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The Management of Urinary Tract Infections
Medical Clinics of North America September, 1941. Boston Number
THE MANAGEMENT OF URINARY TRACT INFECTIONS SAMUEL N. VOSE, M.D., F.A.C.S.* AND
CHARLES H. RAMMELKAMP, M.D.t
RECENT DEVELOPMENTS IN THE FIELDS OF PATHOLOGY AND THERAPEUTICS BACTERIAL infection is the commonest and most important disease affecting the urinary tract, and its control has long been one of the principal objectives of the urologist. Recent developments in the fields of pathology and therapeutics have resulted in new conceptions of the nature of urinary infections, new criteria of cure, and increased efforts at eradication. This is true not only of acute infections, but also of many chronic processes hitherto considered subject only to palliation. Among the significant changes in the conception of the nature of urinary infections is the development of the idea of system injection. A term suggested by von Lichtenberg1 in 1930, the concept is generally accepted but too frequently ignored in practice. Rarely is the infectious process confined to a single organ or to the upper or lower urinary tract. The prevalence of bilateral renal infections, the association of prostatic and seminal vesicle infections with those of the kidney and the rapidity with which profound renal changes may follow relatively minor trauma to the infected urethra, all testify to the interdependence of the individual units of the genitourinary system with respect to infection. Recent studies which indicate the relation of late pyelonephritis to certain cases of vascular hypertension have emphasized the importance of more critical criteria of cure. Disappearance From the Departments of Surgery and Medicine, Boston University School of· Medicine, and the Evans Memorial and Massachusetts Memorial Hospitals. * Associate Professor of Genito-urinary Surgery, Boston University School of Medicine; Surgeon, Massachusetts Memorial Hospitals. t Instructor in Medicine, Boston University School of Medicine; Resident Physician, Evans Memorial, Massachusetts Memorial Hospitals. 1419
1420
SAMUEL N. VaSE, CHARLES H. RAMMELKAMP
of clinical manifestations of infection, including pyuria, should be confirmed by repeated cultural studies and long follow-up observation, as the vascular changes responsible for hypertension appear to result, in many instances, from chronic infections which may take a subclinical course. Greater recognition of the importance, in later years, of the urinary infections of childhood and an appreciation of the role of congenital malformations, obstructive or otherwise, in their etiology have contributed no little to management of longstanding infections of this type. Of all the developments in the history of urinary infections, the most revolutionary has been that brought about by the introduction of chemotherapeutic agents, notably the sulfonamides. Internal urinary antisepsis has long been the mainstay of physicians in the treatment of these conditions, but an attitude which at best might be characterized as a mild defeatism has been changed in short order to one of extreme optimism. Certain conditions, among which may be mentioned infections due to Proteus vulgaris and pyelonephritis of pregnancy, formerly considered almost incurable, are now treated with a considerable measure of success. So powerful is the action of the newer drugs and so far has dependence on them progressed, that one inherent hazard in their use has been greatly increased; that is, the danger of overlooking some serious underlying surgical condition of which the infection is a secondary manifestation. A tendency to treat before diagnosing has been all to common in the past and has been aggravated by the ease with which infection may be controlled by chemotherapy at present. Disservice to the patient may result from the cure of an infection which may be the only sign of damaging obstruction, stone or malignant neoplasm. Uremia from the obstructing prostate may be deadly though unaccompanied by pyuria, and cancer needs no help from infection. ETIOLOGY OF URINARY INFECTIONS
The proper management of urinary infection is dependent on an understanding of the relative importance of the etiologic factors involved in a particular case. In general, these may best be considered as falling in one of three groups: (1) those concerning the invading organism, (2) those affecting resistance,
MANAGEMENT OF URINARY TRACT INFECTIONS
1421
local or general, and (3) that group consisting of obstruction in any part of the urinary tract. The Invading Organism.-In certain instances, as in the case of the gonococcus, the mere presence of the organism is of paramount importance, and disease may result regard;ess of ether factors. In most cases of nonspecific infection, with which this discussion is principally concerned, predisposing factors may cause infection even in the presence of an organism of low virulence, and the removal of such factors may result in spontaneous resolution. Because bacteria vary in their susceptibility to chemotherapy, the identification of the organism by culture is essential. Those most commonly found are Escherichia coli, Aerobacter aerogenes, Staphylococcus aureus and various strains of Streptococci. Resistant infections may be due to Proteus vulgaris and Streptococcus faecalis.
Of extreme importance is the source of the infection, since organisms may reach the urinary tract in one of several ways. A common example of infections occurring by way of the blood stream is the cortical abscess of the kidney, which is preceded by staphylococcal skin infections in a considerable proportion of cases. To some extent other types of infections may occur in a similar manner. Direct extension is a common route for bacterial invasion and particular care regarding asepsis and gentleness is essential in instrumentation. Indwelling drainage tubes, urethral or suprapubic, are usually accompanied by a degree of infection. Regurgitation of urine from the bladder to the kidney may occur, but the incidence of infection by this means is probably small. The low incidence of renal infection following ureteral catheterization, in spite of the frequency of this procedure, indicates that some other factor is necessary for the development of serious or persistent infection in the average case. The role of the lymphatics in the causation of urinary infection is uncertain. In relation to treatment the same considerations apply as in the blood-borne type; all possible sources should be eliminated as far as possible. Resistance to Infection.-Resistance may be adversely affected in many ways. Conditions lowering general resistance are too well known to warrant detailed discussion. Diabetes 2 deserves special mention, and even minor manipulations on the ur~nary tract may result in serious infection in the presence of this disease. Locally, a wide variety of conditions render the urinary tract susceptible to bacterial invasion. Irritation from stone or
1422
SAMUEL N. VOSE, CHARLES H. RAMMELKAMP
foreign body, trauma from various causes, sometimes very minor, may be enough to tip the balance. Overdistention of the bladder may initiate infection. Congenitally malformed organs seem to be particularly 'Prone to this condition. Obstruction.-Of all predisposing causes of infection, that of obstruction to free drainage is far and away the most im~ portant. So frequently is an obstructive lesion found as a background for pyuria that no diagnosis is complete which has not included a search for an obstructing lesion, and no treat~ ment is adequate which has not eliminated any possible cause of stasis. Not infrequently such a lesion is obvious; more often it can be discovered only by thorough investigation. Among the most important of such causes are bladder neck obstruc~ tion, calculi, urethral or ureteral stricture, pregnancy or pres~ sure from other extrinsic masses, diverticulum or tumor of the bladder and congenital conditions of various types. Significant obstruction with small degrees of retention, as a compensatory hyperactivity on the part of the bladder or kidney may exist for a considerable period during which residual bladder urine may be minimal, or anatomic changes in the kidney pelvis or ureter be very minor. The effect relative to infection, however, may be the same. Similar in effect to organic obstructions is the stasis due to neurogenic dysfunctions. DIAGNOSIS
The diagnosis of the presence of urinary infection is usually not difficult; the finding' of pus or bacteria in the urine is the outstanding sign. Pyuria may be only the first of many data which must be secured to fulfill the requirements of a complete diagnosis. The symptoms naturally fall into several groups. 1. Disturbances of the bladder function: frequency, strangury, tenesmus
01'
pain on urination. 2, Pain referred to the affected organ: loin pain, suprapubic or perineal discomfort. 3. Constitutional disturbances: chills and fever, nausea or vomiting, loss of weight, fatigability, headache. 4, Changes in the urine: pyuria, hematuria or bacteriuria.
Any combination of symptoms from one or several groups may exist, depending on the principal organ involved, the chronicity of the process, the type of the infecting organism and the nature of the predisposing factors. Pyuria may be
MANAGEMENT OF URINARY TRACT INFECTIONS
1423
absent in the early stages of pyelonephritis, in "closed pyonephrosis" or cortical infections of the kidney. At some stage of almost every infection, however, pus in varying amounts will be found in the urine or bacteria will be found on smear or culture. Measures necessary to complete the diagnosis vary with the individual case. There exist facilities for investigation of the urinary tract which make available precise information essential to a complete knowledge of the case. There is, however, some difference of opinion as to the proper timing of such procedures in the management of urinary infection. There is general agreement that recurrent infection or infection persisting in spite of adequate drug therapy demands a complete urological survey including catheterization of the ureters, retrograde pyelograms and other diagnostic aids. A certain minimum is advisable even in acute infections. Diagnostic Criteria.-Among the essential bits of information which should be obtained regarding any urinary infection are the following: 1. The identity of the infecting organism. A sterile catheterized specimen is the only reliable material for culture and it should be obtained at the first catheterization, otherwise contamination cannot be excluded. 2. The source oj pus in the urine. In acute infections this must be left to conjecture to some extent. 3. Some information as to kidney junction. Renal insufficiency may render useless or dangerous certain drugs or procedures which might seem indicated. The blood nonprotein nitrogen is the best single method of determining total renal function in acute infections. 4. Observation cystoscopy, in the female, is not attended by appreciable risk and may be carried out in the presence of acute cystitis, often with benefit. In the male, cystoscopy should be deferred until therapy has resulted in improvement of the acute phase, or fulminating renal infection demands interference. 5. Evidence of obstruction. Intravenous pyelograms give adequate information during the acute phase of the infection. Suspicions should be checked by ureter catheterization at a later date in controlled cases or if infection persists.
PROPHYLAXIS
Obviously this resolves itself ,into a matter of removing known predisposing causes, particularly obstructions, before infection occurs, the discovery and cure of sources of infection, and the careful treatment of acute infections before they become chronic. No other physician will have as good a chance to eradicate a urinary infection as he who sees the case through
1424
SAMUEL
N.
VQSE, CHARLES H. RAMMELKAMP
its first acute phase. Special care in catheterization in the presence of obstruction, the use of tidal drainage in retention due to neurogenic disease,s and avoidance of over distention of the bladder are important. TREATMENT
The object of all treatment is to cure the symptoms and to remove the cause of the infection. Certain basic therapeutic measures are applicable to all types of urinary infections. Since, as previously noted, infections are rarely confined to one organ these may be considered as to their effect on the clinical manifestations of the infection. SUPPORTIVE AND LOCAL MEASURES; SURGERY
Acute Infections.-BED REST; DIET; FLuIDs.-Bed rest is essential in febrile states; bland diet and adequate fluid intake are important. No therapeutic agent which demands re-
striction of fluids possesses advantages sufficient to justify its use in acute infections except in very unusual cases. Adequate fluid intake means at least 2000 cc. each twenty-four hours. In cases accompanied by nausea and vomiting or where dehydration is present from other causes, supplementary fluid is essential. Dehydration may exist even when the patient is taking apparently adequate fluid by mouth. Our preference is for intravenous glucose 5 per cent in saline of which 1000 to 3000 cc. each twenty-four hours is usually sufficient. Acidosis which may be present will respond to the intravenous use of sodium racemic lactate-molar solution. Lesser degrees may be combatted by oral alkalies or 2 per cent sodium bicarbonate intravenously or 5 per cent by rectum. Care should be taken not to produce alkalosis from the use of the lactate and carbon dioxide values should be followed from day to day. HEAT; ANTISEPTICs.-Locally, the application of heat is valuable to relieve vesical symptoms. The hot sitz bath is a simple but effective method of applying this agent. Hot rectal irrigations are most valuable in acute prostatitis and cystitis in the male. A two-way rubber catheter inserted into the rectum for sufficient distance to assure a large volume of fluid in the rectum gives good results. A semi-upright position is desirable. The temperature of the fluid should be about 110 0 to 115 0 F. and the irrigation should continue for fifteen or twenty minutes.
MANAGEMENT OF URINARY TRACT INFECTIONS
1425
In the female no harm is done and relief of bladder distress may be secured by instillation of mild antiseptics. A catheter is passed and a specimen obtained for examination and culture. The bladder is emptied and 1 ounce of 5 per cent argyrol is introduced with a hand syringe and the catheter removed. Sterile oil, gomenol or metaphen-in-oil, 1: 5000, may be used instead of argyrol. BLADDER DRAINAGE; SURGERy.-Occasionally constant bladder drainage is advisable in both the male and the female when symptoms are severe or refractory. A self-retaining catheter of the Foley type requiring no adhesive strapping is preferable and its size (16 F.) should be small enough to allow free drainage for urethral secretions. If acute symptoms and fever do not respond rapidly, cystoscopy and ureter catheter drainage of the kidney pelvis may be necessary. Surgical intervention for the removal of obstructing ureteral stone or nephrostomy drainage should not be delayed if recurrent chills and fever indicate a fulminating infection. Nephrectomy, formerly frequently done for cortical infections of the kidney, is rarely necessary at present except in the case of cortical abscess or "carbuncle of the kidney" or where thrombosis of renal vessels has occurred. When indicated, results are often dramatic. Subacute, Chronic or Recurrent Infections.-In these local treatment may play a large part. No extended treatment should be given in this group of cases until a complete diagnosis has been made and every secondary cause of infection discovered and removed if possible. Potassium permanganate 1: 5000 at intervals of one to five days or silver nitrate 1: 10,000 are two solutions most commonly used for bladder irrigations. Instillations may be given as described above. Renal lavage has become less common in recent years, but is still valuable in a small proportion of cases. Its principal value is in the improved drainage of the kidney pelvis, but the beneficial effects of mercurochrome 1 per cent or silver nitrate 1: 1000 cannot be ignored. Sulfanilamide solution for local bladder treatment has not had sufficient trial to be properly evaluated. The few cases in our experience have been most encouraging, 0.8 per cent in distilled water being a proper dilution for this purpose. The sodium salt of sulfathiazole is also recommended for local treatment. A 5 per cent solution may be used.
1426
SAMUEL N. VOSE, CHARLES H. RAMMELKAMP INTERNAL MEDICATIONS
Therapy should be undertaken in the hospital in those pa· tients presenting an acute infection associated with high fever. Patients with chronic or subacute infections may be treated while ambulatory. At the present time there are three urinary antiseptics that deserve extended comment. These three are mandelic acid, suljanilamide and suljathiazole. The dosage and action of each drug will be discussed separately and then compared as to their relative efficiency in the treatment of these infections. Mandelic Acid.-This drug has been used in the treatment of infections of the urinary tract for the past six years. Its successful action is dependent on obtaining a concentration of the drug of 0.5 per cent or greater in a urine that has a pH of 5.5 or less. Mandelic acid may be administered as the am~ monium, sodium or calcium salt. The ammonium salt, in the form of syrup, is given in doses of 8 cc. four times a day. To avoid nausea it is best to administer this drug following meals and just before retiring at night. Therapy with ammonium mandelate may not require additional acidifying salts in order to obtain the proper reaction in the urine. Calcium mandelate, which apparently causes less nausea, is given in doses of 3 gm. four times a day. With this preparation some acidifying agent must be administered. Several drugs may be used; ammonium chloride in doses of from 4 to 8 gm. daily is usually sufficient. While the patient is under this form of therapy, it is essential to follow the reaction of the urine closely. In order to maintain the proper reaction, fluids should be limited to six glasses daily. It is desirable to point out the disadvantages of mandelic acid therapy. In some patients, in spite of large quantities of acidify~ ing salts, it is impossible to maintain a urine of proper acidity, and in these patients poor results are obtained. Successful therapy with mandelic acid demands an intake of fluid that is small. These patients will pass only small amounts of urine and, therefore, lose the beneficial effect of passing large amounts of dilute urine. Certainly, the advisability of limiting fluid in patients with high fever, severe infections or poor renal function is open to question. Mandelic acid produces some toxic effects. Cook 4 finds that nausea and vomiting are the two most frequent complications.
MANAGEMENT OF URINARY TRACT INFECTIONS
1427
Hematuria is observed in about 2 per cent of all cases. It has been stated that mandelic acid was especially effective in colon bacillus infections. s However, Rantz and Keefer 6 observed only a minimal reduction in the number of organisms in the urine following its use. Infections du.e to other bacteria, such as the staphylococci and Aerobacter aerogenes, respond poorly to this drug. 5 Sulfanilamide.-Sulfanilamide has largely replaced mandelic acid in the treatment of these infections. It is now well established that sulfanilamide is a very effective .therapeutic agent. 6 , 7, 8 In order to obtain satisfactory bactericidal action it is advisable to maintain in the urine a concentration of the drug of 80 mg. per cent or above. 6 In general, a dose of 1 gm. three times each day will suffice. The duration of therapy will vary according to the response; however, it is not advisable to continue therapy over fourteen days without searching thoroughly for complicating factors. During therapy, fluids should be forced. It is not necessary to chahge the reaction of the urine when using this drug. 6 Sodium bicarbonate in doses of 3 to 8 gm. daily may be given to prevent acidosis. Sulfanilamide is most effective against infections due to Escherichia coli. It is also somewhat effective against infections caused by Aerobacter aerogenes. In those infections caused by Proteus vulgaris, Staphylococcus aureus and Streptococcus faecalis results have been disappointing, even though high concentrations of the drug are obtained in the urine. Toxicity.-Sulfanilamide has certain undesirable side reactions which are now weII known. Minor effects which at times are annoying are cyanosis, anorexia and headache. If fever is present during the period of treatment, anemia is produced in the majority of instances." More troublesome are the febrile and cutaneous reactions. Other serious reactions are agranulocytosis, acute hemolytic anemia and jaundice. In any of the more serious reactions sulfanilamide therapy should be discontinued immediately and fluids forced.
Sulfathiazole ....,-The results of in vitro and clinical studies have demonstrated that sulfathiazole kills the majority of organisms associated with urinary infections.9 , 10, 11, 12, 13 When administering this drug, the reaction of the urine may be dis· regarded. The amount of fluid ingested should be well over 2500 cc. daily, thus utilizing the mechanical effect of flushing the urinary tract.
1428
SAMUEL N. VOSE, CHARLES H. RAMMELKAMP
Studies on the Effect. of Low and High Concentrations.-Because there are relatively few reports on the amount of sulfathiazole that is necessary to administer to these patients, we have made certain studies to elucidate this matter. In a previous study" of the action of sulfathiazole in twenty-five patients with infections of the urinary tract no correlation could be made between the concentration of the drug in the urine and the clinical response. In these patients the level of free sulfathiazole obtained in the urine varied from 32 to 456 mg. per cent. A comparative study of the effect of sulfathiazole and other sulfonamide derivatives in concentrations of 10 mg. per cent was made on the organisms isolated from these patients. It was evident from these studies that low concentrations of sulfathiazole produced marked bacteriostatic and bactericidal effects. Helmholzu has recently confirmed these observations. These studies suggested, then, that high concentrations of sulfathiazole in the urine of patients with infection were not required. It was first necessary to determine the degree of bacteriostasis produced by various concentrations of sulfathiazole against the common urinary pathogens. In this study a pooled sample of urine with a pH of 6.5 was used as the culture medium. Sterilization was obtained by passage through a Berkefeld filter. The drug was then added to the urine to make final concentrations of 5, 10, 40, 80 and 160 mg. per cent. An inoculum was then added that would produce growth in all the drug-containing cultures so that variations in the degree of killing could be noted. The urine was incubated for twenty-four hours, following which 0.5 cc. was removed a,nd after proper d]utions pour plates were made. The agar used in these plates contained para-amino-benzoic acid. After incubation the number of colonies were counted. TABLE 1 BACTERICIDAL EFFECT OF VARTOUS CONCENTRATIONS OF SULFATIDAZOLE
Number of Organisms After 24 Hours' Incubation Sulfathiazole M~. per 100 cc.
Escherichia coli
Proteus vulgaris
Staphylococcus aureus
Control
320,000,000
50,000,000
190,000,000
5
8
7,000,000
56
10
44
100,000
192
Staphylococcus albus
Streptococcus faecalis
Flexner
1,000,000
305,600
380,000,000
120
260,400
8
20
159,200
20
40
12
364
84
8
24,200
44
80
24
48
144
4
956
24
160
4
160
36
24
°
80
Table 1 shows the results of these studies. In general, it can be said that concentrations of about 10 mg. per cent cause marked killing, and that increasing the concentration does not appreciably increase the bactericidal effect in the majority of experiments. There are two exceptions to this. Proteus vulgaris and Streptococcus faecalis usually show a more marked in-
MANAGEMENT OF URINARY TRACT INFECTIONS
1429
crease in the action of the drug at higher levels, although low concentrations do show a definite effect. Helmholz 14 has shown that the bactericidal !1ction of sulfathiazole is increased only slightly when the concentration is raised from a level of 10 mg . . to a level of 30 mg. per 100 cc. Dosage.-What amount of drug must be administered to patients in order to obtain concentrations of the drug of 10 mg. per cent or greater? Figure 179 shows the concentrations obtained in two normal individuals receiving 0.25 gm. of sulfathiazole three times per day. 025GM
J.
200
PER
.J.
os
lao 0 160
51
~'40
.~
cl
~ 120
~ ~
100
"
ao
~
,0
..
.. 60
~
2 40 20
HOURS 24 HR
OUTPUT
CC
24 • 1743 02386
.a 1581
2868
12 1117
20,.
00 13"86
26159
Fig. 179.-Arrows represent the ingestion of 0.25 gm. of sulfathiazole. Solid dots represent the concentration of free sulfathiazole in individual urine samples of a patient receiving 2000 cc. of fluid each twenty-four hours. Circles represent free sulfathiazole in urine specimens from a patient with an intake of 3000 cc. per twenty-four hours.
One of these subjects was on a constant intake of 2000 cc. daily, the other received 3000 cc. A determination of sulfathiazole was made on each specimen of urine. In only one instance was the concentration below 7 mg. per cent; the majority of samples contained well over 20 mg. per cent. It would appear from these studies, then, that the administration of from 0.25 to 0.5 gm. three times daily is sufficient to maintain concentrations above 10 mg. per cent in the urine. Such levels will give satisfactory results in the majority of patients. Treatment should be continued for a period of about one
1430
SAMUEL N. VaSE, CHARLES H. RAMMELKAMP
week; if all symptoms have not subsided a thorough investigation as to the causative organism and presence of obstruction should be made. When the infecting bacterium is either Proteus vulgaris or Streptococcus jaecalis, it is advisable to administer somewhat larger amounts of the drug. In these infections 1 gm. three times daily is adequate. . 1"oxicity.-The manifestations of sulfathiazole toxicity are now well known. Perhaps the most chara.cteristic is the injection of the conjunctiva. Skin rashes occur not infrequently, and may be associated with fever. Both skin rashes and fever are seen usually about the seventh to tenth day of therapy. The more serious reactions are hemolytic anemia and toxic hepatitis; fortunately these occur only rarely. As with suIfanilamide, when these toxic reactions are encountered, the drug should be discontinued and fluids forced. Careful observation will prevent the serious reactions.
Relative Merits of Urinary Antiseptics.-It is our opinion that sulfathiazole is the drug of choice in the treatment of these infections. Its chief advantages over mandelic acid are ease of administration, a more marked bactericidal action against all bacteria, fluids need not be limited, the reaction of the urine does not have to be regulated, and the effective bactericidal concentration in the urine is more readily obtained. A further important advantage is that sulfathiazole may be given to patients with high fever or with poor renal function. In the latter group of cases, sulfathiazole should be administered in small doses such as 0.25 gm. three times per day. We recently treated a case with marked nitrogen retention with small doses of sulfathiazole. The clinical response in this instance was adequate. When severe vomiting occurs, the sodium salt of sulfathiazole may be administered intravenously in saline. One gram three times daily is sufficient. Sulfanilamide may be given subcutaneously in somewhat larger dosages. What are the chief advantages of sulfathiazole over sulfanilamide? The most important advantage is the marked increase in the bactericidal action of the thiazole compound. Not only does it exhibit an increased killing effect against Escherichia coli, Proteus vulgaris, Staphylococcus aureus and albus, and the typhoid-dysentery organisms, but it is the only agent that appears to exert any effect on Streptococcus jaecalis. As was pointed out above, sulfathiazole is effective in low concentrations, whereas sulfanilamide, in order to exhibit bactericidal
MANAGEMENT OF URINARY TRACT INFECTIONS
1431
. action, requires much higher concentrations. It is clear, then, that the dosage of sulfathiazole may be small, and in cases of poor renal function satisfactory levels may be obtained more readily. The chief disadvantage to the use of sulfathiazole is its toxic effect. Certainly, it causes more serious reactions than mandelic acid. However, if small doses are given over a short period of time (ten days) most of these toxic reactions may be avoided. Those patients receiving sulfathiazole for longer periods should be under close observation. Sulfanilamide and sulfathiazole exhibit about the same degree of toxicity clinically. Patients who are sensitive to one sulfonamide are likely to be sensitive to the other. Methenaminej Neoa.rsphenamine.-Preoccupation with the newer chemotherapeutic agents should not lead to a com~ plete disregard of some of the time-tested internal urinary antiseptics. Occasionally complete intolerance for the sulfonamides and mandelic acid exists or it is desirable to give a urinary antiseptic over a long period of time. M ethenamine has produced many good results in the past in such cases. To be effective it must be given in fairly large doses, 3 to 4 gm. per day, and some acidifying agent must be used. Since its action depends on the liberation of formaldehyde in an acid urine, it is of little value in acute infections. It finds its greatest field of usefulness in the chronic bacillary infections. Resistant coccal infections will sometimes respond to intravenous neoarsphenamine. 15 Doses of 0.45 gm. should be given every two or three days with the usual precautions. If marked improvement is not noted after three or four doses, the drug should be discontinued. The drug is not tolerated as well as when used for antiluetic treatment. SPECIAL TYPES OF URINARY INFECTION
Postoperative Cystitis.-FrequentIy referred to as "catheter cystitis," this condition occurs more often because of . delay in the use of the catheter than because of adequate use. No -general rule as to lapse of time permitted before catheterization is applicable to all cases. The free use of preoperative and postoperative intravenous fluids has undoubtedly shortened the period before bladder distention occurs. Distention is some-
1432
SAMUEL N. VaSE, CHARLES H. RAMMELKAMP
times difficult to detect by abdominal palpation in a freshly operated case and trauma of overdistention renders the bladder susceptible to infection. After one or two catheterizations incomplete bladder function may be established, but with residual urine, which again invites infection.lG Measures which may be taken to prevent postoperative infection include the use of prostigmin, 1 cc. intramuscularly every four hours to stimulate voluntary micturition, the establishment of adequate drainage by the indwelling catheter if distention occurs, the demonstration of no residual urine after re establishment of bladder function and the prophylactic use of sulfathiazole, 0.25 gm. t.i.d. Pyelonephritis of Pregnancy.-Formerly considered rarely curable during the duration of pregnancy, this condition may be treated successfully by chemotherapy, negative cultures having been secured in numerous instances.17 So far as present evidence is trustworthy, no particular danger to the fetus is involved, and doses may be used as in nonpregnant cases. In refractory cases ureter catheterization should be done, and fulminating infections may demand termination of the pregnancy. Infections in Childhood.-In spite of marked progress l8 in the approach to this problem during the past few years, there still exists, in many quarters, a disposition to delay investigation of the urinary tract in children. Cystoscopy and other instrumentations are tolerated fully as well by children as by adults and the incidence of congenital obstructive lesions as a cause of infection is high.19 The age of this group of patients, however young, is no contraindication to procedures which would be indicated under similar circumstances in an adult. CONCLUSIONS
Urinary infections of various types are extremely responsive to chemotherapy, the most effective agent being suljathiazole. Small doses of this drug appear to be adequate and it should be administered in a dosage of 0.5 gm. three times daily. Even smaller doses may be used when renal insufficiency exists. Therapy should be guided by bacteriological studies. Since most urinary infections result from some predisposing factor, a complete diagnostic survey should be made in chronic
MANAGEMENT OF URINARY TRACT INFECTIONS
1433
or recurrent case~ and acute cases should be followed up by a search for an obstructing lesion. Adequate therapy, more critical criteria of cure and followup observation should decrease late complications of urinary infections. BIBLIOGRAPHY 1. Von Lichtenberg, A.: Kidney and Ureteral Lesions Secondary to Adnexal
Disease. J. Urol., 24: 1, 1930.
2. Baldwin, A. D. and Root, H. F.: Infections of the Upper Urinary Tract
in the Diabetic Patient. New Eng. J. Med., 223: 244, 1940.
3. McNeil, A. E. and Bowler, J. P.: Irrigation and Tidal Drainage. New
Eng. J. Med., 223: 128, 1940.
4. Cook, E. N.: Chemotherapy in Infections of the Urinary Tract. J. UroI.,
39: 692, 1938.
5. Carroll, G., Lewis, B. and Kappel, L.: Further Clinical and Laboratory
Observations of Mandelic Acid. J. Urol., 39: 710, 1938.
6. Rantz, L. A. and Keefer, C. S.: SuIfanilamide in Treatment of Infections
of the Urinary Tract due to Bacillus Coli. Arch. Int. Med., 65: 993, 1940.
7. Bumpus, H. C., Jr.: Urinary Infections-Part H. Calif. Western Med.,
50: 351, 1939.
8. MitcheIJ, D. R., Greey, P. H. and Lucas, C. C.: SuIfanilamide in the Treat-
ment of Cystitis and Pyelitis. Canad. M. A. J., 40: 336, 1939.
9. Long, P. H. and Bliss, E. H.: Bacteriostatic Effects of SuJfathiazole upon
Various Micro-organisms. Its Therapeutic Effects in Experimental Pneumococcal Infections. Proc. Soc. Exper. BioI. & Med., 43: 324, 1940. 10. Hill, J. N.: The Comparative in vitro Action of Sulfanilamide, SuIfapyridine and SuJfathiazole in Urine. J. Urol., 43: 491, 1940. 11. Rammelkamp, C. H. and JeweIl, M. L.: Comparative in vitro Study of Various Sulfanilamide Derivatives on Typhoid-Dysentery Organisms. Proc. Soc. Exper. BioI. & Med., 45: 169, 1940. 12. Culp, O. S.: Sulfathiazole Treatment of Urinary Tract Infections. J. Uro!., 44: 116, 1940. 13. Rammelkamp, C. H. and Stoneburner, L. T.: Sulfathiazole: A Clinical and in vitro Study of Its Use in Infections of the Urinary Tract. New Eng. J. Med., 224: 45, 1941. 14. Helmholz, H. F.: A Comparison of the Bactericidal Effect of Low Concentrations of Sulfanilamide and SuIfathiazole on Bacteria from Urinary Infections. Proc. Staff Meet. Mayo Clin., 16: 149, 1941. 15. BuchtcJ, H. A. and Cook, E. N.: Neo-Arsphenamine in the Treatment of Urinary Infections. J. Urol., 43: 417, 1940. 16. Creevy, C. D.: The Care of the Urinary Bladder After Operation. Surg., 7: 423, 1940. 17. Prather, G. C.: Pyelonephritis of Pregnancy. J. Urol., 45: 147, 1941. 18. Carey, B. W.: Urinary Infections in Infants. and Children. New Eng. J. Med., 222: 662, 1940. 19. 'Glenn, J. E.: Results of Untreated Urologic Conditions in Childhood South. Med. J., 33: 388, 1940.
THE MANAGEMENT OF URINARY TRACT INFECTIONS SAMUEL N. VOSE, M.D., F.A.C.S.* AND
CHARLES H. RAMMELKAMP, M.D.t
RECENT DEVELOPMENTS IN THE FIELDS OF PATHOLOGY AND THERAPEUTICS BACTERIAL infection is the commonest and most important disease affecting the urinary tract, and its control has long been one of the principal objectives of the urologist. Recent developments in the fields of pathology and therapeutics have resulted in new conceptions of the nature of urinary infections, new criteria of cure, and increased efforts at eradication. This is true not only of acute infections, but also of many chronic processes hitherto considered subject only to palliation. Among the significant changes in the conception of the nature of urinary infections is the development of the idea of system injection. A term suggested by von Lichtenberg1 in 1930, the concept is generally accepted but too frequently ignored in practice. Rarely is the infectious process confined to a single organ or to the upper or lower urinary tract. The prevalence of bilateral renal infections, the association of prostatic and seminal vesicle infections with those of the kidney and the rapidity with which profound renal changes may follow relatively minor trauma to the infected urethra, all testify to the interdependence of the individual units of the genitourinary system with respect to infection. Recent studies which indicate the relation of late pyelonephritis to certain cases of vascular hypertension have emphasized the importance of more critical criteria of cure. Disappearance From the Departments of Surgery and Medicine, Boston University School of· Medicine, and the Evans Memorial and Massachusetts Memorial Hospitals. * Associate Professor of Genito-urinary Surgery, Boston University School of Medicine; Surgeon, Massachusetts Memorial Hospitals. t Instructor in Medicine, Boston University School of Medicine; Resident Physician, Evans Memorial, Massachusetts Memorial Hospitals. 1419
1420
SAMUEL N. VaSE, CHARLES H. RAMMELKAMP
of clinical manifestations of infection, including pyuria, should be confirmed by repeated cultural studies and long follow-up observation, as the vascular changes responsible for hypertension appear to result, in many instances, from chronic infections which may take a subclinical course. Greater recognition of the importance, in later years, of the urinary infections of childhood and an appreciation of the role of congenital malformations, obstructive or otherwise, in their etiology have contributed no little to management of longstanding infections of this type. Of all the developments in the history of urinary infections, the most revolutionary has been that brought about by the introduction of chemotherapeutic agents, notably the sulfonamides. Internal urinary antisepsis has long been the mainstay of physicians in the treatment of these conditions, but an attitude which at best might be characterized as a mild defeatism has been changed in short order to one of extreme optimism. Certain conditions, among which may be mentioned infections due to Proteus vulgaris and pyelonephritis of pregnancy, formerly considered almost incurable, are now treated with a considerable measure of success. So powerful is the action of the newer drugs and so far has dependence on them progressed, that one inherent hazard in their use has been greatly increased; that is, the danger of overlooking some serious underlying surgical condition of which the infection is a secondary manifestation. A tendency to treat before diagnosing has been all to common in the past and has been aggravated by the ease with which infection may be controlled by chemotherapy at present. Disservice to the patient may result from the cure of an infection which may be the only sign of damaging obstruction, stone or malignant neoplasm. Uremia from the obstructing prostate may be deadly though unaccompanied by pyuria, and cancer needs no help from infection. ETIOLOGY OF URINARY INFECTIONS
The proper management of urinary infection is dependent on an understanding of the relative importance of the etiologic factors involved in a particular case. In general, these may best be considered as falling in one of three groups: (1) those concerning the invading organism, (2) those affecting resistance,
MANAGEMENT OF URINARY TRACT INFECTIONS
1421
local or general, and (3) that group consisting of obstruction in any part of the urinary tract. The Invading Organism.-In certain instances, as in the case of the gonococcus, the mere presence of the organism is of paramount importance, and disease may result regard;ess of ether factors. In most cases of nonspecific infection, with which this discussion is principally concerned, predisposing factors may cause infection even in the presence of an organism of low virulence, and the removal of such factors may result in spontaneous resolution. Because bacteria vary in their susceptibility to chemotherapy, the identification of the organism by culture is essential. Those most commonly found are Escherichia coli, Aerobacter aerogenes, Staphylococcus aureus and various strains of Streptococci. Resistant infections may be due to Proteus vulgaris and Streptococcus faecalis.
Of extreme importance is the source of the infection, since organisms may reach the urinary tract in one of several ways. A common example of infections occurring by way of the blood stream is the cortical abscess of the kidney, which is preceded by staphylococcal skin infections in a considerable proportion of cases. To some extent other types of infections may occur in a similar manner. Direct extension is a common route for bacterial invasion and particular care regarding asepsis and gentleness is essential in instrumentation. Indwelling drainage tubes, urethral or suprapubic, are usually accompanied by a degree of infection. Regurgitation of urine from the bladder to the kidney may occur, but the incidence of infection by this means is probably small. The low incidence of renal infection following ureteral catheterization, in spite of the frequency of this procedure, indicates that some other factor is necessary for the development of serious or persistent infection in the average case. The role of the lymphatics in the causation of urinary infection is uncertain. In relation to treatment the same considerations apply as in the blood-borne type; all possible sources should be eliminated as far as possible. Resistance to Infection.-Resistance may be adversely affected in many ways. Conditions lowering general resistance are too well known to warrant detailed discussion. Diabetes 2 deserves special mention, and even minor manipulations on the ur~nary tract may result in serious infection in the presence of this disease. Locally, a wide variety of conditions render the urinary tract susceptible to bacterial invasion. Irritation from stone or
1422
SAMUEL N. VOSE, CHARLES H. RAMMELKAMP
foreign body, trauma from various causes, sometimes very minor, may be enough to tip the balance. Overdistention of the bladder may initiate infection. Congenitally malformed organs seem to be particularly 'Prone to this condition. Obstruction.-Of all predisposing causes of infection, that of obstruction to free drainage is far and away the most im~ portant. So frequently is an obstructive lesion found as a background for pyuria that no diagnosis is complete which has not included a search for an obstructing lesion, and no treat~ ment is adequate which has not eliminated any possible cause of stasis. Not infrequently such a lesion is obvious; more often it can be discovered only by thorough investigation. Among the most important of such causes are bladder neck obstruc~ tion, calculi, urethral or ureteral stricture, pregnancy or pres~ sure from other extrinsic masses, diverticulum or tumor of the bladder and congenital conditions of various types. Significant obstruction with small degrees of retention, as a compensatory hyperactivity on the part of the bladder or kidney may exist for a considerable period during which residual bladder urine may be minimal, or anatomic changes in the kidney pelvis or ureter be very minor. The effect relative to infection, however, may be the same. Similar in effect to organic obstructions is the stasis due to neurogenic dysfunctions. DIAGNOSIS
The diagnosis of the presence of urinary infection is usually not difficult; the finding' of pus or bacteria in the urine is the outstanding sign. Pyuria may be only the first of many data which must be secured to fulfill the requirements of a complete diagnosis. The symptoms naturally fall into several groups. 1. Disturbances of the bladder function: frequency, strangury, tenesmus
01'
pain on urination. 2, Pain referred to the affected organ: loin pain, suprapubic or perineal discomfort. 3. Constitutional disturbances: chills and fever, nausea or vomiting, loss of weight, fatigability, headache. 4, Changes in the urine: pyuria, hematuria or bacteriuria.
Any combination of symptoms from one or several groups may exist, depending on the principal organ involved, the chronicity of the process, the type of the infecting organism and the nature of the predisposing factors. Pyuria may be
MANAGEMENT OF URINARY TRACT INFECTIONS
1423
absent in the early stages of pyelonephritis, in "closed pyonephrosis" or cortical infections of the kidney. At some stage of almost every infection, however, pus in varying amounts will be found in the urine or bacteria will be found on smear or culture. Measures necessary to complete the diagnosis vary with the individual case. There exist facilities for investigation of the urinary tract which make available precise information essential to a complete knowledge of the case. There is, however, some difference of opinion as to the proper timing of such procedures in the management of urinary infection. There is general agreement that recurrent infection or infection persisting in spite of adequate drug therapy demands a complete urological survey including catheterization of the ureters, retrograde pyelograms and other diagnostic aids. A certain minimum is advisable even in acute infections. Diagnostic Criteria.-Among the essential bits of information which should be obtained regarding any urinary infection are the following: 1. The identity of the infecting organism. A sterile catheterized specimen is the only reliable material for culture and it should be obtained at the first catheterization, otherwise contamination cannot be excluded. 2. The source oj pus in the urine. In acute infections this must be left to conjecture to some extent. 3. Some information as to kidney junction. Renal insufficiency may render useless or dangerous certain drugs or procedures which might seem indicated. The blood nonprotein nitrogen is the best single method of determining total renal function in acute infections. 4. Observation cystoscopy, in the female, is not attended by appreciable risk and may be carried out in the presence of acute cystitis, often with benefit. In the male, cystoscopy should be deferred until therapy has resulted in improvement of the acute phase, or fulminating renal infection demands interference. 5. Evidence of obstruction. Intravenous pyelograms give adequate information during the acute phase of the infection. Suspicions should be checked by ureter catheterization at a later date in controlled cases or if infection persists.
PROPHYLAXIS
Obviously this resolves itself ,into a matter of removing known predisposing causes, particularly obstructions, before infection occurs, the discovery and cure of sources of infection, and the careful treatment of acute infections before they become chronic. No other physician will have as good a chance to eradicate a urinary infection as he who sees the case through
1424
SAMUEL
N.
VQSE, CHARLES H. RAMMELKAMP
its first acute phase. Special care in catheterization in the presence of obstruction, the use of tidal drainage in retention due to neurogenic disease,s and avoidance of over distention of the bladder are important. TREATMENT
The object of all treatment is to cure the symptoms and to remove the cause of the infection. Certain basic therapeutic measures are applicable to all types of urinary infections. Since, as previously noted, infections are rarely confined to one organ these may be considered as to their effect on the clinical manifestations of the infection. SUPPORTIVE AND LOCAL MEASURES; SURGERY
Acute Infections.-BED REST; DIET; FLuIDs.-Bed rest is essential in febrile states; bland diet and adequate fluid intake are important. No therapeutic agent which demands re-
striction of fluids possesses advantages sufficient to justify its use in acute infections except in very unusual cases. Adequate fluid intake means at least 2000 cc. each twenty-four hours. In cases accompanied by nausea and vomiting or where dehydration is present from other causes, supplementary fluid is essential. Dehydration may exist even when the patient is taking apparently adequate fluid by mouth. Our preference is for intravenous glucose 5 per cent in saline of which 1000 to 3000 cc. each twenty-four hours is usually sufficient. Acidosis which may be present will respond to the intravenous use of sodium racemic lactate-molar solution. Lesser degrees may be combatted by oral alkalies or 2 per cent sodium bicarbonate intravenously or 5 per cent by rectum. Care should be taken not to produce alkalosis from the use of the lactate and carbon dioxide values should be followed from day to day. HEAT; ANTISEPTICs.-Locally, the application of heat is valuable to relieve vesical symptoms. The hot sitz bath is a simple but effective method of applying this agent. Hot rectal irrigations are most valuable in acute prostatitis and cystitis in the male. A two-way rubber catheter inserted into the rectum for sufficient distance to assure a large volume of fluid in the rectum gives good results. A semi-upright position is desirable. The temperature of the fluid should be about 110 0 to 115 0 F. and the irrigation should continue for fifteen or twenty minutes.
MANAGEMENT OF URINARY TRACT INFECTIONS
1425
In the female no harm is done and relief of bladder distress may be secured by instillation of mild antiseptics. A catheter is passed and a specimen obtained for examination and culture. The bladder is emptied and 1 ounce of 5 per cent argyrol is introduced with a hand syringe and the catheter removed. Sterile oil, gomenol or metaphen-in-oil, 1: 5000, may be used instead of argyrol. BLADDER DRAINAGE; SURGERy.-Occasionally constant bladder drainage is advisable in both the male and the female when symptoms are severe or refractory. A self-retaining catheter of the Foley type requiring no adhesive strapping is preferable and its size (16 F.) should be small enough to allow free drainage for urethral secretions. If acute symptoms and fever do not respond rapidly, cystoscopy and ureter catheter drainage of the kidney pelvis may be necessary. Surgical intervention for the removal of obstructing ureteral stone or nephrostomy drainage should not be delayed if recurrent chills and fever indicate a fulminating infection. Nephrectomy, formerly frequently done for cortical infections of the kidney, is rarely necessary at present except in the case of cortical abscess or "carbuncle of the kidney" or where thrombosis of renal vessels has occurred. When indicated, results are often dramatic. Subacute, Chronic or Recurrent Infections.-In these local treatment may play a large part. No extended treatment should be given in this group of cases until a complete diagnosis has been made and every secondary cause of infection discovered and removed if possible. Potassium permanganate 1: 5000 at intervals of one to five days or silver nitrate 1: 10,000 are two solutions most commonly used for bladder irrigations. Instillations may be given as described above. Renal lavage has become less common in recent years, but is still valuable in a small proportion of cases. Its principal value is in the improved drainage of the kidney pelvis, but the beneficial effects of mercurochrome 1 per cent or silver nitrate 1: 1000 cannot be ignored. Sulfanilamide solution for local bladder treatment has not had sufficient trial to be properly evaluated. The few cases in our experience have been most encouraging, 0.8 per cent in distilled water being a proper dilution for this purpose. The sodium salt of sulfathiazole is also recommended for local treatment. A 5 per cent solution may be used.
1426
SAMUEL N. VOSE, CHARLES H. RAMMELKAMP INTERNAL MEDICATIONS
Therapy should be undertaken in the hospital in those pa· tients presenting an acute infection associated with high fever. Patients with chronic or subacute infections may be treated while ambulatory. At the present time there are three urinary antiseptics that deserve extended comment. These three are mandelic acid, suljanilamide and suljathiazole. The dosage and action of each drug will be discussed separately and then compared as to their relative efficiency in the treatment of these infections. Mandelic Acid.-This drug has been used in the treatment of infections of the urinary tract for the past six years. Its successful action is dependent on obtaining a concentration of the drug of 0.5 per cent or greater in a urine that has a pH of 5.5 or less. Mandelic acid may be administered as the am~ monium, sodium or calcium salt. The ammonium salt, in the form of syrup, is given in doses of 8 cc. four times a day. To avoid nausea it is best to administer this drug following meals and just before retiring at night. Therapy with ammonium mandelate may not require additional acidifying salts in order to obtain the proper reaction in the urine. Calcium mandelate, which apparently causes less nausea, is given in doses of 3 gm. four times a day. With this preparation some acidifying agent must be administered. Several drugs may be used; ammonium chloride in doses of from 4 to 8 gm. daily is usually sufficient. While the patient is under this form of therapy, it is essential to follow the reaction of the urine closely. In order to maintain the proper reaction, fluids should be limited to six glasses daily. It is desirable to point out the disadvantages of mandelic acid therapy. In some patients, in spite of large quantities of acidify~ ing salts, it is impossible to maintain a urine of proper acidity, and in these patients poor results are obtained. Successful therapy with mandelic acid demands an intake of fluid that is small. These patients will pass only small amounts of urine and, therefore, lose the beneficial effect of passing large amounts of dilute urine. Certainly, the advisability of limiting fluid in patients with high fever, severe infections or poor renal function is open to question. Mandelic acid produces some toxic effects. Cook 4 finds that nausea and vomiting are the two most frequent complications.
MANAGEMENT OF URINARY TRACT INFECTIONS
1427
Hematuria is observed in about 2 per cent of all cases. It has been stated that mandelic acid was especially effective in colon bacillus infections. s However, Rantz and Keefer 6 observed only a minimal reduction in the number of organisms in the urine following its use. Infections du.e to other bacteria, such as the staphylococci and Aerobacter aerogenes, respond poorly to this drug. 5 Sulfanilamide.-Sulfanilamide has largely replaced mandelic acid in the treatment of these infections. It is now well established that sulfanilamide is a very effective .therapeutic agent. 6 , 7, 8 In order to obtain satisfactory bactericidal action it is advisable to maintain in the urine a concentration of the drug of 80 mg. per cent or above. 6 In general, a dose of 1 gm. three times each day will suffice. The duration of therapy will vary according to the response; however, it is not advisable to continue therapy over fourteen days without searching thoroughly for complicating factors. During therapy, fluids should be forced. It is not necessary to chahge the reaction of the urine when using this drug. 6 Sodium bicarbonate in doses of 3 to 8 gm. daily may be given to prevent acidosis. Sulfanilamide is most effective against infections due to Escherichia coli. It is also somewhat effective against infections caused by Aerobacter aerogenes. In those infections caused by Proteus vulgaris, Staphylococcus aureus and Streptococcus faecalis results have been disappointing, even though high concentrations of the drug are obtained in the urine. Toxicity.-Sulfanilamide has certain undesirable side reactions which are now weII known. Minor effects which at times are annoying are cyanosis, anorexia and headache. If fever is present during the period of treatment, anemia is produced in the majority of instances." More troublesome are the febrile and cutaneous reactions. Other serious reactions are agranulocytosis, acute hemolytic anemia and jaundice. In any of the more serious reactions sulfanilamide therapy should be discontinued immediately and fluids forced.
Sulfathiazole ....,-The results of in vitro and clinical studies have demonstrated that sulfathiazole kills the majority of organisms associated with urinary infections.9 , 10, 11, 12, 13 When administering this drug, the reaction of the urine may be dis· regarded. The amount of fluid ingested should be well over 2500 cc. daily, thus utilizing the mechanical effect of flushing the urinary tract.
1428
SAMUEL N. VOSE, CHARLES H. RAMMELKAMP
Studies on the Effect. of Low and High Concentrations.-Because there are relatively few reports on the amount of sulfathiazole that is necessary to administer to these patients, we have made certain studies to elucidate this matter. In a previous study" of the action of sulfathiazole in twenty-five patients with infections of the urinary tract no correlation could be made between the concentration of the drug in the urine and the clinical response. In these patients the level of free sulfathiazole obtained in the urine varied from 32 to 456 mg. per cent. A comparative study of the effect of sulfathiazole and other sulfonamide derivatives in concentrations of 10 mg. per cent was made on the organisms isolated from these patients. It was evident from these studies that low concentrations of sulfathiazole produced marked bacteriostatic and bactericidal effects. Helmholzu has recently confirmed these observations. These studies suggested, then, that high concentrations of sulfathiazole in the urine of patients with infection were not required. It was first necessary to determine the degree of bacteriostasis produced by various concentrations of sulfathiazole against the common urinary pathogens. In this study a pooled sample of urine with a pH of 6.5 was used as the culture medium. Sterilization was obtained by passage through a Berkefeld filter. The drug was then added to the urine to make final concentrations of 5, 10, 40, 80 and 160 mg. per cent. An inoculum was then added that would produce growth in all the drug-containing cultures so that variations in the degree of killing could be noted. The urine was incubated for twenty-four hours, following which 0.5 cc. was removed a,nd after proper d]utions pour plates were made. The agar used in these plates contained para-amino-benzoic acid. After incubation the number of colonies were counted. TABLE 1 BACTERICIDAL EFFECT OF VARTOUS CONCENTRATIONS OF SULFATIDAZOLE
Number of Organisms After 24 Hours' Incubation Sulfathiazole M~. per 100 cc.
Escherichia coli
Proteus vulgaris
Staphylococcus aureus
Control
320,000,000
50,000,000
190,000,000
5
8
7,000,000
56
10
44
100,000
192
Staphylococcus albus
Streptococcus faecalis
Flexner
1,000,000
305,600
380,000,000
120
260,400
8
20
159,200
20
40
12
364
84
8
24,200
44
80
24
48
144
4
956
24
160
4
160
36
24
°
80
Table 1 shows the results of these studies. In general, it can be said that concentrations of about 10 mg. per cent cause marked killing, and that increasing the concentration does not appreciably increase the bactericidal effect in the majority of experiments. There are two exceptions to this. Proteus vulgaris and Streptococcus faecalis usually show a more marked in-
MANAGEMENT OF URINARY TRACT INFECTIONS
1429
crease in the action of the drug at higher levels, although low concentrations do show a definite effect. Helmholz 14 has shown that the bactericidal !1ction of sulfathiazole is increased only slightly when the concentration is raised from a level of 10 mg . . to a level of 30 mg. per 100 cc. Dosage.-What amount of drug must be administered to patients in order to obtain concentrations of the drug of 10 mg. per cent or greater? Figure 179 shows the concentrations obtained in two normal individuals receiving 0.25 gm. of sulfathiazole three times per day. 025GM
J.
200
PER
.J.
os
lao 0 160
51
~'40
.~
cl
~ 120
~ ~
100
"
ao
~
,0
..
.. 60
~
2 40 20
HOURS 24 HR
OUTPUT
CC
24 • 1743 02386
.a 1581
2868
12 1117
20,.
00 13"86
26159
Fig. 179.-Arrows represent the ingestion of 0.25 gm. of sulfathiazole. Solid dots represent the concentration of free sulfathiazole in individual urine samples of a patient receiving 2000 cc. of fluid each twenty-four hours. Circles represent free sulfathiazole in urine specimens from a patient with an intake of 3000 cc. per twenty-four hours.
One of these subjects was on a constant intake of 2000 cc. daily, the other received 3000 cc. A determination of sulfathiazole was made on each specimen of urine. In only one instance was the concentration below 7 mg. per cent; the majority of samples contained well over 20 mg. per cent. It would appear from these studies, then, that the administration of from 0.25 to 0.5 gm. three times daily is sufficient to maintain concentrations above 10 mg. per cent in the urine. Such levels will give satisfactory results in the majority of patients. Treatment should be continued for a period of about one
1430
SAMUEL N. VaSE, CHARLES H. RAMMELKAMP
week; if all symptoms have not subsided a thorough investigation as to the causative organism and presence of obstruction should be made. When the infecting bacterium is either Proteus vulgaris or Streptococcus jaecalis, it is advisable to administer somewhat larger amounts of the drug. In these infections 1 gm. three times daily is adequate. . 1"oxicity.-The manifestations of sulfathiazole toxicity are now well known. Perhaps the most chara.cteristic is the injection of the conjunctiva. Skin rashes occur not infrequently, and may be associated with fever. Both skin rashes and fever are seen usually about the seventh to tenth day of therapy. The more serious reactions are hemolytic anemia and toxic hepatitis; fortunately these occur only rarely. As with suIfanilamide, when these toxic reactions are encountered, the drug should be discontinued and fluids forced. Careful observation will prevent the serious reactions.
Relative Merits of Urinary Antiseptics.-It is our opinion that sulfathiazole is the drug of choice in the treatment of these infections. Its chief advantages over mandelic acid are ease of administration, a more marked bactericidal action against all bacteria, fluids need not be limited, the reaction of the urine does not have to be regulated, and the effective bactericidal concentration in the urine is more readily obtained. A further important advantage is that sulfathiazole may be given to patients with high fever or with poor renal function. In the latter group of cases, sulfathiazole should be administered in small doses such as 0.25 gm. three times per day. We recently treated a case with marked nitrogen retention with small doses of sulfathiazole. The clinical response in this instance was adequate. When severe vomiting occurs, the sodium salt of sulfathiazole may be administered intravenously in saline. One gram three times daily is sufficient. Sulfanilamide may be given subcutaneously in somewhat larger dosages. What are the chief advantages of sulfathiazole over sulfanilamide? The most important advantage is the marked increase in the bactericidal action of the thiazole compound. Not only does it exhibit an increased killing effect against Escherichia coli, Proteus vulgaris, Staphylococcus aureus and albus, and the typhoid-dysentery organisms, but it is the only agent that appears to exert any effect on Streptococcus jaecalis. As was pointed out above, sulfathiazole is effective in low concentrations, whereas sulfanilamide, in order to exhibit bactericidal
MANAGEMENT OF URINARY TRACT INFECTIONS
1431
. action, requires much higher concentrations. It is clear, then, that the dosage of sulfathiazole may be small, and in cases of poor renal function satisfactory levels may be obtained more readily. The chief disadvantage to the use of sulfathiazole is its toxic effect. Certainly, it causes more serious reactions than mandelic acid. However, if small doses are given over a short period of time (ten days) most of these toxic reactions may be avoided. Those patients receiving sulfathiazole for longer periods should be under close observation. Sulfanilamide and sulfathiazole exhibit about the same degree of toxicity clinically. Patients who are sensitive to one sulfonamide are likely to be sensitive to the other. Methenaminej Neoa.rsphenamine.-Preoccupation with the newer chemotherapeutic agents should not lead to a com~ plete disregard of some of the time-tested internal urinary antiseptics. Occasionally complete intolerance for the sulfonamides and mandelic acid exists or it is desirable to give a urinary antiseptic over a long period of time. M ethenamine has produced many good results in the past in such cases. To be effective it must be given in fairly large doses, 3 to 4 gm. per day, and some acidifying agent must be used. Since its action depends on the liberation of formaldehyde in an acid urine, it is of little value in acute infections. It finds its greatest field of usefulness in the chronic bacillary infections. Resistant coccal infections will sometimes respond to intravenous neoarsphenamine. 15 Doses of 0.45 gm. should be given every two or three days with the usual precautions. If marked improvement is not noted after three or four doses, the drug should be discontinued. The drug is not tolerated as well as when used for antiluetic treatment. SPECIAL TYPES OF URINARY INFECTION
Postoperative Cystitis.-FrequentIy referred to as "catheter cystitis," this condition occurs more often because of . delay in the use of the catheter than because of adequate use. No -general rule as to lapse of time permitted before catheterization is applicable to all cases. The free use of preoperative and postoperative intravenous fluids has undoubtedly shortened the period before bladder distention occurs. Distention is some-
1432
SAMUEL N. VaSE, CHARLES H. RAMMELKAMP
times difficult to detect by abdominal palpation in a freshly operated case and trauma of overdistention renders the bladder susceptible to infection. After one or two catheterizations incomplete bladder function may be established, but with residual urine, which again invites infection.lG Measures which may be taken to prevent postoperative infection include the use of prostigmin, 1 cc. intramuscularly every four hours to stimulate voluntary micturition, the establishment of adequate drainage by the indwelling catheter if distention occurs, the demonstration of no residual urine after re establishment of bladder function and the prophylactic use of sulfathiazole, 0.25 gm. t.i.d. Pyelonephritis of Pregnancy.-Formerly considered rarely curable during the duration of pregnancy, this condition may be treated successfully by chemotherapy, negative cultures having been secured in numerous instances.17 So far as present evidence is trustworthy, no particular danger to the fetus is involved, and doses may be used as in nonpregnant cases. In refractory cases ureter catheterization should be done, and fulminating infections may demand termination of the pregnancy. Infections in Childhood.-In spite of marked progress l8 in the approach to this problem during the past few years, there still exists, in many quarters, a disposition to delay investigation of the urinary tract in children. Cystoscopy and other instrumentations are tolerated fully as well by children as by adults and the incidence of congenital obstructive lesions as a cause of infection is high.19 The age of this group of patients, however young, is no contraindication to procedures which would be indicated under similar circumstances in an adult. CONCLUSIONS
Urinary infections of various types are extremely responsive to chemotherapy, the most effective agent being suljathiazole. Small doses of this drug appear to be adequate and it should be administered in a dosage of 0.5 gm. three times daily. Even smaller doses may be used when renal insufficiency exists. Therapy should be guided by bacteriological studies. Since most urinary infections result from some predisposing factor, a complete diagnostic survey should be made in chronic
MANAGEMENT OF URINARY TRACT INFECTIONS
1433
or recurrent case~ and acute cases should be followed up by a search for an obstructing lesion. Adequate therapy, more critical criteria of cure and followup observation should decrease late complications of urinary infections. BIBLIOGRAPHY 1. Von Lichtenberg, A.: Kidney and Ureteral Lesions Secondary to Adnexal
Disease. J. Urol., 24: 1, 1930.
2. Baldwin, A. D. and Root, H. F.: Infections of the Upper Urinary Tract
in the Diabetic Patient. New Eng. J. Med., 223: 244, 1940.
3. McNeil, A. E. and Bowler, J. P.: Irrigation and Tidal Drainage. New
Eng. J. Med., 223: 128, 1940.
4. Cook, E. N.: Chemotherapy in Infections of the Urinary Tract. J. UroI.,
39: 692, 1938.
5. Carroll, G., Lewis, B. and Kappel, L.: Further Clinical and Laboratory
Observations of Mandelic Acid. J. Urol., 39: 710, 1938.
6. Rantz, L. A. and Keefer, C. S.: SuIfanilamide in Treatment of Infections
of the Urinary Tract due to Bacillus Coli. Arch. Int. Med., 65: 993, 1940.
7. Bumpus, H. C., Jr.: Urinary Infections-Part H. Calif. Western Med.,
50: 351, 1939.
8. MitcheIJ, D. R., Greey, P. H. and Lucas, C. C.: SuIfanilamide in the Treat-
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