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Advances in the Treatment of Vaginitis
ADVANCES IN THE TREATMENT OF VAGINITIS
A. E.
RAKOFF,
M.D.'"
PROGRESS in the treatment of vaginal infections and associated dis· orders of the vagina during the past several years has resulted from a better understanding of the biology and physiology. of the vagina in health and disease as well as from the introduction of new chemothera· peutic drugs, antibiotics and hormonal preparations. Also of importance has been the improvement in the technics of applying medications to the vagina particularly with regard to the development of medicaments which could be effectively distributed over the entire lower genital tract and of the proper physical and chemical character to mix intimately with the vaginal and cervical secretions. 1
BIOLOGY OF THE NORMAL VAGINA The effective treatment of infections and discharges of the vagina requires an appreciation of the mechanism by which the normal biologic characteristics of the vagina are maintained. 2 The vaginal mucosa is under the direct influence of the ovarian hormones. The estrogens are the dominant factor in stimulating proliferation of the vaginal epithelium and thus maintaining a vaginal mucosa of normal thickness. The estrogens are also responsible for the deposition of glycogen in high concentration in the vaginal epithelium; progesterone may aid in this process, while androgens inhibit both proliferation and glycogen deposition. By the combined action of enzymes and bacteria the glycogen of the vaginal epithelium is metabolized and broken down to lactic acid. The resulting acidity of the vagina favors the growth of certain acidophilic bacteria, particularly the lactobacilli of Doderlein. These organisms tend to further increase the acidity of the vagina by utilizing glycogen and the carbohydrates resulting from the enzymatic breakdown of glycogen. The resulting pH of the vaginal secretion thus tends to become stabilized at 4.0 to 5.0 in the normal adult during the period of active ovarian function. Since very few other organisms can thrive in so acid an environment, Doderlein's bacilli quite commonly become established in practically pure culture in the normal vaginal tract. By this mechanism the genital tract is protected from exogenous infection. In phases of diminished ovarian function such as in childhood, in the immediate postpartum period and in the postmenopausal years the diminished elaboration of estrogenic hormones produces a vaginal mucosa that is of diminished thickness, with little or no glycogen content and a less acid or even alkaline secretion ranging from pH 5.0 to 8.0. Under these latter circumstances Doderlein's bacilli tend to disappear from the vaginal secretion. The presence or absence of the lactobacilli is thus largely dependent upon the vaginal acidity. Almost all patients with a vaginal flora of Doderlein's bacilli alone (so called Grade I vaginal flora) have a vaginal pH ranging from 3.9 to 5.0. The majority of patients with a
From the Departments of Obstetrics and Gynecology, Jefferson Medical College and Hospital, Philadelphia. .. Assistant Demonstrator in Obstetrics, Instructor in Gynecology, Jefferson Medical College. Director of the Endocrine Laboratories, Jefferson Hospital. 1354
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Grade 11 flora (Doderlein's bacilli plus other organisms) have a vaginal pH ranging from 4.6 to 5.5. In the Grade III type (a mixed flora in which there are no Doderlein's bacilli) the pH generally ranges from 5.1 to 6.0 and even higher in the presence of certain infections. It is thus quite apparent that, in addition to demonstrating the presence or absence of some specific infecting organism, it is of equal importance to study the vaginal secretion for its cytologic content-as an index of estrogenic function, glycogen content, pH and type of Iilacterial flora in order adequately to evaluate and treat various types of vaginal infections and discharges. "NONSPECIFIC" INFECTIONS
Low grade nonspecific infections of the vagina are very commonly encountered. They may occur whenever there has been interference with the mechanism for maintaining the normal physiology of the vagina. In ovarian dysfunctions associated with estrogen deficiencies, glycogen concentration becomes diminished, the vaginal acidity is reduced and Doderlein's bacilli are replaced by a variety of organisms. The result is an alteration in the character of the vaginal secretion and not infrequently a low grade diffuse vaginitis. The pH of the vaginal secretion can also be altered by the persistent use of alkaline or irritating chemical douches thus resulting in the displacement of Doderlein's bacilli by less favorable organisms; but once the latter have established themselves and have created an inflammatory reaction of the vaginal mucosa, this abnormal mechanism may continue despite normal ovarian function. Mechanical trauma such as may occur from the long continued use of pessaries can also produce an inflammatory reaction. Cervical infections also quite commonly produce a nonspecific vaginitis by constantly decreasing the vaginal acidity with copious amounts of alkaline cervical discharge. The treatment of these nonspecific infec.tions obviously necessitates the correction of the underlying etiologic factor. If there is an associated ovarian deficiency, this should be corrected by appropriate endocrine therapy. If the cervix is infected, cauterization or conization should be employed where necessary. The use of all irritating douches, the application of irritating chemicals and mechanical trauma should be discontinued. Finally, measures to favor the return of the normal vaginal flora should be instituted. This can be most readily accomplished by creating an acid vaginal media. The use of acid vaginal douches several times daily is quite commonly recommended. For this purpose one may employ simple vinegar, 1 tablespoonful to 2 quarts of water, a saturated solution of boric acid, or lactic acid. 3 A suitable prescription is as follows: Gm. or Cc. Chlorthymol............................................ 1.3 Menthol ................................................ 2.0 Methyl salicylate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.0 Lactic in sufficient quantity ................... to make 180.0 Mix and label: A teaspoon in 2 quarts of hot water, to be used as a vaginal douche morning and evening. ~
1356
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Much more satisfactory than the acid douche is the use of a waterdispersable acid vaginal jelly· which can be introduced into the vagina once or twice daily and· which remains in contact with the vaginal mucosa over a prolonged period of time and thus more effectively creates a suitable acid medium. 4 , 5, 6 A very satisfactory preparation· consists of acetic acid, oxyquinoline sulfate, ricinoleic acid, boric acid and glycerine in a suitable vehicle. This jelly may be introduced at bedtime by the use of a special vaginal applicator containing 5 cc., which is followed in the morning by a simple acid douche. Persistent use of the vaginal jelly for several weeks generally leads to restoration of the normal vaginal flora which tends to persist provided any other underlying factors have been corrected. ATROPHIC VAGINITIS
In the presence of a marked ovarian deficiency the vaginal mucosa may atrophy to a thin tissue-paperIike structure consisting of only a few layers of cells. Because of the susceptibility of this thin tIssue to trauma and because of the associated decrease in vaginal acidity, inflammation, ulceration and infection readily result. This type of condition can be readily corrected by administering estrogenic hormones in sufficient amount to cause proliferation of the vaginal epithelium and by treating the associated nonspecific infection by the methods already prescribed. A much more specific and rapid cure can be effected by applying the estrogenic hormone locally to the vaginal mucosa. This can be accomplished by the use of vaginal suppositories containing natural and synthetic estrogens or even better we have found the use of a water-dispersable acid jelly containing stilbestrolt in concentration of 0.5 mg. per cc. Five cubic centimeters of this jelly can be introduced nightly into the vagina by means of a special applicator and followed the next morning with a simple acid douche. By applying the hormone to the vagina locally intense cornification can be rapidly induced without producing excessive systemic effects of hyperestrogenism. After initial cure has been obtained the jelly may be used once or twice weekly as required to maintain a healthy vaginal mucosa. POSTPARTUM VAGINITIS
A nonspecific vaginitis frequently occurs in the postpartum period because of trauma from delivery, the bathing of the vaginal mucosa with the alkaline secretions from the uterus and cervix, and because the vaginal mucosa has become thin and glycogen-poor in this phase of diminished ovarian function. This type of infection responds quickly to an acid vaginal jelly and acid douches. Even more satisfactory is the .. Aci-Jel supplied by Ortho Pharmaceutical Corp., Linden, New Jersey. t Generously supplied to us for investigational use as "Gynecological Cream" by Ortho Pharmaceutical Corp., Linden, New Jersey.
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response which can be obtained with local use of an acid jelly containing stilbestrol as described above. A procedure which we have found very satisfactory in our postnatal clinic is to have patients with excessive discharge or frank vaginitis use an acid jelly and an acid douche from the fourth to the eighth weeks postpartum. At that time any cauterization of the cervix which is necessary can be carried out. If vaginitis persists after the cervix has healed, the use of the stilbestrol jelly will generally effect a rapid cure. When used locally in this fashion it generally does not interfere with lactation. HYPERHORMONAL LEUKORRHEA
An excessive amount of normal vaginal secretion is sometimes encountered, particularly in adolescent girls and young unmarried women. This type of discharge is due to excessive stimulation of the lower genital tract by estrogens, resulting either from a state of hyperestrogenism or marked responsiveness of the vagina and cervix to normal estrogen concentrations. This type of discharge quite normally occurs during pregnancy. The treatment of this type of leukorrhea is very unsatisfactory. Much can be accomplished by assuring the patient that the discharge is of normal character and not due to infection. A simple saline douche twice daily helps to keep the patient more comfortable. In very troublesome cases methyl testosterone, 5 mg. daily, can be given by mouth; this often diminishes the estrogen effect and in this dosage rarely gives rise to untoward androgenic symptoms. TRICHOMONAS VAGINITIS
Trichomonas infestation of the vagina remains one of the most troublesome problems in gynecology. Despite the fact that the condition is extremely prevalent, affecting as much as 25 per cent of some population groups, 7 the method of transmission of the disease is not completely known; consequently there is no specific method of prophylaxis. It is probable that the organism is transferred most commonly from one woman to another by contact with vaginal secretion present on toilet articles, toilet seats, bed pans, and similar hygienic mishaps. Transmission through still water pools is also a possibility. Since. 5 to 27 per cents of some groups of men are now known to harbor the oganisms in the urethra or prostate, usually in very small numbers, transmission through sexual contact undoubtedly sometimes occurs. It is unlikely that infestation of the vagina occurs with trichomonads from the mouth or intestinal tract since the species of trichomonads from these sources differ morphologically and physiologically from Trichomonas vaginalis. Although it is quite easy to obtain symptomatic relief from Trichomonas vaginitis, permanent cure of the condition is often extremely
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difficult and prolonged. The trichomonads can be readily killed in the laboratory by simple drying or by exposing them to relatively low concentrations of a great many antiseptics or common laboratory reagents. 9 Even in the vagina the organisms are rapidly destroyed on contact with a great many therapeutic agents. Unfortunately, however, occasional organisms can "hide out" in folds of tissue in the vagina or introitus, in the cervical canal, in the cervical glands, in the urethra10 and Skene's glands, in the bladder and in Bartholin's glands. vVithin twenty-four to forty-eight hours after local treatment it is not at all uncommon to again find large numbers of the flagellates in the vaginal tract. Unfortunately it is not possible to reach these occasional organisms which are responsible for reinfestation by systemic chemotherapy. Sulfonamides given by mouth in adequate dosage and penicillin given by injection fail to destroy the organisms. It is, therefore, my studied opinion that the technic of treatment in these resistant cases is often far more important than the drug employed. Symptomatic relief in almost all cases can be readily obtained by douching persistently twice daily with a simple acid douche, but only rarely will this effect a cure. Even the use of medicated douches containing permanganate, iodine, mercurials or other antiseptic is of no additional help in permanently eradicating the flagellates. The use of acid vaginal jellies likewise affords symptomatic relief and persistent, twice-daily use cures some of the milder cases. Sulfonamide jellies when used persistently will effect cures in perhaps a somewhat greater percentage of patients but in our experience have not been useful for the more resistant cases. The sulfonamide jellies are helpful particularly as an adjunct in those cases in which there are associated streptococcal infections. The sulfonamides per se are not highly trichomonadicidal. Medicated suppositories are generally not as effective as the medicated jellies since they do not diffuse as effectively and frequently do not mix well with the vaginal secretions. For local treatment of the vagina no technic works as well as the introduction of the drug to be used in powder form diluted with a drying base such as kaolin. Many such preparations are available including arsenicals such as aldarsone, acetarsone and carbarsone, silver picrate, argyrol, mercurials, sulfanomides and numerous other antiseptics. Although I have a preference for the pentavalent arsenicals, particularly aldarsone,l1 I have been able to obtain satisfactory results with a considerable number of the antiseptic powders diluted with kaolin if the method of treatment has been appropiate. The essentials of obtaining a cure involve thoroughness, frequency and persistence of treatment. The entire vaginal tract should first be cleansed with saline, 5 per cent sodium bicarbonate or suspensions of kaolin to remove all secretion and mucus. Particular care should be given to the cleansing of the cervix and introitus and any folds or
ADVANCES IN THE TREATMENT OF VAGINITIS
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tissue about the urethra. It is also helpful to dry the tissues of the lower genital tract with a stream of warm air. The powder to be used is then insufflated into the vagina by means of an efficient vaginal insufflator of which there are several available such as the Shelanski or Holmes vaginal spray. The material must be thoroughly dispersed over the entire vagina and some of it should also be blown over the tissues of the introitus. The powder is allowed to remain overnight and the following morning a simple cleansing douche is used. It is important that at the onset treatment should be given daily, preferably every day for five or six days. If it is not possible for the patient to be treated by the physician so frequently she may be taught to give the insufflations herself, while lying in the bathtub, taking due precaution to avoid increasing the intravaginal pressure by removing the vaginal guard from the insufflator. The treatment can be effectively and safely given by the patient on those days when it is not possible for her to see the physician. After the initial treatments, insufflations can be given every second day, then every three days and then at less frequent intervals depending upon her progress. The physician must of course guard against cumulative or toxic effects of the particular drug used. Before treatment is started, particularly in patients who have been unsuccessfully treated previously, it is wise to make a careful search for flagellates in the cervix and urethra by obtaining material from these sources on a bacteriologic loop which is immediately suspended in salt solution and examined at once under the microscope. The urine sediment from a centrifuged catheterized urine specimen should also be thoroughly examined for organisms. In married patients with persistent infestation examination of the prostatic and urethral secretions may also be necessary to rule out the husband as a source of reinfection. In all persistent or recurrent cases it has been our practice to keep the patient under treatment for three months. After the initial series of treatments, insufflations are given twice weekly and are increased to ·once daily for two or three days just before and just after menstruation, since this is the period when reinfections are most commonly noted. It has also been our custom to have the patients douche daily with an acid douche throughout the entire menstrual flow. In those cases in which reinfection appears to be coming from the urinary tract or from the tissues anterior to the vagina the patients are advised to powder between the labia with the same medicament that is used for insufflation. This is done three or four times daily. In addition, a urinary antiseptic is prescribed. We have found pyridium to be very satisfactory for this purpose, one tablet four times daily. When the trichomonads have disappeared from the lower genital tract, it is very helpful in obtaining a permanent cure to restore the normal vaginal flora and acidity as rapidly as possible. This is particularly necessary since Trichomonas vaginitis is almost always associated with II Grade III flora. For this purpose we employ an acid vaginal
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A. E. RAKOFF
jelly and an acid douche which is used for several months on days when insufRations are not given. Another problem which sometimes complicates the treatment of some severe cases of Trichomonas vaginitis is marked sensitivity of the patient to many drugs. This is sometimes a true allergy but more often the sensitivity is due to the extreme inflammation of the parts. Severe burning, irritation and edema may occur in such individuals after treatment. In this event treatment for the next several days should consist of simple saline douches every few hours, and cold compresses to the labia. After the acute inflammation has subsided insufRations with kaolin alone should be started, and thc:n small increasing amounts of drug gradually added at each treatment. VAGINAL MONILIASIS
Infections of the vagina with monilia and related yeastlike fungi have received considerable attention in the past several years. The infection produces a vulvovaginitis which gives rise to severe itching of the parts often with swelling of the labia and dermatitis of the surrounding skin areas. The discharge is not profuse but has a characteristic thick, cheesy consistency. The vaginal mucosa is generally coated with "thrush" patches. The infection is quite common during pregnancy, occurring in as many as 10 per cent in some prenatal clinics, but it is much less fn~quent in nonpregnant women. It also has a tendency to occur quite. commonly among diabetic women. A high carbohydrate content and increased vaginal acidity favor the growth of the yeastlike fungi, thus explaining the increased frequency in pregnancy and among diabetics. In pregnant women infection may be transmitted to the baby at the time of delivery, thus giving rise to "thrush" in the newborn. Infection of the nipples of lactating women is also occasionally observed. Moniliasis is a persistent infection and difficult to cure particularly in pregnant women. 12 The hyphae of the fungi tend to grow well into the epithelial layers making it difficult to remove the thrush patches by simple cleansing. Moreover, the yeast cells and spores are not easily destroyed by antiseptics. Treatment consists in the removal of all thrush patches by gently but thoroughly swabbing the vagina with a 5 per cent solution of sodium bicarbonate or a diluted solution of green soap. The entire lower genital tract is then gently dried with cotton balls or a stream of warm air. The entire mucous membrane, introitus and labia are then painted with an antiseptic solution. There is no question but that gentian violet, 1 or 2 per cent aqueous solution, affords the most relief from the itching and in controlling the infection. However, the disagreeable staining and messiness is a great disadvantage. A considerable advance has resulted from the introduction of a vaginal cream which combines a low concentration of gentian violet with quaternary ammonium salts and possesses no staining properties whatsoever. The
ADVANCES IN THE TREATMENT OF VAGINITIS
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detergent effects of the quaternary salts permits the use of lesser conconcentrations of gentian violet.· Moreover, we have found that the use of a jelly or cream base alone even without any added medicament is helpful because it mechanically loosens the thrush patches from the vaginal mucosa and washes them from the vagina. Five cubic centimeters of the cream is introduced into the vagina twice daily. This is followed by the use of a mild alkaline douche, an example of which follows: Gm. or Cc. Zinc sulfate ............................................. 2.0 Menthol ................................................ 2.0 Camphor ............................................... 2.0 Sodium biborate ....................................... 90 Sodium bicarbonate .................................... 90 Mix and label: A teaspoon in 2 quarts of water as a douche.
n
If the vulvar skin has become infected with the fungus, persistent treatment of these areas with the gentian violet jelly or other fungicidal ointments may be necessary. During pregnancy it is at times necessary to treat the patient off and on throughout the entire gestation. We have never seen this result in any harm. Following delivery these patients frequently make a dramatic spontaneous cure due to the rapidly diminishing supply of glycogen in the lower genital tract. It should be borne in mind that the male can be infected with monilia resulting in rather severe balanitis. The male can also serve as a source for reinfection of the wife. IS , FUSOSPIRILLOSIS (VINCENT'S INFECTION)
Vaginal infection due to Vincent's organisms are usually associated with and favored by uncleanliness. Not infrequently they may result from abnormal sexual practices or auto inoculation from the mouth of women suffering with Vincent's infection of the gums. It also quite commonly occurs as a secondary infection superimposed on other ulcerated lesions especially those of a granulomatous character. The vaginal mucosa and introitus present a "raw beef" appearance and frequently there are deep ulcerations. The discharge is usually profuse, yellow and foul. Similar infections may be produced by other types of spirilla and spirochetes. In this condition it is essential to recognize and treat any underlying iqfection and then to institute effective hygienic measures. The fusospirillosis generally responds rapidly to insufflation with an arsenical • This preparation was generously supplied to us for clinical investigation in the form of Gentersal Vaginal Cream by Ortho Pharmaceutical Corp., Linden, New Jersey. (The active ingredients may be identified as methyl rosaniline (gentian violet), quaternary ammonium compound and glycerine in a suitable vehicle containing a parahydroxybenzoic acid ester as a preservative.)
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A. E. RAKOFF
drying powder such as that described for Trichomonas vaginitis, or frequent daily application of neoarsphenamine, 10 per cent in glycerin, or frequent applications of gentian violet. We have found the use of sulfonamide jellies or creams to be highly effective in the treatment of this condition and much more convenient than the previous methods. For this purpose we have used particularly a cream containing three sulfonamides* each of which becomes effective at different pH levels. Five cubic centimeters of the cream are introduced twice daily into the vagina and removed after eight hours by a simple cleansing douche. Recent studies indicate that jellies containing penicillin are also effective in the treatment of this condition, as is penicillin given parenterally.14 VULVOVAGINITIS IN CHILDREN
Vulvovaginitis in children is generally classified as "specific" when it is caused by the gonococcus· or "nonspecific" when due to other causes. The nonspecific type of vaginitis in children may result from the introduction of foreign bodies into the vagina, local irritation from manipulation or tight clothing, uncleanliness or low grade infections with a variety of organisms. Because of the delicate nature of the epithelial lining of the vagina together with its neutral or alkaline secretion, this structure in little girls is especially susceptible to bacterial infection. In the treatment of gonococcal vulvovaginitis the first essential is strict isolation in order to prevent contamination of the other children in the household or institution. Care should be taken to prevent infection of the eyes or spread of the infection to the rectum. The local use of antiseptics and douches which formerly required many months and sometimes years of persistent therapy to effect a cure have now been replaced by treatment with estrogenic hormone, suIfonamides or penicillin. Each of these methods possess certain advantages and disadvantages. Estrogenic therapy may be given to cooperative children in the form of vaginal suppositories. A suppository containing 0.05 to 0.1 mg. of stilbestrol is inserted each night into the vagina. This is continued for three weeks after which smears are taken at weekly intervals until three negative smears have been obtained. If a cure cannot be effected with two courses of estrogenic therapy it is usually better to proceed with either suIfonamides or penicillin in order to avoid inducing premature sexual changes. In children in whom local treatment is not possible or feasible, stilbestrol may be given orally 0.1 mg. daily for two to three weeks. If * Triple-Sulfa Cream, generously supplied to us for clinical investigation by
Ortho Pharmaceutical Corp., Linden, New Jersey, contains micronized "sulfa" drugs (identified as sulfathiazole, acetylsulfonamide and benzylsulfanilamide) in a suitable base, nonbuffered to permit optimal pH effectiveness for the "sulfa" compounds.
ADVA~CES IN THE TREATMENT OF VAGINITIS
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any tendency toward growth of pubic hair or tenderness of the breast is noted this type of treatment should be stopped at once. • A high percentage of successful results can be obtained with estrogenic therapy in children. In refractory or recurrent cases, examination of the cervix with a cystoscope should be made and the rectum should also be examined for infection. If either of these structures is infected, treatment with sulfonamides or penicillin is indicated. In a number of clinics treatment with sulfonamides is preferred from the onset. In other clinics estrogens are preferred in order to avoid sensitization to the sulfonamides. Sulfathiazole is the most commonly employed preparation for sulfonamide therapy. The generally recommended dosage is 0.5 gram per pound of body weight per day in four divided doses with an equal amount of sodium bicarbonate which is continued for seven to fourteen days, never longer than three weeks. Good results can also be obtained with sulfadiazine in half the dose for sulfathiazole. Preliminary results with penicillin administered locally and parenterally indicate that it is highly effective and will probably prove to be a most valuable method of treatment. 15 , 16 As yet the best method of administration and dosage requires further investigation. In the nonspecific infections of children the most important factor is the removal of any underlying cause such as foreign bodies as sources of local irritation. The infection itself will generally respond to the use of antiseptics, suppositories or jellies used persistently through a number of weeks. In the more persistent or severe cases, treatment with the estrogens as described for the gonococcal cases will generally effect a rapid cure. Sulfonamide therapy is not generally indicated in the nonspecific infections. BIBLIOGRAPHY 1. Rakoff, A. E. and Caspar, S. L.: The Technic of Vaginal Medication. Pennsylvania M. J., 46:582, 1943.
2. Rakoff, A. E., Feo, L. G. and Goldstein, L.: The Biologic Characteristics of the Normal Vagina. Am. J. Ob st. & Gynec., 47:467, 1944. 3. Karnaky, K. J.: Normal Physiologic Douches. South. M. J.,30:69, 1937. 4. Bland, P. B. and Rakoff, A. E.: Leukorrhea, Clinical and Therapeutic Aspects. ].A.M.A., 1S5:1013, 1940. 5. Chrisman, R. B., Jr.: Clinical Results with the Use of a Buffered Acid Jelly, pH 4.5 and Other Jellies of Vaiying pH, in Gynecologic Infections: Study of 129 Cases. J. Tennessee State M. A., 35:455, 1942. 6. Allen, E. and Baum, H. C.: The Treatment of Vaginitis. Am. J. Ohst. & Gynec., 45:246, 1943. 7. Bland, P. B. and Rakoff, A. E.: The Incidence of Trichomonads in the Vagina, Mouth and Rectum. J.A.M.A., 188:2013, 1937. 8. Roth, R. B.: Trichomonas Urethritis and Prostatitis. Ven. Dis. Inform., 25:163, 1944.
9. Johnson, G. and Trussell, R. E.: Experimental Basis for the Chemotherapy of Trichomonas Vaginalis Infestations. 1. Proc. Soc. Exper. BioI. & Med., 54:245, 1943.
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10. Bland, P. B. and Rakoff, A. E.: Trichomonas Infestation of the Female Urinary Tract. Uro!' & Cutan. Rev., 44:698, 1940.
11. Bland. P. B. and Rakoff, A. E.: The Investigation of a New Pentavalent Arsenical, Aldarsone, in the Treatment of Trichomonas Vaginitis. Am. J.' Obst. & Gynec., 32:835, 1936. 12. Hesseltine, H. C.: Experimental & Clinical Therapy of Vulvovaginal Mycoses. Am. J. Obst. & Gynec., 34:439, 1937. 13. Bland, P. B., Rakoff, A. E. and Pincus, I. J.: Experimental Vaginal & Cutaneous Moniliasis. Arch. Derm. & Syph., 36:760, 1937. 14. Herrell, W. E.: Penicillin and Other Antibiotic Agents. Philadelphia, W. B. Saunders Co., 1945, p. 247. 15. Sandes, G. M.: Vulvovaginitis in Children. Brit. M. J., 1:160, 1944. 16. Cohn, A., Studdiford, W. E. and Grunstein, I.: Penicillin Treatment of Sulfonamide Resistant Gonococci Infections in Female Patients; Preliminary Report. J.A.MA., 124:1124, 1944.
A. E.
RAKOFF,
M.D.'"
PROGRESS in the treatment of vaginal infections and associated dis· orders of the vagina during the past several years has resulted from a better understanding of the biology and physiology. of the vagina in health and disease as well as from the introduction of new chemothera· peutic drugs, antibiotics and hormonal preparations. Also of importance has been the improvement in the technics of applying medications to the vagina particularly with regard to the development of medicaments which could be effectively distributed over the entire lower genital tract and of the proper physical and chemical character to mix intimately with the vaginal and cervical secretions. 1
BIOLOGY OF THE NORMAL VAGINA The effective treatment of infections and discharges of the vagina requires an appreciation of the mechanism by which the normal biologic characteristics of the vagina are maintained. 2 The vaginal mucosa is under the direct influence of the ovarian hormones. The estrogens are the dominant factor in stimulating proliferation of the vaginal epithelium and thus maintaining a vaginal mucosa of normal thickness. The estrogens are also responsible for the deposition of glycogen in high concentration in the vaginal epithelium; progesterone may aid in this process, while androgens inhibit both proliferation and glycogen deposition. By the combined action of enzymes and bacteria the glycogen of the vaginal epithelium is metabolized and broken down to lactic acid. The resulting acidity of the vagina favors the growth of certain acidophilic bacteria, particularly the lactobacilli of Doderlein. These organisms tend to further increase the acidity of the vagina by utilizing glycogen and the carbohydrates resulting from the enzymatic breakdown of glycogen. The resulting pH of the vaginal secretion thus tends to become stabilized at 4.0 to 5.0 in the normal adult during the period of active ovarian function. Since very few other organisms can thrive in so acid an environment, Doderlein's bacilli quite commonly become established in practically pure culture in the normal vaginal tract. By this mechanism the genital tract is protected from exogenous infection. In phases of diminished ovarian function such as in childhood, in the immediate postpartum period and in the postmenopausal years the diminished elaboration of estrogenic hormones produces a vaginal mucosa that is of diminished thickness, with little or no glycogen content and a less acid or even alkaline secretion ranging from pH 5.0 to 8.0. Under these latter circumstances Doderlein's bacilli tend to disappear from the vaginal secretion. The presence or absence of the lactobacilli is thus largely dependent upon the vaginal acidity. Almost all patients with a vaginal flora of Doderlein's bacilli alone (so called Grade I vaginal flora) have a vaginal pH ranging from 3.9 to 5.0. The majority of patients with a
From the Departments of Obstetrics and Gynecology, Jefferson Medical College and Hospital, Philadelphia. .. Assistant Demonstrator in Obstetrics, Instructor in Gynecology, Jefferson Medical College. Director of the Endocrine Laboratories, Jefferson Hospital. 1354
ADVANCES IN THE TREATMENT OF VAGINITIS
1355
Grade 11 flora (Doderlein's bacilli plus other organisms) have a vaginal pH ranging from 4.6 to 5.5. In the Grade III type (a mixed flora in which there are no Doderlein's bacilli) the pH generally ranges from 5.1 to 6.0 and even higher in the presence of certain infections. It is thus quite apparent that, in addition to demonstrating the presence or absence of some specific infecting organism, it is of equal importance to study the vaginal secretion for its cytologic content-as an index of estrogenic function, glycogen content, pH and type of Iilacterial flora in order adequately to evaluate and treat various types of vaginal infections and discharges. "NONSPECIFIC" INFECTIONS
Low grade nonspecific infections of the vagina are very commonly encountered. They may occur whenever there has been interference with the mechanism for maintaining the normal physiology of the vagina. In ovarian dysfunctions associated with estrogen deficiencies, glycogen concentration becomes diminished, the vaginal acidity is reduced and Doderlein's bacilli are replaced by a variety of organisms. The result is an alteration in the character of the vaginal secretion and not infrequently a low grade diffuse vaginitis. The pH of the vaginal secretion can also be altered by the persistent use of alkaline or irritating chemical douches thus resulting in the displacement of Doderlein's bacilli by less favorable organisms; but once the latter have established themselves and have created an inflammatory reaction of the vaginal mucosa, this abnormal mechanism may continue despite normal ovarian function. Mechanical trauma such as may occur from the long continued use of pessaries can also produce an inflammatory reaction. Cervical infections also quite commonly produce a nonspecific vaginitis by constantly decreasing the vaginal acidity with copious amounts of alkaline cervical discharge. The treatment of these nonspecific infec.tions obviously necessitates the correction of the underlying etiologic factor. If there is an associated ovarian deficiency, this should be corrected by appropriate endocrine therapy. If the cervix is infected, cauterization or conization should be employed where necessary. The use of all irritating douches, the application of irritating chemicals and mechanical trauma should be discontinued. Finally, measures to favor the return of the normal vaginal flora should be instituted. This can be most readily accomplished by creating an acid vaginal media. The use of acid vaginal douches several times daily is quite commonly recommended. For this purpose one may employ simple vinegar, 1 tablespoonful to 2 quarts of water, a saturated solution of boric acid, or lactic acid. 3 A suitable prescription is as follows: Gm. or Cc. Chlorthymol............................................ 1.3 Menthol ................................................ 2.0 Methyl salicylate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.0 Lactic in sufficient quantity ................... to make 180.0 Mix and label: A teaspoon in 2 quarts of hot water, to be used as a vaginal douche morning and evening. ~
1356
A. E. RAKOFF
Much more satisfactory than the acid douche is the use of a waterdispersable acid vaginal jelly· which can be introduced into the vagina once or twice daily and· which remains in contact with the vaginal mucosa over a prolonged period of time and thus more effectively creates a suitable acid medium. 4 , 5, 6 A very satisfactory preparation· consists of acetic acid, oxyquinoline sulfate, ricinoleic acid, boric acid and glycerine in a suitable vehicle. This jelly may be introduced at bedtime by the use of a special vaginal applicator containing 5 cc., which is followed in the morning by a simple acid douche. Persistent use of the vaginal jelly for several weeks generally leads to restoration of the normal vaginal flora which tends to persist provided any other underlying factors have been corrected. ATROPHIC VAGINITIS
In the presence of a marked ovarian deficiency the vaginal mucosa may atrophy to a thin tissue-paperIike structure consisting of only a few layers of cells. Because of the susceptibility of this thin tIssue to trauma and because of the associated decrease in vaginal acidity, inflammation, ulceration and infection readily result. This type of condition can be readily corrected by administering estrogenic hormones in sufficient amount to cause proliferation of the vaginal epithelium and by treating the associated nonspecific infection by the methods already prescribed. A much more specific and rapid cure can be effected by applying the estrogenic hormone locally to the vaginal mucosa. This can be accomplished by the use of vaginal suppositories containing natural and synthetic estrogens or even better we have found the use of a water-dispersable acid jelly containing stilbestrolt in concentration of 0.5 mg. per cc. Five cubic centimeters of this jelly can be introduced nightly into the vagina by means of a special applicator and followed the next morning with a simple acid douche. By applying the hormone to the vagina locally intense cornification can be rapidly induced without producing excessive systemic effects of hyperestrogenism. After initial cure has been obtained the jelly may be used once or twice weekly as required to maintain a healthy vaginal mucosa. POSTPARTUM VAGINITIS
A nonspecific vaginitis frequently occurs in the postpartum period because of trauma from delivery, the bathing of the vaginal mucosa with the alkaline secretions from the uterus and cervix, and because the vaginal mucosa has become thin and glycogen-poor in this phase of diminished ovarian function. This type of infection responds quickly to an acid vaginal jelly and acid douches. Even more satisfactory is the .. Aci-Jel supplied by Ortho Pharmaceutical Corp., Linden, New Jersey. t Generously supplied to us for investigational use as "Gynecological Cream" by Ortho Pharmaceutical Corp., Linden, New Jersey.
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response which can be obtained with local use of an acid jelly containing stilbestrol as described above. A procedure which we have found very satisfactory in our postnatal clinic is to have patients with excessive discharge or frank vaginitis use an acid jelly and an acid douche from the fourth to the eighth weeks postpartum. At that time any cauterization of the cervix which is necessary can be carried out. If vaginitis persists after the cervix has healed, the use of the stilbestrol jelly will generally effect a rapid cure. When used locally in this fashion it generally does not interfere with lactation. HYPERHORMONAL LEUKORRHEA
An excessive amount of normal vaginal secretion is sometimes encountered, particularly in adolescent girls and young unmarried women. This type of discharge is due to excessive stimulation of the lower genital tract by estrogens, resulting either from a state of hyperestrogenism or marked responsiveness of the vagina and cervix to normal estrogen concentrations. This type of discharge quite normally occurs during pregnancy. The treatment of this type of leukorrhea is very unsatisfactory. Much can be accomplished by assuring the patient that the discharge is of normal character and not due to infection. A simple saline douche twice daily helps to keep the patient more comfortable. In very troublesome cases methyl testosterone, 5 mg. daily, can be given by mouth; this often diminishes the estrogen effect and in this dosage rarely gives rise to untoward androgenic symptoms. TRICHOMONAS VAGINITIS
Trichomonas infestation of the vagina remains one of the most troublesome problems in gynecology. Despite the fact that the condition is extremely prevalent, affecting as much as 25 per cent of some population groups, 7 the method of transmission of the disease is not completely known; consequently there is no specific method of prophylaxis. It is probable that the organism is transferred most commonly from one woman to another by contact with vaginal secretion present on toilet articles, toilet seats, bed pans, and similar hygienic mishaps. Transmission through still water pools is also a possibility. Since. 5 to 27 per cents of some groups of men are now known to harbor the oganisms in the urethra or prostate, usually in very small numbers, transmission through sexual contact undoubtedly sometimes occurs. It is unlikely that infestation of the vagina occurs with trichomonads from the mouth or intestinal tract since the species of trichomonads from these sources differ morphologically and physiologically from Trichomonas vaginalis. Although it is quite easy to obtain symptomatic relief from Trichomonas vaginitis, permanent cure of the condition is often extremely
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difficult and prolonged. The trichomonads can be readily killed in the laboratory by simple drying or by exposing them to relatively low concentrations of a great many antiseptics or common laboratory reagents. 9 Even in the vagina the organisms are rapidly destroyed on contact with a great many therapeutic agents. Unfortunately, however, occasional organisms can "hide out" in folds of tissue in the vagina or introitus, in the cervical canal, in the cervical glands, in the urethra10 and Skene's glands, in the bladder and in Bartholin's glands. vVithin twenty-four to forty-eight hours after local treatment it is not at all uncommon to again find large numbers of the flagellates in the vaginal tract. Unfortunately it is not possible to reach these occasional organisms which are responsible for reinfestation by systemic chemotherapy. Sulfonamides given by mouth in adequate dosage and penicillin given by injection fail to destroy the organisms. It is, therefore, my studied opinion that the technic of treatment in these resistant cases is often far more important than the drug employed. Symptomatic relief in almost all cases can be readily obtained by douching persistently twice daily with a simple acid douche, but only rarely will this effect a cure. Even the use of medicated douches containing permanganate, iodine, mercurials or other antiseptic is of no additional help in permanently eradicating the flagellates. The use of acid vaginal jellies likewise affords symptomatic relief and persistent, twice-daily use cures some of the milder cases. Sulfonamide jellies when used persistently will effect cures in perhaps a somewhat greater percentage of patients but in our experience have not been useful for the more resistant cases. The sulfonamide jellies are helpful particularly as an adjunct in those cases in which there are associated streptococcal infections. The sulfonamides per se are not highly trichomonadicidal. Medicated suppositories are generally not as effective as the medicated jellies since they do not diffuse as effectively and frequently do not mix well with the vaginal secretions. For local treatment of the vagina no technic works as well as the introduction of the drug to be used in powder form diluted with a drying base such as kaolin. Many such preparations are available including arsenicals such as aldarsone, acetarsone and carbarsone, silver picrate, argyrol, mercurials, sulfanomides and numerous other antiseptics. Although I have a preference for the pentavalent arsenicals, particularly aldarsone,l1 I have been able to obtain satisfactory results with a considerable number of the antiseptic powders diluted with kaolin if the method of treatment has been appropiate. The essentials of obtaining a cure involve thoroughness, frequency and persistence of treatment. The entire vaginal tract should first be cleansed with saline, 5 per cent sodium bicarbonate or suspensions of kaolin to remove all secretion and mucus. Particular care should be given to the cleansing of the cervix and introitus and any folds or
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tissue about the urethra. It is also helpful to dry the tissues of the lower genital tract with a stream of warm air. The powder to be used is then insufflated into the vagina by means of an efficient vaginal insufflator of which there are several available such as the Shelanski or Holmes vaginal spray. The material must be thoroughly dispersed over the entire vagina and some of it should also be blown over the tissues of the introitus. The powder is allowed to remain overnight and the following morning a simple cleansing douche is used. It is important that at the onset treatment should be given daily, preferably every day for five or six days. If it is not possible for the patient to be treated by the physician so frequently she may be taught to give the insufflations herself, while lying in the bathtub, taking due precaution to avoid increasing the intravaginal pressure by removing the vaginal guard from the insufflator. The treatment can be effectively and safely given by the patient on those days when it is not possible for her to see the physician. After the initial treatments, insufflations can be given every second day, then every three days and then at less frequent intervals depending upon her progress. The physician must of course guard against cumulative or toxic effects of the particular drug used. Before treatment is started, particularly in patients who have been unsuccessfully treated previously, it is wise to make a careful search for flagellates in the cervix and urethra by obtaining material from these sources on a bacteriologic loop which is immediately suspended in salt solution and examined at once under the microscope. The urine sediment from a centrifuged catheterized urine specimen should also be thoroughly examined for organisms. In married patients with persistent infestation examination of the prostatic and urethral secretions may also be necessary to rule out the husband as a source of reinfection. In all persistent or recurrent cases it has been our practice to keep the patient under treatment for three months. After the initial series of treatments, insufflations are given twice weekly and are increased to ·once daily for two or three days just before and just after menstruation, since this is the period when reinfections are most commonly noted. It has also been our custom to have the patients douche daily with an acid douche throughout the entire menstrual flow. In those cases in which reinfection appears to be coming from the urinary tract or from the tissues anterior to the vagina the patients are advised to powder between the labia with the same medicament that is used for insufflation. This is done three or four times daily. In addition, a urinary antiseptic is prescribed. We have found pyridium to be very satisfactory for this purpose, one tablet four times daily. When the trichomonads have disappeared from the lower genital tract, it is very helpful in obtaining a permanent cure to restore the normal vaginal flora and acidity as rapidly as possible. This is particularly necessary since Trichomonas vaginitis is almost always associated with II Grade III flora. For this purpose we employ an acid vaginal
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jelly and an acid douche which is used for several months on days when insufRations are not given. Another problem which sometimes complicates the treatment of some severe cases of Trichomonas vaginitis is marked sensitivity of the patient to many drugs. This is sometimes a true allergy but more often the sensitivity is due to the extreme inflammation of the parts. Severe burning, irritation and edema may occur in such individuals after treatment. In this event treatment for the next several days should consist of simple saline douches every few hours, and cold compresses to the labia. After the acute inflammation has subsided insufRations with kaolin alone should be started, and thc:n small increasing amounts of drug gradually added at each treatment. VAGINAL MONILIASIS
Infections of the vagina with monilia and related yeastlike fungi have received considerable attention in the past several years. The infection produces a vulvovaginitis which gives rise to severe itching of the parts often with swelling of the labia and dermatitis of the surrounding skin areas. The discharge is not profuse but has a characteristic thick, cheesy consistency. The vaginal mucosa is generally coated with "thrush" patches. The infection is quite common during pregnancy, occurring in as many as 10 per cent in some prenatal clinics, but it is much less fn~quent in nonpregnant women. It also has a tendency to occur quite. commonly among diabetic women. A high carbohydrate content and increased vaginal acidity favor the growth of the yeastlike fungi, thus explaining the increased frequency in pregnancy and among diabetics. In pregnant women infection may be transmitted to the baby at the time of delivery, thus giving rise to "thrush" in the newborn. Infection of the nipples of lactating women is also occasionally observed. Moniliasis is a persistent infection and difficult to cure particularly in pregnant women. 12 The hyphae of the fungi tend to grow well into the epithelial layers making it difficult to remove the thrush patches by simple cleansing. Moreover, the yeast cells and spores are not easily destroyed by antiseptics. Treatment consists in the removal of all thrush patches by gently but thoroughly swabbing the vagina with a 5 per cent solution of sodium bicarbonate or a diluted solution of green soap. The entire lower genital tract is then gently dried with cotton balls or a stream of warm air. The entire mucous membrane, introitus and labia are then painted with an antiseptic solution. There is no question but that gentian violet, 1 or 2 per cent aqueous solution, affords the most relief from the itching and in controlling the infection. However, the disagreeable staining and messiness is a great disadvantage. A considerable advance has resulted from the introduction of a vaginal cream which combines a low concentration of gentian violet with quaternary ammonium salts and possesses no staining properties whatsoever. The
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detergent effects of the quaternary salts permits the use of lesser conconcentrations of gentian violet.· Moreover, we have found that the use of a jelly or cream base alone even without any added medicament is helpful because it mechanically loosens the thrush patches from the vaginal mucosa and washes them from the vagina. Five cubic centimeters of the cream is introduced into the vagina twice daily. This is followed by the use of a mild alkaline douche, an example of which follows: Gm. or Cc. Zinc sulfate ............................................. 2.0 Menthol ................................................ 2.0 Camphor ............................................... 2.0 Sodium biborate ....................................... 90 Sodium bicarbonate .................................... 90 Mix and label: A teaspoon in 2 quarts of water as a douche.
n
If the vulvar skin has become infected with the fungus, persistent treatment of these areas with the gentian violet jelly or other fungicidal ointments may be necessary. During pregnancy it is at times necessary to treat the patient off and on throughout the entire gestation. We have never seen this result in any harm. Following delivery these patients frequently make a dramatic spontaneous cure due to the rapidly diminishing supply of glycogen in the lower genital tract. It should be borne in mind that the male can be infected with monilia resulting in rather severe balanitis. The male can also serve as a source for reinfection of the wife. IS , FUSOSPIRILLOSIS (VINCENT'S INFECTION)
Vaginal infection due to Vincent's organisms are usually associated with and favored by uncleanliness. Not infrequently they may result from abnormal sexual practices or auto inoculation from the mouth of women suffering with Vincent's infection of the gums. It also quite commonly occurs as a secondary infection superimposed on other ulcerated lesions especially those of a granulomatous character. The vaginal mucosa and introitus present a "raw beef" appearance and frequently there are deep ulcerations. The discharge is usually profuse, yellow and foul. Similar infections may be produced by other types of spirilla and spirochetes. In this condition it is essential to recognize and treat any underlying iqfection and then to institute effective hygienic measures. The fusospirillosis generally responds rapidly to insufflation with an arsenical • This preparation was generously supplied to us for clinical investigation in the form of Gentersal Vaginal Cream by Ortho Pharmaceutical Corp., Linden, New Jersey. (The active ingredients may be identified as methyl rosaniline (gentian violet), quaternary ammonium compound and glycerine in a suitable vehicle containing a parahydroxybenzoic acid ester as a preservative.)
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drying powder such as that described for Trichomonas vaginitis, or frequent daily application of neoarsphenamine, 10 per cent in glycerin, or frequent applications of gentian violet. We have found the use of sulfonamide jellies or creams to be highly effective in the treatment of this condition and much more convenient than the previous methods. For this purpose we have used particularly a cream containing three sulfonamides* each of which becomes effective at different pH levels. Five cubic centimeters of the cream are introduced twice daily into the vagina and removed after eight hours by a simple cleansing douche. Recent studies indicate that jellies containing penicillin are also effective in the treatment of this condition, as is penicillin given parenterally.14 VULVOVAGINITIS IN CHILDREN
Vulvovaginitis in children is generally classified as "specific" when it is caused by the gonococcus· or "nonspecific" when due to other causes. The nonspecific type of vaginitis in children may result from the introduction of foreign bodies into the vagina, local irritation from manipulation or tight clothing, uncleanliness or low grade infections with a variety of organisms. Because of the delicate nature of the epithelial lining of the vagina together with its neutral or alkaline secretion, this structure in little girls is especially susceptible to bacterial infection. In the treatment of gonococcal vulvovaginitis the first essential is strict isolation in order to prevent contamination of the other children in the household or institution. Care should be taken to prevent infection of the eyes or spread of the infection to the rectum. The local use of antiseptics and douches which formerly required many months and sometimes years of persistent therapy to effect a cure have now been replaced by treatment with estrogenic hormone, suIfonamides or penicillin. Each of these methods possess certain advantages and disadvantages. Estrogenic therapy may be given to cooperative children in the form of vaginal suppositories. A suppository containing 0.05 to 0.1 mg. of stilbestrol is inserted each night into the vagina. This is continued for three weeks after which smears are taken at weekly intervals until three negative smears have been obtained. If a cure cannot be effected with two courses of estrogenic therapy it is usually better to proceed with either suIfonamides or penicillin in order to avoid inducing premature sexual changes. In children in whom local treatment is not possible or feasible, stilbestrol may be given orally 0.1 mg. daily for two to three weeks. If * Triple-Sulfa Cream, generously supplied to us for clinical investigation by
Ortho Pharmaceutical Corp., Linden, New Jersey, contains micronized "sulfa" drugs (identified as sulfathiazole, acetylsulfonamide and benzylsulfanilamide) in a suitable base, nonbuffered to permit optimal pH effectiveness for the "sulfa" compounds.
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any tendency toward growth of pubic hair or tenderness of the breast is noted this type of treatment should be stopped at once. • A high percentage of successful results can be obtained with estrogenic therapy in children. In refractory or recurrent cases, examination of the cervix with a cystoscope should be made and the rectum should also be examined for infection. If either of these structures is infected, treatment with sulfonamides or penicillin is indicated. In a number of clinics treatment with sulfonamides is preferred from the onset. In other clinics estrogens are preferred in order to avoid sensitization to the sulfonamides. Sulfathiazole is the most commonly employed preparation for sulfonamide therapy. The generally recommended dosage is 0.5 gram per pound of body weight per day in four divided doses with an equal amount of sodium bicarbonate which is continued for seven to fourteen days, never longer than three weeks. Good results can also be obtained with sulfadiazine in half the dose for sulfathiazole. Preliminary results with penicillin administered locally and parenterally indicate that it is highly effective and will probably prove to be a most valuable method of treatment. 15 , 16 As yet the best method of administration and dosage requires further investigation. In the nonspecific infections of children the most important factor is the removal of any underlying cause such as foreign bodies as sources of local irritation. The infection itself will generally respond to the use of antiseptics, suppositories or jellies used persistently through a number of weeks. In the more persistent or severe cases, treatment with the estrogens as described for the gonococcal cases will generally effect a rapid cure. Sulfonamide therapy is not generally indicated in the nonspecific infections. BIBLIOGRAPHY 1. Rakoff, A. E. and Caspar, S. L.: The Technic of Vaginal Medication. Pennsylvania M. J., 46:582, 1943.
2. Rakoff, A. E., Feo, L. G. and Goldstein, L.: The Biologic Characteristics of the Normal Vagina. Am. J. Ob st. & Gynec., 47:467, 1944. 3. Karnaky, K. J.: Normal Physiologic Douches. South. M. J.,30:69, 1937. 4. Bland, P. B. and Rakoff, A. E.: Leukorrhea, Clinical and Therapeutic Aspects. ].A.M.A., 1S5:1013, 1940. 5. Chrisman, R. B., Jr.: Clinical Results with the Use of a Buffered Acid Jelly, pH 4.5 and Other Jellies of Vaiying pH, in Gynecologic Infections: Study of 129 Cases. J. Tennessee State M. A., 35:455, 1942. 6. Allen, E. and Baum, H. C.: The Treatment of Vaginitis. Am. J. Ohst. & Gynec., 45:246, 1943. 7. Bland, P. B. and Rakoff, A. E.: The Incidence of Trichomonads in the Vagina, Mouth and Rectum. J.A.M.A., 188:2013, 1937. 8. Roth, R. B.: Trichomonas Urethritis and Prostatitis. Ven. Dis. Inform., 25:163, 1944.
9. Johnson, G. and Trussell, R. E.: Experimental Basis for the Chemotherapy of Trichomonas Vaginalis Infestations. 1. Proc. Soc. Exper. BioI. & Med., 54:245, 1943.
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10. Bland, P. B. and Rakoff, A. E.: Trichomonas Infestation of the Female Urinary Tract. Uro!' & Cutan. Rev., 44:698, 1940.
11. Bland. P. B. and Rakoff, A. E.: The Investigation of a New Pentavalent Arsenical, Aldarsone, in the Treatment of Trichomonas Vaginitis. Am. J.' Obst. & Gynec., 32:835, 1936. 12. Hesseltine, H. C.: Experimental & Clinical Therapy of Vulvovaginal Mycoses. Am. J. Obst. & Gynec., 34:439, 1937. 13. Bland, P. B., Rakoff, A. E. and Pincus, I. J.: Experimental Vaginal & Cutaneous Moniliasis. Arch. Derm. & Syph., 36:760, 1937. 14. Herrell, W. E.: Penicillin and Other Antibiotic Agents. Philadelphia, W. B. Saunders Co., 1945, p. 247. 15. Sandes, G. M.: Vulvovaginitis in Children. Brit. M. J., 1:160, 1944. 16. Cohn, A., Studdiford, W. E. and Grunstein, I.: Penicillin Treatment of Sulfonamide Resistant Gonococci Infections in Female Patients; Preliminary Report. J.A.MA., 124:1124, 1944.