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Urinary Antisepsis
URINARY ANTISEPSIS CLINICAL RESULTS FOLLOWING THE ORAL ADMINISTRATION OF ACRIFLAVINE 1 EDvVIN DAVIS From the Department of Urology, the University of Nebraska College of Medicine, Omaha, Nebraska
Received for publication June 25, 1923
It is the chief purpose of this paper to briefly outline the experimental work which has led up to the internal administration of acriflavine, and to summarize the results obtained by the clinical use of this dye. The lack of an efficient drug for the purpose of internal urjna1;y antisepsis, and the wide field of application open to such a drug is too apparent to require dis-cussion before this audience. SUMMARY OF EXPERIMENTAL WORK WITH ACRIFLAVINE,
The investigation summarized below had as its goal the discovery or the synthesis of a drug which might be administered orally without toxic effect, and which would be excreted un-changed in the urine, there to exert an antiseptic action. A survey of the literature pertaining to urinary antisepsis reveals a surp'rising absence of sound experimental or clinical evidence of the fitness of any known drug for this purpose. · As early as 1916, investigations were started with phenolsulphonephthalein as a basis. The properties of this remarkable compound are known to alL It is chemically sta'.ble, it is non-toxic and non-irritating, it is eliminated by the kidney with incredible rapidity and completeness, and hence possesses all of the properties essential to the ideal urinary antiseptic, 1 Read before the American Urological Association, Rochester, Minn., Ma~ 17 and 18, 1923.
· 29
30
EDWIN DAVIS
with the exception that it is totally lacking in antiseptic power. With the cooperation of Dr. E. C. White of the Brady Urological Insitute, a large number of closely related compounds were synthesized and studied, with regard to antiseptic properties and renal elimination. Among many others were thymolsulphonephthalein, salicylsulphonephthalein, cresolsulphonephthalein, tetra-aminophenolsulphonephthalein, alphanaphtholsulphonephthalein and guaicacolsulphonephthalein. This study afforded interesting results which have been elsewhere recorded (1), and not a few of these compounds fulfilled all but one of the required properties. It was possible to establish a certain relationship between chemical structure and renal excretion, and to predict with reasonable accuracy which of these drugs would appear in the urine. One of these, chior-mercury fluorescein, an organo-mercury phthalein derivative, was experimentally successful in that the intravenous administration of this drug in minute dosage to dogs and tabbits caused the secretion of an antiseptic urine for a definite period of time. Further clinical investigation of this drug was not carried on for fear of renal injury due to its mercury content (2) . In 1917, my attention was attracted to acriflavine by publications in the English literature by Browning and others of (of the Bland Sutton Institute of Pathology, Middlesex Hospital, London), who showed the antiseptic action of this drug to be increased in the presence of serum. In other words they proved that acriflavine could inhibit the colon bacillus in higher dilution in serum than in peptone water. This phenomenon Browning referred to as the "serum uplift." As a result of these publications, and through the assistance of Dr. Hugh Young, a small supply of acriflavine was obtained from Browning, which was to the best of my knowledge the first sample of this drug to be used in America. It was found that acriflavine in test-tube experiments, inhibits the colon bacillus and the staphylococcus in high dilution in urine of an alkaline reaction. It was also determined that this drug rapidly appears in the urine after intravenous and oral administration, and is excreted in large quantities. Preliminary
URINARY ANTISEPSIS •.'
31
experiments at this time showed that it is possible to cause rabbits and dogs to secrete antiseptic urine following intravenous administration of acriflavine (3). Including the sulphonephthaleins and related compounds, and also the investigation of a large number of anilin dyes, later published in the American Journal of the Medical Sciences (4), a total of more than four hundred compounds were studied with regard to antiseptic properties, renal excretion and toxicity. Acriflavine was found to more nearly fulfill the requirements for the ideal internal urinary antiseptic than any one of these. The next step was to duplicate the above experimental results in man. As was published in the Journal of Urology in March, 1921 (5), it was possible to conclusively prove that acriflavine in small dosage (0.1 gram), administered orally to a normal individual, will cause the secretion of antiseptic urine, provided the reaction of the latter is alkaline. This drug should therefore theoretically be of clinical value in the treatment of various infections of the urinary tract, including pyelitis of infancy, chronic pyelitis of adults, acute pyelonephritis, and in acute and chronic cystitis. During the treatment of acute anterior gonorrheal urethritis, this drug should also be of theoretical .value administered internally as a prophylactic against the development of posterior urethritis. It should also deserve a trial in the treatment of early posterior urethritis and trigonitis. SELECTION OF CASES
In undertaking the accurate tabulation of clinical results, in order to permit reliable conclusions, of primary importance is the proper selection of cases. That a given case of uninvestigated pyuria or bacteriuria should either improve or fail to .improve, following the administration of a given drug, is not evidence of particular value either for or against the efficiency of that drug. Numerous so-called accessary or predisposing causes of urinary infection must first be eliminated. There are certain well-defined and well-recognized, "intra-urinary," predisposing factors, which may be grouped under the main headings, retention, calculus, new growth and tuberculosis. The folly
32
EDWIN DAVIS
of attempting the cure by drug therapy of a urinary infection which is primarily dependent upon one of the above-named mechanical factors, is qui.te apparent. Concerning the systemic or "extra-urinary" predisposing causes of urinary infection our knowledge is relatively scant and unsatisfactory. There are those cases of pyuria or bacteriuria, occurring during the course of acute infectious diseases, and there is that large group of cases in which it is considered that chronic focal local infection plays a role. Whether our predisposing or underlying cause of infection be intra-urinary or systemic, to disregard this primary cause, and to attempt a cure by merely rendering the urine antiseptic, is obviously ridiculous. Therefore, if accurate information is to be obtained, the essential preliminaries in selecting cases suitable for internal urinary therapy are (a) complete general physical examination and (b) complete urological examination. It should be further noted that favorable results can not be expected in far advanced cases, as, for example, bilateral pyelonephritis, of long duration, with extensive destruction of renal tissue and lowering of renal function. TECHNIQUE
Conclusive evidence of the clinical efficiency of a given urinary antiseptic is not easily obtained. We are all familiar with what may be termed the spontaneous or automatic variations which may occur at any time in the pus and bacterial content of infected urines. The urine which is cloudy one day with pus or swarming with bacteria, may be clear the next, and vice versa, with no apparent explanation. It is only too easy to ascribe such changes to drug therapy, particularly if these are the changes which we are hoping and expecting to see. Furthermore, there may occur spontaneous changes in the patient's general condition, in his temperature, and in his bladder symptoms. More reliable than the patient's symptoms and the macroscopic appearance of the urine, in accurately determining the effect of drug therapy, is the method of daily culture of the urine, with an estimation of the number of bacteria per unit volume. The routine used was as follows:
URINARY ANTISEPSIS
33
As an essential preliminary to dye administration, each patient was started on large doses of sodium bicarbonate; sufficient to render the urine alkaline. This was usually accomplished by a total of 2 or 3 drachms daily. During the succeed-ing several days, the patient's condition was daily noted, and records of daily urine examinations were made, including reaction, gross appearance, microscopical content, and culture. The method of culture was to plate a unit volume and to count the approxixnate number of colonies. After a sufficient number of days of such routine to serve as a control, the acriflavine was started, the bicarbonate being continued. The average dose of acriflavine was 0.1 gram (by capsule), twice daily. As indicated in charts 1 and 2, in the favorable cases there occurred an improvement so immediate and so striking as to rule out mere coincidence. The improvement was measured by a drop in temperature, an improvement in bladder symptoms, a macroscopic and microscopic clearing of the urine, and a disappearance of colonies from the agar plates. CLINICAL RESULTS
After the elimination of all cases with accessory causes of urinary infection, and after ruling out cases not controlled by a preliminary period of several days of observation and urine culture prior to dye administration, the total number of carefully observed cases has been reduced to a very small figure. For this reason, and because of rather a wide variation in results obtained 1 it may only be said that experience to date is insufficient to justify a final opinion. Results are herewith presented for your consideration, and with the hope that the experience of others may aid in determining the clinical value of this drug. It should be here distinctly understood that in the light of our present knowledge promiscuous medication with acriflavine, in unselected cases is distinctly inadvisable, For convenience of consideration, the clinical cases which have received acriflavine by mouth have been roughly classified as follows:
34
EDWIN DAVIS
1. Acute urinary infections, including acute cystitis, and acute non-surgical kidney infections, with staphylococci or bacilli in the urine. 2. Chronic urinary infections, including chronic cystitis and chronic pyelonephritis. 3. Acute anterior gonorrheal urethritis, in which the dye has been administered orally with the purpose of preventing the development of a posterior infection. 4. Acute posterior gonorrheal urethritis, in which the dye has been administered orally with the purpose of relieving symptoms. Acute urinary infections. It was in this group that the most satisfactory results were obtained. Out of a small series of 18 cases, in 13 there occurred an improvement characterized by a drop in temperature, a cessation of bladder symptcms and a disappearance of pus and bacteria from the urine cuin j _~ _-,nt with the starting of the dye. In the remaining 5 there was no apparent effect. The tendency toward spontaneous recovery in these cases is of course recognized, yet the fact that these particular patients remained under observation for a prefoyjnary period of several days without improvement should tend to rule out mere coincidence. Two of these patients had a recurrence of symptoms three months later, and again responded to t.he dye. A tonsillectomy was done following the second attack in one of these, and the patient has been symptom-free since. It is safe to say that 50 per cent of the others have remained well to date over a period of several months. Chronic urinary injections. As indicated above, the patients in this group were of the chronic bacteriuria or pyuria type, without demonstrable surgical lesion, and without marked impairment of kidney function. The results were not so good as obtained in the acute series. Out of a total of 27, there were 11 in which the treatment produced no appreciable effect. The remaining 16 showed a distinct improvement in bladder symptoms and a macroscopic and microscopic clearing of the urine, together with a lessening of the number or a complete disappearance of bacteria from the urine, as indicated by daily plating
URINARY ANTISEPSIS
35
of unit volumes. The discouraging feature, however, in the series of chronic cases, was the marked tendency toward recurrence of infection in the urine after discontinuing the dye. In 12 out of 16 cases which had responded to treatment, the bacteria reappeared shortly after the urine became drug-free. This is in keeping with the theory that bacteria may be continuously "fed" into the urinary tract from extra-urinary sources. Acute anterior gonorrheal urethritis. In view of the extreme dilution in which acriflavine will inhibit the development of the gonococcus, it seemed logical to expect that the oral administration of this drug during the course of an acute anterior gonorrheal urethritis, should serve as an · efficient method of prophylaxis to prevent the development of a pbsterior infection. Clinically this expectation has not been borne out. The progress of gonorrheal urethritis from anterior to posterior, in spite of the presence of acriflavine in the urine, has been observed in a sufficient number of cases to warrant the conclusion that the internal administration of acriflavine is not a dependable method of preventing posterior infection. · Acute posterior gonorrheal urethritis. Although the oral administration of acriflavine may not be depended upon to prevent the development of a posterior urethral infection, this drug administered internally seems to be of distinct value in the treatment of acute posterior gonorrheal urethritis. This opinion is based upon the observation of a small series of such cases in which there was noted a disappearance of the urinary frequency, pain, tenesmus and terminal haematuria, and a clearing of the macroscopic pyuria, coincident with the starting of the dye by mouth. This statement is not intended to imply that it is possible to cure with any conceivable drug, a gonorrheal prostatitis. It is my belief, however, that the duration and the severity of the acute symptoms of posterior gonorrheal urethritis may be lessened. TOXICITY
The oral administration of acriflavine is not without its contra-indications. Approximately 30 per cent of the patients reported a slight nausea or a mild catharsis. The nausea was
36
EDWIN DAVIS
in part due to the bicarbonate, since in some instances this symptom preceded the dye administration. The description of the cathartic action by the majority of the patients, as being very mild, and free from gripping or straining, and with a formed soft stool, is such as to suggest the possible value of acriflavine as a cathartic. In fact, it has been mentioned that the action of acriflavine as a urinary antiseptic may be in part explained by the clearing of the intestinal canal. In the occasional case, (about 5 per cent) however, the gastrointestinal symptoms, characterized by vomiting and diarrhea, are of sufficient severity to contraindicate the use of the drug. Although, even ip_ the severe cases, these symptoms have been transient and without ill effect, this possibility constitutes a serious drawback to the routine use of the drug. CONCLUSIONS
Experimentally, acriflavine administered by mouth in 0.1 gram dosage, to normal individuals is secreted in the urine in sufficient concentration to render the latter an unfit culture medium for the colon bacillus and staphylococcus, provided the reaction of the urine is alkaline. After this dosage, the antiseptic action persists in the urine for at least eight hours. Clinically, results to date in a small series of cases are as follows: 1. Acute urinary infections. A large proportion of these cases have shown a prompt improvement, characterized by a drop in temperature, a disappearance of bladder symptoms, a macroscopic clE:>aring of the urine and a disappearance of bacteria from the urine. Relapses in these cases have been the exception. 2. Chronic urinary infections have not readily responded. Improvement was noted in only 60 per cent of cases, and in most of these the pus and bacteria reappeared in the urine after discontinuing the treatment. 3. Acute anterior gonorrheal urethritis. Acriflavine administered orally is not a dependable prophylactic for preventing the extension of the infection to the posterior urethra.
URINARY ANTISEPSIS
37
4. Acute posterior gonorrheal urethritis. Acriflavine administered orally is of benefit in this condition in lessening the duration and the severity of the acute symptoms. Mild catharsis or slight nausea was observed in approximately 30 per cent of the patients. This was due in part to the bicarbonate, since in some instances these symptoms preceded the dye administration. In 5 per cent of the cases vomiting and diarrhea were such as to contraindicate the use of the drug. No further ill effects have been noted. The indiscriminate use of acriflavine by mouth, in unselected cases, and without regard to the elimination of the "accessary" causes of urinary infection, is distinctly inadvisable. All experimental and clinical results have been obtained with the brand of acriflavine put out by Poulenc Freres, Paris. APPENDIX
Acrifiavine as a local injection in the treatment of gonorrheal urethriti:s. The above discussion takes into consideration only the internal admini-stration of acriflavine. In view of the wide digergence of opinion that exists concerning the value of acrifiavine used as a local injection in the treatment of gonorrheal urethritis, it seems worth while to take this occasion to add as an appendix a brief statement concerning this subject. I am well aware of considerable adverse comment. For the discrepancies in the results obtained by different observers, there are but two apparent explanations: (1) variations in the chemical purity of the drug, and (2) variations in the technique of treatment. 1. Acriflavine is synthesized and purified with difficulty. The earlier experimental and clinical work was done with the English product (Boots), and later the French product (Poulenc Freres) 2 has been almost exclusively used. I have had no experience with the various American brands. 2 For those who are interested in obtaining this drug I may add that the restrictions placed by the American Chemical Foundation have long been an obstacle in the way of obtaining the foreign brands of Acriflavine. At present the French product, put out by Poulenc Frerers, Paris, may be obtained by writing directly to their agent in the United States, George J. Wallau, 6 Cliff Street, New York City. The English product, put out by the Boots Pure Drug Company, Nottingham, England, may be obtained by addressing, The United Drug Company, Boston, Mass.
38
EDWIN DAVIS
2. For faulty technique of treatment, probably the original publication (Davis and Harrell (6)) is largely responsible. This paper was hastily gotten out in 1918, just before going into the service, and at this time our experience had not been sufficient to determine that a concentration of 1: 1000 is quite irritating, and is very often responsible for . a, chemical urethritis. With the present technique a solution of 1: 8000 is used, made up in normal saline solution instead of distilled water. In addition to frequent injections of a 1: 8000 solution, retained for five minutes, one daily injection of 1 :4000 solution is given if tolerated without urethral irritation. A report of series of cases of acute gonorrheal urethritis treated by this method is at present in preparation. I make no extravagant claims for the value of acriflavine in gonorrhea, and wish to here acknowledge the failures. The large majority, however, of satisfactory results, and the frequent cases of immediate, brilliant and permanent cure, offer sufficient justification for the belief that acriflavine, of proper chemical purity and properly administered, will eventually come to be the drug of preference in the treatment of acute anterior gonorrheal urethritis. REFERENCES (1) DAVIS, EDWIN, AND WHITE, E. C,: Urinary antisepsis: Further studies of the antiseptic properties and renal excretion of compounds related to phenolsulphonephthalein. Jour . Urol., 1918, ii, 107. ,(2) DAVIS, EDWIN, '\VHITE, E. C., AND RosEN, ROBERT: Urinary antisepsis: The secretion of antiseptic urin·e following the intravenous administration of an organo-mercury phthalein derivative. Jour. Urol., 1918, ii, 277. (3) DAVIS, EDWIN, AND WHITE, E. C.: Urinary antisepsis: The secretion of antiseptic urine following the intravenous administration of acriflavine and proflavine. Preliminary report . · Jour . Urol., 1918, ii, 299. (4) DAVIS, EDWIN: Urinary antisepsis: A study of the antiseptic properties and the renal excretion of 204 anilian dyes . Amer. Jour. Med. Sc., 1921, clxi, 251. (5) DA:VIS, EDWIN: Urinary antisepsis: The secretion of antiseptic urine by man following the oral administration of proflavine and acriflavine. Preliminary report. Jour. Urol., 1921, iii, 5, 215 . {6) DAVIS, EDWIN AND HARRELL, _B . E.: Acriflavine in the treatment of gonorrhoea. An experimental and clinical study. Jour. Urol., 1918, ii, 257.
Received for publication June 25, 1923
It is the chief purpose of this paper to briefly outline the experimental work which has led up to the internal administration of acriflavine, and to summarize the results obtained by the clinical use of this dye. The lack of an efficient drug for the purpose of internal urjna1;y antisepsis, and the wide field of application open to such a drug is too apparent to require dis-cussion before this audience. SUMMARY OF EXPERIMENTAL WORK WITH ACRIFLAVINE,
The investigation summarized below had as its goal the discovery or the synthesis of a drug which might be administered orally without toxic effect, and which would be excreted un-changed in the urine, there to exert an antiseptic action. A survey of the literature pertaining to urinary antisepsis reveals a surp'rising absence of sound experimental or clinical evidence of the fitness of any known drug for this purpose. · As early as 1916, investigations were started with phenolsulphonephthalein as a basis. The properties of this remarkable compound are known to alL It is chemically sta'.ble, it is non-toxic and non-irritating, it is eliminated by the kidney with incredible rapidity and completeness, and hence possesses all of the properties essential to the ideal urinary antiseptic, 1 Read before the American Urological Association, Rochester, Minn., Ma~ 17 and 18, 1923.
· 29
30
EDWIN DAVIS
with the exception that it is totally lacking in antiseptic power. With the cooperation of Dr. E. C. White of the Brady Urological Insitute, a large number of closely related compounds were synthesized and studied, with regard to antiseptic properties and renal elimination. Among many others were thymolsulphonephthalein, salicylsulphonephthalein, cresolsulphonephthalein, tetra-aminophenolsulphonephthalein, alphanaphtholsulphonephthalein and guaicacolsulphonephthalein. This study afforded interesting results which have been elsewhere recorded (1), and not a few of these compounds fulfilled all but one of the required properties. It was possible to establish a certain relationship between chemical structure and renal excretion, and to predict with reasonable accuracy which of these drugs would appear in the urine. One of these, chior-mercury fluorescein, an organo-mercury phthalein derivative, was experimentally successful in that the intravenous administration of this drug in minute dosage to dogs and tabbits caused the secretion of an antiseptic urine for a definite period of time. Further clinical investigation of this drug was not carried on for fear of renal injury due to its mercury content (2) . In 1917, my attention was attracted to acriflavine by publications in the English literature by Browning and others of (of the Bland Sutton Institute of Pathology, Middlesex Hospital, London), who showed the antiseptic action of this drug to be increased in the presence of serum. In other words they proved that acriflavine could inhibit the colon bacillus in higher dilution in serum than in peptone water. This phenomenon Browning referred to as the "serum uplift." As a result of these publications, and through the assistance of Dr. Hugh Young, a small supply of acriflavine was obtained from Browning, which was to the best of my knowledge the first sample of this drug to be used in America. It was found that acriflavine in test-tube experiments, inhibits the colon bacillus and the staphylococcus in high dilution in urine of an alkaline reaction. It was also determined that this drug rapidly appears in the urine after intravenous and oral administration, and is excreted in large quantities. Preliminary
URINARY ANTISEPSIS •.'
31
experiments at this time showed that it is possible to cause rabbits and dogs to secrete antiseptic urine following intravenous administration of acriflavine (3). Including the sulphonephthaleins and related compounds, and also the investigation of a large number of anilin dyes, later published in the American Journal of the Medical Sciences (4), a total of more than four hundred compounds were studied with regard to antiseptic properties, renal excretion and toxicity. Acriflavine was found to more nearly fulfill the requirements for the ideal internal urinary antiseptic than any one of these. The next step was to duplicate the above experimental results in man. As was published in the Journal of Urology in March, 1921 (5), it was possible to conclusively prove that acriflavine in small dosage (0.1 gram), administered orally to a normal individual, will cause the secretion of antiseptic urine, provided the reaction of the latter is alkaline. This drug should therefore theoretically be of clinical value in the treatment of various infections of the urinary tract, including pyelitis of infancy, chronic pyelitis of adults, acute pyelonephritis, and in acute and chronic cystitis. During the treatment of acute anterior gonorrheal urethritis, this drug should also be of theoretical .value administered internally as a prophylactic against the development of posterior urethritis. It should also deserve a trial in the treatment of early posterior urethritis and trigonitis. SELECTION OF CASES
In undertaking the accurate tabulation of clinical results, in order to permit reliable conclusions, of primary importance is the proper selection of cases. That a given case of uninvestigated pyuria or bacteriuria should either improve or fail to .improve, following the administration of a given drug, is not evidence of particular value either for or against the efficiency of that drug. Numerous so-called accessary or predisposing causes of urinary infection must first be eliminated. There are certain well-defined and well-recognized, "intra-urinary," predisposing factors, which may be grouped under the main headings, retention, calculus, new growth and tuberculosis. The folly
32
EDWIN DAVIS
of attempting the cure by drug therapy of a urinary infection which is primarily dependent upon one of the above-named mechanical factors, is qui.te apparent. Concerning the systemic or "extra-urinary" predisposing causes of urinary infection our knowledge is relatively scant and unsatisfactory. There are those cases of pyuria or bacteriuria, occurring during the course of acute infectious diseases, and there is that large group of cases in which it is considered that chronic focal local infection plays a role. Whether our predisposing or underlying cause of infection be intra-urinary or systemic, to disregard this primary cause, and to attempt a cure by merely rendering the urine antiseptic, is obviously ridiculous. Therefore, if accurate information is to be obtained, the essential preliminaries in selecting cases suitable for internal urinary therapy are (a) complete general physical examination and (b) complete urological examination. It should be further noted that favorable results can not be expected in far advanced cases, as, for example, bilateral pyelonephritis, of long duration, with extensive destruction of renal tissue and lowering of renal function. TECHNIQUE
Conclusive evidence of the clinical efficiency of a given urinary antiseptic is not easily obtained. We are all familiar with what may be termed the spontaneous or automatic variations which may occur at any time in the pus and bacterial content of infected urines. The urine which is cloudy one day with pus or swarming with bacteria, may be clear the next, and vice versa, with no apparent explanation. It is only too easy to ascribe such changes to drug therapy, particularly if these are the changes which we are hoping and expecting to see. Furthermore, there may occur spontaneous changes in the patient's general condition, in his temperature, and in his bladder symptoms. More reliable than the patient's symptoms and the macroscopic appearance of the urine, in accurately determining the effect of drug therapy, is the method of daily culture of the urine, with an estimation of the number of bacteria per unit volume. The routine used was as follows:
URINARY ANTISEPSIS
33
As an essential preliminary to dye administration, each patient was started on large doses of sodium bicarbonate; sufficient to render the urine alkaline. This was usually accomplished by a total of 2 or 3 drachms daily. During the succeed-ing several days, the patient's condition was daily noted, and records of daily urine examinations were made, including reaction, gross appearance, microscopical content, and culture. The method of culture was to plate a unit volume and to count the approxixnate number of colonies. After a sufficient number of days of such routine to serve as a control, the acriflavine was started, the bicarbonate being continued. The average dose of acriflavine was 0.1 gram (by capsule), twice daily. As indicated in charts 1 and 2, in the favorable cases there occurred an improvement so immediate and so striking as to rule out mere coincidence. The improvement was measured by a drop in temperature, an improvement in bladder symptoms, a macroscopic and microscopic clearing of the urine, and a disappearance of colonies from the agar plates. CLINICAL RESULTS
After the elimination of all cases with accessory causes of urinary infection, and after ruling out cases not controlled by a preliminary period of several days of observation and urine culture prior to dye administration, the total number of carefully observed cases has been reduced to a very small figure. For this reason, and because of rather a wide variation in results obtained 1 it may only be said that experience to date is insufficient to justify a final opinion. Results are herewith presented for your consideration, and with the hope that the experience of others may aid in determining the clinical value of this drug. It should be here distinctly understood that in the light of our present knowledge promiscuous medication with acriflavine, in unselected cases is distinctly inadvisable, For convenience of consideration, the clinical cases which have received acriflavine by mouth have been roughly classified as follows:
34
EDWIN DAVIS
1. Acute urinary infections, including acute cystitis, and acute non-surgical kidney infections, with staphylococci or bacilli in the urine. 2. Chronic urinary infections, including chronic cystitis and chronic pyelonephritis. 3. Acute anterior gonorrheal urethritis, in which the dye has been administered orally with the purpose of preventing the development of a posterior infection. 4. Acute posterior gonorrheal urethritis, in which the dye has been administered orally with the purpose of relieving symptoms. Acute urinary infections. It was in this group that the most satisfactory results were obtained. Out of a small series of 18 cases, in 13 there occurred an improvement characterized by a drop in temperature, a cessation of bladder symptcms and a disappearance of pus and bacteria from the urine cuin j _~ _-,nt with the starting of the dye. In the remaining 5 there was no apparent effect. The tendency toward spontaneous recovery in these cases is of course recognized, yet the fact that these particular patients remained under observation for a prefoyjnary period of several days without improvement should tend to rule out mere coincidence. Two of these patients had a recurrence of symptoms three months later, and again responded to t.he dye. A tonsillectomy was done following the second attack in one of these, and the patient has been symptom-free since. It is safe to say that 50 per cent of the others have remained well to date over a period of several months. Chronic urinary injections. As indicated above, the patients in this group were of the chronic bacteriuria or pyuria type, without demonstrable surgical lesion, and without marked impairment of kidney function. The results were not so good as obtained in the acute series. Out of a total of 27, there were 11 in which the treatment produced no appreciable effect. The remaining 16 showed a distinct improvement in bladder symptoms and a macroscopic and microscopic clearing of the urine, together with a lessening of the number or a complete disappearance of bacteria from the urine, as indicated by daily plating
URINARY ANTISEPSIS
35
of unit volumes. The discouraging feature, however, in the series of chronic cases, was the marked tendency toward recurrence of infection in the urine after discontinuing the dye. In 12 out of 16 cases which had responded to treatment, the bacteria reappeared shortly after the urine became drug-free. This is in keeping with the theory that bacteria may be continuously "fed" into the urinary tract from extra-urinary sources. Acute anterior gonorrheal urethritis. In view of the extreme dilution in which acriflavine will inhibit the development of the gonococcus, it seemed logical to expect that the oral administration of this drug during the course of an acute anterior gonorrheal urethritis, should serve as an · efficient method of prophylaxis to prevent the development of a pbsterior infection. Clinically this expectation has not been borne out. The progress of gonorrheal urethritis from anterior to posterior, in spite of the presence of acriflavine in the urine, has been observed in a sufficient number of cases to warrant the conclusion that the internal administration of acriflavine is not a dependable method of preventing posterior infection. · Acute posterior gonorrheal urethritis. Although the oral administration of acriflavine may not be depended upon to prevent the development of a posterior urethral infection, this drug administered internally seems to be of distinct value in the treatment of acute posterior gonorrheal urethritis. This opinion is based upon the observation of a small series of such cases in which there was noted a disappearance of the urinary frequency, pain, tenesmus and terminal haematuria, and a clearing of the macroscopic pyuria, coincident with the starting of the dye by mouth. This statement is not intended to imply that it is possible to cure with any conceivable drug, a gonorrheal prostatitis. It is my belief, however, that the duration and the severity of the acute symptoms of posterior gonorrheal urethritis may be lessened. TOXICITY
The oral administration of acriflavine is not without its contra-indications. Approximately 30 per cent of the patients reported a slight nausea or a mild catharsis. The nausea was
36
EDWIN DAVIS
in part due to the bicarbonate, since in some instances this symptom preceded the dye administration. The description of the cathartic action by the majority of the patients, as being very mild, and free from gripping or straining, and with a formed soft stool, is such as to suggest the possible value of acriflavine as a cathartic. In fact, it has been mentioned that the action of acriflavine as a urinary antiseptic may be in part explained by the clearing of the intestinal canal. In the occasional case, (about 5 per cent) however, the gastrointestinal symptoms, characterized by vomiting and diarrhea, are of sufficient severity to contraindicate the use of the drug. Although, even ip_ the severe cases, these symptoms have been transient and without ill effect, this possibility constitutes a serious drawback to the routine use of the drug. CONCLUSIONS
Experimentally, acriflavine administered by mouth in 0.1 gram dosage, to normal individuals is secreted in the urine in sufficient concentration to render the latter an unfit culture medium for the colon bacillus and staphylococcus, provided the reaction of the urine is alkaline. After this dosage, the antiseptic action persists in the urine for at least eight hours. Clinically, results to date in a small series of cases are as follows: 1. Acute urinary infections. A large proportion of these cases have shown a prompt improvement, characterized by a drop in temperature, a disappearance of bladder symptoms, a macroscopic clE:>aring of the urine and a disappearance of bacteria from the urine. Relapses in these cases have been the exception. 2. Chronic urinary infections have not readily responded. Improvement was noted in only 60 per cent of cases, and in most of these the pus and bacteria reappeared in the urine after discontinuing the treatment. 3. Acute anterior gonorrheal urethritis. Acriflavine administered orally is not a dependable prophylactic for preventing the extension of the infection to the posterior urethra.
URINARY ANTISEPSIS
37
4. Acute posterior gonorrheal urethritis. Acriflavine administered orally is of benefit in this condition in lessening the duration and the severity of the acute symptoms. Mild catharsis or slight nausea was observed in approximately 30 per cent of the patients. This was due in part to the bicarbonate, since in some instances these symptoms preceded the dye administration. In 5 per cent of the cases vomiting and diarrhea were such as to contraindicate the use of the drug. No further ill effects have been noted. The indiscriminate use of acriflavine by mouth, in unselected cases, and without regard to the elimination of the "accessary" causes of urinary infection, is distinctly inadvisable. All experimental and clinical results have been obtained with the brand of acriflavine put out by Poulenc Freres, Paris. APPENDIX
Acrifiavine as a local injection in the treatment of gonorrheal urethriti:s. The above discussion takes into consideration only the internal admini-stration of acriflavine. In view of the wide digergence of opinion that exists concerning the value of acrifiavine used as a local injection in the treatment of gonorrheal urethritis, it seems worth while to take this occasion to add as an appendix a brief statement concerning this subject. I am well aware of considerable adverse comment. For the discrepancies in the results obtained by different observers, there are but two apparent explanations: (1) variations in the chemical purity of the drug, and (2) variations in the technique of treatment. 1. Acriflavine is synthesized and purified with difficulty. The earlier experimental and clinical work was done with the English product (Boots), and later the French product (Poulenc Freres) 2 has been almost exclusively used. I have had no experience with the various American brands. 2 For those who are interested in obtaining this drug I may add that the restrictions placed by the American Chemical Foundation have long been an obstacle in the way of obtaining the foreign brands of Acriflavine. At present the French product, put out by Poulenc Frerers, Paris, may be obtained by writing directly to their agent in the United States, George J. Wallau, 6 Cliff Street, New York City. The English product, put out by the Boots Pure Drug Company, Nottingham, England, may be obtained by addressing, The United Drug Company, Boston, Mass.
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EDWIN DAVIS
2. For faulty technique of treatment, probably the original publication (Davis and Harrell (6)) is largely responsible. This paper was hastily gotten out in 1918, just before going into the service, and at this time our experience had not been sufficient to determine that a concentration of 1: 1000 is quite irritating, and is very often responsible for . a, chemical urethritis. With the present technique a solution of 1: 8000 is used, made up in normal saline solution instead of distilled water. In addition to frequent injections of a 1: 8000 solution, retained for five minutes, one daily injection of 1 :4000 solution is given if tolerated without urethral irritation. A report of series of cases of acute gonorrheal urethritis treated by this method is at present in preparation. I make no extravagant claims for the value of acriflavine in gonorrhea, and wish to here acknowledge the failures. The large majority, however, of satisfactory results, and the frequent cases of immediate, brilliant and permanent cure, offer sufficient justification for the belief that acriflavine, of proper chemical purity and properly administered, will eventually come to be the drug of preference in the treatment of acute anterior gonorrheal urethritis. REFERENCES (1) DAVIS, EDWIN, AND WHITE, E. C,: Urinary antisepsis: Further studies of the antiseptic properties and renal excretion of compounds related to phenolsulphonephthalein. Jour . Urol., 1918, ii, 107. ,(2) DAVIS, EDWIN, '\VHITE, E. C., AND RosEN, ROBERT: Urinary antisepsis: The secretion of antiseptic urin·e following the intravenous administration of an organo-mercury phthalein derivative. Jour. Urol., 1918, ii, 277. (3) DAVIS, EDWIN, AND WHITE, E. C.: Urinary antisepsis: The secretion of antiseptic urine following the intravenous administration of acriflavine and proflavine. Preliminary report . · Jour . Urol., 1918, ii, 299. (4) DAVIS, EDWIN: Urinary antisepsis: A study of the antiseptic properties and the renal excretion of 204 anilian dyes . Amer. Jour. Med. Sc., 1921, clxi, 251. (5) DA:VIS, EDWIN: Urinary antisepsis: The secretion of antiseptic urine by man following the oral administration of proflavine and acriflavine. Preliminary report. Jour. Urol., 1921, iii, 5, 215 . {6) DAVIS, EDWIN AND HARRELL, _B . E.: Acriflavine in the treatment of gonorrhoea. An experimental and clinical study. Jour. Urol., 1918, ii, 257.