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The treatment of trichomoniasis with metronidazole
The treatment of trichomoniasis with metronidazole RAMA LUTHRA, M.D.
J.
R. BOYD, M.D.
Vancouver, British Columbia
UN T r L recently almost all methods for the treatment of trichomoniasis in women have been directed locally at the vaginal infestation. With the increasing conviction that the resistance of the Trichomonas vaginalis organism to therapy was due both to its venereal transmission by the male and also to its ability to live in the female bladder, urethra, and paraurethral glands, the necessity for some form of systemic therapy applicable to both male and female subjects has become apparent. In 1955 Nakamura 1 isolated azomycin ( 2-nitroimidazole), an antibiotic which was thought to be orally effective but which has proved clinically unsa tis£ actory. 2 Cosar and Julou" experimented with chemical derivatives of azomycin and in 1959 reported on the trichomonacidal properties of metronidazole* ( 1-2'-hydroxyethyl)2-methyl-5-nitroimidazole) in experimental animals. It was found to be highly efficacious and of low toxicity. Clinical studies carried out by Durel and associates 4 on human subjects, both male and female, seemed promising indeed. This work was continued in Montreal by Fortier 5 and Sylvestre and Gallai, 6 and their very encouraging results stimulated us to undertake the present study.
Durel showed that the oral administration of metronidazole rendered the serum trichomonacidal in a dilution of 1:10 for 3 hours and the urine trichomonacidal in a dilution of 1:1,000 for more than 4 hours. He further showed no toxic effects on the white blood cells and no important general toxic effect~ have been reported thus far. Trichomonacidal activity in the vaginal secretions after oral therapy has not been demonstrated so far, and for this reason there is considerable divergence of opinion at present as to the best mode of therapy. There is no doubt as to the highly trichomonacidal effect of metronidazole administered vaginally. Fortier treated 31 patients by combined oral and vaginal therapy ( 250 mg. twice a day by mouth and one 500 mg. vaginal suppository daily) for 10 to 20 days and, after 26 patients were followed for 6 to 12 weeks, no recurrences were detected by culture methods. Of 7 patients treated by the oral route alone, treatment failed in 3. These patients were subsequently cured bv the combined method. Fortier also treated 7 husbands noted to be infected with Trichomonas with complete success. Subsequent to the institution of our study, several interesting reports have been received pertaining especially to the dosage, route, and schedule and to tlie treatment of the man. Bouziane and Desranleau/ using a combined approach, reported 100 per cent cure m 41 women after 2 weeks of treatment.
From the Department of Obstetrics and Gynaecology of the University of British Columbia, and the Vancouver General Hospital. *Metronidazole used in this study was supplied as Flagvl through the courtesy of Poulenc, Ltd.
1288
Volume 83
Treatment of trichomoniasis with metronidazole
1289
.'o:umber IU
Durel and associates 8 in a later publication advocated combined therapy for 15 to 20 days. They noted an unsatisfactory cure rate when either vaginal or oral administration alone was used. Watt and Jennison" treated 50 patients by the oral route alone for 7 days with immediate cure in 44. Rodin and associates'" treated 82 women orally for 7 days with 4 initial failures; in 52 patients observed for 3 months, there were 10 failures. Nicol, Barrow, and Redmond 11 obtained essentially similar results with only 5 days of oral therapy, as did Willcox 2 with 7 days of therapy. Treatment of the men, as reported by Rodin and associates, 10 Nicol, Barrow, and Redmond, 11 and Sylvestre, Belanger, and Gallai, 12 with oral therapy for 5 to 10 days has apparently been completely successful.
Materials and methods From July 1, 1960, to Feb. 28, 1961, a total of 158 women with vaginitis were examined and treated in the Women's Clinic, Vancouver General Hospital. Of these, 94 were found to have T. vagina/is. In the formulation of our study several practical factors had to be taken into consideration: Our patient population is a fairly representative one, including married and unmarried pregnant women and surgical and nonsurgical gynecologic patients of all ages. No selection was attempted. Since it appeared that husbands or consorts would be impossible to reach in many cases, it was decided to ignore the male factor altogether. As cultures for Trichomonas were not available, our patients were followed with the standard wet smear as carefully as possible. The decision to use the combined approach and schedule of Fortier was made initially. When early results seemed satisfactory, it was decided to continue it. Age. The age range was from 15 to 54 years. The median age of the 41 pregnant women was 2+ years and of the 53 nonpregnant women 31 years. Pregnancy. Of the 94 patients, 41 were pregnant. Symptoms. All 94 patients had typical
symptoms of vagm1t1s to a degree. These varied from merely excessive discharge to severe vulvovaginitis with ulceration. As will be noted below, a substantial number of these women had coincidental Monilia, and for that reason it is uncertain which etiological agent was chiefly responsible for symptoms. The duration of symptoms varied from 1 month to 9 years. As might be anticipated, 50 per cent of the patients had had symptoms for 1 to 6 months. Previous treatment. Only 15 of the 94 patients had had previous therapy for trichomoniasis in our clinic. This is not surprising in view of the relatively short average duration of symptoms. It is, of course, impossible to judge in those previously treated whether we wt>re dealing with the continuation of an infection or a reinfection. Diagnosis. Every patient included in this study was examined at each visit by the same attendant ( R. L.). A routine of examination was carried out which we believe to be simple and reliable: Before any examination other than inspection of the vulva was carried out, a speculum moistened only with warm water was inserted into the vagina. After cursory inspection a swab was taken from the posterior fornix and placed immediately in 3 c.c. of warm physiologic saline solution. A second swab was then taken which was subsequently cultured for Monilia on Nickerson's medium, and smears for cytology and gonorrhea were taken as indicated. The remainder of the pelvic examination was then carried out. As soon as possible a few drops of the saline suspension were examined under the microscope. A cover slip was not used. A careful search was made for pus cells and motile organisms, and, in many cases, after the addition of 10 per cent potassium hydroxide a further search was made for Monilia. Treatment. The 94 patients in whom the motile T. vagina/is organisms were identified were in every case put on a course of metronidazole in the following dosage: one 250
1290
May 1.\ l'lbc
Luthro and Boyd
\m.
Table I. Results of follow-up in 94 patients treated with metronidazole Follow-up (months)
Patients
15 74 63 53
0
1 2 3
Failures 1
2 2
·---------~---~···
Total
94
5
Table II. Coincidental infections
Trichomoniasis Trichomoniasis Trichomoniasis vaginitis Trichomoniasis
alone and moniliasis and nonspecific
49
37 6
2
and
------~-~-'----~-~- -·-----~·
Total
94 --~·--·--·----
Table III. The relationship of pregnancy and moniliasis in patients treated for trichomoniasis 53
Nonpregnant patients
Trichomoniasis alone Trichomoniasis and moniliasis Pregnant patients Trichomoniasis alone Trichomoniasis and moniliasis
39 i4 41 18
23
mg. tablet orally morning and night and one 500 mg. vaginal suppository at bedtime, concurrently for 10 consecutive daysa The patient was specifically instructed not to douche, and no instruction was given regarding intercourse. No instruction or treatment was given the husband or sexual consort in any case. Even when moniliasis was diagnosed or suspected initially, our policy was to treat the Trichomoniasis first. The patients were instructed to return in one month, but in several cases they returned sooner with troublesome symptoms due to Monilia. When moniliasis was concurrently diagnosed, it was subsequently treated with nystatin vaginal suppositories, 100,000 units twice a day for 10 days, or chlordantoin cream vaginaliy ior 2 weeks, or occasionaiiy both. Neither of these substances has been
J.
Ohst. & Gynec.
observed to have any effect on Trichomonas. Patients with concurrent gonorrhea Wt're u;ivcn the usual penicillin treatment. On the return visits, which as often as possible were timed for a week after the menses, a similar routine was carried out. If on this examination no trichomonads were found, the patient was recalled again immediately after the next period. Regular examinations were thus carried out until 3 months or more had elapsed. Results Of the 94 patients treated, 53 were followed for 3 consecutive months. Too few were followed longer to be meaningful except in a few cases noted below. The results of follow-up are noted in Table I. Effects of coincidental infection. Coincidental infections were noted in 45 patients as shown in Table II. Coincidental gonorrhea was treated with penicillin and appeared to have no effect on the metronidazole therapy, which was successful in both cases. Coincidental nonspecific vaginitis was diagnosed in 6 patients who, following successful treatment for trichomoniasis, had a persistent discharge which responded satisfactorily to vaginal sulfonamide therapy. Thirty-seven of the patients had coincidental Monilia cultured at the time of the original examination. In 31 patients, soon after the institution of metronidazole therapy, there was an increase in symptoms of vaginal and vulvar irritation. Re-examination showed findings typical of monilial vaginitis and of sufficient severity to necessitate anti-Monilia treatment in these cases. In 5 cases it was necessary to stop the metronidazole therapy for a few days to control the Monilia. The relatively large number of patients harboring Monilia was no doubt in part due to the large number of pregnant women in the series. The relationship of pregnancy and moniliasis is shown in Table III. Effects of coincidental pregnancy. As can be seen in Table III, about 45 per cent of
Volume 83 Number iO
Treatment of trichomoniasis with metronidazole
Side effects. In 5 cases, therapy was halted until the monilial infection could be brought under controL In one other case it was necessary to alter treatment because of the development of an irritating vulvar rash on the eighth day. Treatment was discontinued and the eruption promptly subsided. It \Vas found that the gastrointestinal symptoms were controlled by instructing the patient to take the oral medication immediately after food.
our patients were pregnant at the time of treatment. This had no observable effect on the success of the metronidazole therapy. The results shown in Table I are further broken down to illustrate the distribution of cases relevant to pregnancy and coincirln....... +-LQJ. ..... 1 U\.....~.1
,..~,... ..... ~1~~"'~ ...
.l.lH.J.l.l.l.l.lCl,.;:).l;"}
;-n Tl'lhl.o. T\T "'-lJ..l\...-
J..l.l
..L
.L
"
1291
•
It would appear that pregnancy and/or
moniliasis had no effect on the failure rate. Failures. Case 1. Nonpregnant. Patient mistakenly 11sed both oral and vaginal tablets vaginally. Re-treated with correct schedule and negatin~ for 3 months. Case 2. Pregnant. Not seen at I and 2 months. Positive at 3 months. Re-treated with negative follow-up. Case 3. Nonpregnant. Unable to tolerate oral tablets. Negative for 2 months. Positive at 3 months. Retreated with suppositories alone. Patient very promiscuous. Case 4. Pregnant. Positive at 2 months. Re-treated. Case 5. Pregnant. Positive at 2 months, which was also 6 weeks post partum. Retreated with 3 month cure. In addition, in the small group of patients which have been followed for a longer period, there have been two later recurrences. One patient was pregnant and findings were negative for 4 months; at the fifth month (which was 2 months post partum) findings were positive. The second patient showed negative findings for 6 months while in jail: on discharge, she had a recurrence and was retreated. The patient is promisnious.
Comment
The objection may be raised that culture methods were not used for test of cure. Our view is that if the results of repeated careful search for trichomonads are negative and if clinical signs and symptoms are absent, there is little reason at 3 months to question a cure. Studies 13 • 14 comparing careful wet smear with cultures suggest the error to be small. From a practical point of view, cultures are not available to the average clinician, so that our method duplicates what might reasonably be expected to obtain in practice. The fact that male consorts were not treated or intercourse interdicted in this series casts serious doubt on the general necessity for these measures. However, when early reinfection seems to be the cause of treatment failure, it would seem logical to treat the consort. Our study throws no light on the advisability of concurrent oral and vaginal therapy as opposed to oral therapy alone. Our results, however, are as good as or better than
Table IV. Effect of pregnancy and moniliasis on the treatment of trichomoniasis with metronidazole Follow-uP I month Infection
Pregnant
I
2 months
Nonpregnant
Pregnant
Total cases Trichomoniasis alone Trichomoniasis and moniliasis
14 19
27
8
14
20
Failures Trichomoniasis alone Trichomoniasis and moniliasis
0 0
1 0
0
2
3 months Non-
Nonpregnant
Pregnant
23 1:!
7
19
19
8
0 0
0 1
1 0
I pregnant
1292
May 15,
Luthra and Boyd
,\m.
Table V. Side effects of metronidazole therapy Symptom
No. of patients
Bitter taste in mouth Abdominal discomfort ~ausea and vomiting Headache Vulvar rash Worsening of symptoms due to moniliasis
:2 1 3 1 1 31
any senes reported in which the oral route alone was used. Although it may be argued that oral therapy is much more acceptable to the patient, we encountered resistance or lack of cooperation in only one case. \¥e have no doubt that in the future it may seem wise to carry out oral treatment alone initially and to resort to combined therapy, quite possibly including treatment of the male consort, in case of failure. Because when this study was being carried out we were for another reason closely studying monilial infections, we have a very accuratt> check on the effects of metronidazole on the yeast infestation. There is no doubt in our minds that in some cases the monilial growth was encouraged by metronidazole. The problem of monilial overgrowth has not been considered important in most series reported: Rees 15 and Rodin and associatesl<' studied patients noted to have a positive culture for moniliasis and reported no exacerbation of symptoms; on the other hand, Scott-Gray1 " and Moffett 17 believed that monilial growth was encouraged. Possibly the most important observation was that of Durel and associates, 8 who noted monilial overgrowth twice as often in patients on vaginal therapy as in patients on oral ther-
REFERENCES
1. Nakamura, S.: Pharmacal. Bull. Japan 3: 379, 1955. 2. Willcox, R. R.: Brit . .f. Vf'n. Dis. 36: 17'\
1960.
:>. Cosar. C:., and Julou, L.: Ann. Inst. Pastf'ur 96: 238, 1959. 4. Dur<'l, P., Roiron, V.. Siboulet, A., Borel, L. J.: Rev. prat. 9: 2528, 1959.
and
J.
196~
Obst. & Gyrwc.
apy. In any case, it is most important to sec the patient a few days after the institution of metronidazole therapy to make sure that the irritation due to trichomoniasis has not been replaced by irritation due to moniliasis. If, at the initial examination, hoth moniliasis and trichomoniasis arc diagnosed. on the basis of our experience it would seem wise to treat the two conditions simultaneously. Undesirable but not serious side cff ec ts were noted in a few patients (Table V\ and were similar to those reported in most other series. Although skin rashes have been infrequently noted, to our knowledge thes~· have not been reported to involve the vulva: the occurrence of such an eruption seems worth noting as a possible source of clinical confusion. It should be noted that although 5 of om cases are reported as failures, Cases 1 and 3 did not receive full treatment. The 2 cases of late recurrence seem most probably to be reinfections. Summary
l. Ninety-four women, including 41 who were pregnant, were treated for Trichomonas vaginitis with metronidazole by the combined oral and vaginal routes. In the 5:) who were followed for 3 months, there were 5 failures. 2. The husbands or sexual consorts we-re not treated. :"\. Pregnancy or concurrent gonorrhea. moniliasis, or nonspecific vaginitis did not interfere with the efficacy of the treatment. 4. Thirty-seven women were noted to haw coincidental moniliasis and in 31 this was apparently worsened. Other side eft'ects were unimportant.
'l. Fortin·, L.: Gynecologia 149: suppl., 1960. 6. Syl\Tstrf', L., and Gallai. Z.: Union rned. Canada 89: 7:>5, 1960. 7. Rouziane, N. R., and Desranleau, .f. M.: L1 nion m~d. Canada 89: 759, 1960. 8. Durd, P., Couture, J., Collart, P., and Girot, C.: Brit. J. Ven. Dis. 36: 154, 1960. 9. Watt, L .. and JPnnison, R. G.: Brit. M. J.
2: 902, 1960.
Volume 83
Treatment of trichomoniasis with metronidazole
Number 10
10. Rodin, P., King, A. J., Nicol, C. S., and Barrow, J.: Brit. J. Ven. Dis. 36: 147, 1960. 11. Nicol, C. S., Barrow, ]., and Redmond, A.: Brit. J. Ven. Dis. 36: 152, 1960. 12. Sylvestre, L., Belanger, M., and Gallai, Z.: ~~~n~ri
................ u ...........
1\K ... ,.. .....
A"-• JT. ._.. R'l· 11 Q~ , 1... Qt;() .................... """"'-'•
~
14. 15. 16.
! 3. Trussd, R. E.: Trichomonas Vaginalis and
17.
1293
194 7, Trichomoniasis, Springfield, Ill.. Charles C Thomas, Publisher, p. 122. Perl, G., Guttmacher, A., and Raggazoni, H.: Obst. & Gynec. 7: 128, 1956. Rees, E., Brit. M. J. 2: 906, 1960. Scott-Gray, ~1.: Brit. J. \Ten. Dis. 36: 158 . 1960. Moffett, M.: Brit. M. ]. 2: 910, 1960.
J.
R. BOYD, M.D.
Vancouver, British Columbia
UN T r L recently almost all methods for the treatment of trichomoniasis in women have been directed locally at the vaginal infestation. With the increasing conviction that the resistance of the Trichomonas vaginalis organism to therapy was due both to its venereal transmission by the male and also to its ability to live in the female bladder, urethra, and paraurethral glands, the necessity for some form of systemic therapy applicable to both male and female subjects has become apparent. In 1955 Nakamura 1 isolated azomycin ( 2-nitroimidazole), an antibiotic which was thought to be orally effective but which has proved clinically unsa tis£ actory. 2 Cosar and Julou" experimented with chemical derivatives of azomycin and in 1959 reported on the trichomonacidal properties of metronidazole* ( 1-2'-hydroxyethyl)2-methyl-5-nitroimidazole) in experimental animals. It was found to be highly efficacious and of low toxicity. Clinical studies carried out by Durel and associates 4 on human subjects, both male and female, seemed promising indeed. This work was continued in Montreal by Fortier 5 and Sylvestre and Gallai, 6 and their very encouraging results stimulated us to undertake the present study.
Durel showed that the oral administration of metronidazole rendered the serum trichomonacidal in a dilution of 1:10 for 3 hours and the urine trichomonacidal in a dilution of 1:1,000 for more than 4 hours. He further showed no toxic effects on the white blood cells and no important general toxic effect~ have been reported thus far. Trichomonacidal activity in the vaginal secretions after oral therapy has not been demonstrated so far, and for this reason there is considerable divergence of opinion at present as to the best mode of therapy. There is no doubt as to the highly trichomonacidal effect of metronidazole administered vaginally. Fortier treated 31 patients by combined oral and vaginal therapy ( 250 mg. twice a day by mouth and one 500 mg. vaginal suppository daily) for 10 to 20 days and, after 26 patients were followed for 6 to 12 weeks, no recurrences were detected by culture methods. Of 7 patients treated by the oral route alone, treatment failed in 3. These patients were subsequently cured bv the combined method. Fortier also treated 7 husbands noted to be infected with Trichomonas with complete success. Subsequent to the institution of our study, several interesting reports have been received pertaining especially to the dosage, route, and schedule and to tlie treatment of the man. Bouziane and Desranleau/ using a combined approach, reported 100 per cent cure m 41 women after 2 weeks of treatment.
From the Department of Obstetrics and Gynaecology of the University of British Columbia, and the Vancouver General Hospital. *Metronidazole used in this study was supplied as Flagvl through the courtesy of Poulenc, Ltd.
1288
Volume 83
Treatment of trichomoniasis with metronidazole
1289
.'o:umber IU
Durel and associates 8 in a later publication advocated combined therapy for 15 to 20 days. They noted an unsatisfactory cure rate when either vaginal or oral administration alone was used. Watt and Jennison" treated 50 patients by the oral route alone for 7 days with immediate cure in 44. Rodin and associates'" treated 82 women orally for 7 days with 4 initial failures; in 52 patients observed for 3 months, there were 10 failures. Nicol, Barrow, and Redmond 11 obtained essentially similar results with only 5 days of oral therapy, as did Willcox 2 with 7 days of therapy. Treatment of the men, as reported by Rodin and associates, 10 Nicol, Barrow, and Redmond, 11 and Sylvestre, Belanger, and Gallai, 12 with oral therapy for 5 to 10 days has apparently been completely successful.
Materials and methods From July 1, 1960, to Feb. 28, 1961, a total of 158 women with vaginitis were examined and treated in the Women's Clinic, Vancouver General Hospital. Of these, 94 were found to have T. vagina/is. In the formulation of our study several practical factors had to be taken into consideration: Our patient population is a fairly representative one, including married and unmarried pregnant women and surgical and nonsurgical gynecologic patients of all ages. No selection was attempted. Since it appeared that husbands or consorts would be impossible to reach in many cases, it was decided to ignore the male factor altogether. As cultures for Trichomonas were not available, our patients were followed with the standard wet smear as carefully as possible. The decision to use the combined approach and schedule of Fortier was made initially. When early results seemed satisfactory, it was decided to continue it. Age. The age range was from 15 to 54 years. The median age of the 41 pregnant women was 2+ years and of the 53 nonpregnant women 31 years. Pregnancy. Of the 94 patients, 41 were pregnant. Symptoms. All 94 patients had typical
symptoms of vagm1t1s to a degree. These varied from merely excessive discharge to severe vulvovaginitis with ulceration. As will be noted below, a substantial number of these women had coincidental Monilia, and for that reason it is uncertain which etiological agent was chiefly responsible for symptoms. The duration of symptoms varied from 1 month to 9 years. As might be anticipated, 50 per cent of the patients had had symptoms for 1 to 6 months. Previous treatment. Only 15 of the 94 patients had had previous therapy for trichomoniasis in our clinic. This is not surprising in view of the relatively short average duration of symptoms. It is, of course, impossible to judge in those previously treated whether we wt>re dealing with the continuation of an infection or a reinfection. Diagnosis. Every patient included in this study was examined at each visit by the same attendant ( R. L.). A routine of examination was carried out which we believe to be simple and reliable: Before any examination other than inspection of the vulva was carried out, a speculum moistened only with warm water was inserted into the vagina. After cursory inspection a swab was taken from the posterior fornix and placed immediately in 3 c.c. of warm physiologic saline solution. A second swab was then taken which was subsequently cultured for Monilia on Nickerson's medium, and smears for cytology and gonorrhea were taken as indicated. The remainder of the pelvic examination was then carried out. As soon as possible a few drops of the saline suspension were examined under the microscope. A cover slip was not used. A careful search was made for pus cells and motile organisms, and, in many cases, after the addition of 10 per cent potassium hydroxide a further search was made for Monilia. Treatment. The 94 patients in whom the motile T. vagina/is organisms were identified were in every case put on a course of metronidazole in the following dosage: one 250
1290
May 1.\ l'lbc
Luthro and Boyd
\m.
Table I. Results of follow-up in 94 patients treated with metronidazole Follow-up (months)
Patients
15 74 63 53
0
1 2 3
Failures 1
2 2
·---------~---~···
Total
94
5
Table II. Coincidental infections
Trichomoniasis Trichomoniasis Trichomoniasis vaginitis Trichomoniasis
alone and moniliasis and nonspecific
49
37 6
2
and
------~-~-'----~-~- -·-----~·
Total
94 --~·--·--·----
Table III. The relationship of pregnancy and moniliasis in patients treated for trichomoniasis 53
Nonpregnant patients
Trichomoniasis alone Trichomoniasis and moniliasis Pregnant patients Trichomoniasis alone Trichomoniasis and moniliasis
39 i4 41 18
23
mg. tablet orally morning and night and one 500 mg. vaginal suppository at bedtime, concurrently for 10 consecutive daysa The patient was specifically instructed not to douche, and no instruction was given regarding intercourse. No instruction or treatment was given the husband or sexual consort in any case. Even when moniliasis was diagnosed or suspected initially, our policy was to treat the Trichomoniasis first. The patients were instructed to return in one month, but in several cases they returned sooner with troublesome symptoms due to Monilia. When moniliasis was concurrently diagnosed, it was subsequently treated with nystatin vaginal suppositories, 100,000 units twice a day for 10 days, or chlordantoin cream vaginaliy ior 2 weeks, or occasionaiiy both. Neither of these substances has been
J.
Ohst. & Gynec.
observed to have any effect on Trichomonas. Patients with concurrent gonorrhea Wt're u;ivcn the usual penicillin treatment. On the return visits, which as often as possible were timed for a week after the menses, a similar routine was carried out. If on this examination no trichomonads were found, the patient was recalled again immediately after the next period. Regular examinations were thus carried out until 3 months or more had elapsed. Results Of the 94 patients treated, 53 were followed for 3 consecutive months. Too few were followed longer to be meaningful except in a few cases noted below. The results of follow-up are noted in Table I. Effects of coincidental infection. Coincidental infections were noted in 45 patients as shown in Table II. Coincidental gonorrhea was treated with penicillin and appeared to have no effect on the metronidazole therapy, which was successful in both cases. Coincidental nonspecific vaginitis was diagnosed in 6 patients who, following successful treatment for trichomoniasis, had a persistent discharge which responded satisfactorily to vaginal sulfonamide therapy. Thirty-seven of the patients had coincidental Monilia cultured at the time of the original examination. In 31 patients, soon after the institution of metronidazole therapy, there was an increase in symptoms of vaginal and vulvar irritation. Re-examination showed findings typical of monilial vaginitis and of sufficient severity to necessitate anti-Monilia treatment in these cases. In 5 cases it was necessary to stop the metronidazole therapy for a few days to control the Monilia. The relatively large number of patients harboring Monilia was no doubt in part due to the large number of pregnant women in the series. The relationship of pregnancy and moniliasis is shown in Table III. Effects of coincidental pregnancy. As can be seen in Table III, about 45 per cent of
Volume 83 Number iO
Treatment of trichomoniasis with metronidazole
Side effects. In 5 cases, therapy was halted until the monilial infection could be brought under controL In one other case it was necessary to alter treatment because of the development of an irritating vulvar rash on the eighth day. Treatment was discontinued and the eruption promptly subsided. It \Vas found that the gastrointestinal symptoms were controlled by instructing the patient to take the oral medication immediately after food.
our patients were pregnant at the time of treatment. This had no observable effect on the success of the metronidazole therapy. The results shown in Table I are further broken down to illustrate the distribution of cases relevant to pregnancy and coincirln....... +-LQJ. ..... 1 U\.....~.1
,..~,... ..... ~1~~"'~ ...
.l.lH.J.l.l.l.l.lCl,.;:).l;"}
;-n Tl'lhl.o. T\T "'-lJ..l\...-
J..l.l
..L
.L
"
1291
•
It would appear that pregnancy and/or
moniliasis had no effect on the failure rate. Failures. Case 1. Nonpregnant. Patient mistakenly 11sed both oral and vaginal tablets vaginally. Re-treated with correct schedule and negatin~ for 3 months. Case 2. Pregnant. Not seen at I and 2 months. Positive at 3 months. Re-treated with negative follow-up. Case 3. Nonpregnant. Unable to tolerate oral tablets. Negative for 2 months. Positive at 3 months. Retreated with suppositories alone. Patient very promiscuous. Case 4. Pregnant. Positive at 2 months. Re-treated. Case 5. Pregnant. Positive at 2 months, which was also 6 weeks post partum. Retreated with 3 month cure. In addition, in the small group of patients which have been followed for a longer period, there have been two later recurrences. One patient was pregnant and findings were negative for 4 months; at the fifth month (which was 2 months post partum) findings were positive. The second patient showed negative findings for 6 months while in jail: on discharge, she had a recurrence and was retreated. The patient is promisnious.
Comment
The objection may be raised that culture methods were not used for test of cure. Our view is that if the results of repeated careful search for trichomonads are negative and if clinical signs and symptoms are absent, there is little reason at 3 months to question a cure. Studies 13 • 14 comparing careful wet smear with cultures suggest the error to be small. From a practical point of view, cultures are not available to the average clinician, so that our method duplicates what might reasonably be expected to obtain in practice. The fact that male consorts were not treated or intercourse interdicted in this series casts serious doubt on the general necessity for these measures. However, when early reinfection seems to be the cause of treatment failure, it would seem logical to treat the consort. Our study throws no light on the advisability of concurrent oral and vaginal therapy as opposed to oral therapy alone. Our results, however, are as good as or better than
Table IV. Effect of pregnancy and moniliasis on the treatment of trichomoniasis with metronidazole Follow-uP I month Infection
Pregnant
I
2 months
Nonpregnant
Pregnant
Total cases Trichomoniasis alone Trichomoniasis and moniliasis
14 19
27
8
14
20
Failures Trichomoniasis alone Trichomoniasis and moniliasis
0 0
1 0
0
2
3 months Non-
Nonpregnant
Pregnant
23 1:!
7
19
19
8
0 0
0 1
1 0
I pregnant
1292
May 15,
Luthra and Boyd
,\m.
Table V. Side effects of metronidazole therapy Symptom
No. of patients
Bitter taste in mouth Abdominal discomfort ~ausea and vomiting Headache Vulvar rash Worsening of symptoms due to moniliasis
:2 1 3 1 1 31
any senes reported in which the oral route alone was used. Although it may be argued that oral therapy is much more acceptable to the patient, we encountered resistance or lack of cooperation in only one case. \¥e have no doubt that in the future it may seem wise to carry out oral treatment alone initially and to resort to combined therapy, quite possibly including treatment of the male consort, in case of failure. Because when this study was being carried out we were for another reason closely studying monilial infections, we have a very accuratt> check on the effects of metronidazole on the yeast infestation. There is no doubt in our minds that in some cases the monilial growth was encouraged by metronidazole. The problem of monilial overgrowth has not been considered important in most series reported: Rees 15 and Rodin and associatesl<' studied patients noted to have a positive culture for moniliasis and reported no exacerbation of symptoms; on the other hand, Scott-Gray1 " and Moffett 17 believed that monilial growth was encouraged. Possibly the most important observation was that of Durel and associates, 8 who noted monilial overgrowth twice as often in patients on vaginal therapy as in patients on oral ther-
REFERENCES
1. Nakamura, S.: Pharmacal. Bull. Japan 3: 379, 1955. 2. Willcox, R. R.: Brit . .f. Vf'n. Dis. 36: 17'\
1960.
:>. Cosar. C:., and Julou, L.: Ann. Inst. Pastf'ur 96: 238, 1959. 4. Dur<'l, P., Roiron, V.. Siboulet, A., Borel, L. J.: Rev. prat. 9: 2528, 1959.
and
J.
196~
Obst. & Gyrwc.
apy. In any case, it is most important to sec the patient a few days after the institution of metronidazole therapy to make sure that the irritation due to trichomoniasis has not been replaced by irritation due to moniliasis. If, at the initial examination, hoth moniliasis and trichomoniasis arc diagnosed. on the basis of our experience it would seem wise to treat the two conditions simultaneously. Undesirable but not serious side cff ec ts were noted in a few patients (Table V\ and were similar to those reported in most other series. Although skin rashes have been infrequently noted, to our knowledge thes~· have not been reported to involve the vulva: the occurrence of such an eruption seems worth noting as a possible source of clinical confusion. It should be noted that although 5 of om cases are reported as failures, Cases 1 and 3 did not receive full treatment. The 2 cases of late recurrence seem most probably to be reinfections. Summary
l. Ninety-four women, including 41 who were pregnant, were treated for Trichomonas vaginitis with metronidazole by the combined oral and vaginal routes. In the 5:) who were followed for 3 months, there were 5 failures. 2. The husbands or sexual consorts we-re not treated. :"\. Pregnancy or concurrent gonorrhea. moniliasis, or nonspecific vaginitis did not interfere with the efficacy of the treatment. 4. Thirty-seven women were noted to haw coincidental moniliasis and in 31 this was apparently worsened. Other side eft'ects were unimportant.
'l. Fortin·, L.: Gynecologia 149: suppl., 1960. 6. Syl\Tstrf', L., and Gallai. Z.: Union rned. Canada 89: 7:>5, 1960. 7. Rouziane, N. R., and Desranleau, .f. M.: L1 nion m~d. Canada 89: 759, 1960. 8. Durd, P., Couture, J., Collart, P., and Girot, C.: Brit. J. Ven. Dis. 36: 154, 1960. 9. Watt, L .. and JPnnison, R. G.: Brit. M. J.
2: 902, 1960.
Volume 83
Treatment of trichomoniasis with metronidazole
Number 10
10. Rodin, P., King, A. J., Nicol, C. S., and Barrow, J.: Brit. J. Ven. Dis. 36: 147, 1960. 11. Nicol, C. S., Barrow, ]., and Redmond, A.: Brit. J. Ven. Dis. 36: 152, 1960. 12. Sylvestre, L., Belanger, M., and Gallai, Z.: ~~~n~ri
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A"-• JT. ._.. R'l· 11 Q~ , 1... Qt;() .................... """"'-'•
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14. 15. 16.
! 3. Trussd, R. E.: Trichomonas Vaginalis and
17.
1293
194 7, Trichomoniasis, Springfield, Ill.. Charles C Thomas, Publisher, p. 122. Perl, G., Guttmacher, A., and Raggazoni, H.: Obst. & Gynec. 7: 128, 1956. Rees, E., Brit. M. J. 2: 906, 1960. Scott-Gray, ~1.: Brit. J. \Ten. Dis. 36: 158 . 1960. Moffett, M.: Brit. M. ]. 2: 910, 1960.