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The Treatment of Urinary Tract Infections by Means other than the Ketogenic Diet
Medical Clinics oj North America March, 1937. Boston Number
CLINIC OF DR. E. GRANVILLE CRAB TREE BETH ISRAEL HOSPITAL
THE TREATMENT OF URINARY TRACT INFECTIONS BY MEANS OTHER THAN THE KETOGENIC DIET THERE is no perfect universal antiseptic for the treatment of urinary tract infections. Antisepsis alone is far too simple an approach to be adequate for cure in difficult cases. Even if it produces apparent cure recurrence often promptly takes place. For successful combat against stubborn infections other factors besides drug administration must be understood by the attendant physician if he is to be able to furnish that attention to detail which is an essential to success in the treatment of the infection and a safeguard to the patient. A perfect antiseptic for the urinary tract would be a menace to the patient if it permitted prompt removal of the signs of gross disease, which is often infection alone, without that condition having been recognized. Considered numerically, it is probable that most infections which occur recover spontaneously. Treatment of this group gives abundant optimism for many forms of therapy. The relation of pH to recovery in these cases may be important. That relation is not yet proved. However, I have noted that in my surgical patients in whom urinary tract infection has been introduced in the course of surgery of the bladder or kidney, if prompt clearing of the infections takes place, the urine is almost always quite definitely acid, below pH 5.5, in reaction. Exceptions to this rule are noted. At this stage in our knowledge of therapy it is sufficient to recognize three types of bacteria, about which we can accomplish considerable in treatment, namely, the colon bacillus 593
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group, Bacillus proteus and the gram-positive cocci, staphylococcus and streptococcus. There are some definite differences in the method of attack for cure in the three groups mentioned. As a preliminary to treatment, identification of the bacteria in the infected urine, and a sufficient number of determinations of the reaction of the urine to indicate the average pH, is important. Culture of the urine will often be misleading since, in mixed infections, the colon bacillus or Bacillus proteus may overgrow and mask the other slow-growing forms of bacteria present, such as staphylococcus. Gram's stain, when applied to the urinary sediment, will help to clear up the question of mixed infections. Culture is necessary, particularly in bacillary infections, to distinguish other forms of gram-negative bacilli, particularly B. proteus, from the colon bacillus group. Just how far mutations of bacteria influence treatment has not yet been determined. There is important progress to be made here, particularly in relation to virulence of the .infection. At times it seems that in virulent infections acidification of the urine alone may give rise to symptoms in subacute cases. Certainly concentration of urine often gives temperature rises. Where sugar is present recognition and proper handling is essential to successful treatment. Neither in my own experience nor in the literature, have I found sufficient data to enable me to make a statement as to the significance of high blood sugar readings or the presence of urinary sugar in acidification therapy. If nephritic conditions exist, closer observation of the urine during treatment by acidification therapy would naturally be given to detect signs of irritation early if they should occur. If renal damage is considerable the drug will not be excreted in sufficient concentration to be effective and storage will endanger the patient. Even where ~he same bacterium, such as Bacillus coli, is the infecting agent, treatment is modified by four conditions in which an essentially normal urinary tract, as distinguished from gross pathologic changes, exists. These are acute febrile infections, subacute or chronic infections, infections in pregmincy"'and the puerperium, and urogenital infections. Need-
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less to say, during acute febrile stages of infection, instrumentation, acidification of the urine, and concentration of urine are contraindicated. In the chronic form of infection one has the most favorable field for medication. In pregnancy there is a physiological dilatation of the pelves and ureters which is to some degree always present in pregnancy and which persists into the puerperium to a degree sufficient to modify treatment. Finally, in the male, pyelonephritis is so commonly complicated by prostatic infection, the symptoms of which are often 9vershadowed by the renal symptoms, that it is not recognized, receives no treatment and persists as the focus for chronic urinary tract infection with exacerbations. So minor a procedure as catheterization of postoperative retentions in the male with resu1t~nt minor degrees of cystitis may initiate such prostatitis which will remain unnoted, but eventually prove to underlie recurrent or persistent urinary infection. A survey of the extensive studies made, over a considerable period of time, in the value of antiseptics in acute febrile pyelonephritis leads me to two very definite conclusions. The first is that it makes very little difference at this stage of the infection what the infecting organism is. The second is, that any form of active bactericidal therapy is unsound. The bacterium or bacteria concerned are in a virulent state, rapidly growing, producing fever, nausea, often severe vomiting, with attendant acidosis and shortage of fluid intake and excretion. The kidneys are edematous, subnormal in excretory ability and irritated to the point of albumin loss. This is no time for irritants such as hexamethylenamine with acidification, limitation of fluids as required in administration of some antiseptics, the use of heavy metals as in mercurochrome, or arsenicals. The addition of acidity to the acidosis already present especially in the face of diminished excretion, or the burdening of the system with dyes which will be excreted so poorly as to be present in the urine in sub-bacteriostatic or -bactericidal amounts, is equally without supporting logic. These patients have three major requirements. Rest in bed is essential. In home surroundings frequent trips to adjoining bathrooms are
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to be discouraged. Even that amount of activity tends to prolong the disease. Vermooten 1 has called attention to the value of the elevated foot and lowered head of the bed with but one pillow as a means of shortening the course of pyelitis. Certainly the bed rest and the cramped sitting postures are to be condemned. The second requirement is abundant fluid intake and excretion. Diminished excretory ability on the part of the kidneys in their inflamed condition, together with increased toxic products in the blood stream as a result of the febrile state, indicates the requirement for abnormal amounts of fluids to carry away even normal quantities of waste products to say nothing of the increased quantities which exist in the acute ill- . ness. If begun early in the disease this fluid can be taken by mouth up to 6000 cc. a day. Four thousand five hundred cc. will be the average requirement. If the patient is toxic when seen, to the point of nausea and vomiting, hypodermoclysis given slowly, preferably'by multiple needles, will supply 4000 to 5000 cc. in twenty-four hours. This may either be normal saline or 2.5 per cent glucose. Saline is adequate without the glucose. Intravenous drip may be employed. It is less popular with me because failure to absorb from the tissues is a warning which intravenous fluid administration lacks. Seldom is more than one day of fluid administration by either method required before adequate fluid can be taken by mouth. The third requirement is alkalinization. High degrees of fever and prostration from acute urinary tract infection can be tolerated without acidosis, nausea and vomiting, if sufficient alkali is administered to produce a pH of '7 to 7.5, 45 grains of either sodium or potassium citrate or 60 grains of sodium bicarbonate is usually adequate to produce this result. More should be administered if necessary to produce the result aimed for. The dangers attendant on instrumentation during acute febrile urinary tract infections are now well recognized. The e~ception is infection in pregnancy. This exception is made because of the pelvic residual urine which is characteristic of
.
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this disease. Cystoscopic treatment here does far more good than harm. The possibility: that an obstruction to drainage might exist, either in the upper or lower urinhry channels, must not be lost sight of, but sought for, and promptly relieved where definite findings indicate its presence. Obstruction of ureters by pus plugs is a 'ghost which has not yet be~n completely laid. Partial obstructions, as from stones, can be temporized with safety in most instances until some abatement of acute symptoms has occurred, It should be the purpose of treatment of acute febrile infections to shorten the duration of the acute symptoms as much as possible. Often mismanagement of the early stages of infection~ of the urinary tract is responsible for troublesome persistence through protracted fevers, starvation, anemias and debility which could have been avoided. There is no contraindication to a liberal diet including proteins. Development of anemias is often extremely rapid. The alkalinized patient need miss but few meals. A patient emerging from acute urinary tract infections becomes safe for further urological investigation, local treatment or treatment by antiseptics, or for allowing out of bed after not less than four or five days of normal temperature and the loss of renal tenderness. Some patients require a longer delay. Previous to this time intravenous urography is apt to show the kidneys poorly, cystoscopy with retrograde pyelography to cause febrile reactions, and acidification of the urine especially when concentrated for therapeutic reasons to cause a return of fever. The type of antisepsis employed at· this time will, in great measure, depend upon the organism found to be responsible for the infection. For the colon bacillus group of bacteria, acidification of the urine with ammonium chloride, sufficient to produce pH 5-5.4, and the administration of hexamethylenamine in 7%-grain doses, three times daily, is usually adequate and up to the introduction of the salts of mandelic acid, was the most efficient form of therapy. I do not see how it is possible to carry out treatment successfully along this line without pH determination. Simple apparatus is avail-
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able for the purpose and should be used. Chlorphenol red test paper is of some help if kept in good condition until the time of use. The acidity of the urine is capable of great variation. Without pH determinations valuable time may be lost with the best of intentions toward the patient. Do not forget that old men have already, or acqU'ire during fevers, residual urines.· Women in bed are notoriously poor at emptying bladders without leaving residual urine and that both men and women have urethral strictures. Addition of bladder washes with nitrate of silver made up freshly from distilled water at three- to five-day intervals, will clear the bladder walls of adherent pus flakes and debris as well as have antiseptic value particularly in the above cases of small residual urines and the atonic postpartum bladder. A satisfactory silver nitrate solution, almost universally tolerated by the patient, can be made up quickly with I-grain tablet of silver nitrate dissolved in 16 ounces of warm, distilled water. Do not throw an inflamed bladder into painful spasm with cold solution. Repeated fillings of the bladder are not well tolerated. A second filling will, of necessity, be at a lower capacity from the first if discomfort is to be avoided. Mercurochrome injections of 0.5 to 1 per cent solutions are used. Also argyrol in strength of 10 per cent, or other silver salts are used as an injection after lavage with boric acid solution. Silver is better. If cleansing only is desired, daily lavage with a bland solution such as boric acid solution 2 per cent, potassium permanganate 1: 8000, and acriflavine, may be used. . Staphylococcus and streptococcus infections of the urinary tract are usually stubborn infections. Heathcote2 has shown that the growth of staphylococcus was not definitely reduced at a pH of 5 by three hours' exposure to any concentration of formaldehyde in the urine that could be tolerated by the patient. Treatment by mandelic acid produces some cures. In one of my cases nineteen days of treatment at a pH between 4.7 and 4.9, failed to more than inhibit the growth. Often either acidification with ammonium chloride and hexamethylenamine or' mandelic acid has cleared Bacillus coli from mixed infec-
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tions and left the staphylococci or streptococci in pure culture. If the staphylococcus is still resistant to medication by salts of mandelic acid, alkalinization of the urine should be done to a pH of 7-7.5 and acriflavine, % grain in enteric coated tablets, administered three times daily with the urine concentrated by an intake of 1500 to 1800 cc. Another medication, sometimes effective, is methylene blue in 2-grain chocolate-coated tablets administered three times a day. Greenberg3 has pointed out that the gastro-intestinal symptoms sometimes encountered in methylene blue therapy, are due to zinc salt impurities. Unfortunately the purified dye has not been produced commercially. Where all else has failed neoarsphenamine given in 0.3-Gm. doses at five-day intervals for from 3 to 6 doses, is almost specific for the gram-positive cocci. It is reserved as a last resort because of the dangers attendant upon its administration In a condition by no means of the significance of syphilis. It must be given only after study of the patient and the attendant risk of administration and preferably by one expert in the treatment of syphilis. Proteus infections will often yield to the salts of mandelic acid. In some of the apparent failures added lavage with silver nitrate has accomplished a cure. In those proteus infections in which acidification does not occur even with heavy doses of ammonium chloride, I know of little that can be done to combat this form of infection. Administration of mandelate or hexamethylamine then becomes wasteful. Fortunately, with all three forms of bacteria, the normal urinary tract is prone to rid itself spontaneously of infections in time. For this reason resorting to elaborate courses of antisepsis, or the more drastic forms of treatment, is hardly justified in the subacute stages of urinary infections. Shifting from acidity to alkaiinity with the avowed purpose of complicating the home conditions of bacteria in the urinary tract has an appealing and delightful simplicity suggestive of the practical joke, the purpose of which seems not often to be effectively grasped by the bacteria concerned. (Note the above remarks on spontaneous cures.) The effect of acidification of
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the urine alone is bacteriostatic but not bactericidal in the lower pH ranges of 5.4 and under. No such bacteriostatic action has been recorded for alkalinity in experiments with any form of bacteria. There is no theoretical ground for expecting benefit other than the bacteriostatic effect of acidification when shifts from acidity to alkalinity are made. If acidification is attempted, as is commonly done, by the use of sodium acid phosphate, even that effect is not obtained since strong acidification cannot be produced by this drug. After the elimination of those acute and subacute infections which either recover spontaneously or reach an early cure by the common forms of therapy, there is left a troublesome remnant of a few cases which are chronic infections. This group has been variously estimated as comprising from 5 to 10 per cent of the whole. They can be grouped into persistent infections or recurrent infections dependent on whether the urine becomes bacteria-free between exacerbations of symptoms. If the urine fails to clear at any time, gross pathology in the urinary tract, particularly conditions (if urinary stasis, are probable. If complete clearing of the urinary tract from infections (as demonstrated by absence of bacteria, not pus cells) occurs, the likelihood of gross pathology is less but the probability of systemic causes is greater. Chronic infections can best be approached for both diagnosis and treatment if the persistence of the infection is attributed to one of three major causes: 1. The condition of the patient, 2. Foci of infection, 3. Gross pathology, and investigation conducted with the purpose of placing the patient in this classification. I have already commented on the desirability of intelligent handling of the acute stages of infection that the patient may not emerge from them anemic and debilitated from a protracted illness, and suggested effective measures for the prevention of that condition. Unfortunately, urinary tract infections freql,lendy occur as complications of surgery and debility from
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other illnesses. They may then get dug in and reach the state of chronic infections before convalescence from the major illness takes place. Many Americans live in a constant state of exhaustion from overwork and overactivity in an attempt to enjoy all the possibilities of our modern life. There is also the faulty diet patient. One such with recurrent autumnal infection was found to have a dislike for summer foods and ate little, lost weight and acquired a yearly autumnal infection. Another patient reaches extremes of exhaustion in her social life. Her infections can almost always be predicted by watching the social columns in the newspapers. A mother, who was a confirmed Christmas shopper, with five children of school age who were all home with their friends at vacation time, had three recurrent infections in the five strenuous years of that activity all of which were in January or February of the new year. I find a higher percentage of recurrent infections in the upper classes with neither foci of infection, nor gross pathology encountered, than in the working classes. The working man has more gross pathology with his pus and bacteria. In addition some chronic infections are cured on adjusting metabolic problems. Foci of infection seem to me to be the third in importance in these three groups. Teeth, tonsils and sinuses are occasionally incriminated yet it is surprising how often massive sepsis in these areas shows little relation to urinary tract infection either in its presence or after it has been cleared. It is most important in children. It must not be ignored. Bowel conditions play a very conspicuous part both in the incidence and the chronic stages of infection. A chronically overloaded bowel is perhaps most commonly found in these cases, and diverticulitis of the sigmoid is a very serious complication. The occasional case of perforation of such a condition into the bladder must not be overlooked. In the male a symptomless prostatitis which is participating in a urogenital infection but receiving no treatment is perhaps the most common focus of infection. It may be responsible for a persistent infection with a constantly cloudy urine or for
E. GRANVILLE CRABTREE
recurrent infections which take place during exacerbations of prostatitis, which may be even a few years apart. Gross pathology in the urinary tract either in the form of lower urinary obstruction with bladder residual urine, bladder malformations, diverticula, upper urinary, ureteral and pelvic obstructions all produce stagnant urine from which infection, is eradicated with great difficulty by any known means short of correction of the defect. Stones and tumors are the other aids to retention of infections. The physiological changes in the kidneys and ureters due to pregnancy make these cases more nearly associated with this group although the obstructive factor is of necessity limited in duration to nine months. The chief danger is that if the degree of pathology is small the infection might be cured through the more effective measures now available in antisepsis and allow the condition to progress unnoted. Valuable time is often wasted in treatment to the detriment of the patient as in the case of a lady who received 156 pelvic lavages for infected hydronephrosis with stones, after many other antiseptic procedures had failed already. Infection may be the only indication of the presence of serious disease. The commonly employed urinary antiseptics may be listed as follows: the dye group, the formalin-bearing drugs, the antiseptic acids, and the arsenicals. The Dye Drugs.-Here are found methylene blue, acriflavine, pyridium and serenium, and mercurochrome. There are many others of less importance. All have other properties than the dye property. Methylene blue, when administered in 2-grain chocolatecoated tablets three times daily in an alkaline urine with a pH above 7, has certain fields of usefulness. Thomas and Wang4 found it of some value as an inhibitor and less value as a germicide against Bacillus coli and Staphylococcus aureus when the patient was limited to a fluid intake of 3 glasses of water daily. Hinman5 found it more effective in staphylococcus and streptococcus infections than in the bacillary group when administered in alJ.vlline urines with concentration. Greenberg used it succes'sfully as .,a palliative in tuberculosis.
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Acriflavine in doses of %-grain enteric coated tablets three to four times daily in concentrated alkaline urine showed bacteriostatic effects on both bacillary and coccal types of bacteria in half the cases (WaIther6 ). Davis7 had better success with 0.1 Gm. twice daily in concentrated alkaline urines infected with either staphylococci or Bacillus coli, producing cures in 13 out of 18 acute cases with 5 failures. In 27 chronic colon bacillus infections there were no cures. I have found it of most value in staphylococcus and streptococcus infections. There are better treatment agents for the gram-negative bacilli. Pyridium and serenium have had in my hands no appreciable bactericidal or bacteriostatic effect on either the bacillary or the coccal forms of infection. Many other observers agree with this opinion. In a series of experiments in pyelitis in pregnancy the picture presented through the microscope of motile colon bacilli swimming sturdily along through a concentrated urine deeply stained with pyridium, went far to destroy my hopes of much help from these drugs. No other source of experience or information has revived my interest in them. Mercurochrome, in spite of all that has been written, should be confined in its use to local applications to the pelvis or bladder. Hexylresorcinol while not a dye drug is discussed here. It is administered in dosages of 0.3 to 0.6 Gm. three times a day and treatment is to be continued two weeks beyond the negative culture. The drug has not lived up to the promise with which it made its initial bow in 1924. Methylene blue and acriflavine, even though both may produce gastro-intestinal symptoms, are the most effective, drugs in this group. They are applicable to the coccal infections. Other forms of treatment are preferable by far for the bacillary infections. If gastro-intestinal symptoms occur the drug can be resumed after a short rest and tolerance for it seems to be acquired. Formalin-bearing Drugs.-The second group to be· considered is the formalin-bearing drugs. Hexamethylenamine is
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the form in which this therapy is commonly and most effec, tively administered. Hexamethylenamine in acid urine has been the best therapeutic measure for treatment of the bacH lary group of urinary tract infections previous to the introduction of mandelic acid. In properly acidified urine formalin is freed in antiseptic strength at the kidney level as well as in the bladder, namely, 0.005 to 0.007 per cent formaldehyde. In many instances it is adequate treatment for cure. It fails to cure some strains of Bacillus coli. MitchelI and Scott8 found that certain strains of organisms were resistant to formaldehyde with marked correlation between test tube and clinical studies If hexamethylenamine killed the organism in the urine, formalin killed it in the test tube. If it failed clinically it failed also in the test tube. The optimum pH for liberation of formaldehyde from hexamethylenamine in the urine is pH 5-5.4. The common use of sodium acid phosphate with hexamethylenamine does not produce that degree of acidity from alkalinity. It is much preferable to use ammonium chloride to produce the acidity and to observe frequently to note if the proper acidity is maintained during treatment. Ammonium chloride should only be used in enteric coated tablets if gastric symptoms are to be minimized. So important is acidification therapy both for the use of hexamethylenamine and mandelic acid that the theory and practice of acidification and alkalinization should be taken up here. Acidification of the Urine.-The true pH of normal urine depends in great measure on the phosphates by dissociation of NaH2P0 4 to Na2HP04 with liberation of an hydrogen ion. With complete dissociation of phosphate the pH lies commonly between 5 and 5.2. Increase in hydrogen ion concentration is accompanied by increase in ammonia excretion. Urinary volume seems to be inversely proportional to hydrogen ion concentration. Gamble9 places the lower limits of normal acidity at about pH 4.8 and doubts if acidity can be produced below pH 4. He finds that the upper limit of alkalinity is pH 8, even"" when large amounts of alkali are administered. GreylO
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considers pH below 5, or above 7, pathological. The idea being that the bacterial infections have changed the normal pH, when figures below and above those readings are obtained. Marlowl l found in his study of 141 normal young adults that the pH variation was from 5.1 to 6.8. Administration of drugs by mouth as acidifiers is an attempt to produce as much free acid radical as is possible to be done. Regulatory factors convey an excess of acid over fixed base into the urine. The commonly employed acidifiers are: Sodium acid phosphate . . .......... Ammonium acid phosphate . ................. .......... . ... Ammonium chloride .... Ammonium nitrate ........ . . . . . . . . . . . . . . .. Ammonium benzoate ........................
20 20 15 15 40
grains grains grains grains grains
4 times a day 4 times a day 3 to 4 times a day 3 times a day daily
.Sodium acid phosphate has been most widely used for urinary acidification but is the least effective of the group. Stockman and Johnson12 find that it acts practically not at all in normally slightly acid urine. It produces slight acidity when the reaction of the urine is well on the alkaline side The ammonium salts of hydrochloric acid, nitric acid and phosphoric acid are the best acidifiers. Their action is due to decomposition of the salt into ammonia and hydrochloric, nitric or phosphoric acid radicals. The ammonia is converted into urea and excreted by the kidneys. The acid is neutralized in the blood and tissues at the expense of the alkali reserve. Serious acidosis does not follow the administration of the usual doses of these drugs if the renal function is good. The same doses with moderate to severe renal impairment may produce marked deviation from the normal acid-base eqUilibrium with resultant changes in metabolic functions and the production of definite and severe symptoms of acidosis and even death. It is probably best to select one acidifier and familiarize oneself with its use. Ammonium chloride is on the whole the most satisfactory. Alkalinization of the Urine (Gamble9 ).-Where excesses of fixed base over acid is produced by the administration of al•
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kalis there is need for an acid substance abundantly at hand which can be placed in the urine under control. Carbonic acid both suits these requirements and is available in practically unlimited quantities. Routinely it leaves the body base free by way of the lungs, but when needed can, to a regulated extent, be deflected into the urine. The concentration of free carbonic acid in the urine is of a stationary value of approximately the magnitude of that in blood plasma. As a consequence of this fixed value for carbonic acid, excess of base in the blood plasma is excreted as bicarbonate in the urine. Thus as the urinary pH rises above that of the blood plasma (pH 7.4) the concentration of bicarbonate in the urine becomes greater. This concentration of bicarbonate which, in the presence of a fixed level for carbonic acid, would be necessary to force the pH of urine above 8 is terminated by the limit of total concentration of substances in urine. It has also been determined experimentally that ingestion of large amounts of alkali will not produce an alkalinity above pH 8. Antiseptic Acid Therapy.-Mandelic acid is a recent addition to our armamentarium for treatment of urinary tract infections. Its place is not yet definitely established. None will deny that for the colon bacillus group of invaders it is the most satisfactory agent yet produced. Many will question its universal application and success with the cocci and some of the less common organisms. The enthusiastic, almost fanatical rush to administer the drug at all times and often carelessly, as regards renal deficiency, acidity and toxicity of the patient in acute conditions has already made some doubt its efficacy. Its use is well established in the steep curve of acceptance with which we commonly greet an important novelty, then COndemn and abandon it only later to take it up at somewhere near its true value. Mandelic acid is a member of the benzoic acid group. It was selected for experimentation as an antiseptic because of all the acids tested it was found to be the most bacteriostatic in vitro. It has been known since 1883 that it would be excreted _l!nchanged and not metabolized by passage th~ough animals.
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In vitro at a pH 5.3, all bacterial life is killed at a concentration of 1 per cent. Mandelic acid cannot be administered as acid because of its irritating effect upon the stomach. Salts of mandelic acid must be used as the vehicle by which a proper concentration of the acid is made to reach the urine. As in the case of acidifiers of the urine the ammonium salt of mandelic acid is preferable because the ammonia radical will be excreted as urea leaving the acid free, thereby avoiding an unnecessary base. In an average normal patient, 12 Gm. of ammonium mandelate administered in twenty-four hours will produce a pH 5.3. Helmholz and Osterberg13 have demonstrated its diuretic action and cumulative rate of excretion at an established pH 5, with ammonium chloride. It is, therefore, an essentially short treatment course drug. These observers indicated a cumulative rate of excretion from 0.32 to 1.14 per cent in twelve hours during which 12 Gm. of mandelate were administered in 4 doses. They also showed that at a urine pH of 5 and concentration of mandelic acid to 0.25 per cent it was bactericidal for most organisms. The same results could be obtained at pH 5.3 with 0.5 per cent concentration or at 5.7 with 1 per cent concentration. These tests were made using sodium mandelate. They obtained approximately the same results by adding mandelic acid to normal urine of similar pH reading. There is no test for the acid in the urine. These de terminations must be made through recovery of the acid from the urine. Although mandelic acid may be considered as a foreign body in the circulation and in the urine, the need for adequate acidification to ensure its effectiveness introduces the question of acidification which is a chemi~al process within the body. The two drugs, the acidifier and the salt of mandelic acid, must, therefore, be considered together. Mandelic acid 3 Gm. with sodium bicarbonate 1.6 Gm., combined in solution to form sodium mandelate, is not neutral but has a pH 4.5. In consideration of the use of mandelic acid as an antiseptic one must take into consideration the combined acidifying power of the salt of mandelic acid and the acidifier. Helmholz and Oster-
It is impotent except with strong acidity.
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berg found that, by measur~ment of the urea clearance test, a dog suffered no permanent renal damage when 700 cc. of 1 per cent mandelic acid was injected intravenously over, a seven-hour period. Presumably the dog had normal kidneys. Acidification in nephritis, owing to diminished selective secretion by the damaged kidneys, at least justifies reasonable apprehension as to the safety of the procedure. HoIling and Platt14 report 2 cases of renal edema without apparent effect on the nephritis. Lyon and Dunlop15 observed the CO 2 combining power which they checked before and after the treatment in a number of cases. They found it to be within normal limits except in one case in which 360 Gm. of ammonium chloride was administered in a futile attempt at acidification of the urine. The figure fell from 63 to 46 per cent (C0 2 combining power). Untoward signs and symptoms may accompany treatment with mandelic acid. The use of acidifiers alone or in conjunction with salts of mandelic acid may produce red blood cells, casts, and albumin in the urine. Cubitti6 found no ill effects from continued treatment when occasional casts and red cells appeared. Rosenheim17 found one case with albuminuria showed increased amounts of albumin. In two of my own cases, the appearance of red blood cells was accompanied by bladder tenesmus where no bladder symptoms had been present before. Apparently after prompt cessation of medication all these signs quickly disappear. The chief symptoms which may occur in the absence of renal insufficiency are buzzing in the ears, temporary deafness, nausea, vomiting, and dyspnea from acidosis. Minor symptoms are acid taste about the teeth particularly about fillings and general uneasiness when either from exercise or climate perspiration is profuse. In renal insufficiency symptoms may be extreme degrees of acidosis and even death. Administration of the drug has been at the beginning through the use of sodium mandelate. Rosenheim's prescription for its use was 3 Gm. of mandelic acid and 1.6 Gm. sodium bicarbonate with flavoring of lemon and water sufficient to
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make 1 fluidounce, put up in 16-ounce amounts. The administration was 1 ounce four times daily. If the acidity of the urine was not adequate, sufficient ammonium chloride was added. Since that time there have appeared other preparations. Ammonium mandelate combined with ammonium chloride in aromatic syrup has been marketed, under the trade name of syrup amdelate. Each fluidounce contains 12 Gm. of mandelic acid. The dose is 2 teaspoonfuls four times daily. Elixir of mandelic acid is also obtainable. It contains mandelic acid, 124 grains, instead of 185 grains, to the fluidounce, as compared with the syrup. Phosphomandelate is also on the market as a combination of ammonium phosphate and mandelic acid. The dosages are provided in separate envelopes with directions. As Cubitt has pointed out and my own experiences confirm, there is great variation in the amount of acidifier necessary to produce the desired pH 5.3 or less, at which mandelic acid acts best, both in different patients and in the same patient at different times. My preference would be for ammonium mandelate without ammonium chloride in syrup form. Sufficient acidifier could be added from day to day as the patient required. After many and varied approaches, I have found that the most satisfactory method of administering the treatment was through preliminary acidification of the urine,. by means of ammonium chloride until pH of 5-5.4 was obtained. This usually requires but from one to three days. Syrup of ammonium mandelate was· then administered four times daily under daily observation of the urine. The ammonium chloride intake can be gradually diminished or often dropped altogether in twentyfour to forty-eight hours and the pH held up. Most of the cases of bacillary infections become bacteria free in that time. The mandelate is continued at a pH of 4.8-5.2 for a total of six to seven days after which a single dose daily of mandelate with 15 grains of ammonium chloride is administered for six to seven days longer, then the same dose on alternate days for a week more. Fluids are restricted to 1200 cc. for the first week then to 2000 cc. for the second week and fluids as deVOL. 2I-39
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E. GRANVILLE CRAB TREE
sired allowed during the third week. If recurrence of the infection should take place, treatment in regular dosages as in the first week will usually suffice to eliminate it, but often need not be carried beyond a day or two. pH readings of 5.5 or lower will often be noted for ten days to three weeks after medication has ceased. The effectiveness of mandelic acid on both cystitis and pyelitis seems to me not yet to be clearly established. There is general agreement that it is eminently successful in the colon bacillus group of bacteria. Here it is at its best in the absence of any considerable degree of urinary stasis. That it will be successful with some degree of stasis is shown by the successful clearing of 9 out of 13 cases of pyelitis in pregnancy treated after the acute symptoms had subsided. Three of these cases are our own, the remainder collected cases. The proteus bacillus cases have been less constant. Presumably if sufficient acidification can be produced, cure may be effected. Where acidification does not occur it is useless. Both other observers and my own cases show instances where" with mixed infections all bacteria are killed, both the bacillary and the coccal .forms. In other instances the bacilli are eliminated leaving behind a pure flora of cocci. In one instance with a pH under 5 for nineteen days coccal infection remained unchanged under ammonium mandelate treatment. There is no doubt but that complicated cases with gross pathology cannot be looked upon as suitable cases for mandelic acid therapy. It is, furthermore, to be hoped that no other antiseptic will ever be found which, by its use, might conceal to the careless observer pathology of much more significance than the infection which disclosed it. In the male there are encountered many chronic bacillary urogenital infections. They are persistent over years. Many of these yield to mandelic add therapy. Usually there are bacilli demonstrated in the renal and bladder urines and in the prostatic secretions. I have treated them in two ways, either by antiseptics first, then by massage, or by a course of mas!age given previous to antiseptics. In the former group
THE TREATMENT OF URINARY TRAcr INFEcrIONS
6rr
some persist as pyurias without bacteriuria for a considerable period of time and often recur. The second group is much more satisfactory. In this connection I should mention that several observers have noted that the semen is frequently found stained after oral administration of dye antiseptics. Disappearance of the colon bacillus from the vesicle and prostatic secretions in some of these cases under treatment with mandelic acid might indicate a similar drug distribution. Arsenicals.-For the remnant of intractable coccal infections there is still one form of therapy which offers cure. That is the use of arsenicals. Neoarsphenamine, when administered in O.3-Gm. doses at five-day intervals for a total of 3 to 6 treatments when required, will eradicate many of the stubborn coccal infections. Its administration is to be taken as seriously as when given for syphilis. There is less justification in producing complications by misuse of the drug when the nature of the infecting agent is of so much less significance than syphilis. Its use in coccal infections should be limited to the chronic type of infection. Vaccine therapy need no longer be considered seriously in any except the very unusual case. BmLIOGRAPHY 1. Vermooten, V.: So. African Med. Jour., June 9,1934.
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
Heathcote, R.: Brit. Jour. Urol., 1935, p. 9. Greenberg, Davis and Armstrong: Jour. Urol., 33: 2, 1935. Thomas, B. A. and Wang, I. K.: Jour. Uro!., 22: 22, 1929. Hinman, F.: Jour. Amer. Med. Assoc., 65: 1769-1772,1915. Walther, H. W. E.: South. Med. Jour., 22: 161-165, 1929. Davis, E.: Jour. Uro!., 11: 29-38,1924. MitcheIl, D. R. and Scott, J. M.: Brit. Jour. Uro!., 5: 225, 1933. Gamble, J. L.: The Kidney in Health and Disease. Berglund et al., 1935. Grey, F.: Brit. Jour. Urol., 1934, p. 221. MarIow, L.: Jour. Uro!., 35: 674, 1936. Stockman and Johnson: Edinburgh Med. Jour., 34: 223, 1927. Helmholz, H. F. and Osterberg, A. E.: Proceedings of the Staff Meetings of the Mayo Clinic, 11: June 10, 1936. Holling, H. E. and Platt, R.: Lancet, 1: 769-771, 1936. Lyon, D. M. and Dunlop, D. N.: Brit. Med, Jour., 2: 1096-1097, Dec. 71 1935. Cubitt, A. W.: Lancet, 1: 922, 1936. Rosenheim, M. L.: Lancet, 1: 1032,1935.
CLINIC OF DR. E. GRANVILLE CRAB TREE BETH ISRAEL HOSPITAL
THE TREATMENT OF URINARY TRACT INFECTIONS BY MEANS OTHER THAN THE KETOGENIC DIET THERE is no perfect universal antiseptic for the treatment of urinary tract infections. Antisepsis alone is far too simple an approach to be adequate for cure in difficult cases. Even if it produces apparent cure recurrence often promptly takes place. For successful combat against stubborn infections other factors besides drug administration must be understood by the attendant physician if he is to be able to furnish that attention to detail which is an essential to success in the treatment of the infection and a safeguard to the patient. A perfect antiseptic for the urinary tract would be a menace to the patient if it permitted prompt removal of the signs of gross disease, which is often infection alone, without that condition having been recognized. Considered numerically, it is probable that most infections which occur recover spontaneously. Treatment of this group gives abundant optimism for many forms of therapy. The relation of pH to recovery in these cases may be important. That relation is not yet proved. However, I have noted that in my surgical patients in whom urinary tract infection has been introduced in the course of surgery of the bladder or kidney, if prompt clearing of the infections takes place, the urine is almost always quite definitely acid, below pH 5.5, in reaction. Exceptions to this rule are noted. At this stage in our knowledge of therapy it is sufficient to recognize three types of bacteria, about which we can accomplish considerable in treatment, namely, the colon bacillus 593
594
E. GRANVILLE CRABTREE
group, Bacillus proteus and the gram-positive cocci, staphylococcus and streptococcus. There are some definite differences in the method of attack for cure in the three groups mentioned. As a preliminary to treatment, identification of the bacteria in the infected urine, and a sufficient number of determinations of the reaction of the urine to indicate the average pH, is important. Culture of the urine will often be misleading since, in mixed infections, the colon bacillus or Bacillus proteus may overgrow and mask the other slow-growing forms of bacteria present, such as staphylococcus. Gram's stain, when applied to the urinary sediment, will help to clear up the question of mixed infections. Culture is necessary, particularly in bacillary infections, to distinguish other forms of gram-negative bacilli, particularly B. proteus, from the colon bacillus group. Just how far mutations of bacteria influence treatment has not yet been determined. There is important progress to be made here, particularly in relation to virulence of the .infection. At times it seems that in virulent infections acidification of the urine alone may give rise to symptoms in subacute cases. Certainly concentration of urine often gives temperature rises. Where sugar is present recognition and proper handling is essential to successful treatment. Neither in my own experience nor in the literature, have I found sufficient data to enable me to make a statement as to the significance of high blood sugar readings or the presence of urinary sugar in acidification therapy. If nephritic conditions exist, closer observation of the urine during treatment by acidification therapy would naturally be given to detect signs of irritation early if they should occur. If renal damage is considerable the drug will not be excreted in sufficient concentration to be effective and storage will endanger the patient. Even where ~he same bacterium, such as Bacillus coli, is the infecting agent, treatment is modified by four conditions in which an essentially normal urinary tract, as distinguished from gross pathologic changes, exists. These are acute febrile infections, subacute or chronic infections, infections in pregmincy"'and the puerperium, and urogenital infections. Need-
THE TREATMENT OF URINARY TRACT INFECTIONS
595
less to say, during acute febrile stages of infection, instrumentation, acidification of the urine, and concentration of urine are contraindicated. In the chronic form of infection one has the most favorable field for medication. In pregnancy there is a physiological dilatation of the pelves and ureters which is to some degree always present in pregnancy and which persists into the puerperium to a degree sufficient to modify treatment. Finally, in the male, pyelonephritis is so commonly complicated by prostatic infection, the symptoms of which are often 9vershadowed by the renal symptoms, that it is not recognized, receives no treatment and persists as the focus for chronic urinary tract infection with exacerbations. So minor a procedure as catheterization of postoperative retentions in the male with resu1t~nt minor degrees of cystitis may initiate such prostatitis which will remain unnoted, but eventually prove to underlie recurrent or persistent urinary infection. A survey of the extensive studies made, over a considerable period of time, in the value of antiseptics in acute febrile pyelonephritis leads me to two very definite conclusions. The first is that it makes very little difference at this stage of the infection what the infecting organism is. The second is, that any form of active bactericidal therapy is unsound. The bacterium or bacteria concerned are in a virulent state, rapidly growing, producing fever, nausea, often severe vomiting, with attendant acidosis and shortage of fluid intake and excretion. The kidneys are edematous, subnormal in excretory ability and irritated to the point of albumin loss. This is no time for irritants such as hexamethylenamine with acidification, limitation of fluids as required in administration of some antiseptics, the use of heavy metals as in mercurochrome, or arsenicals. The addition of acidity to the acidosis already present especially in the face of diminished excretion, or the burdening of the system with dyes which will be excreted so poorly as to be present in the urine in sub-bacteriostatic or -bactericidal amounts, is equally without supporting logic. These patients have three major requirements. Rest in bed is essential. In home surroundings frequent trips to adjoining bathrooms are
E. GRANVILLE CRABTREE
to be discouraged. Even that amount of activity tends to prolong the disease. Vermooten 1 has called attention to the value of the elevated foot and lowered head of the bed with but one pillow as a means of shortening the course of pyelitis. Certainly the bed rest and the cramped sitting postures are to be condemned. The second requirement is abundant fluid intake and excretion. Diminished excretory ability on the part of the kidneys in their inflamed condition, together with increased toxic products in the blood stream as a result of the febrile state, indicates the requirement for abnormal amounts of fluids to carry away even normal quantities of waste products to say nothing of the increased quantities which exist in the acute ill- . ness. If begun early in the disease this fluid can be taken by mouth up to 6000 cc. a day. Four thousand five hundred cc. will be the average requirement. If the patient is toxic when seen, to the point of nausea and vomiting, hypodermoclysis given slowly, preferably'by multiple needles, will supply 4000 to 5000 cc. in twenty-four hours. This may either be normal saline or 2.5 per cent glucose. Saline is adequate without the glucose. Intravenous drip may be employed. It is less popular with me because failure to absorb from the tissues is a warning which intravenous fluid administration lacks. Seldom is more than one day of fluid administration by either method required before adequate fluid can be taken by mouth. The third requirement is alkalinization. High degrees of fever and prostration from acute urinary tract infection can be tolerated without acidosis, nausea and vomiting, if sufficient alkali is administered to produce a pH of '7 to 7.5, 45 grains of either sodium or potassium citrate or 60 grains of sodium bicarbonate is usually adequate to produce this result. More should be administered if necessary to produce the result aimed for. The dangers attendant on instrumentation during acute febrile urinary tract infections are now well recognized. The e~ception is infection in pregnancy. This exception is made because of the pelvic residual urine which is characteristic of
.
THE TREATMENT OF URINARY TRACT INFECTIONS
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this disease. Cystoscopic treatment here does far more good than harm. The possibility: that an obstruction to drainage might exist, either in the upper or lower urinhry channels, must not be lost sight of, but sought for, and promptly relieved where definite findings indicate its presence. Obstruction of ureters by pus plugs is a 'ghost which has not yet be~n completely laid. Partial obstructions, as from stones, can be temporized with safety in most instances until some abatement of acute symptoms has occurred, It should be the purpose of treatment of acute febrile infections to shorten the duration of the acute symptoms as much as possible. Often mismanagement of the early stages of infection~ of the urinary tract is responsible for troublesome persistence through protracted fevers, starvation, anemias and debility which could have been avoided. There is no contraindication to a liberal diet including proteins. Development of anemias is often extremely rapid. The alkalinized patient need miss but few meals. A patient emerging from acute urinary tract infections becomes safe for further urological investigation, local treatment or treatment by antiseptics, or for allowing out of bed after not less than four or five days of normal temperature and the loss of renal tenderness. Some patients require a longer delay. Previous to this time intravenous urography is apt to show the kidneys poorly, cystoscopy with retrograde pyelography to cause febrile reactions, and acidification of the urine especially when concentrated for therapeutic reasons to cause a return of fever. The type of antisepsis employed at· this time will, in great measure, depend upon the organism found to be responsible for the infection. For the colon bacillus group of bacteria, acidification of the urine with ammonium chloride, sufficient to produce pH 5-5.4, and the administration of hexamethylenamine in 7%-grain doses, three times daily, is usually adequate and up to the introduction of the salts of mandelic acid, was the most efficient form of therapy. I do not see how it is possible to carry out treatment successfully along this line without pH determination. Simple apparatus is avail-
E. GRANVILLE CRABTREE
able for the purpose and should be used. Chlorphenol red test paper is of some help if kept in good condition until the time of use. The acidity of the urine is capable of great variation. Without pH determinations valuable time may be lost with the best of intentions toward the patient. Do not forget that old men have already, or acqU'ire during fevers, residual urines.· Women in bed are notoriously poor at emptying bladders without leaving residual urine and that both men and women have urethral strictures. Addition of bladder washes with nitrate of silver made up freshly from distilled water at three- to five-day intervals, will clear the bladder walls of adherent pus flakes and debris as well as have antiseptic value particularly in the above cases of small residual urines and the atonic postpartum bladder. A satisfactory silver nitrate solution, almost universally tolerated by the patient, can be made up quickly with I-grain tablet of silver nitrate dissolved in 16 ounces of warm, distilled water. Do not throw an inflamed bladder into painful spasm with cold solution. Repeated fillings of the bladder are not well tolerated. A second filling will, of necessity, be at a lower capacity from the first if discomfort is to be avoided. Mercurochrome injections of 0.5 to 1 per cent solutions are used. Also argyrol in strength of 10 per cent, or other silver salts are used as an injection after lavage with boric acid solution. Silver is better. If cleansing only is desired, daily lavage with a bland solution such as boric acid solution 2 per cent, potassium permanganate 1: 8000, and acriflavine, may be used. . Staphylococcus and streptococcus infections of the urinary tract are usually stubborn infections. Heathcote2 has shown that the growth of staphylococcus was not definitely reduced at a pH of 5 by three hours' exposure to any concentration of formaldehyde in the urine that could be tolerated by the patient. Treatment by mandelic acid produces some cures. In one of my cases nineteen days of treatment at a pH between 4.7 and 4.9, failed to more than inhibit the growth. Often either acidification with ammonium chloride and hexamethylenamine or' mandelic acid has cleared Bacillus coli from mixed infec-
THE TREATMENT OF URINARY TRACT INFECTIONS
599
tions and left the staphylococci or streptococci in pure culture. If the staphylococcus is still resistant to medication by salts of mandelic acid, alkalinization of the urine should be done to a pH of 7-7.5 and acriflavine, % grain in enteric coated tablets, administered three times daily with the urine concentrated by an intake of 1500 to 1800 cc. Another medication, sometimes effective, is methylene blue in 2-grain chocolate-coated tablets administered three times a day. Greenberg3 has pointed out that the gastro-intestinal symptoms sometimes encountered in methylene blue therapy, are due to zinc salt impurities. Unfortunately the purified dye has not been produced commercially. Where all else has failed neoarsphenamine given in 0.3-Gm. doses at five-day intervals for from 3 to 6 doses, is almost specific for the gram-positive cocci. It is reserved as a last resort because of the dangers attendant upon its administration In a condition by no means of the significance of syphilis. It must be given only after study of the patient and the attendant risk of administration and preferably by one expert in the treatment of syphilis. Proteus infections will often yield to the salts of mandelic acid. In some of the apparent failures added lavage with silver nitrate has accomplished a cure. In those proteus infections in which acidification does not occur even with heavy doses of ammonium chloride, I know of little that can be done to combat this form of infection. Administration of mandelate or hexamethylamine then becomes wasteful. Fortunately, with all three forms of bacteria, the normal urinary tract is prone to rid itself spontaneously of infections in time. For this reason resorting to elaborate courses of antisepsis, or the more drastic forms of treatment, is hardly justified in the subacute stages of urinary infections. Shifting from acidity to alkaiinity with the avowed purpose of complicating the home conditions of bacteria in the urinary tract has an appealing and delightful simplicity suggestive of the practical joke, the purpose of which seems not often to be effectively grasped by the bacteria concerned. (Note the above remarks on spontaneous cures.) The effect of acidification of
600
E. GRANVILLE CRABTREE
the urine alone is bacteriostatic but not bactericidal in the lower pH ranges of 5.4 and under. No such bacteriostatic action has been recorded for alkalinity in experiments with any form of bacteria. There is no theoretical ground for expecting benefit other than the bacteriostatic effect of acidification when shifts from acidity to alkalinity are made. If acidification is attempted, as is commonly done, by the use of sodium acid phosphate, even that effect is not obtained since strong acidification cannot be produced by this drug. After the elimination of those acute and subacute infections which either recover spontaneously or reach an early cure by the common forms of therapy, there is left a troublesome remnant of a few cases which are chronic infections. This group has been variously estimated as comprising from 5 to 10 per cent of the whole. They can be grouped into persistent infections or recurrent infections dependent on whether the urine becomes bacteria-free between exacerbations of symptoms. If the urine fails to clear at any time, gross pathology in the urinary tract, particularly conditions (if urinary stasis, are probable. If complete clearing of the urinary tract from infections (as demonstrated by absence of bacteria, not pus cells) occurs, the likelihood of gross pathology is less but the probability of systemic causes is greater. Chronic infections can best be approached for both diagnosis and treatment if the persistence of the infection is attributed to one of three major causes: 1. The condition of the patient, 2. Foci of infection, 3. Gross pathology, and investigation conducted with the purpose of placing the patient in this classification. I have already commented on the desirability of intelligent handling of the acute stages of infection that the patient may not emerge from them anemic and debilitated from a protracted illness, and suggested effective measures for the prevention of that condition. Unfortunately, urinary tract infections freql,lendy occur as complications of surgery and debility from
THE TREATMENT OF URINARY TRACT INFECTIONS
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other illnesses. They may then get dug in and reach the state of chronic infections before convalescence from the major illness takes place. Many Americans live in a constant state of exhaustion from overwork and overactivity in an attempt to enjoy all the possibilities of our modern life. There is also the faulty diet patient. One such with recurrent autumnal infection was found to have a dislike for summer foods and ate little, lost weight and acquired a yearly autumnal infection. Another patient reaches extremes of exhaustion in her social life. Her infections can almost always be predicted by watching the social columns in the newspapers. A mother, who was a confirmed Christmas shopper, with five children of school age who were all home with their friends at vacation time, had three recurrent infections in the five strenuous years of that activity all of which were in January or February of the new year. I find a higher percentage of recurrent infections in the upper classes with neither foci of infection, nor gross pathology encountered, than in the working classes. The working man has more gross pathology with his pus and bacteria. In addition some chronic infections are cured on adjusting metabolic problems. Foci of infection seem to me to be the third in importance in these three groups. Teeth, tonsils and sinuses are occasionally incriminated yet it is surprising how often massive sepsis in these areas shows little relation to urinary tract infection either in its presence or after it has been cleared. It is most important in children. It must not be ignored. Bowel conditions play a very conspicuous part both in the incidence and the chronic stages of infection. A chronically overloaded bowel is perhaps most commonly found in these cases, and diverticulitis of the sigmoid is a very serious complication. The occasional case of perforation of such a condition into the bladder must not be overlooked. In the male a symptomless prostatitis which is participating in a urogenital infection but receiving no treatment is perhaps the most common focus of infection. It may be responsible for a persistent infection with a constantly cloudy urine or for
E. GRANVILLE CRABTREE
recurrent infections which take place during exacerbations of prostatitis, which may be even a few years apart. Gross pathology in the urinary tract either in the form of lower urinary obstruction with bladder residual urine, bladder malformations, diverticula, upper urinary, ureteral and pelvic obstructions all produce stagnant urine from which infection, is eradicated with great difficulty by any known means short of correction of the defect. Stones and tumors are the other aids to retention of infections. The physiological changes in the kidneys and ureters due to pregnancy make these cases more nearly associated with this group although the obstructive factor is of necessity limited in duration to nine months. The chief danger is that if the degree of pathology is small the infection might be cured through the more effective measures now available in antisepsis and allow the condition to progress unnoted. Valuable time is often wasted in treatment to the detriment of the patient as in the case of a lady who received 156 pelvic lavages for infected hydronephrosis with stones, after many other antiseptic procedures had failed already. Infection may be the only indication of the presence of serious disease. The commonly employed urinary antiseptics may be listed as follows: the dye group, the formalin-bearing drugs, the antiseptic acids, and the arsenicals. The Dye Drugs.-Here are found methylene blue, acriflavine, pyridium and serenium, and mercurochrome. There are many others of less importance. All have other properties than the dye property. Methylene blue, when administered in 2-grain chocolatecoated tablets three times daily in an alkaline urine with a pH above 7, has certain fields of usefulness. Thomas and Wang4 found it of some value as an inhibitor and less value as a germicide against Bacillus coli and Staphylococcus aureus when the patient was limited to a fluid intake of 3 glasses of water daily. Hinman5 found it more effective in staphylococcus and streptococcus infections than in the bacillary group when administered in alJ.vlline urines with concentration. Greenberg used it succes'sfully as .,a palliative in tuberculosis.
THE TREATMENT OF URINARY TRACT INFECTIONS
603
Acriflavine in doses of %-grain enteric coated tablets three to four times daily in concentrated alkaline urine showed bacteriostatic effects on both bacillary and coccal types of bacteria in half the cases (WaIther6 ). Davis7 had better success with 0.1 Gm. twice daily in concentrated alkaline urines infected with either staphylococci or Bacillus coli, producing cures in 13 out of 18 acute cases with 5 failures. In 27 chronic colon bacillus infections there were no cures. I have found it of most value in staphylococcus and streptococcus infections. There are better treatment agents for the gram-negative bacilli. Pyridium and serenium have had in my hands no appreciable bactericidal or bacteriostatic effect on either the bacillary or the coccal forms of infection. Many other observers agree with this opinion. In a series of experiments in pyelitis in pregnancy the picture presented through the microscope of motile colon bacilli swimming sturdily along through a concentrated urine deeply stained with pyridium, went far to destroy my hopes of much help from these drugs. No other source of experience or information has revived my interest in them. Mercurochrome, in spite of all that has been written, should be confined in its use to local applications to the pelvis or bladder. Hexylresorcinol while not a dye drug is discussed here. It is administered in dosages of 0.3 to 0.6 Gm. three times a day and treatment is to be continued two weeks beyond the negative culture. The drug has not lived up to the promise with which it made its initial bow in 1924. Methylene blue and acriflavine, even though both may produce gastro-intestinal symptoms, are the most effective, drugs in this group. They are applicable to the coccal infections. Other forms of treatment are preferable by far for the bacillary infections. If gastro-intestinal symptoms occur the drug can be resumed after a short rest and tolerance for it seems to be acquired. Formalin-bearing Drugs.-The second group to be· considered is the formalin-bearing drugs. Hexamethylenamine is
E.
G~LLE
CRABTREE
the form in which this therapy is commonly and most effec, tively administered. Hexamethylenamine in acid urine has been the best therapeutic measure for treatment of the bacH lary group of urinary tract infections previous to the introduction of mandelic acid. In properly acidified urine formalin is freed in antiseptic strength at the kidney level as well as in the bladder, namely, 0.005 to 0.007 per cent formaldehyde. In many instances it is adequate treatment for cure. It fails to cure some strains of Bacillus coli. MitchelI and Scott8 found that certain strains of organisms were resistant to formaldehyde with marked correlation between test tube and clinical studies If hexamethylenamine killed the organism in the urine, formalin killed it in the test tube. If it failed clinically it failed also in the test tube. The optimum pH for liberation of formaldehyde from hexamethylenamine in the urine is pH 5-5.4. The common use of sodium acid phosphate with hexamethylenamine does not produce that degree of acidity from alkalinity. It is much preferable to use ammonium chloride to produce the acidity and to observe frequently to note if the proper acidity is maintained during treatment. Ammonium chloride should only be used in enteric coated tablets if gastric symptoms are to be minimized. So important is acidification therapy both for the use of hexamethylenamine and mandelic acid that the theory and practice of acidification and alkalinization should be taken up here. Acidification of the Urine.-The true pH of normal urine depends in great measure on the phosphates by dissociation of NaH2P0 4 to Na2HP04 with liberation of an hydrogen ion. With complete dissociation of phosphate the pH lies commonly between 5 and 5.2. Increase in hydrogen ion concentration is accompanied by increase in ammonia excretion. Urinary volume seems to be inversely proportional to hydrogen ion concentration. Gamble9 places the lower limits of normal acidity at about pH 4.8 and doubts if acidity can be produced below pH 4. He finds that the upper limit of alkalinity is pH 8, even"" when large amounts of alkali are administered. GreylO
THE TREATMENT OF URINARY TRACT INFECTIONS
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considers pH below 5, or above 7, pathological. The idea being that the bacterial infections have changed the normal pH, when figures below and above those readings are obtained. Marlowl l found in his study of 141 normal young adults that the pH variation was from 5.1 to 6.8. Administration of drugs by mouth as acidifiers is an attempt to produce as much free acid radical as is possible to be done. Regulatory factors convey an excess of acid over fixed base into the urine. The commonly employed acidifiers are: Sodium acid phosphate . . .......... Ammonium acid phosphate . ................. .......... . ... Ammonium chloride .... Ammonium nitrate ........ . . . . . . . . . . . . . . .. Ammonium benzoate ........................
20 20 15 15 40
grains grains grains grains grains
4 times a day 4 times a day 3 to 4 times a day 3 times a day daily
.Sodium acid phosphate has been most widely used for urinary acidification but is the least effective of the group. Stockman and Johnson12 find that it acts practically not at all in normally slightly acid urine. It produces slight acidity when the reaction of the urine is well on the alkaline side The ammonium salts of hydrochloric acid, nitric acid and phosphoric acid are the best acidifiers. Their action is due to decomposition of the salt into ammonia and hydrochloric, nitric or phosphoric acid radicals. The ammonia is converted into urea and excreted by the kidneys. The acid is neutralized in the blood and tissues at the expense of the alkali reserve. Serious acidosis does not follow the administration of the usual doses of these drugs if the renal function is good. The same doses with moderate to severe renal impairment may produce marked deviation from the normal acid-base eqUilibrium with resultant changes in metabolic functions and the production of definite and severe symptoms of acidosis and even death. It is probably best to select one acidifier and familiarize oneself with its use. Ammonium chloride is on the whole the most satisfactory. Alkalinization of the Urine (Gamble9 ).-Where excesses of fixed base over acid is produced by the administration of al•
606
E. GRANVILLE CRABTREE
kalis there is need for an acid substance abundantly at hand which can be placed in the urine under control. Carbonic acid both suits these requirements and is available in practically unlimited quantities. Routinely it leaves the body base free by way of the lungs, but when needed can, to a regulated extent, be deflected into the urine. The concentration of free carbonic acid in the urine is of a stationary value of approximately the magnitude of that in blood plasma. As a consequence of this fixed value for carbonic acid, excess of base in the blood plasma is excreted as bicarbonate in the urine. Thus as the urinary pH rises above that of the blood plasma (pH 7.4) the concentration of bicarbonate in the urine becomes greater. This concentration of bicarbonate which, in the presence of a fixed level for carbonic acid, would be necessary to force the pH of urine above 8 is terminated by the limit of total concentration of substances in urine. It has also been determined experimentally that ingestion of large amounts of alkali will not produce an alkalinity above pH 8. Antiseptic Acid Therapy.-Mandelic acid is a recent addition to our armamentarium for treatment of urinary tract infections. Its place is not yet definitely established. None will deny that for the colon bacillus group of invaders it is the most satisfactory agent yet produced. Many will question its universal application and success with the cocci and some of the less common organisms. The enthusiastic, almost fanatical rush to administer the drug at all times and often carelessly, as regards renal deficiency, acidity and toxicity of the patient in acute conditions has already made some doubt its efficacy. Its use is well established in the steep curve of acceptance with which we commonly greet an important novelty, then COndemn and abandon it only later to take it up at somewhere near its true value. Mandelic acid is a member of the benzoic acid group. It was selected for experimentation as an antiseptic because of all the acids tested it was found to be the most bacteriostatic in vitro. It has been known since 1883 that it would be excreted _l!nchanged and not metabolized by passage th~ough animals.
THE TREATMENT OF URINARY TRACT INFECTIONS
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In vitro at a pH 5.3, all bacterial life is killed at a concentration of 1 per cent. Mandelic acid cannot be administered as acid because of its irritating effect upon the stomach. Salts of mandelic acid must be used as the vehicle by which a proper concentration of the acid is made to reach the urine. As in the case of acidifiers of the urine the ammonium salt of mandelic acid is preferable because the ammonia radical will be excreted as urea leaving the acid free, thereby avoiding an unnecessary base. In an average normal patient, 12 Gm. of ammonium mandelate administered in twenty-four hours will produce a pH 5.3. Helmholz and Osterberg13 have demonstrated its diuretic action and cumulative rate of excretion at an established pH 5, with ammonium chloride. It is, therefore, an essentially short treatment course drug. These observers indicated a cumulative rate of excretion from 0.32 to 1.14 per cent in twelve hours during which 12 Gm. of mandelate were administered in 4 doses. They also showed that at a urine pH of 5 and concentration of mandelic acid to 0.25 per cent it was bactericidal for most organisms. The same results could be obtained at pH 5.3 with 0.5 per cent concentration or at 5.7 with 1 per cent concentration. These tests were made using sodium mandelate. They obtained approximately the same results by adding mandelic acid to normal urine of similar pH reading. There is no test for the acid in the urine. These de terminations must be made through recovery of the acid from the urine. Although mandelic acid may be considered as a foreign body in the circulation and in the urine, the need for adequate acidification to ensure its effectiveness introduces the question of acidification which is a chemi~al process within the body. The two drugs, the acidifier and the salt of mandelic acid, must, therefore, be considered together. Mandelic acid 3 Gm. with sodium bicarbonate 1.6 Gm., combined in solution to form sodium mandelate, is not neutral but has a pH 4.5. In consideration of the use of mandelic acid as an antiseptic one must take into consideration the combined acidifying power of the salt of mandelic acid and the acidifier. Helmholz and Oster-
It is impotent except with strong acidity.
608
E. GRANVILLE CRABTREE
berg found that, by measur~ment of the urea clearance test, a dog suffered no permanent renal damage when 700 cc. of 1 per cent mandelic acid was injected intravenously over, a seven-hour period. Presumably the dog had normal kidneys. Acidification in nephritis, owing to diminished selective secretion by the damaged kidneys, at least justifies reasonable apprehension as to the safety of the procedure. HoIling and Platt14 report 2 cases of renal edema without apparent effect on the nephritis. Lyon and Dunlop15 observed the CO 2 combining power which they checked before and after the treatment in a number of cases. They found it to be within normal limits except in one case in which 360 Gm. of ammonium chloride was administered in a futile attempt at acidification of the urine. The figure fell from 63 to 46 per cent (C0 2 combining power). Untoward signs and symptoms may accompany treatment with mandelic acid. The use of acidifiers alone or in conjunction with salts of mandelic acid may produce red blood cells, casts, and albumin in the urine. Cubitti6 found no ill effects from continued treatment when occasional casts and red cells appeared. Rosenheim17 found one case with albuminuria showed increased amounts of albumin. In two of my own cases, the appearance of red blood cells was accompanied by bladder tenesmus where no bladder symptoms had been present before. Apparently after prompt cessation of medication all these signs quickly disappear. The chief symptoms which may occur in the absence of renal insufficiency are buzzing in the ears, temporary deafness, nausea, vomiting, and dyspnea from acidosis. Minor symptoms are acid taste about the teeth particularly about fillings and general uneasiness when either from exercise or climate perspiration is profuse. In renal insufficiency symptoms may be extreme degrees of acidosis and even death. Administration of the drug has been at the beginning through the use of sodium mandelate. Rosenheim's prescription for its use was 3 Gm. of mandelic acid and 1.6 Gm. sodium bicarbonate with flavoring of lemon and water sufficient to
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make 1 fluidounce, put up in 16-ounce amounts. The administration was 1 ounce four times daily. If the acidity of the urine was not adequate, sufficient ammonium chloride was added. Since that time there have appeared other preparations. Ammonium mandelate combined with ammonium chloride in aromatic syrup has been marketed, under the trade name of syrup amdelate. Each fluidounce contains 12 Gm. of mandelic acid. The dose is 2 teaspoonfuls four times daily. Elixir of mandelic acid is also obtainable. It contains mandelic acid, 124 grains, instead of 185 grains, to the fluidounce, as compared with the syrup. Phosphomandelate is also on the market as a combination of ammonium phosphate and mandelic acid. The dosages are provided in separate envelopes with directions. As Cubitt has pointed out and my own experiences confirm, there is great variation in the amount of acidifier necessary to produce the desired pH 5.3 or less, at which mandelic acid acts best, both in different patients and in the same patient at different times. My preference would be for ammonium mandelate without ammonium chloride in syrup form. Sufficient acidifier could be added from day to day as the patient required. After many and varied approaches, I have found that the most satisfactory method of administering the treatment was through preliminary acidification of the urine,. by means of ammonium chloride until pH of 5-5.4 was obtained. This usually requires but from one to three days. Syrup of ammonium mandelate was· then administered four times daily under daily observation of the urine. The ammonium chloride intake can be gradually diminished or often dropped altogether in twentyfour to forty-eight hours and the pH held up. Most of the cases of bacillary infections become bacteria free in that time. The mandelate is continued at a pH of 4.8-5.2 for a total of six to seven days after which a single dose daily of mandelate with 15 grains of ammonium chloride is administered for six to seven days longer, then the same dose on alternate days for a week more. Fluids are restricted to 1200 cc. for the first week then to 2000 cc. for the second week and fluids as deVOL. 2I-39
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E. GRANVILLE CRAB TREE
sired allowed during the third week. If recurrence of the infection should take place, treatment in regular dosages as in the first week will usually suffice to eliminate it, but often need not be carried beyond a day or two. pH readings of 5.5 or lower will often be noted for ten days to three weeks after medication has ceased. The effectiveness of mandelic acid on both cystitis and pyelitis seems to me not yet to be clearly established. There is general agreement that it is eminently successful in the colon bacillus group of bacteria. Here it is at its best in the absence of any considerable degree of urinary stasis. That it will be successful with some degree of stasis is shown by the successful clearing of 9 out of 13 cases of pyelitis in pregnancy treated after the acute symptoms had subsided. Three of these cases are our own, the remainder collected cases. The proteus bacillus cases have been less constant. Presumably if sufficient acidification can be produced, cure may be effected. Where acidification does not occur it is useless. Both other observers and my own cases show instances where" with mixed infections all bacteria are killed, both the bacillary and the coccal .forms. In other instances the bacilli are eliminated leaving behind a pure flora of cocci. In one instance with a pH under 5 for nineteen days coccal infection remained unchanged under ammonium mandelate treatment. There is no doubt but that complicated cases with gross pathology cannot be looked upon as suitable cases for mandelic acid therapy. It is, furthermore, to be hoped that no other antiseptic will ever be found which, by its use, might conceal to the careless observer pathology of much more significance than the infection which disclosed it. In the male there are encountered many chronic bacillary urogenital infections. They are persistent over years. Many of these yield to mandelic add therapy. Usually there are bacilli demonstrated in the renal and bladder urines and in the prostatic secretions. I have treated them in two ways, either by antiseptics first, then by massage, or by a course of mas!age given previous to antiseptics. In the former group
THE TREATMENT OF URINARY TRAcr INFEcrIONS
6rr
some persist as pyurias without bacteriuria for a considerable period of time and often recur. The second group is much more satisfactory. In this connection I should mention that several observers have noted that the semen is frequently found stained after oral administration of dye antiseptics. Disappearance of the colon bacillus from the vesicle and prostatic secretions in some of these cases under treatment with mandelic acid might indicate a similar drug distribution. Arsenicals.-For the remnant of intractable coccal infections there is still one form of therapy which offers cure. That is the use of arsenicals. Neoarsphenamine, when administered in O.3-Gm. doses at five-day intervals for a total of 3 to 6 treatments when required, will eradicate many of the stubborn coccal infections. Its administration is to be taken as seriously as when given for syphilis. There is less justification in producing complications by misuse of the drug when the nature of the infecting agent is of so much less significance than syphilis. Its use in coccal infections should be limited to the chronic type of infection. Vaccine therapy need no longer be considered seriously in any except the very unusual case. BmLIOGRAPHY 1. Vermooten, V.: So. African Med. Jour., June 9,1934.
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
Heathcote, R.: Brit. Jour. Urol., 1935, p. 9. Greenberg, Davis and Armstrong: Jour. Urol., 33: 2, 1935. Thomas, B. A. and Wang, I. K.: Jour. Uro!., 22: 22, 1929. Hinman, F.: Jour. Amer. Med. Assoc., 65: 1769-1772,1915. Walther, H. W. E.: South. Med. Jour., 22: 161-165, 1929. Davis, E.: Jour. Uro!., 11: 29-38,1924. MitcheIl, D. R. and Scott, J. M.: Brit. Jour. Uro!., 5: 225, 1933. Gamble, J. L.: The Kidney in Health and Disease. Berglund et al., 1935. Grey, F.: Brit. Jour. Urol., 1934, p. 221. MarIow, L.: Jour. Uro!., 35: 674, 1936. Stockman and Johnson: Edinburgh Med. Jour., 34: 223, 1927. Helmholz, H. F. and Osterberg, A. E.: Proceedings of the Staff Meetings of the Mayo Clinic, 11: June 10, 1936. Holling, H. E. and Platt, R.: Lancet, 1: 769-771, 1936. Lyon, D. M. and Dunlop, D. N.: Brit. Med, Jour., 2: 1096-1097, Dec. 71 1935. Cubitt, A. W.: Lancet, 1: 922, 1936. Rosenheim, M. L.: Lancet, 1: 1032,1935.