Metronidazole is used topically for the treatment of inflammatory lesions (papules and pustules) associated with rosacea (acne rosacea). Topical metronidazole has been designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this condition. Although periods of remission may be induced, metronidazole, like other currently available therapies, appears to be only palliative in the treatment of rosacea and does not appear to alter the underlying disease process; when the drug is withdrawn, manifestations appear to recur commonly. In addition, chronic therapy (usually intermittent) may be necessary, particularly for moderate to severe disease.
Rosacea is a chronic, progressive, dermatologic syndrome of unknown etiology generally characterized by recurrent inflammatory papules and pustules on the face, facial flushing, erythema, and telangiectasia. Ocular manifestations such as blepharitis, conjunctivitis, keratitis, and corneal scarring also may be present; in some patients (usually males), rhinophyma also may develop (secondary to soft tissue hypertrophy of the nose). Optimum treatment of rosacea has not been determined, although the inflammatory lesions may respond to long-term therapy with oral anti-infective agents (e.g., doxycycline, tetracycline, erythromycin, ampicillin, metronidazole) or topical anti-infective agents (e.g., metronidazole). In addition to anti-infective therapy, adjunctive measures often are recommended to decrease exposure to factors that may provoke the inflammatory and vascular manifestations of rosacea (e.g., excessive sunlight, wind, hot liquids, spicy food, alcohol, extremes of heat and cold). Other agents (e.g., isotretinoin for severe recalcitrant rosacea, sulfur) also have been used with some success.
In a placebo-controlled clinical study in adults with moderate rosacea, once-daily application of metronidazole 1% topical gel or vehicle alone resulted in a 50.7 or 32.6% reduction in the number of inflammatory lesions at 10 weeks of therapy, respectively; 38.42 or 27.51% of patients, respectively, met the criteria of clear or almost clear on the Investigator Global Assessment Scale at week 10.
In clinical studies in adults with rosacea, therapy with metronidazole 1% topical cream, metronidazole 0.75% topical lotion, or metronidazole 0.75% topical gel (no longer commercially available in the US) resulted in clinical improvement in inflammatory lesions in 68-96% of patients based on objective clinical assessment and photographic evaluation. A controlled study using metronidazole 1% topical cream indicates that topical metronidazole therapy is as effective as oral tetracycline (250 mg twice daily) in reducing the number of inflammatory lesions and improving erythema associated with rosacea. In 2 placebo-controlled clinical studies in adults with rosacea (excluding patients with nodules, moderate or severe rhinophyma, dense telangiectases, plaque-like facial edema, ocular involvement, or those whose infection did not respond to previous metronidazole therapy), once-daily application of metronidazole 1% topical cream or vehicle alone resulted in a 49-58 or 17-30% reduction in number of papules and pustules at 10 weeks of therapy, respectively; the erythema severity scores were reduced by 40-42 or 19-25% at 10 weeks of therapy, respectively, in patients receiving the cream or vehicle alone. Topical metronidazole has been effective in patients whose rosacea failed to respond adequately to, or relapsed with, other therapies (e.g., tetracycline).
In a controlled study in adults with moderate to severe rosacea, twice-daily application of metronidazole 0.75% topical lotion or vehicle alone for 12 weeks resulted in definite improvement in 32 or 15%, marked improvement in 32 or 20%, and clearing of lesions in 8 or 0% of patients, respectively, based on investigator's global assessment of improvement. There was worsening of rosacea in 5 or 15%, no change in 12 or 27%, and minimal improvement in 11 or 23% of patients, respectively, applying metronidazole lotion or vehicle alone. Treatment with metronidazole lotion or the vehicle alone resulted in a mean 55 or 20% reduction, respectively, in the number of inflammatory papules and pustules at 12 weeks of therapy.
Relapse rates 3-6 months after discontinuance of 2 or 4 months of daily therapy with metronidazole 1% cream were about 50 or 25%, respectively, in a study in a limited number of patients with varying degrees of severity of rosacea. Further study is needed to determine the rate of relapse after therapy with metronidazole 0.75% topical lotion. Topical metronidazole therapy has no effect on telangiectasia, rhinophyma, or ocular manifestations of rosacea.
Oral metronidazole also has been used with some success in the treatment of rosacea and has decreased total numbers of inflammatory lesions associated with the disease. However, long-term therapy generally is required to control the inflammatory lesions of rosacea, and use of oral metronidazole in the disease has been limited by concerns over adverse systemic effects and toxicity of the drug. There are no studies to date comparing efficacy and safety of topical and oral metronidazole therapy in the treatment of rosacea.
Metronidazole is used intravaginally (e.g., as a vaginal gel) or orally, administered as immediate-release tablets or as extended-release tablets, for the treatment of bacterial vaginosis (formerly called Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, Corynebacterium vaginitis, or anaerobic vaginosis).
Bacterial vaginosis is a noninflammatory vaginal syndrome characterized by replacement of the normal vaginal flora (predominantly hydrogen peroxide-producing Lactobacillus) with a mixed flora including Gardnerella vaginalis, anaerobes (e.g., Bacteroides ureolyticus, Prevotella, Porphyromonas, Peptostreptococcus, Mobiluncus), and Mycoplasma hominis; vaginal discharge may be an unreliable indicator of infection since many women are asymptomatic. While Gardnerella previously was thought to be the sole causative agent of this syndrome, it currently is thought that bacterial vaginosis is a polymicrobial condition in which Gardnerella acts synergistically with anaerobic bacteria and genital mycoplasmas. Clinical diagnosis of the syndrome generally is established by characteristic vaginal manifestations rather than bacteriologic determinations. The presence of at least 3 of the following manifestations is considered diagnostic for bacterial vaginosis: a nonirritating, odoriferous, thin, homogeneous, grayish-white, noninflammatory vaginal discharge that smoothly coats the vaginal walls; a vaginal pH exceeding 4.5; the elaboration of malodorous amines (''fishy'' odor) from discharge fluid after alkalinization with potassium hydroxide 10% (''whiff test''); and/or microscopic smears containing small coccobacillary organisms adherent to epithelial cells (''clue cells''). The presence of clue cells on wet mount examination of vaginal secretions is one of the most reliable indicators of bacterial vaginosis.
Gram stain results consistent with a diagnosis of bacterial vaginosis include markedly reduced or absent Lactobacillus morphology and predominance of Gardnerella morphotype. Although Gram stain of vaginal secretions also has been employed as a diagnostic test for bacterial vaginosis, accuracy of this method depends on evaluation by an experienced microbiologist; thus, this technique is used more often in research and hospital settings whereas diagnosis by clinical criteria typically is performed in an office setting.Gardnerella can be isolated from vaginal cultures in a large proportion of healthy women; because of this lack of specificity, culture for the organism is not recommended as a diagnostic method for bacterial vaginosis, and it is not used to guide therapy. The possibility of other pathogens commonly associated with vulvovaginitis or cervicitis (e.g., Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, Candida albicans, herpes simplex viruses) generally should be ruled out, particularly since coinfection with these organisms may occur.
Goals of treatment and recommended therapy for bacterial vaginosis differ for nonpregnant versus pregnant women. However, relief of signs and symptoms of infection is a principal goal of therapy, and all women with symptomatic bacterial vaginosis should be treated regardless of pregnancy status.
The principal goal in the treatment of bacterial vaginosis in nonpregnant women is to provide relief of vaginal manifestations and signs of infection. Other potential benefits include a reduction in other infectious complications (e.g., human immunodeficiency virus [HIV] infection) or other sexually transmitted diseases.
The US Centers for Disease Control and Prevention (CDC) states that treatment of bacterial vaginosis is indicated in all nonpregnant women who are symptomatic. The regimens recommended by the CDC for the treatment of bacterial vaginosis in nonpregnant women are a 7-day regimen of oral metronidazole (500 mg twice daily), a 5-day regimen of intravaginal metronidazole gel, or a 7-day regimen of intravaginal clindamycin cream. Alternative regimens recommended by the CDC for these women are a 7-day regimen of oral clindamycin or a 3-day regimen of intravaginal clindamycin suppositories.
Intravaginal metronidazole therapy results in clinical cure rates comparable to those reported with a 7-day oral metronidazole regimen; intravaginal clindamycin cream appears to be less effective than the metronidazole regimens. Regardless of the therapy chosen, relapse or recurrence of bacterial vaginosis is common, and some clinicians suggest that an alternative regimen (e.g., oral therapy when intravaginal therapy was used initially) can be employed in such infections.
Results of controlled studies indicate that metronidazole vaginal gel is more effective than placebo for the treatment of bacterial vaginosis. Patients with bacterial vaginosis who were treated with 5 g of metronidazole 0.75% vaginal gel (approximately 37.5 mg of the drug) twice daily for 5 days had clinical cure rates of 78-87% at the first follow-up visit (1-3 weeks after completion of treatment); microbiologic response to therapy paralleled clinical response. In a randomized, single-blind, comparative study in nonpregnant patients with bacterial vaginosis, clinical cure rates at 4 weeks following completion of therapy were 53 or 57% in patients receiving 5-day therapy with metronidazole vaginal gel once or twice daily, respectively. In one placebo-controlled study with a limited number of patients, the recurrence rate (15%) with metronidazole vaginal gel 1 month after treatment was comparable to that reported for oral metronidazole. In a randomized controlled trial, similar cure rates were obtained with intravaginal metronidazole (75%), oral metronidazole (84%), or intravaginal clindamycin (86%) at 7-14 days following completion of therapy; interpretation of these results is limited by the statistical limitations of this study (i.e., small sample size, inadequate power, short-term follow-up). Long-term follow-up of patients suggests high recurrence rates for bacterial vaginosis regardless of initial therapy.
An increased risk of obstetric complications, including intraamniotic infection, chorioamnionitis, premature rupture of membranes, preterm delivery, and low-birthweight infants, is associated with the presence of bacterial vaginosis in pregnant women, and the organisms found in increased concentrations in the genital flora of women with bacterial vaginosis are frequently found in patients with postpartum or postcesarean endometritis. Evidence from randomized, controlled trials indicates that systemic treatment of bacterial vaginosis reduces the rate of preterm birth in pregnant women at high risk for complications of pregnancy.
Because of an increased risk of adverse pregnancy outcomes associated with the presence of bacterial vaginosis, the CDC recommends that all symptomatic pregnant women be tested and treated for bacterial vaginosis. In addition, because there is evidence from randomized studies that treatment of bacterial vaginosis in asymptomatic pregnant women at high risk for complications of pregnancy (e.g., those who previously delivered a premature infant) has reduced preterm delivery, some experts recommend that all women at high risk be screened and treated for bacterial vaginosis. The CDC recommends that screening for bacterial vaginosis (if conducted) should be performed at the first prenatal visit and treatment initiated if needed. for a complete discussion of screening and treatment for bacterial vaginosis in pregnant women.)
The preferred regimens for the treatment of symptomatic bacterial vaginosis in pregnant women and for the treatment of asymptomatic women at high risk for complications of pregnancy are a 7-day regimen of oral metronidazole (500 mg twice daily or 250 mg 3 times daily) or a 7-day regimen of oral clindamycin (300 mg twice daily). Although some experts state that intravaginal therapy may be used solely for symptomatic relief (and not for prevention of adverse pregnancy outcomes) in women at low risk for preterm delivery, other experts prefer use of systemic therapy for all pregnant women, regardless of degree of risk for complications of pregnancy, because systemic treatment may be required to eradicate upper genital tract infection that may be associated with bacterial vaginosis. No adequate and controlled studies have been performed to date to establish the safety and efficacy of intravaginal metronidazole for the treatment of bacterial vaginosis in pregnant women.
(See Cautions: Pregnancy, Fertility, and Lactation)Because recurrence of bacterial vaginosis is not unusual, and the treatment of this condition may prevent adverse pregnancy outcomes, particularly in women at high risk for complications of pregnancy, follow-up at 1 month to assess for cure and evaluate the need for additional treatment should be considered.
Women Undergoing Gynecologic Procedures and Surgery
The goal of treatment of symptomatic bacterial vaginosis in women undergoing hysterectomy or abortion is to reduce the risk of infectious complications (e.g., pelvic inflammatory disease [PID]) following these procedures.
Treatment of asymptomatic bacterial vaginosis in patients who are about to undergo an invasive gynecologic procedure (e.g., endometrial biopsy, hysteroscopy, hysterosalpingography, hysterectomy, placement of an intrauterine device, uterine curettage), abortion, vaginal surgery, or abdominal surgery may be a reasonable consideration because of the association between this condition and various gynecologic infections (e.g., endometritis, PID, vaginal cuff cellulitis). While a reduction in postoperative pelvic inflammatory disease in women with bacterial vaginosis undergoing first-trimester elective abortion has been established in at least one study employing oral metronidazole, further study is needed to determine the value of treating asymptomatic bacterial vaginosis in patients who are about to undergo other invasive procedures.
Recommendations for treatment and preferred regimens for treatment of bacterial vaginosis in patients with concurrent human immunodeficiency virus (HIV) infection are the same as those for patients without HIV infection.
Results of several randomized, double-blind, placebo-controlled trials indicate that concurrent treatment of male sexual contacts of a woman with symptomatic bacterial vaginosis generally does not affect the clinical cure rate, including the risk of relapse or recurrence of the syndrome, in the woman. Therefore, routine treatment of male sexual contacts currently is not recommended. However, despite the lack of controlled studies showing any benefit, some clinicians believe that treatment of male sexual contacts (with similar oral dosages) of women who have relapsing or recurrent bacterial vaginosis may be reasonable. Further study is needed to elucidate the possible role, if any, of sexual transmission in bacterial vaginosis.
Decubitus and Other Ulcers
Metronidazole has been used topically as a 0.75% gel (no longer commercially available in the US) or a 1% aqueous solution or suspension (not commercially available in the US) for the treatment of infected decubitus ulcers, and has been designated an orphan drug by the FDA for use in the treatment of grade III or IV, anaerobically infected, decubitus ulcers. Metronidazole also has been used with some success in a limited number of patients for the topical treatment of infected ulcers of the feet associated with diabetes mellitus, ulcers associated with varicose veins, and postirradiation ulcers. In several uncontrolled studies in nonambulatory geriatric patients, a 1% aqueous solution or suspension of metronidazole applied topically to infected decubitus ulcers 3 times daily resulted in clinically apparent improvement, including decreased odor and drainage, clearing of surrounding cellulitis, and development of clean granulation within 48-72 hours. Topical administration of metronidazole gel to malodorous decubitus ulcers has decreased or eliminated odor. The drug also has been used orally for the treatment of infected decubitus ulcers and of malodorous (presumably anaerobically infected) ulcers associated with breast tumors.
Metronidazole has been used topically with some success in the treatment of dry socket (alveolar osteitis) after routine dental extraction. In one placebo-controlled study in patients with a painful tooth socket (alveolalgia) following recent tooth extraction and partial or total loss of the blood clot, a dressing containing metronidazole 10% in a carboxymethylcellulose gelatin vehicle (Orabase) applied to affected sockets appeared to decrease pain and shorten the treatment period when compared with the vehicle alone. Metronidazole also has been used topically as a 25% gel (not commercially available in the US) as an adjunct to conventional mechanical therapy in the treatment of periodontitis, but such topical anti-infective therapy may not provide any substantial clinical benefit compared with use of mechanical therapy alone. However, there is some evidence that adjunctive use of oral metronidazole alone or in conjunction with oral amoxicillin in patients with periodontitis may result in better clinical and microbiologic results than use of mechanical therapy alone.
Intravaginal metronidazole is unlikely to achieve therapeutic concentrations in the urethra and perivaginal glands and therefore is considerably less effective than oral metronidazole for the treatment of trichomoniasis caused by Trichomonas vaginalis.T. vaginalis infection usually extends beyond the vagina (e.g., to the urethra, cervical glands, and/or Skene's and Bartholin's glands) and systemic therapy is necessary. In a study comparing intravaginal metronidazole 0.75% gel twice daily for 7 days with oral metronidazole 250 mg 3 times daily for 7 days, microbiologic cure occurred in only 44% of women treated intravaginally versus in 100% of women treated orally. The CDC and other clinicians currently recommend oral metronidazole or oral tinidazole as the treatment of choice for trichomoniasis.
While intravaginal metronidazole has been used as an adjunct to oral metronidazole for the treatment of trichomoniasis in selected cases, substantial evidence that such concurrent therapy is superior to oral therapy alone is lacking. There is limited anecdotal evidence that adjunctive intravaginal metronidazole therapy combined with extended and/or high-dose oral therapy (with or without acetic acid vaginal douches) may be useful in treating certain intractable cases of trichomoniasis; however, the preparations of metronidazole used intravaginally in these studies (i.e., 500-mg suppositories [not commercially available in the US] 1-g extemporaneously prepared suppositories, 250- or 500-mg intravaginally inserted oral tablets) contained the drug in concentrations substantially higher than that in the currently available vaginal gel (i.e., 37.5 mg of drug per dose). Therefore, while some clinicians have suggested that metronidazole 0.75% vaginal gel may be useful as an adjunct to oral metronidazole in refractory cases of trichomoniasis, the role, if any, of the commercially available gel in the treatment of this infection remains to be established.
Metronidazole topical cream or gel has been used for the treatment of perioral dermatitis, and the gel has been designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this condition.