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- Treat bacterial vaginosis with oral or intravaginal metronidazole or with clindamycin (SOR: A);recurrences are common (SOR:C).
- Oral and intravaginal imidazoles are equally effective in the treatment of candidiasis (SOR:A); alternate therapies for resistant cases have been little studied. Oral metronidazole is the standard therapy for trichomoniasis (SOR: A).
- Oral tinidazole, newly available in the US in 2004, should be used in resistant cases (SOR: B).
Antifungal medications for intravaginal use have been available in the United States for more than a decade. Women may be inclined to self-diagnose yeast infections with any vaginal discharge or other vulvovaginal symptoms that they deem abnormal. As we saw in the first part of this article, “Abnormal vaginal discharge: Using office diagnostic testing more effectively” (JFP2004; 53[10]:805–814), abnormal discharge is more likely to be bacterial vaginosis or no pathogen at all. Potential delay in diagnosis and treatment of a sexually transmitted disease is also a concern. Increasing resistance of Candida sp. to imidazoles is associated with indiscriminate use of over-the-counter products.
Bacterial vaginosis
The standard treatment for bacterial vaginosis (BV) has been oral metronidazole (Flagyl) 500 mg twice daily for 5 to 7 days. Intravaginal 0.75% metronidazole gel (MetroGel) has been shown to be as effective as oral metronidazole (SOR: A).1,2
Oral metronidazole can cause nausea and abdominal pain in some patients; vaginal treatment may be preferable for them. A meta-analysis of 52 studies of regimens of oral metronidazole at a dose of 2 g daily of varying duration showed similar initial cure rates of 85%, 87%, 86%, and 87% for 1, 2, 5, and 7 days, respectively (strength of recommendation [SOR]: A).3 Single-dose therapy may improve adherence (SOR: C).
Clindamycin (Cleocin), orally or in vaginal cream, for 5 days is also effective for BV (SOR: A).4-8 Clindamycin cream is used at a dose of 5 g daily and a concentration of 2%. Lower concentration (1%) has been less effective.6 Oral regimens range from 300 mg twice daily to 450 mg 3 times daily. Oral and vaginal preparations have shown equal efficacy in direct comparisons (SOR: A).8 A 3-day course of vaginal clindamycin is as effective as a 5-day course (SOR: B).9
Several studies have compared clindamycin and metronidazole head to head. They have shown similar cure rates that were not statistically different in the 75% to 90% range (SOR: A).4,5,10,11 Other antibiotics that have shown in vitro efficacy for treating the spectrum of microbes associated with BV are amoxicillin-clavulanate (Augmentin), imipenem (Primaxin), and cefmetazole (Zefazone) (SOR: C).8,12 Some Mobiluncus strains show resistance to metronidazole (SOR: C).12
Recurrences of BV are common. The initial regimen or an alternative regimen may be used. A longer, 10- to 14-day, course of antibiotic therapy has been recommended by one expert for treating relapses (SOR: C).13 Recolonizing the vagina with lactobacilli by eating yogurt or using bacteria-containing suppositories is an approach that deserves further study (SOR: C).14 Suppressive therapy such as intravaginal metronidazole twice weekly may also be considered as maintenance therapy to prevent recurrences (SOR: C).
BV and pregnancy
A number of studies have been published on screening for BV in pregnancy using Gram stain and on treating positive cases with antibiotics. While studies that used metronidazole for treatment have not shown consistently good results, more recent studies using clindamycin orally or intravaginally have been promising (SOR: B).7,15 Oral dosing at 300 mg twice daily, at 12 to 22 weeks gestation, has reduced preterm delivery for pregnant women with BV diagnosed by Nugent’s criteria (number needed to treat [NNT]=10).7 Likewise, for women with BV treated at 13 to 20 weeks gestation, intravaginal clindamycin therapy for 3 days has reduced the incidence of preterm births (NNT=17).15
Clindamycin appears to be the treatment of choice for BV in pregnancy (SOR: C) since it is considered safe (category B) throughout pregnancy, and because use of metronidazole in the first trimester is controversial.
Candidiasis
Treating vulvovaginal candidiasis (VVC) with intravaginal imidazoles reduces symptoms with NNT=3 after 1 month (SOR: A) ( Table ).16 No difference has been seen in outcomes with the various imidazoles or with treatment durations of 1 to 14 days. Intravaginal nystatin also decreases symptoms of VVC, with a NNT of 3 after 1 week compared with placebo (SOR: B).
Data showing that imidazoles are more effective than nystatin are not strong (SOR: B). A Clinical Evidencereview16 identified 1 trial comparing intravaginal miconazole, clotrimazole, econazole, and nystatin; symptomatic relapse was lower with intravaginal imidazoles than with nystatin. Another trial comparing clotrimazole and nystatin showed no difference in the proportion of women with persistent symptoms after 4 weeks. An open label study17 comparing econazole, miconazole, and nystatin showed that the imidazoles had more antifungal activity, but there was no difference in clinical outcome assessment.
Oral treatments are popular, most commonly a single dose of fluconazole. Oral itraconazole and ketoconazole have also been used successfully (SOR: A).18-21 A systematic review of oral vs vaginal azoles showed similar efficacy, but more side effects occurred with oral therapy (SOR: A).22 Gastrointestinal side effects occur in up to 15% of women.23
TABLE
Antifungal medications used to treat vulvovaginal candidiasis
| Generic name | Trade name | Dose | Duration | Cost per course of treatment* |
|---|---|---|---|---|
| Over the counter | ||||
| Butoconazole 2% cream | Femstat-3 Mycelex-3 generic | 5 g every night | 3 days | $5–$34 |
| Clotrimazole 1% cream | Mycelex-7 generic | 5 g every night | 7–10 days | $2–$7 |
| Clotrimazole 200 mg suppository | Gyne-Lotrimin generic | 1 every night | 3 days | $2–$9 |
| Miconazole 100 mg suppository | Monistat generic | 1 every night | 7 days | $2–$14 |
| Miconazole 2% cream | Monistat generic | 5 g every night | 7–10 days | $2–$11 |
| Miconazole 200 mg suppository | Monistat-3 | 1 every night | 3 days | $3–$22 |
| Miconazole 100 mg suppository plus 2% external cream | Gyne-Lotrimin generic | 1 every night | 5 days | $5–$12 |
| Tioconazole 6.5% ointment | Vagistat-1 generic | 4.6 g | 1 day | $2–$19 |
| Prescription | ||||
| Econazole 1% cream | Spectazole | 5 g | 3–6 days | $18 for 15 g $31 for 30 g |
| Terconazole 0.4% cream | Terazol-7 | 5 g | 7 days | $41 |
| Terconazole 0.8% cream | Terazol-3 | 5 g | 3 days | $41 |
| Terconazole 80 mg suppository | Terazol-3 | 1 every night | 3 days | $41 |
| Nystatin 100,000 U vaginal tablets | Generic | 1 every night | 7–14 days | $14–$35 |
| Fluconazole 150 mg tablet | Diflucan | 1 orally daily | 1 day | $14 |
| Itraconazole 100 mg tablet | Sporonox | 2 orally daily 4 orally | 3 days 1 day | $56 $37 ($281 for 30 tablets) |
| Ketoconazole 200 mg tablet | Nizoral generic | 2 orally daily | 5 days | $32–$43 ($95 for 30 generic tablets) |
| *Average wholesale price for entire regimen in US dollars. | ||||
Treating complicated VVC
About 5% of women diagnosed with VVC will have frequent recurrences, 4 or more per year.24 Current therapies are fungistatic rather than fungicidal, so the yeast are reduced but not eradicated. Hypersensitivity and allergic reactions to topical preparations may be confused with recurrences. Experts recommend that, if wet mount or culture results confirm recurrent vaginitis, topical therapy should be increased from 5 to 7 days up to 10 to 14 days, or that a second oral fluconazole tablet be given 3 days after the first (SOR: C).24 Women with severe cases of VVC also benefit from 2 sequential doses of fluconazole given 3 days apart (SOR: B).25
Suppressive therapy may be used after initial treatment for 6 months or more (SOR: B). Suppressive therapy options include oral fluconazole 150 mg or vaginal clotrimazole 500 mg once a week, oral or intravaginal nystatin twice weekly, and oral itraconazole 200 mg monthly.24,26
Non-albicans species tend to be more resistant to oral and topical azoles (SOR: B).27-29 If this species is detected on culture, a long course of suppressive therapy should be attempted (SOR: C).24 If imidazole therapy fails to control symptoms, suspect resistance.
Resistance to azoles may be demonstrated by in vitro susceptibility testing. Cross-resistance to topical and oral (fluconazole) azoles has been documented.30 There have been few studies of alternatives to azoles for treatment of resistant yeast vaginitis. One little-studied alternative is intravaginal boric acid, which may be used as a 14-day course of 600 mg daily in gelatin capsules (SOR: C).31 Nystatin and flucytosine (Ancoban) for 7 to 14 days are other alternatives (SOR: C).24
Candida in pregnancy
Commonly used topical imidazoles are classified as category C in pregnancy and have not been associated with increased risk of birth defects.
Trichomoniasis
Current treatment for trichomoniasis is oral metronidazole, given as a 2-g single dose, 250 mg 3 times daily for 7 days or 500 mg twice a day for 7 days. Treatment should also be given to the woman’s partner (SOR: A).32 Intravaginal therapy is not effective, probably due to the parasite’s presence in inaccessible areas such as the vaginal glands and urethra.33,34 Short-term treatment is comparable with long-term treatment, with similar rates of nausea and vomiting (SOR: A).32 A 1.5-g single-dose treatment has been shown to be equivalent to 2 g (SOR: B).35
The incidence metronidazole-resistant trichomoniasis has been estimated at 5%.36 In such cases, higher-dose therapy may be still be effective. For low to moderate resistance, 2 too 2.5 g daily for 3 to 10 days has been recommended (SOR: B).37 Intravenous high-dose metronidazole, 2 g every 8 hours for 3 days, has been reported to successfully treat highly resistant trichomonas (SOR: C).38 Another case report of 2 women with presumed allergy to metronidazole were successfully treated with incremental dosing of IV metronidazole (SOR: C).39 A small case series of women with metronidazole allergy or resistance treated with paromomycin cream intravaginally showed cure in 6 of 9 cases (SOR: C).40 Oral tinidazole has been approved in 2004 for use in the treatment of metronidazole-resistant trichomoniasis (SOR: B).41
Corresponding author
Linda French, MD, Associate Professor, Department of Family Practice, College of Human Medicine, Michigan State University, B101 Clinical Center, East Lansing, MI 48824. E-mail: [email protected].
1. Hillier SL, Lipinski C, Briselden AM, Eschenbach DA. Efficacy of intravaginal 0.75% metronidazole gel for the treatment of bacterial vaginosis. Obstet Gynecol 1993;81:963-967.
2. Hanson JM, McGregor JA, Hillier SL, et al. Metronidazole for bacterial vaginosis. A comparison of vaginal gel vs. oral therapy. J Reprod Med 2000;45:889-896.
3. Lugo-Miro VI, Green M, Mazur L. Comparison of different metronidazole therapeutic regimens for bacterial vaginosis. A meta-analysis. JAMA 1992;268:92-95.
4. Ferris DG, Litaker MS, Woodward L, Mathis D, Hendrich J. Treatment of bacterial vaginosis: a comparison of oral metronidazole, metronidazole vaginal gel, and clindamycin vaginal cream. J Fam Pract 1995;41:443-449.
5. Fischbach F, Petersen EE, Weissenbacher ER, Martius J, Hosmann J, Mayer H. Efficacy of clindamycin vaginal cream versus oral metronidazole in the treatment of bacterial vaginosis. Obstet Gynecol 1993;82:405-410.
6. Hillier S, Krohn MA, Watts DH, Wolner-Hanssen P, Eschenbach D. Microbiologic efficacy of intravaginal clindamycin cream for the treatment of bacterial vaginosis. Obstet Gynecol 1990;76:407-413.
7. Ugwumadu A, Manyonda I, Reid F, Hay P. Effect of early oral clindamycin on late miscarriage and preterm delivery in asymptomatic women with abnormal vaginal flora and bacterial vaginosis: a randomised controlled trial. Lancet 2003;361:983-988.
8. Mikamo H, Kawazoe K, Izumi K, Watanabe K, Ueno K, Tamaya T. Comparative study on vaginal or oral treatment of bacterial vaginosis. Chemotherapy 1997;43:60-68.
9. Ahmed-Jushuf IH, Shahmanesh M, Arya OP. The treatment of bacterial vaginosis with a 3 day course of 2% clindamycin cream: results of a multicentre, double blind, placebo controlled trial. B V Investigators Group. Genitourin Med 1995;71:254-256.
10. Schmitt C, Sobel JD, Meriwether C. Bacterial vaginosis: treatment with clindamycin cream versus oral metronidazole. Obstet Gynecol 1992;79:1020-1023.
11. Paavonen J, Mangioni C, Martin MA, Wajszczuk CP. Vaginal clindamycin and oral metronidazole for bacterial vaginosis: a randomized trial. Obstet Gynecol 2000;96:256-260.
12. Puapermpoonsiri S, Watanabe K, Kato N, Ueno K. In vitro activities of 10 antimicrobial agents against bacterial vaginosis-associated anaerobic isolates from pregnant Japanese and Thai women. Antimicrob Agents Chemother 1997;41:2297-2299.
13. Sobel JD. Vaginitis. N Engl J Med 1997;337:1896-1903.
14. Shalev E, Battino S, Weiner E, Colodner R, Keness Y. Ingestion of yogurt containing Lactobacillus acidophilus compared with pasteurized yogurt as prophylaxis for recurrent candidal vaginitis and bacterial vaginosis. Arch Fam Med 1996;5:593-596.
15. Lamont RF, Jones BM, Mandal D, Hay PE, Sheehan M. The efficacy of vaginal clindamycin for the treatment of abnormal genital tract flora in pregnancy. Infect Dis Obstet Gynecol 2003;11:181-189.
16. Marrazzo J. Vulvovaginal candidiasis. BMJ 2002;325:586.
17. Emele FE, Fadahunsi AA, Anyiwo CE, Ogunleye O. A comparative clinical evaluation of econazole nitrate, miconazole, and nystatin in the treatment of vaginal candidiasis. West Afr J Med 2000;19:12-15.
18. Stein GE, Mummaw N. Placebo controlled trial of itraconazole for treatment of acute vaginal candidiasis. Antimicrob Agents Chemother 1993;37:89-92.
19. Van der Pas H, Peeters F, Janssens D, Snauwaert E, Van Cutsem J. Treatment of vaginal candidosis with oral ketoconazole. Eur J Obstet Gynecol Reprod Biol 1983;14:399-404.
20. Sanz Sanz F, del Palacio Hernanz A. Randomized comparative trial of three regimens of itraconazole for treatment of vaginal mycoses. Rev Infect Dis 1987;9 Suppl 1:S139-S142.
21. Silva-Cruz A, Andrade L, Sobral L, Francisca A. Itraconazole versus placebo in the management of vaginal candidiasis. Int J Gynaecol Obstet 1991;36:229-232.
22. Watson MC, Grimshaw JM, Bond CM, Mollison J, Ludbrook A. Oral versus intravaginal imidazole and triazole anti-fungal agents for the treatment of uncomplicated vulvovaginal candidiasis (thrush): a systematic review. BJOG 2002;109:85-95.
23. van Heusden AM, Merkus HM, Corbeij RS, et al. Single-dose oral fluconazole versus single-dose topical miconazole for the treatment of acute vulvovaginal candidosis. Acta Obstet Gynecol Scand 1990;69:417-422.
24. Sobel JD. Vulvovaginitis. When Candida becomes a problem. Dermatol Clin 1998;16:763-768,xii.-
25. Sobel JD, Kapernick PS, Zervos M, et al. Treatment of complicated Candida vaginitis: comparison of single and sequential doses of fluconazole. Am J Obstet Gynecol 2001;185:363-369.
26. Creatsas GC, Charalambidis VM, Zagotzidou EH, Anthopoulou HN, Michailidis DC, Aravantinos DI. Chronic or recurrent vaginal candidosis: short-term treatment and prophylaxis with itraconazole. Clin Ther 1993;15:662-671.
27. Horowitz BJ, Giaquinta D, Ito S. Evolving pathogens in vulvovaginal candidiasis: implications for patient care. J Clin Pharmacol 1992;32:248-255.
28. del Palacio A, Sanz F, Sanchez-Alor G, et al. Double-blind randomized dose-finding study in acute vulvovaginal can-didosis. Comparison of flutrimazole site-release cream (1, 2 and 4%) with placebo site-release vaginal cream. Mycoses 2000;43:355-365.
29. Singh S, Sobel JD, Bhargava P, Boikov D, Vazquez JA. Vaginitis due to Candida krusei: epidemiology, clinical aspects, and therapy. Clin Infect Dis 2002;35:1066-1070.
30. Cross EW, Park S, Perlin DS. Cross-Resistance of clinical isolates of Candida albicans and Candida glabrata to over-the-counter azoles used in the treatment of vaginitis. Microb Drug Resist 2000;6:155-161.
31. Sobel JD, Chaim W. Treatment of Torulopsis glabrata vaginitis: retrospective review of boric acid therapy. Clin Infect Dis 1997;24:649-652.
32. Forna F, Gulmezoglu AM. Interventions for treating trichomoniasis in women. Cochrane Database Syst Rev 2003(2);CD000218.
33. duBouchet L, McGregor JA, Ismail M, McCormack WM. A pilot study of metronidazole vaginal gel versus oral metronidazole for the treatment of Trichomonas vaginalis vaginitis. Sex Transm Dis 1998;25:176-179.
34. Tidwell BH, Lushbaugh WB, Laughlin MD, Cleary JD, Finley RW. A double-blind placebo-controlled trial of single-dose intravaginal versus single-dose oral metronidazole in the treatment of trichomonal vaginitis. J Infect Dis 1994;170:242-246.
35. Spence MR, Harwell TS, Davies MC, Smith JL. The minimum single oral metronidazole dose for treating trichomoniasis: a randomized, blinded study. Obstet Gynecol 1997;89:699-703.
36. Petrin D, Delgaty K, Bhatt R, Garber G. Clinical and microbiological aspects of Trichomonas vaginalis. Clin Microbiol Rev 1998;11:300-317.
37. Lossick JG, Kent HL. Trichomoniasis: trends in diagnosis and management. Am J Obstet Gynecol 1991;165:1217-1222.
38. Dombrowski MP, Sokol RJ, Brown WJ, Bronsteen RA. Intravenous therapy of metronidazole-resistant Trichomonas vaginalis. Obstet Gynecol 1987;69:524-525.
39. Pearlman MD, Yashar C, Ernst S, Solomon W. An incremental dosing protocol for women with severe vaginal trichomoniasis and adverse reaction to metronidazole. Am J Obstet Gynecol 1996;174:934-936.
40. Nyirjesy P, Sobel JD, Weitz MV, Leaman DJ, Gelone SP. Difficult-to-treat trichomoniasis: results with paromomycin cream. Clin Infect Dis. 1998;26:986-988.
41. Sobel JD, Nyirjesy P, Brown W. Tinidazole therapy for metronidazole resistant vaginal trichomoniasis. Clin Infect Dis 2001;33:1341-1346.
- Treat bacterial vaginosis with oral or intravaginal metronidazole or with clindamycin (SOR: A);recurrences are common (SOR:C).
- Oral and intravaginal imidazoles are equally effective in the treatment of candidiasis (SOR:A); alternate therapies for resistant cases have been little studied. Oral metronidazole is the standard therapy for trichomoniasis (SOR: A).
- Oral tinidazole, newly available in the US in 2004, should be used in resistant cases (SOR: B).
Antifungal medications for intravaginal use have been available in the United States for more than a decade. Women may be inclined to self-diagnose yeast infections with any vaginal discharge or other vulvovaginal symptoms that they deem abnormal. As we saw in the first part of this article, “Abnormal vaginal discharge: Using office diagnostic testing more effectively” (JFP2004; 53[10]:805–814), abnormal discharge is more likely to be bacterial vaginosis or no pathogen at all. Potential delay in diagnosis and treatment of a sexually transmitted disease is also a concern. Increasing resistance of Candida sp. to imidazoles is associated with indiscriminate use of over-the-counter products.
Bacterial vaginosis
The standard treatment for bacterial vaginosis (BV) has been oral metronidazole (Flagyl) 500 mg twice daily for 5 to 7 days. Intravaginal 0.75% metronidazole gel (MetroGel) has been shown to be as effective as oral metronidazole (SOR: A).1,2
Oral metronidazole can cause nausea and abdominal pain in some patients; vaginal treatment may be preferable for them. A meta-analysis of 52 studies of regimens of oral metronidazole at a dose of 2 g daily of varying duration showed similar initial cure rates of 85%, 87%, 86%, and 87% for 1, 2, 5, and 7 days, respectively (strength of recommendation [SOR]: A).3 Single-dose therapy may improve adherence (SOR: C).
Clindamycin (Cleocin), orally or in vaginal cream, for 5 days is also effective for BV (SOR: A).4-8 Clindamycin cream is used at a dose of 5 g daily and a concentration of 2%. Lower concentration (1%) has been less effective.6 Oral regimens range from 300 mg twice daily to 450 mg 3 times daily. Oral and vaginal preparations have shown equal efficacy in direct comparisons (SOR: A).8 A 3-day course of vaginal clindamycin is as effective as a 5-day course (SOR: B).9
Several studies have compared clindamycin and metronidazole head to head. They have shown similar cure rates that were not statistically different in the 75% to 90% range (SOR: A).4,5,10,11 Other antibiotics that have shown in vitro efficacy for treating the spectrum of microbes associated with BV are amoxicillin-clavulanate (Augmentin), imipenem (Primaxin), and cefmetazole (Zefazone) (SOR: C).8,12 Some Mobiluncus strains show resistance to metronidazole (SOR: C).12
Recurrences of BV are common. The initial regimen or an alternative regimen may be used. A longer, 10- to 14-day, course of antibiotic therapy has been recommended by one expert for treating relapses (SOR: C).13 Recolonizing the vagina with lactobacilli by eating yogurt or using bacteria-containing suppositories is an approach that deserves further study (SOR: C).14 Suppressive therapy such as intravaginal metronidazole twice weekly may also be considered as maintenance therapy to prevent recurrences (SOR: C).
BV and pregnancy
A number of studies have been published on screening for BV in pregnancy using Gram stain and on treating positive cases with antibiotics. While studies that used metronidazole for treatment have not shown consistently good results, more recent studies using clindamycin orally or intravaginally have been promising (SOR: B).7,15 Oral dosing at 300 mg twice daily, at 12 to 22 weeks gestation, has reduced preterm delivery for pregnant women with BV diagnosed by Nugent’s criteria (number needed to treat [NNT]=10).7 Likewise, for women with BV treated at 13 to 20 weeks gestation, intravaginal clindamycin therapy for 3 days has reduced the incidence of preterm births (NNT=17).15
Clindamycin appears to be the treatment of choice for BV in pregnancy (SOR: C) since it is considered safe (category B) throughout pregnancy, and because use of metronidazole in the first trimester is controversial.
Candidiasis
Treating vulvovaginal candidiasis (VVC) with intravaginal imidazoles reduces symptoms with NNT=3 after 1 month (SOR: A) ( Table ).16 No difference has been seen in outcomes with the various imidazoles or with treatment durations of 1 to 14 days. Intravaginal nystatin also decreases symptoms of VVC, with a NNT of 3 after 1 week compared with placebo (SOR: B).
Data showing that imidazoles are more effective than nystatin are not strong (SOR: B). A Clinical Evidencereview16 identified 1 trial comparing intravaginal miconazole, clotrimazole, econazole, and nystatin; symptomatic relapse was lower with intravaginal imidazoles than with nystatin. Another trial comparing clotrimazole and nystatin showed no difference in the proportion of women with persistent symptoms after 4 weeks. An open label study17 comparing econazole, miconazole, and nystatin showed that the imidazoles had more antifungal activity, but there was no difference in clinical outcome assessment.
Oral treatments are popular, most commonly a single dose of fluconazole. Oral itraconazole and ketoconazole have also been used successfully (SOR: A).18-21 A systematic review of oral vs vaginal azoles showed similar efficacy, but more side effects occurred with oral therapy (SOR: A).22 Gastrointestinal side effects occur in up to 15% of women.23
TABLE
Antifungal medications used to treat vulvovaginal candidiasis
| Generic name | Trade name | Dose | Duration | Cost per course of treatment* |
|---|---|---|---|---|
| Over the counter | ||||
| Butoconazole 2% cream | Femstat-3 Mycelex-3 generic | 5 g every night | 3 days | $5–$34 |
| Clotrimazole 1% cream | Mycelex-7 generic | 5 g every night | 7–10 days | $2–$7 |
| Clotrimazole 200 mg suppository | Gyne-Lotrimin generic | 1 every night | 3 days | $2–$9 |
| Miconazole 100 mg suppository | Monistat generic | 1 every night | 7 days | $2–$14 |
| Miconazole 2% cream | Monistat generic | 5 g every night | 7–10 days | $2–$11 |
| Miconazole 200 mg suppository | Monistat-3 | 1 every night | 3 days | $3–$22 |
| Miconazole 100 mg suppository plus 2% external cream | Gyne-Lotrimin generic | 1 every night | 5 days | $5–$12 |
| Tioconazole 6.5% ointment | Vagistat-1 generic | 4.6 g | 1 day | $2–$19 |
| Prescription | ||||
| Econazole 1% cream | Spectazole | 5 g | 3–6 days | $18 for 15 g $31 for 30 g |
| Terconazole 0.4% cream | Terazol-7 | 5 g | 7 days | $41 |
| Terconazole 0.8% cream | Terazol-3 | 5 g | 3 days | $41 |
| Terconazole 80 mg suppository | Terazol-3 | 1 every night | 3 days | $41 |
| Nystatin 100,000 U vaginal tablets | Generic | 1 every night | 7–14 days | $14–$35 |
| Fluconazole 150 mg tablet | Diflucan | 1 orally daily | 1 day | $14 |
| Itraconazole 100 mg tablet | Sporonox | 2 orally daily 4 orally | 3 days 1 day | $56 $37 ($281 for 30 tablets) |
| Ketoconazole 200 mg tablet | Nizoral generic | 2 orally daily | 5 days | $32–$43 ($95 for 30 generic tablets) |
| *Average wholesale price for entire regimen in US dollars. | ||||
Treating complicated VVC
About 5% of women diagnosed with VVC will have frequent recurrences, 4 or more per year.24 Current therapies are fungistatic rather than fungicidal, so the yeast are reduced but not eradicated. Hypersensitivity and allergic reactions to topical preparations may be confused with recurrences. Experts recommend that, if wet mount or culture results confirm recurrent vaginitis, topical therapy should be increased from 5 to 7 days up to 10 to 14 days, or that a second oral fluconazole tablet be given 3 days after the first (SOR: C).24 Women with severe cases of VVC also benefit from 2 sequential doses of fluconazole given 3 days apart (SOR: B).25
Suppressive therapy may be used after initial treatment for 6 months or more (SOR: B). Suppressive therapy options include oral fluconazole 150 mg or vaginal clotrimazole 500 mg once a week, oral or intravaginal nystatin twice weekly, and oral itraconazole 200 mg monthly.24,26
Non-albicans species tend to be more resistant to oral and topical azoles (SOR: B).27-29 If this species is detected on culture, a long course of suppressive therapy should be attempted (SOR: C).24 If imidazole therapy fails to control symptoms, suspect resistance.
Resistance to azoles may be demonstrated by in vitro susceptibility testing. Cross-resistance to topical and oral (fluconazole) azoles has been documented.30 There have been few studies of alternatives to azoles for treatment of resistant yeast vaginitis. One little-studied alternative is intravaginal boric acid, which may be used as a 14-day course of 600 mg daily in gelatin capsules (SOR: C).31 Nystatin and flucytosine (Ancoban) for 7 to 14 days are other alternatives (SOR: C).24
Candida in pregnancy
Commonly used topical imidazoles are classified as category C in pregnancy and have not been associated with increased risk of birth defects.
Trichomoniasis
Current treatment for trichomoniasis is oral metronidazole, given as a 2-g single dose, 250 mg 3 times daily for 7 days or 500 mg twice a day for 7 days. Treatment should also be given to the woman’s partner (SOR: A).32 Intravaginal therapy is not effective, probably due to the parasite’s presence in inaccessible areas such as the vaginal glands and urethra.33,34 Short-term treatment is comparable with long-term treatment, with similar rates of nausea and vomiting (SOR: A).32 A 1.5-g single-dose treatment has been shown to be equivalent to 2 g (SOR: B).35
The incidence metronidazole-resistant trichomoniasis has been estimated at 5%.36 In such cases, higher-dose therapy may be still be effective. For low to moderate resistance, 2 too 2.5 g daily for 3 to 10 days has been recommended (SOR: B).37 Intravenous high-dose metronidazole, 2 g every 8 hours for 3 days, has been reported to successfully treat highly resistant trichomonas (SOR: C).38 Another case report of 2 women with presumed allergy to metronidazole were successfully treated with incremental dosing of IV metronidazole (SOR: C).39 A small case series of women with metronidazole allergy or resistance treated with paromomycin cream intravaginally showed cure in 6 of 9 cases (SOR: C).40 Oral tinidazole has been approved in 2004 for use in the treatment of metronidazole-resistant trichomoniasis (SOR: B).41
Corresponding author
Linda French, MD, Associate Professor, Department of Family Practice, College of Human Medicine, Michigan State University, B101 Clinical Center, East Lansing, MI 48824. E-mail: [email protected].
- Treat bacterial vaginosis with oral or intravaginal metronidazole or with clindamycin (SOR: A);recurrences are common (SOR:C).
- Oral and intravaginal imidazoles are equally effective in the treatment of candidiasis (SOR:A); alternate therapies for resistant cases have been little studied. Oral metronidazole is the standard therapy for trichomoniasis (SOR: A).
- Oral tinidazole, newly available in the US in 2004, should be used in resistant cases (SOR: B).
Antifungal medications for intravaginal use have been available in the United States for more than a decade. Women may be inclined to self-diagnose yeast infections with any vaginal discharge or other vulvovaginal symptoms that they deem abnormal. As we saw in the first part of this article, “Abnormal vaginal discharge: Using office diagnostic testing more effectively” (JFP2004; 53[10]:805–814), abnormal discharge is more likely to be bacterial vaginosis or no pathogen at all. Potential delay in diagnosis and treatment of a sexually transmitted disease is also a concern. Increasing resistance of Candida sp. to imidazoles is associated with indiscriminate use of over-the-counter products.
Bacterial vaginosis
The standard treatment for bacterial vaginosis (BV) has been oral metronidazole (Flagyl) 500 mg twice daily for 5 to 7 days. Intravaginal 0.75% metronidazole gel (MetroGel) has been shown to be as effective as oral metronidazole (SOR: A).1,2
Oral metronidazole can cause nausea and abdominal pain in some patients; vaginal treatment may be preferable for them. A meta-analysis of 52 studies of regimens of oral metronidazole at a dose of 2 g daily of varying duration showed similar initial cure rates of 85%, 87%, 86%, and 87% for 1, 2, 5, and 7 days, respectively (strength of recommendation [SOR]: A).3 Single-dose therapy may improve adherence (SOR: C).
Clindamycin (Cleocin), orally or in vaginal cream, for 5 days is also effective for BV (SOR: A).4-8 Clindamycin cream is used at a dose of 5 g daily and a concentration of 2%. Lower concentration (1%) has been less effective.6 Oral regimens range from 300 mg twice daily to 450 mg 3 times daily. Oral and vaginal preparations have shown equal efficacy in direct comparisons (SOR: A).8 A 3-day course of vaginal clindamycin is as effective as a 5-day course (SOR: B).9
Several studies have compared clindamycin and metronidazole head to head. They have shown similar cure rates that were not statistically different in the 75% to 90% range (SOR: A).4,5,10,11 Other antibiotics that have shown in vitro efficacy for treating the spectrum of microbes associated with BV are amoxicillin-clavulanate (Augmentin), imipenem (Primaxin), and cefmetazole (Zefazone) (SOR: C).8,12 Some Mobiluncus strains show resistance to metronidazole (SOR: C).12
Recurrences of BV are common. The initial regimen or an alternative regimen may be used. A longer, 10- to 14-day, course of antibiotic therapy has been recommended by one expert for treating relapses (SOR: C).13 Recolonizing the vagina with lactobacilli by eating yogurt or using bacteria-containing suppositories is an approach that deserves further study (SOR: C).14 Suppressive therapy such as intravaginal metronidazole twice weekly may also be considered as maintenance therapy to prevent recurrences (SOR: C).
BV and pregnancy
A number of studies have been published on screening for BV in pregnancy using Gram stain and on treating positive cases with antibiotics. While studies that used metronidazole for treatment have not shown consistently good results, more recent studies using clindamycin orally or intravaginally have been promising (SOR: B).7,15 Oral dosing at 300 mg twice daily, at 12 to 22 weeks gestation, has reduced preterm delivery for pregnant women with BV diagnosed by Nugent’s criteria (number needed to treat [NNT]=10).7 Likewise, for women with BV treated at 13 to 20 weeks gestation, intravaginal clindamycin therapy for 3 days has reduced the incidence of preterm births (NNT=17).15
Clindamycin appears to be the treatment of choice for BV in pregnancy (SOR: C) since it is considered safe (category B) throughout pregnancy, and because use of metronidazole in the first trimester is controversial.
Candidiasis
Treating vulvovaginal candidiasis (VVC) with intravaginal imidazoles reduces symptoms with NNT=3 after 1 month (SOR: A) ( Table ).16 No difference has been seen in outcomes with the various imidazoles or with treatment durations of 1 to 14 days. Intravaginal nystatin also decreases symptoms of VVC, with a NNT of 3 after 1 week compared with placebo (SOR: B).
Data showing that imidazoles are more effective than nystatin are not strong (SOR: B). A Clinical Evidencereview16 identified 1 trial comparing intravaginal miconazole, clotrimazole, econazole, and nystatin; symptomatic relapse was lower with intravaginal imidazoles than with nystatin. Another trial comparing clotrimazole and nystatin showed no difference in the proportion of women with persistent symptoms after 4 weeks. An open label study17 comparing econazole, miconazole, and nystatin showed that the imidazoles had more antifungal activity, but there was no difference in clinical outcome assessment.
Oral treatments are popular, most commonly a single dose of fluconazole. Oral itraconazole and ketoconazole have also been used successfully (SOR: A).18-21 A systematic review of oral vs vaginal azoles showed similar efficacy, but more side effects occurred with oral therapy (SOR: A).22 Gastrointestinal side effects occur in up to 15% of women.23
TABLE
Antifungal medications used to treat vulvovaginal candidiasis
| Generic name | Trade name | Dose | Duration | Cost per course of treatment* |
|---|---|---|---|---|
| Over the counter | ||||
| Butoconazole 2% cream | Femstat-3 Mycelex-3 generic | 5 g every night | 3 days | $5–$34 |
| Clotrimazole 1% cream | Mycelex-7 generic | 5 g every night | 7–10 days | $2–$7 |
| Clotrimazole 200 mg suppository | Gyne-Lotrimin generic | 1 every night | 3 days | $2–$9 |
| Miconazole 100 mg suppository | Monistat generic | 1 every night | 7 days | $2–$14 |
| Miconazole 2% cream | Monistat generic | 5 g every night | 7–10 days | $2–$11 |
| Miconazole 200 mg suppository | Monistat-3 | 1 every night | 3 days | $3–$22 |
| Miconazole 100 mg suppository plus 2% external cream | Gyne-Lotrimin generic | 1 every night | 5 days | $5–$12 |
| Tioconazole 6.5% ointment | Vagistat-1 generic | 4.6 g | 1 day | $2–$19 |
| Prescription | ||||
| Econazole 1% cream | Spectazole | 5 g | 3–6 days | $18 for 15 g $31 for 30 g |
| Terconazole 0.4% cream | Terazol-7 | 5 g | 7 days | $41 |
| Terconazole 0.8% cream | Terazol-3 | 5 g | 3 days | $41 |
| Terconazole 80 mg suppository | Terazol-3 | 1 every night | 3 days | $41 |
| Nystatin 100,000 U vaginal tablets | Generic | 1 every night | 7–14 days | $14–$35 |
| Fluconazole 150 mg tablet | Diflucan | 1 orally daily | 1 day | $14 |
| Itraconazole 100 mg tablet | Sporonox | 2 orally daily 4 orally | 3 days 1 day | $56 $37 ($281 for 30 tablets) |
| Ketoconazole 200 mg tablet | Nizoral generic | 2 orally daily | 5 days | $32–$43 ($95 for 30 generic tablets) |
| *Average wholesale price for entire regimen in US dollars. | ||||
Treating complicated VVC
About 5% of women diagnosed with VVC will have frequent recurrences, 4 or more per year.24 Current therapies are fungistatic rather than fungicidal, so the yeast are reduced but not eradicated. Hypersensitivity and allergic reactions to topical preparations may be confused with recurrences. Experts recommend that, if wet mount or culture results confirm recurrent vaginitis, topical therapy should be increased from 5 to 7 days up to 10 to 14 days, or that a second oral fluconazole tablet be given 3 days after the first (SOR: C).24 Women with severe cases of VVC also benefit from 2 sequential doses of fluconazole given 3 days apart (SOR: B).25
Suppressive therapy may be used after initial treatment for 6 months or more (SOR: B). Suppressive therapy options include oral fluconazole 150 mg or vaginal clotrimazole 500 mg once a week, oral or intravaginal nystatin twice weekly, and oral itraconazole 200 mg monthly.24,26
Non-albicans species tend to be more resistant to oral and topical azoles (SOR: B).27-29 If this species is detected on culture, a long course of suppressive therapy should be attempted (SOR: C).24 If imidazole therapy fails to control symptoms, suspect resistance.
Resistance to azoles may be demonstrated by in vitro susceptibility testing. Cross-resistance to topical and oral (fluconazole) azoles has been documented.30 There have been few studies of alternatives to azoles for treatment of resistant yeast vaginitis. One little-studied alternative is intravaginal boric acid, which may be used as a 14-day course of 600 mg daily in gelatin capsules (SOR: C).31 Nystatin and flucytosine (Ancoban) for 7 to 14 days are other alternatives (SOR: C).24
Candida in pregnancy
Commonly used topical imidazoles are classified as category C in pregnancy and have not been associated with increased risk of birth defects.
Trichomoniasis
Current treatment for trichomoniasis is oral metronidazole, given as a 2-g single dose, 250 mg 3 times daily for 7 days or 500 mg twice a day for 7 days. Treatment should also be given to the woman’s partner (SOR: A).32 Intravaginal therapy is not effective, probably due to the parasite’s presence in inaccessible areas such as the vaginal glands and urethra.33,34 Short-term treatment is comparable with long-term treatment, with similar rates of nausea and vomiting (SOR: A).32 A 1.5-g single-dose treatment has been shown to be equivalent to 2 g (SOR: B).35
The incidence metronidazole-resistant trichomoniasis has been estimated at 5%.36 In such cases, higher-dose therapy may be still be effective. For low to moderate resistance, 2 too 2.5 g daily for 3 to 10 days has been recommended (SOR: B).37 Intravenous high-dose metronidazole, 2 g every 8 hours for 3 days, has been reported to successfully treat highly resistant trichomonas (SOR: C).38 Another case report of 2 women with presumed allergy to metronidazole were successfully treated with incremental dosing of IV metronidazole (SOR: C).39 A small case series of women with metronidazole allergy or resistance treated with paromomycin cream intravaginally showed cure in 6 of 9 cases (SOR: C).40 Oral tinidazole has been approved in 2004 for use in the treatment of metronidazole-resistant trichomoniasis (SOR: B).41
Corresponding author
Linda French, MD, Associate Professor, Department of Family Practice, College of Human Medicine, Michigan State University, B101 Clinical Center, East Lansing, MI 48824. E-mail: [email protected].
1. Hillier SL, Lipinski C, Briselden AM, Eschenbach DA. Efficacy of intravaginal 0.75% metronidazole gel for the treatment of bacterial vaginosis. Obstet Gynecol 1993;81:963-967.
2. Hanson JM, McGregor JA, Hillier SL, et al. Metronidazole for bacterial vaginosis. A comparison of vaginal gel vs. oral therapy. J Reprod Med 2000;45:889-896.
3. Lugo-Miro VI, Green M, Mazur L. Comparison of different metronidazole therapeutic regimens for bacterial vaginosis. A meta-analysis. JAMA 1992;268:92-95.
4. Ferris DG, Litaker MS, Woodward L, Mathis D, Hendrich J. Treatment of bacterial vaginosis: a comparison of oral metronidazole, metronidazole vaginal gel, and clindamycin vaginal cream. J Fam Pract 1995;41:443-449.
5. Fischbach F, Petersen EE, Weissenbacher ER, Martius J, Hosmann J, Mayer H. Efficacy of clindamycin vaginal cream versus oral metronidazole in the treatment of bacterial vaginosis. Obstet Gynecol 1993;82:405-410.
6. Hillier S, Krohn MA, Watts DH, Wolner-Hanssen P, Eschenbach D. Microbiologic efficacy of intravaginal clindamycin cream for the treatment of bacterial vaginosis. Obstet Gynecol 1990;76:407-413.
7. Ugwumadu A, Manyonda I, Reid F, Hay P. Effect of early oral clindamycin on late miscarriage and preterm delivery in asymptomatic women with abnormal vaginal flora and bacterial vaginosis: a randomised controlled trial. Lancet 2003;361:983-988.
8. Mikamo H, Kawazoe K, Izumi K, Watanabe K, Ueno K, Tamaya T. Comparative study on vaginal or oral treatment of bacterial vaginosis. Chemotherapy 1997;43:60-68.
9. Ahmed-Jushuf IH, Shahmanesh M, Arya OP. The treatment of bacterial vaginosis with a 3 day course of 2% clindamycin cream: results of a multicentre, double blind, placebo controlled trial. B V Investigators Group. Genitourin Med 1995;71:254-256.
10. Schmitt C, Sobel JD, Meriwether C. Bacterial vaginosis: treatment with clindamycin cream versus oral metronidazole. Obstet Gynecol 1992;79:1020-1023.
11. Paavonen J, Mangioni C, Martin MA, Wajszczuk CP. Vaginal clindamycin and oral metronidazole for bacterial vaginosis: a randomized trial. Obstet Gynecol 2000;96:256-260.
12. Puapermpoonsiri S, Watanabe K, Kato N, Ueno K. In vitro activities of 10 antimicrobial agents against bacterial vaginosis-associated anaerobic isolates from pregnant Japanese and Thai women. Antimicrob Agents Chemother 1997;41:2297-2299.
13. Sobel JD. Vaginitis. N Engl J Med 1997;337:1896-1903.
14. Shalev E, Battino S, Weiner E, Colodner R, Keness Y. Ingestion of yogurt containing Lactobacillus acidophilus compared with pasteurized yogurt as prophylaxis for recurrent candidal vaginitis and bacterial vaginosis. Arch Fam Med 1996;5:593-596.
15. Lamont RF, Jones BM, Mandal D, Hay PE, Sheehan M. The efficacy of vaginal clindamycin for the treatment of abnormal genital tract flora in pregnancy. Infect Dis Obstet Gynecol 2003;11:181-189.
16. Marrazzo J. Vulvovaginal candidiasis. BMJ 2002;325:586.
17. Emele FE, Fadahunsi AA, Anyiwo CE, Ogunleye O. A comparative clinical evaluation of econazole nitrate, miconazole, and nystatin in the treatment of vaginal candidiasis. West Afr J Med 2000;19:12-15.
18. Stein GE, Mummaw N. Placebo controlled trial of itraconazole for treatment of acute vaginal candidiasis. Antimicrob Agents Chemother 1993;37:89-92.
19. Van der Pas H, Peeters F, Janssens D, Snauwaert E, Van Cutsem J. Treatment of vaginal candidosis with oral ketoconazole. Eur J Obstet Gynecol Reprod Biol 1983;14:399-404.
20. Sanz Sanz F, del Palacio Hernanz A. Randomized comparative trial of three regimens of itraconazole for treatment of vaginal mycoses. Rev Infect Dis 1987;9 Suppl 1:S139-S142.
21. Silva-Cruz A, Andrade L, Sobral L, Francisca A. Itraconazole versus placebo in the management of vaginal candidiasis. Int J Gynaecol Obstet 1991;36:229-232.
22. Watson MC, Grimshaw JM, Bond CM, Mollison J, Ludbrook A. Oral versus intravaginal imidazole and triazole anti-fungal agents for the treatment of uncomplicated vulvovaginal candidiasis (thrush): a systematic review. BJOG 2002;109:85-95.
23. van Heusden AM, Merkus HM, Corbeij RS, et al. Single-dose oral fluconazole versus single-dose topical miconazole for the treatment of acute vulvovaginal candidosis. Acta Obstet Gynecol Scand 1990;69:417-422.
24. Sobel JD. Vulvovaginitis. When Candida becomes a problem. Dermatol Clin 1998;16:763-768,xii.-
25. Sobel JD, Kapernick PS, Zervos M, et al. Treatment of complicated Candida vaginitis: comparison of single and sequential doses of fluconazole. Am J Obstet Gynecol 2001;185:363-369.
26. Creatsas GC, Charalambidis VM, Zagotzidou EH, Anthopoulou HN, Michailidis DC, Aravantinos DI. Chronic or recurrent vaginal candidosis: short-term treatment and prophylaxis with itraconazole. Clin Ther 1993;15:662-671.
27. Horowitz BJ, Giaquinta D, Ito S. Evolving pathogens in vulvovaginal candidiasis: implications for patient care. J Clin Pharmacol 1992;32:248-255.
28. del Palacio A, Sanz F, Sanchez-Alor G, et al. Double-blind randomized dose-finding study in acute vulvovaginal can-didosis. Comparison of flutrimazole site-release cream (1, 2 and 4%) with placebo site-release vaginal cream. Mycoses 2000;43:355-365.
29. Singh S, Sobel JD, Bhargava P, Boikov D, Vazquez JA. Vaginitis due to Candida krusei: epidemiology, clinical aspects, and therapy. Clin Infect Dis 2002;35:1066-1070.
30. Cross EW, Park S, Perlin DS. Cross-Resistance of clinical isolates of Candida albicans and Candida glabrata to over-the-counter azoles used in the treatment of vaginitis. Microb Drug Resist 2000;6:155-161.
31. Sobel JD, Chaim W. Treatment of Torulopsis glabrata vaginitis: retrospective review of boric acid therapy. Clin Infect Dis 1997;24:649-652.
32. Forna F, Gulmezoglu AM. Interventions for treating trichomoniasis in women. Cochrane Database Syst Rev 2003(2);CD000218.
33. duBouchet L, McGregor JA, Ismail M, McCormack WM. A pilot study of metronidazole vaginal gel versus oral metronidazole for the treatment of Trichomonas vaginalis vaginitis. Sex Transm Dis 1998;25:176-179.
34. Tidwell BH, Lushbaugh WB, Laughlin MD, Cleary JD, Finley RW. A double-blind placebo-controlled trial of single-dose intravaginal versus single-dose oral metronidazole in the treatment of trichomonal vaginitis. J Infect Dis 1994;170:242-246.
35. Spence MR, Harwell TS, Davies MC, Smith JL. The minimum single oral metronidazole dose for treating trichomoniasis: a randomized, blinded study. Obstet Gynecol 1997;89:699-703.
36. Petrin D, Delgaty K, Bhatt R, Garber G. Clinical and microbiological aspects of Trichomonas vaginalis. Clin Microbiol Rev 1998;11:300-317.
37. Lossick JG, Kent HL. Trichomoniasis: trends in diagnosis and management. Am J Obstet Gynecol 1991;165:1217-1222.
38. Dombrowski MP, Sokol RJ, Brown WJ, Bronsteen RA. Intravenous therapy of metronidazole-resistant Trichomonas vaginalis. Obstet Gynecol 1987;69:524-525.
39. Pearlman MD, Yashar C, Ernst S, Solomon W. An incremental dosing protocol for women with severe vaginal trichomoniasis and adverse reaction to metronidazole. Am J Obstet Gynecol 1996;174:934-936.
40. Nyirjesy P, Sobel JD, Weitz MV, Leaman DJ, Gelone SP. Difficult-to-treat trichomoniasis: results with paromomycin cream. Clin Infect Dis. 1998;26:986-988.
41. Sobel JD, Nyirjesy P, Brown W. Tinidazole therapy for metronidazole resistant vaginal trichomoniasis. Clin Infect Dis 2001;33:1341-1346.
1. Hillier SL, Lipinski C, Briselden AM, Eschenbach DA. Efficacy of intravaginal 0.75% metronidazole gel for the treatment of bacterial vaginosis. Obstet Gynecol 1993;81:963-967.
2. Hanson JM, McGregor JA, Hillier SL, et al. Metronidazole for bacterial vaginosis. A comparison of vaginal gel vs. oral therapy. J Reprod Med 2000;45:889-896.
3. Lugo-Miro VI, Green M, Mazur L. Comparison of different metronidazole therapeutic regimens for bacterial vaginosis. A meta-analysis. JAMA 1992;268:92-95.
4. Ferris DG, Litaker MS, Woodward L, Mathis D, Hendrich J. Treatment of bacterial vaginosis: a comparison of oral metronidazole, metronidazole vaginal gel, and clindamycin vaginal cream. J Fam Pract 1995;41:443-449.
5. Fischbach F, Petersen EE, Weissenbacher ER, Martius J, Hosmann J, Mayer H. Efficacy of clindamycin vaginal cream versus oral metronidazole in the treatment of bacterial vaginosis. Obstet Gynecol 1993;82:405-410.
6. Hillier S, Krohn MA, Watts DH, Wolner-Hanssen P, Eschenbach D. Microbiologic efficacy of intravaginal clindamycin cream for the treatment of bacterial vaginosis. Obstet Gynecol 1990;76:407-413.
7. Ugwumadu A, Manyonda I, Reid F, Hay P. Effect of early oral clindamycin on late miscarriage and preterm delivery in asymptomatic women with abnormal vaginal flora and bacterial vaginosis: a randomised controlled trial. Lancet 2003;361:983-988.
8. Mikamo H, Kawazoe K, Izumi K, Watanabe K, Ueno K, Tamaya T. Comparative study on vaginal or oral treatment of bacterial vaginosis. Chemotherapy 1997;43:60-68.
9. Ahmed-Jushuf IH, Shahmanesh M, Arya OP. The treatment of bacterial vaginosis with a 3 day course of 2% clindamycin cream: results of a multicentre, double blind, placebo controlled trial. B V Investigators Group. Genitourin Med 1995;71:254-256.
10. Schmitt C, Sobel JD, Meriwether C. Bacterial vaginosis: treatment with clindamycin cream versus oral metronidazole. Obstet Gynecol 1992;79:1020-1023.
11. Paavonen J, Mangioni C, Martin MA, Wajszczuk CP. Vaginal clindamycin and oral metronidazole for bacterial vaginosis: a randomized trial. Obstet Gynecol 2000;96:256-260.
12. Puapermpoonsiri S, Watanabe K, Kato N, Ueno K. In vitro activities of 10 antimicrobial agents against bacterial vaginosis-associated anaerobic isolates from pregnant Japanese and Thai women. Antimicrob Agents Chemother 1997;41:2297-2299.
13. Sobel JD. Vaginitis. N Engl J Med 1997;337:1896-1903.
14. Shalev E, Battino S, Weiner E, Colodner R, Keness Y. Ingestion of yogurt containing Lactobacillus acidophilus compared with pasteurized yogurt as prophylaxis for recurrent candidal vaginitis and bacterial vaginosis. Arch Fam Med 1996;5:593-596.
15. Lamont RF, Jones BM, Mandal D, Hay PE, Sheehan M. The efficacy of vaginal clindamycin for the treatment of abnormal genital tract flora in pregnancy. Infect Dis Obstet Gynecol 2003;11:181-189.
16. Marrazzo J. Vulvovaginal candidiasis. BMJ 2002;325:586.
17. Emele FE, Fadahunsi AA, Anyiwo CE, Ogunleye O. A comparative clinical evaluation of econazole nitrate, miconazole, and nystatin in the treatment of vaginal candidiasis. West Afr J Med 2000;19:12-15.
18. Stein GE, Mummaw N. Placebo controlled trial of itraconazole for treatment of acute vaginal candidiasis. Antimicrob Agents Chemother 1993;37:89-92.
19. Van der Pas H, Peeters F, Janssens D, Snauwaert E, Van Cutsem J. Treatment of vaginal candidosis with oral ketoconazole. Eur J Obstet Gynecol Reprod Biol 1983;14:399-404.
20. Sanz Sanz F, del Palacio Hernanz A. Randomized comparative trial of three regimens of itraconazole for treatment of vaginal mycoses. Rev Infect Dis 1987;9 Suppl 1:S139-S142.
21. Silva-Cruz A, Andrade L, Sobral L, Francisca A. Itraconazole versus placebo in the management of vaginal candidiasis. Int J Gynaecol Obstet 1991;36:229-232.
22. Watson MC, Grimshaw JM, Bond CM, Mollison J, Ludbrook A. Oral versus intravaginal imidazole and triazole anti-fungal agents for the treatment of uncomplicated vulvovaginal candidiasis (thrush): a systematic review. BJOG 2002;109:85-95.
23. van Heusden AM, Merkus HM, Corbeij RS, et al. Single-dose oral fluconazole versus single-dose topical miconazole for the treatment of acute vulvovaginal candidosis. Acta Obstet Gynecol Scand 1990;69:417-422.
24. Sobel JD. Vulvovaginitis. When Candida becomes a problem. Dermatol Clin 1998;16:763-768,xii.-
25. Sobel JD, Kapernick PS, Zervos M, et al. Treatment of complicated Candida vaginitis: comparison of single and sequential doses of fluconazole. Am J Obstet Gynecol 2001;185:363-369.
26. Creatsas GC, Charalambidis VM, Zagotzidou EH, Anthopoulou HN, Michailidis DC, Aravantinos DI. Chronic or recurrent vaginal candidosis: short-term treatment and prophylaxis with itraconazole. Clin Ther 1993;15:662-671.
27. Horowitz BJ, Giaquinta D, Ito S. Evolving pathogens in vulvovaginal candidiasis: implications for patient care. J Clin Pharmacol 1992;32:248-255.
28. del Palacio A, Sanz F, Sanchez-Alor G, et al. Double-blind randomized dose-finding study in acute vulvovaginal can-didosis. Comparison of flutrimazole site-release cream (1, 2 and 4%) with placebo site-release vaginal cream. Mycoses 2000;43:355-365.
29. Singh S, Sobel JD, Bhargava P, Boikov D, Vazquez JA. Vaginitis due to Candida krusei: epidemiology, clinical aspects, and therapy. Clin Infect Dis 2002;35:1066-1070.
30. Cross EW, Park S, Perlin DS. Cross-Resistance of clinical isolates of Candida albicans and Candida glabrata to over-the-counter azoles used in the treatment of vaginitis. Microb Drug Resist 2000;6:155-161.
31. Sobel JD, Chaim W. Treatment of Torulopsis glabrata vaginitis: retrospective review of boric acid therapy. Clin Infect Dis 1997;24:649-652.
32. Forna F, Gulmezoglu AM. Interventions for treating trichomoniasis in women. Cochrane Database Syst Rev 2003(2);CD000218.
33. duBouchet L, McGregor JA, Ismail M, McCormack WM. A pilot study of metronidazole vaginal gel versus oral metronidazole for the treatment of Trichomonas vaginalis vaginitis. Sex Transm Dis 1998;25:176-179.
34. Tidwell BH, Lushbaugh WB, Laughlin MD, Cleary JD, Finley RW. A double-blind placebo-controlled trial of single-dose intravaginal versus single-dose oral metronidazole in the treatment of trichomonal vaginitis. J Infect Dis 1994;170:242-246.
35. Spence MR, Harwell TS, Davies MC, Smith JL. The minimum single oral metronidazole dose for treating trichomoniasis: a randomized, blinded study. Obstet Gynecol 1997;89:699-703.
36. Petrin D, Delgaty K, Bhatt R, Garber G. Clinical and microbiological aspects of Trichomonas vaginalis. Clin Microbiol Rev 1998;11:300-317.
37. Lossick JG, Kent HL. Trichomoniasis: trends in diagnosis and management. Am J Obstet Gynecol 1991;165:1217-1222.
38. Dombrowski MP, Sokol RJ, Brown WJ, Bronsteen RA. Intravenous therapy of metronidazole-resistant Trichomonas vaginalis. Obstet Gynecol 1987;69:524-525.
39. Pearlman MD, Yashar C, Ernst S, Solomon W. An incremental dosing protocol for women with severe vaginal trichomoniasis and adverse reaction to metronidazole. Am J Obstet Gynecol 1996;174:934-936.
40. Nyirjesy P, Sobel JD, Weitz MV, Leaman DJ, Gelone SP. Difficult-to-treat trichomoniasis: results with paromomycin cream. Clin Infect Dis. 1998;26:986-988.
41. Sobel JD, Nyirjesy P, Brown W. Tinidazole therapy for metronidazole resistant vaginal trichomoniasis. Clin Infect Dis 2001;33:1341-1346.