonephritis is indeed an important disease. Another reason for our interest in pyelonephritis is that it seems to us to be, in general, a poorly managed disease. This rather dogmatic statement is made for two reasons : First, if we let figure 1 represent the life span of a patient with typical pyelonephritis, it is evident that there has been no continuity in treatment. The chills and fever which first appeared in childhood were, of course, treated by a pediatrician. The patient was then relatively free of symptoms until she married at the age of 18 years, when the so-typical "honeymoon pyelitis" developed. She consulted a gynecologist, who probably forced fluids and administered small doses of sulfonamides and, again, she apparently recovered. Shortly afterward I
I
I
I
PEDlATRICIA~: GY~!ECOW615T\ OB5TRETICIAl-l! UROUJGIST: INTERWIST
I
I
I I
/,GE-Yes.
I
1
15
1
20 1
I
30 1
chills.Fever :t-bneymoon iroxemi.dof : llii.nary \ 1.Jremia Pyu.ria. : 'Pya.hb..s" : Prepno.ncy i Trad i 1 / I lnfczcbon i
Fm. 1. Schematic representation of natural history of pyelonephritis
she became pregnant and once again symptoms of pyelonephritis, with or without toxemia of pregnancy,7 · 8 developed. At that time, of course, she was treated by her obstetrician. Finally, at about the age of 30 years the chills, fever, back pain and dysuria returned. Since symptoms were referable to the urinary tract, she consulted a urologist, who made the necessary examinations and treated her with mandelic acid, or possibly 0.5 gm. of gantrisin 4 times a day. Under this regimen the acute episode subsided, and she never again complained of chills, fever or even dysuria. However, she soon began to tire easily, looked pale, and had to force herself to complete her routine daily chores. Finally, she returned to the urologist, who discovered that she was anemic, the blood urea nitrogen was elevated, phenolsulfonphthalein excretion was depressed, erythrocyte sedi6 Longcope, W. T. and Winkenwerder, W. L.: Bull. Johns Hopkins Hosp., 63: 255-287, 1933. 7 Peters, J.P.: New Eng. J. Med., 213: 653-659, 1935. 8 Peters, J. P., Lavietes, P. H. and Zimmerman, H. M.: Am. J. Obst. & Gynec., 32: 911-927, 1936.
800
ROBERT BIRCHALL
mentation rate was greatly elevated and an excretory urogram showed minimal concentration of the dye. She was considered to have bilateral renal disease and therefore transferred to the medical service. This history, and it is fairly typical of pyelonephritis, suggests that the early stages of the disease are too often treated as entities by the pediatrician, obstetrician and even urologist, and not until terminal renal insufficiency appears is the internist consulted. This lack of continuity in observation and management has tended to absolve each from the responsibility of devising better means of eradicating the initial infection and so helping to prevent recurrence and chronicity. Secondly, it seems clearly established, both from the natural history and from the pathology, that pyelonephritis is simply a bacterial infection in the interstitial tissue of the kidney. If that be true, the judicious use of antibiotics should completely eradicate the disease and terminal chronic pyelonephritis should be rare. Unfortunately, it is still a much too common cause of death. With these as introductory remarks, the therapeutic problem posed by pyelonephritis may now be considered. If we define the disease as an infection in the interstitial tissue of the kidney which, if not eradicated or if permitted to recur repeatedly, will progressively and inexorably destroy an ever increasing area of contiguous nephrons until too few remain to maintain life, we actually arrive at the crux of the problem, that is, the difference between the therapeutic approach of the internist and the urologist. It is almost as if, to borrow from Robert Frost, "Two roads diverged in a wood and I-I took the one less traveled by." The congested road, as followed I believe by most urologists, leads directly to sterilization of the urine. In order to achieve this, the optimum dosage of any antibiotic is the one which will, by virtue of the concentrating ability of the cells of the distal convoluted tubules, provide a bacteriostatic concentration of antibiotic in the urine. It is almost possible to calcu,late this mathematically. To use the sulfonamides as an example, it was soon established that a urinary sulfonamide concentration of 50 to 200 mg. per 100 cc is adequate to sterilize the urine against almost all organisms.9 - 15 Therefore, if a urinary output of 1000 cc in 24 hours is anticipated, and it is assumed that 100 per cent of the total amount of drug ingested is absorbed, 90 per cent is excreted in the urine, and approximately 30 per cent of this is converted to the ineffective acetylated form, it is clear that a dosage of 4 gm. a day will produce an effective urinary concentration of approximately 250 mg. per 100 cc: 4000 X 1.0 X 0.9 X 0.7 = 250 mg. per l00 cc 10 Since a urinary concentration of 50 mg. per cent is adequate for the majority of infections, it seemed rational to recommend a dosage of 0.5 gm. three or four Alyea, E. P. and Roberts, L. C.: J. A. M.A., 115: 1345-1350, 1940. Helmholz, H. F.: J. Urol., 45: 135-145, 1941. Borst, R. C.: New York State J. Med.: 42: 217-224, 1942. 12 Rammelkamp, C.H. and Stoneburner, L. T., III: New Eng. J. Med., 224: 45-52, ,1941. 13 Alyea, E. P.: J. Urol., 47: 219-223, :1942. 14 Long, P.H. and Bliss, E. A.: South .Med. J., 31: 308-315, 1938. 16 Peterson, 0. L. and Finland, M.: Am. J. M. Sc., 202: 757-772, 1941. 9
10
11
INTERNIST RESPONSIBILITY IN PYELONEPHRITIS
801
times a day. Such a scheme of therapy can be expected to inhibit multiplication of organisms in the pelvis, ureter and bladder, decrease the likelihood of re-infection by sterilizing the urine and reduce the superficial inflammation of the mucosa by direct perfusion and absorption of the drug. In turn, this will alleviate the symptoms of associated or secondary cystitis and urethritis. Although
Fw. 2. Diagrammatic sketch showing calculated concentration of sulfadiazine in interstitial tissue of kidney when plasma concentration of sulfadiazine is 4 mg. %- A, plasma concentration of sulfadiazine = 4 mg. %- Tissue concentration of diffusable sulfadiazine = 3.4 mg.%; pH = 7.4. B, amount of fluid reabsorbed per minute= 119 cc. Amount of sulfadiazine reabsorbed per minute = 2.7 mg. Concentration of sulfadiazine in tubular reabsorbate = 2.4 mg.%; pH = 7.4. C, amount of fluid filtered per minute = 120 cc. Amount of sulfadiazine filtered per minute = 4.1 mg. Concentration of sulfadiazine in glomerular filtrate = 3.4 mg.%; pH = 7.4. D, amount of urine formed per minute = 1 cc. Amount of sulfadiazine excreted per minute = 1.4 mg. Concentration of sulfadiazine in urine = 140 mg. %; pH = 5.5.
this regimen is apparently successful in the majority of patients with acute pyelonephritis, the formidable number of patients in whom terminal chronic pyelonephritis ultimately develops casts considerable doubt on its actual efficacy and calls into question the wisdom of directing our efforts toward sterilization of the urine. On the other hand, if one actually considers pyelonephritis to be an infection
802
ROBERT BIRCHALL
of the interstitial tissue of the kidney, he cannot be content with simple sterilization of the exudate that appears in the urine. Comparison with the obvious futility of treating a patient with empyema by simply sterilizing the fluid in the intrapleural space seems valid. Instead, he must "take the road less traveled by" and devise a scheme of therapy aimed at eradicating the infection in the interstitial tissue of the kidney by maintaining an effective antibiotic level at the actual site of the infection. As is illustrated in figure 2, glomerular filtrate is neither concentrated nor acidified until it reaches the distal tubular segment. Therefore, the concentration of any antibiotic in the interstitial fluid of the kidney is entirely independent of its subsequently attained concentration in the urine, and can at no time exceed its concentration in the plasma. Furthermore, it should be remembered that mandelic acid and mandelamine are effective only at a pH of 5.5 or less. Since the pH of the interstitial tissue of the kidney ranges from 7.2 to 7.4, it is clear that these two drugs have no place in the treatment of pyelonephritis, and should be reserved for those rare patients who present evidence of uncomplicated cystitis or infection of the lower urinary conduit. Therefore, with this concept in mind, a few general principles to be applied to the treatment of acute, recurrent and chronic pyelonephritis may now be presented. 1. Acute and recurrent pyelonephritis a) The appropriate sulfonamide or combination of sulfonamides is usually, but of course not always, the drug of choice. Adequate urinary output and alkalinity of the urine should be assured. b) Dosage of the sulfonamides should be that which will maintain a plasma level of 8 to 10 mg. per 100 cc. The dosage of other antibiotics should be proportionate. c) Duration of therapy should be arbitrarily fixed at 7 to 10 days. d) Cure should be established only by the demonstration of 2 or 3 negative urinary cultures obtained after all traces of antibiotics have disappeared from the urine. This probably seems drastic, but it must be remembered that acute pyelonephritis may be a formidable and rapidly progressing disease. Necrotizing arteriolitis secondary to pyelonephritis has been demonstrated at the autopsy of a baby 6 months old. 1 Recently, with the Department of Urology, we saw a physician's wife in whom severe renal insufficiency developed within one year of her first recognizable attack of acute pyelonephritis. Still more recently, with the Department of Urology, we observed a young girl in whom the excretory urogram was normal but urine culture yielded a positive result. She received a full course of chloramphenicol but failed to return for follow-up cultures. She was seen again just 5 months later with not only a positive urine culture but also easily demonstrable hydronephrosis and obstruction at the ureteropelvic junction. It is for such reasons that, regardless of the antibiotics selected or the dosage employed, several follow-up urinary cultures must be negative before cure can be established. 2. Chronic pyelonephritis a) The antibiotic should be selected according to combined urinary culture
INTERNIST RESPONSIBILITY IN PYELONEPHRITIS
803
and sensitivity studies, coupled with a consideration of the spectra covered by each antibiotic. b) Duration of treatment should be at least 7 to 10 days. c) Intensity of treatment should be as much antibiotic as the patient can or will tolerate. d) Urine should be cultured after treatment has been discontinued and, if still positive, a dillerent and more intensive regimen, vvith consideration of combination of antibiotics, should be devised. The problem of treating a patient with chronic pyelonephritis is difficult. Usually a prolonged and expensive investment, in many ways it is similar to that of treating a patient with subacute bacterial endocarditis. Despite the greatly reduced renal blood flow and the prevalence of avascular scar tissue, we are faced with the problem of delivering as much antibiotic as possible to the infected area. Since the renal blood flow cannot be effectively increased, the only recourse is to increase, to the upper limits of tolerance, the concentration of antibiotic in what little blood actually reaches the infected area. Most antibiotics in extremely high dosage produce almost intolerable reactions; it is this which, in most cases, limits the duration of therapy and tests one's ability to cajole, to sedate and, if necessary, almost to force the patient to accept a treatment which soon becomes repulsive. Moreover, neither should the physician nor the patient be unduly disturbed if the first course of therapy is unsuccessful. There are always other antibiotics and other combinations of them, and perserverance together with designing and redesigning the therapeutic regimen will almost certainly succeed in overcoming the infection. Repeated short courses of intensive antibiotic therapy would appear to be more efficacious than a single prolonged course administered in doses so low that at no time is the infection in the interstitial tissue of the kidney exposed to an adequate concentration of the drug. Destroyed nephrons cannot be replaced, but hypertrophy of others and subsidence of the inflammatory reaction will probably result in some degree of permanent improvement in renal function. In conclusion, let me say that in no other field should close cooperation between the internist and the urologist be so fruitful. Infection in itself, regardless of the organ where it lodges, is the domain of the internist. An infection which does not drain cannot be effectively treated. Evaluation of the drainage and actual construction of adequate drainage of an infected kidney, if it does not initially exist, is the domain of the urologist. It would thus seem appropriate for both specialties to combine their efforts in an attempt to eradicate at the onset this potentially fatal disease.