Pharmaceutical Services Division (PSD) requested a systematic review of Clindesse for the treatment of non-pregnant women ≥ 18 years of age with bacterial vaginosis.
Clindesse is a semi-solid white cream containing 2% clindamycin phosphate, which is a water-soluble ester of the semi-synthetic antibiotic produced by a 7 (S)-chloro-substitution of the 7(R)-hydroxyl group of the parent antibiotic, lincomycea. The recommended dose is a single intravaginal administration on one day.
Bacterial vaginosis is a common vaginal infection caused by an imbalance in the vaginal flora. In bacterial vaginosis there is suppression of lactobacilli, a rise in pH and overgrowth of other organisms, most commonly Gardnerella vaginalis. The overgrowth of these bacteria causes an increase in pH and a white or grey-like vaginal discharge accompanied by an unpleasant fishy odour.
In clinical practice bacterial vaginosis is diagnosed using the Amsel criteria of which at least three of the four following criteria must be met: thin, white, yellow, homogeneous discharge, clue cells on microscopy, pH of vaginal fluid >4.5, release of a fishy odour on adding alkali. For diagnosis in asymptomatic women and for clinical trials the FDA also requires use of the Nugent score which requires the use of a gram stained vaginal smear where the vaginal flora are examined and graded as: 0–3 normal (lactobacillus predominant), 4–6 intermediate, 7+ indicative of BV.
Once diagnosis is confirmed the mainstay of treatment is antibiotic therapy. Antimicrobials, which include the 5-nitroimidazoles (metronidazole, tinidazole, secnidazole), and the lincosamide clindamycin, inhibit anaerobes that support Gardnerella vaginalis but do not affect lactobacilli, and thus reduce the risk of relapse.
- In double blind randomized controlled trials does clindamycin phosphate 2% vaginal cream provide a therapeutic advantage over other medications used in the treatment of bacterial vaginosis in non-pregnant women ≥ 18 years of age?
- In double blind randomized controlled trials are there any safety or toxicity considerations with respect to clindamycin phosphate 2% vaginal cream compared to other medications used to treat bacterial vaginosis in non-pregnant women ≥18 years of age?
Randomized controlled trials (double blind, single blind or open label) comparing Clindesse to metronidazole or other formulations of clindamycin.
- Non-fatal Serious Adverse Events (SAEs)
- Therapeutic cure, defined as clinical cure: resolution of all 4 Amsel criteria and investigator cure and Nugent score: 0-3 for normal bacterial morphotypes
- Treatment failure, defined as at least three Amsel criteria and Nugent Score 7-10 at seven days after treatment or one to two month follow up (relapse in symptomatic women)
- Relapse rates within 12 months
- Incidence of endometritis; pelvic inflammatory disease, or other infections (fungal, HIV)
- Total adverse events (metallic taste, nausea, diarrhea, hypersensitivity, pseudomembranous colitis)
- Withdrawal due to adverse events
Search strategy and findings: The search included the following electronic databases: Medline (1966-July 2009), Embase (1988-July 2009), Cochrane Database of Systematic Reviews and Cochrane Central Registry of Clinical Studies. Key search words included bacterial vaginosis, clindamycin, Clindesse, metronidazole. The U.S. FDA and EMEA websites were also searched.
One trial (Faro et al 2005) comparing clindamycin single dose (Clindesse) to 7-day clindamycin (Cleocin) met the inclusion criteria for this review. However, because the per protocol analysis in the published trial included less than half of the total randomized population, results from the ITT and modified ITT analyses of the FDA review of Clindesse are presented.
Overall there were no clinically or statistically significant differences in serious morbidity therapeutic cure, withdrawals, treatment failure, incidence of pelvic inflammatory disease, vaginosis, fungal infections, incidence of other infections that were reported (Urinary tract infection), additional treatment required for bacterial vaginosis, total adverse events, and withdrawals due to adverse events for Clindesse versus Cleocin.
Treatment failure or cure in asymptomatic women and incidence of endometritis were not reported. Since the trial follow-up was for 21-30 days from start of treatment there is no data on the incidence of relapse.
Long-term adverse events are unknown.
In a 4-week single-blinded randomized controlled trial there was no significant difference between single dose clindamycin cream (Clindesse) versus clindamycin vaginal cream administered once daily for 7 days (Cleocin).
- Akinbiyi AA, Watson R, Feyi-Waboso P. Prevalence of Candida albicans and bacterial vaginosis in asymptomatic pregnant women in South Yorkshire, United Kingdom. Outcome of a prospective study. Archives of Gynecology & Obstetrics 2008; 278(5): 463-6.
- Bradshaw CS, Morton AN, Hocking J, Garland SM, Morris MB, Moss LM et al. High recurrence rates of bacterial vaginosis over the course of 12 months after oral metronidazole therapy and factors associated with recurrence. Journal of Infectious Diseases 2006; 193;(11): 1478-1486.
- Faro S, Skokos CK, Clindesse Investigators Group. The efficacy and safety of a single dose of Clindesse vaginal cream versus a seven-dose regimen of Cleocin vaginal cream in patients with bacterial vaginosis. Infectious Diseases in Obstetrics & Gynecology 2005; 13(3):155-60.
- FDA.Center for Drug Evaluation and Research. Application No. 50-793: Pharmacology Review. 2003.
- FDA.Center for Drug Evaluation and Research. Application number 50-793: Medical Review. 2004;1-131.
- Holzman C, Leventhal JM, Qiu H, Jones NM, Wang J, BV Study Group. Factors linked to bacterial vaginosis in non-pregnant women. American Journal of Public Health 2001; 91(10): 1664-70.
- Larsson PG, Platz-Christensen JJ, Thejls H, Forsum U, Pahlson C. Incidence of pelvic inflammatory disease after first-trimester legal abortion in women with bacterial vaginosis after treatment with metronidazole: a double-blind, randomized study. American Journal of Obstetrics & Gynecology 1992; 166(1 Pt 1): 100-3.
- Leitich H, Bodner-Adler B, Brunbauer M, Kaider A, Egarter C, Husslein P. Bacterial vaginosis as a risk factor for preterm delivery: a meta-analysis. American Journal of Obstetrics & Gynecology 2003; 189(1): 139-47.
- Martin HL, Richardson BA, Nyange PM, Lavreys L, Hillier SL, Chohan B et al. Vaginal lactobacilli, microbial flora, and risk of human immunodeficiency virus type 1 and sexually transmitted disease acquisition. Journal of Infectious Diseases 1999; 180(6): 1863-8.
- Ness RB, Hillier SL, Kip KE, Soper DE, Stamm CA, McGregor JA et al. Bacterial vaginosis and risk of pelvic inflammatory disease. Obstetrics & Gynecology 2004; 104(4): 761-9.
- Nyirjesy P, McIntosh MJ, Steinmetz JI, Schumacher RJ, Joffrion JL. The effects of intravaginal clindamycin and metronidazole therapy on vaginal mobiluncus morphotypes in patients with bacterial vaginosis. Sexually Transmitted Diseases 2007; 34(4): 197-202.
- Oduyebo OO, Anorlu RI, Ogunsola FT. The effects of antimicrobial therapy on bacterial vaginosis in non-pregnant women [Review]. Cochrane Database of Systematic Reviews 2009;(3).
- Schwebke JR, Hillier SL, Sobel JD, McGregor JA, Sweet RL. Validity of the vaginal gram stain for the diagnosis of bacterial vaginosis. Obstetrics & Gynecology 1996; 88(4 Pt 1): 573-6.
- Sha BE, Chen HY, Wang QJ, Zariffard MR, Cohen MH, Spear GT. Utility of Amsel criteria, Nugent score, and quantitative PCR for Gardnerella vaginalis, Mycoplasma hominis, and Lactobacillus spp. for diagnosis of bacterial vaginosis in human immunodeficiency virus-infected women. Journal of Clinical Microbiology 2005; 43(9): 4607-12.
- Soper DE. Bacterial vaginosis and postoperative infections. [Review] [25 refs]. American Journal of Obstetrics & Gynecology 1993; 169(2 Pt 2): 467-9.
- Thomas KK, Sanchez S, Garcia PJ, Holmes KK. Why do different criteria for ‘cure’ yield different conclusions in comparing two treatments for bacterial vaginosis? Sexually Transmitted Diseases 2005; 32(9): 526-30.
- Weir E. Bacterial vaginosis: more questions than answers. [Review] [3 refs]. Canadian Medical Association Journal 2004; 171(5): 448.