AHFS Class:

• Antibacterials 84:04.04

Generic Name(s):

• metroNIDAZOLE

Metronidazole is a synthetic, nitroimidazole-derivative3 antibacterial and antiprotozoal agent1,2,27,29,47,183 and also has direct anti-inflammatory effects1,2,14,17,21,28,180 and effects on neutrophil motility, lymphocyte transformation, and some aspects of cell-mediated immunity.2,10,32,33,34,35

Rosacea

Metronidazole is used topically for the treatment of inflammatory lesions (papules and pustules) associated with rosacea (acne rosacea).1,2,8,9,10,16,17,18,19,20,21,47,180,184,207 Topical metronidazole has been designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this condition.23 Although periods of remission may be induced,17,18,19 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treatment of rosacea and does not appear to alter the underlying disease process;17,18,19,47,81,61,99 when the drug is withdrawn, manifestations appear to recur commonly.17,18,19,47,61,99 In addition, chronic therapy (usually intermittent) may be necessary, particularly for moderate to severe disease.61,99

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.10,12,21,47,80,81,82 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).10,12,21,47,80,82,83 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)10,11,12,13,15,16,17,20,21,47,80,82 or topical anti-infective agents (e.g., metronidazole).2,8,9,10,16,17,18,19,20,21,47,80,81,82 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).2,12,80 Other agents (e.g., isotretinoin for severe recalcitrant rosacea, sulfur) also have been used with some success.10,17,80,82,83,84,85,86,87,88,89,90

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 10.1

In clinical studies in adults with rosacea, therapy with metronidazole 1% topical cream,9,10,16,18,19,20,29 metronidazole 0.75% topical lotion,207 or metronidazole 0.75% topical gel (no longer commercially available in the US)2,17,19,21,62,81 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.16 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.184 Topical metronidazole has been effective in patients whose rosacea failed to respond adequately to, or relapsed with, other therapies (e.g., tetracycline).2,10,17,21,62

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.207 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.207 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.207

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,18 in a study in a limited number of patients with varying degrees of severity of rosacea.9,18 Further study is needed to determine the rate of relapse after therapy with metronidazole 0.75% topical lotion.17,19 Topical metronidazole therapy has no effect on telangiectasia,2,9,10,17,19,21,47 rhinophyma,47 or ocular manifestations of rosacea.47,83

Oral metronidazole also has been used with some success in the treatment of rosacea†10,11,13,15,17,21,47 and has decreased total numbers of inflammatory lesions associated with the disease.10,11,13,15 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.17,47 There are no studies to date comparing efficacy and safety of topical and oral metronidazole therapy in the treatment of rosacea.

Bacterial Vaginosis

Metronidazole is used intravaginally (e.g., as a vaginal gel)109,111,112,114,115,119,120,122,123,139,153,183,214 or orally, administered as immediate-release tablets30,109,114,116,119,122,153 or as extended-release tablets187 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.109,110,117,119,120,122,123,134,153,155 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.110,138,153 Clinical diagnosis of the syndrome generally is established by characteristic vaginal manifestations rather than bacteriologic determinations.109,110,116,118,119,120,122,123,153 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”).109,110,116,118,119,120,122,123,153,155 The presence of clue cells on wet mount examination of vaginal secretions is one of the most reliable indicators of bacterial vaginosis.118,176

Gram stain results consistent with a diagnosis of bacterial vaginosis include markedly reduced or absent Lactobacillus morphology and predominance of Gardnerella morphotype.110,118,183 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.110,122,176,177,178 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,109,110,120,122,153,188 and it is not used to guide therapy.110,119,120,153,183 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,183 particularly since coinfection with these organisms may occur.110,176

Goals of treatment and recommended therapy for bacterial vaginosis differ for nonpregnant versus pregnant women.109 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.109

Nonpregnant Women

The principal goal in the treatment of bacterial vaginosis in nonpregnant women is to provide relief of vaginal manifestations and signs of infection.109,110,122 Other potential benefits include a reduction in other infectious complications (e.g., human immunodeficiency virus [HIV] infection) or other sexually transmitted diseases.109

The US Centers for Disease Control and Prevention (CDC) states that treatment of bacterial vaginosis is indicated in all nonpregnant women who are symptomatic .109 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.109 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.109

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.109 Regardless of the therapy chosen, relapse or recurrence of bacterial vaginosis is common,109,110,120,122,138,153,162 and some clinicians suggest that an alternative regimen (e.g., oral therapy when intravaginal therapy was used initially) can be employed in such infections.122

Results of controlled studies indicate that metronidazole vaginal gel is more effective than placebo for the treatment of bacterial vaginosis.111,112,115,119 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);111,112,115,119 microbiologic response to therapy paralleled clinical response.111,112,119 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.183 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.111 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).189 Long-term follow-up of patients suggests high recurrence rates for bacterial vaginosis regardless of initial therapy.109,160,162

Pregnant Women

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,109,190,191,192,193,194 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.109,195 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.109,196,197

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.109 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.109 The CDC recommends that screening for bacterial vaginosis (if conducted) should be performed at the first prenatal visit and treatment initiated if needed.109

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).109 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,206 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.109,195,200 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.119,183 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.109,195

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.109

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).109,120,121,122,153 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,121,122 further study is needed to determine the value of treating asymptomatic bacterial vaginosis in patients who are about to undergo other invasive procedures.122,176,177

HIV-infected Women

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.109

Sexual Contacts

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.109,113,123,201,202,203 Therefore, routine treatment of male sexual contacts currently is not recommended.109,110,116,122,153 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.120,138,153,203 Further study is needed to elucidate the possible role, if any, of sexual transmission in bacterial vaginosis.110,120,138,153,201

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†,27,39,40,41,42,212 and has been designated an orphan drug by the FDA for use in the treatment of grade III or IV, anaerobically infected, decubitus ulcers.23 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†.42,43 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.39,40 Topical administration of metronidazole gel to malodorous decubitus ulcers has decreased or eliminated odor.212,213 The drug also has been used orally for the treatment of infected decubitus ulcers100,101 and of malodorous (presumably anaerobically infected) ulcers associated with breast tumors.102,103,104

Dental Conditions

Metronidazole has been used topically with some success in the treatment of dry socket† (alveolar osteitis) after routine dental extraction.36,37 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.36 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.146,147 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.208,209

Trichomoniasis

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 .109 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.109,122,148,150,151,152,205 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.205 The CDC and other clinicians currently recommend oral metronidazole or oral tinidazole as the treatment of choice for trichomoniasis.109,114,123,215,216

While intravaginal metronidazole has been used as an adjunct to oral metronidazole for the treatment of trichomoniasis† in selected cases,78,148 substantial evidence that such concurrent therapy is superior to oral therapy alone is lacking.147,148,149,150 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;77,78,151,152,153,157,158 however, the preparations of metronidazole used intravaginally in these studies (i.e., 500-mg suppositories [not commercially available in the US],146 1-g extemporaneously prepared suppositories, 250- or 500-mg intravaginally inserted oral tablets)77,151,157,158 contained the drug in concentrations substantially higher than that in the currently available vaginal gel (i.e., 37.5 mg of drug per dose).183 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,156,205 the role, if any, of the commercially available gel in the treatment of this infection remains to be established.109,122,176,205

Other Uses

Metronidazole topical cream or gel has been used for the treatment of perioral dermatitis†,210,211 and the gel has been designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this condition.23

Administration

Metronidazole is applied topically to the skin1,180,184,207 or intravaginally183,214 in appropriate formulations.

Topical Administration

Metronidazole is applied topically to the skin as a 0.75 or 1% cream, 1% gel, or 0.75% lotion.1,19,180,184,207 The drug also has been applied topically to the skin as a 1% aqueous solution† or suspension†27,39,40,41,42 (not commercially available in the US).

Metronidazole topical preparations are for external use only and should not be used orally or intravaginally and contact with the eyes should be avoided.1,180,184,207

Prior to application of metronidazole 1% topical gel, 0.75 or 1% topical cream, or 0.75% lotion, affected areas should be washed1,180,184,207 with a mild, nonirritating cleanser.2,180 A thin film of the drug should then be applied;1,180,184,207 the gel or cream should be rubbed into the affected areas.1,180,184 To minimize the risk of local irritation, some clinicians suggest that application of the drug be delayed for about 15-20 minutes after cleansing the skin.99 Cosmetics may be applied to the skin after application of metronidazole 1% topical gel, 0.75 or 1% topical cream, or 0.75% topical lotion;1,47,180,184,207 the lotion should be allowed to dry for at least 5 minutes before applying cosmetics.207 A moisturizer also can be used if the skin is dry.47

Intravaginal Administration

Metronidazole is administered intravaginally as an intravaginal gel containing 0.75% of the drug.109,111,112,113,114,115,119,183,214 Patients should be instructed in the use of the vaginal applicator.183,214 Metronidazole also has been administered intravaginally as a vaginal cream,170 suppository,106,151,152,153,171 sponge,172,173 or tablet,174,175 but such preparations currently are not commercially available in the US.77,157

Metronidazole vaginal preparations are for intravaginal administration only and should not be used orally, topically on the skin, or near or in the eyes.177

Dosage

Rosacea

For the treatment of inflammatory lesions (papules and pustules) and erythema of rosacea, a thin film of metronidazole 0.75% cream180 or 0.75% lotion207 should be applied and rubbed into the cleansed, affected areas twice daily, in the morning and evening. Alternatively, metronidazole 1% topical cream184 or 1% topical gel1 should be applied and rubbed in the cleansed, affected area once daily.

Clinical improvement usually occurs within 3 weeks.17,21 Once an adequate response is obtained, the frequency and duration of therapy should be adjusted according to the course of the disease.47 Although periods of remission may be induced,17,18,19 the optimum duration of topical metronidazole therapy has not been established,10,17,18,19,21,47,81 and relapse appears to occur commonly following discontinuance of the drug.17,18,19,47,61,99 In clinical studies, topical metronidazole therapy for rosacea has been continued for up to at least 21 weeks.2,9,10,16,17,18,19,20,21,29

Bacterial Vaginosis

For the treatment of bacterial vaginosis in nonpregnant women, one applicatorful (approximately 5 g) of metronidazole 0.75% vaginal gel (approximately 37.5 mg of the drug) is administered intravaginally once (at bedtime) or twice daily (in the morning and in the evening), for 5 consecutive days.109,111,112,115,119,183,214

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 women109,119,183,214 and intravaginal metronidazole is not included in current CDC recommendations for the treatment of bacterial vaginosis in pregnant women.109

Decubitus Ulcers

For the treatment of infected decubitus ulcers†, metronidazole 0.75% topical gel (no longer commercially available in the US) has been applied to the ulcers.212,213 Alternatively, a 1% aqueous solution or suspension of metronidazole has been prepared extemporaneously from crushed metronidazole tablets, sterilized, and applied 3 times daily.39,40

Dosage in Hepatic Impairment

Patients with severe hepatic disease metabolize metronidazole slowly, which can result in the accumulation of the drug and its metabolites in plasma.183,214 Therefore, the manufacturers recommend that metronidazole vaginal gel be used with caution in patients with severe hepatic disease.183,214

Adverse Effects

Topical Preparations

Local Effects

Topically applied metronidazole appears to have a low order of toxicity and generally is well tolerated.9,16,17,20,21,29,47

The principal adverse effects of topical metronidazole preparations are local reactions,180,184,207 including transient redness180,207 and mild dryness,184,207 pruritus,180 aggravated rosacea180,184,207 or acne,184 burning,180,207 irritation,1,180,207 and stinging,47,180,207 which have occurred in less than 3% of patients.47 Topical metronidazole preparations have caused watery or tearing eyes when applied too close to the eyes,17,47,180,207 and conjunctivitis (associated with topical use of metronidazole on the face) has been reported.184

Assessment of local reactions to topical metronidazole may be difficult in patients with rosacea17,21 since the disease is an inflammatory disorder characterized by facial papules, pustules, erythema, edema, pruritus, burning, and stinging.2,10,12,17,21

Contact dermatitis has not been reported to date in patients receiving metronidazole 0.75% topical gel (no longer commercially available in the US) or the gel vehicle alone,2,17,21 and dermatotoxicity studies in rabbits and adults have not revealed evidence of local irritation, contact sensitization, phototoxicity, or photoallergic dermatitis with either metronidazole 0.75% topical gel or the gel vehicle alone.2 In one study, no contact or photocontact sensitization or phototoxicity was reported in individuals receiving metronidazole 1% cream.184 Slight irritant reactions have occurred when patch tests were done in adults with rosacea using metronidazole 1% cream, but it was unclear whether these reactions were caused by the drug or the vehicle.9,10 In a controlled study in adults with rosacea, contact dermatitis occurred in 3 or 1%, local allergic reaction in 3 or 0%, and erythema in 6 or 0%, of patients using metronidazole 0.75% topical lotion or the lotion vehicle alone, respectively.207

Systemic Effects

Topically applied metronidazole does not have an appreciable effect on the microflora of the skin or feces of patients with rosacea.2,10,29 In one study in adults with rosacea who received topical metronidazole 1% cream twice daily for 30 days, there were no substantial alterations in aerobic or anaerobic skin or fecal microflora during or after treatment with the drug.2,29

Since only minimal amounts of topical metronidazole preparations are absorbed systematically following application to the skin,1,2,9,10,21,47 abnormal hematologic, renal, or hepatic function test results17 have not been reported with the use of topical metronidazole preparations.2,21,47 However, other adverse systemic effects, including metallic taste,1,180,207 nausea,1,180,207 paresthesia,184 and tingling or numbness of the extremities,1,180,207 have been reported in patients receiving topical preparations of metronidazole.1,180

Intravaginal Preparations

Intravaginally applied metronidazole generally is well tolerated.111,112,113,115,119,183 Adverse effects occurred in about 39% of nonpregnant patients receiving metronidazole vaginal gel during clinical trials; discontinuance (occasionally because of abdominal/pelvic cramps, loose stools, or mild vaginal burning) of the drug because of adverse effects was required in about 0.4-1% of patients.119,183 These symptoms resolved following discontinuance of the drug.183 Incidence of adverse effects was similar in patients receiving metronidazole vaginal gel once or twice daily.183 While systemically achieved concentrations of the drug generally are low at usual intravaginal dosages,119,131,132,183 this route of administration is not devoid of adverse systemic effects.115,119,183

Local and Genitourinary Effects

The most common adverse effects of therapy with metronidazole vaginal gel are vaginal discharge, symptomatic Candida cervicitis/vaginitis, and vulvovaginal irritation occurring in 12, 10, and 9% of patients receiving the drug, respectively.183

Known or previously unrecognized vaginal candidiasis may become prominently symptomatic during therapy with metronidazole vaginal gel.183 However, metronidazole is inactive against most lactobacilli normally resident in the vagina, even at the high concentrations achieved with local application, and in vitro data suggest that intravaginal application of metronidazole at usual concentrations may be less likely than intravaginal application of clindamycin to disrupt this flora.119,124 Limited evidence from a comparative study suggests that similar rates of vulvovaginal candidiasis occur following treatment with intravaginal metronidazole, intravaginal clindamycin, or oral metronidazole;189 however, further study is needed to establish the relative risk of this effect.176 Approximately 6-10% of patients have been reported to develop symptomatic candidal vaginitis during or immediately following therapy with metronidazole vaginal gel,111,112,183 although a higher rate of 30% was recorded in one small comparative study.189 Abdominal or pelvic discomfort/cramps183 reportedly occur in about 3% and dark urine 183 occurs in less than 1% of patients receiving intravaginal metronidazole therapy with the gel.

Vaginal candidiasis, dyspareunia, decreased libido, proctitis, dysuria, urinary tract infections (cystitis), polyuria, incontinence, dryness of the vagina or vulva, dark urine, and pelvic pressure have been reported in patients receiving oral or parenteral metronidazole.183

GI Effects

GI effects including GI discomfort, nausea/vomiting, and unusual taste have been reported in 7, 4, and 2% of patients receiving metronidazole vaginal gel.183 Diarrhea/loose stools and decreased appetite occurred in 1% of patients183 while abdominal bloating/gas,183 thirst,183 and dry mouth183 were reported in less than 1% of patients receiving intravaginal metronidazole as the gel.

Abdominal discomfort/cramping, nausea, vomiting, diarrhea, unpleasant metallic taste, anorexia, epigastric distress, constipation, furry tongue, dry mouth, glossitis, stomatitis, pancreatitis, and changes in taste perception of alcoholic beverages have been reported in patients receiving oral or parenteral metronidazole.183

Nervous System Effects

Headache and dizziness have been reported in 5 and 2% of patients receiving metronidazole vaginal gel, respectively,183 while depression183 and fatigue183 occurred in less than 1% of patients.

Headache, dizziness, syncope, ataxia, confusion, seizures, peripheral neuropathy, vertigo, incoordination, irritability, depression, weakness, and insomnia have been reported in patients receiving oral or parenteral metronidazole.30,183

Dermatologic and Sensitivity Reactions

Generalized pruritus or rash occurred in less than 1% of patients receiving metronidazole vaginal gel.183

Hypersensitivity reactions including urticaria, pruritus, erythematous rash, flushing, nasal congestion, fever, and fleeting joint pains have been reported in patients receiving oral or parenteral metronidazole.30,183

Other Adverse Effects

Leukopenia or leukocytosis has been reported in about 1.7% of patients receiving metronidazole vaginal gel while unspecified cramping occurred in 1% of patients receiving metronidazole intravaginally as the gel.183

Flattening of the T-wave has been reported rarely in ECG tracings of patients receiving oral or parenteral metronidazole.30,183 Reversible neutropenia and reversible thrombocytopenia have been reported in patients receiving oral or parenteral metronidazole.30,183

The possibility that other adverse effects associated with topical (e.g., local irritation, transient local erythema, local dryness and burning) or systemic metronidazole therapy could occur with intravaginal therapy should be considered.151,183

Precautions and Contraindications

Patients receiving metronidazole 0.75 or 1% topical cream, 1% topical gel, or 0.75% topical lotion should be instructed to use the drug only as directed by their physician and only for the disorder for which it was prescribed.1,180,184,207 Commercially available topical metronidazole preparations are for external use only.1,180,184,207 Because the topical preparations have caused ocular irritation, contact with the eyes should be avoided.1,180,184,207 If a reaction suggesting local irritation occurs, patients should be directed to use topical metronidazole preparations less frequently or discontinue use.180,184,207 Patients should be advised to report any adverse effects to their clinician.1,184,207

Although adverse hematologic effects have not been reported to date with topical metronidazole, the manufacturers state that the drug is a nitroimidazole and should be used with caution in patients with evidence or history of blood dyscrasia.1,180,184,207

Patients should be instructed to not engage in vaginal intercourse111,112,113,183,214 and to refrain from use of other vaginal products (tampons, douches) during the entire course of therapy with metronidazole vaginal gel111,112,113,214 since vaginal intercourse or vaginal products could reduce the efficacy of the gel (e.g., by dislodgement and/or dilution, by increased vaginal pH secondary to deposition of semen).111,122,176,177 In addition, although serum metronidazole concentrations are substantially lower with usual intravaginal doses of the 0.75% vaginal gel compared with usual oral doses, patients should be cautioned about the use of alcohol during therapy with metronidazole vaginal gel.183,214

Because the vaginal gel may cause ocular burning and irritation, contact with the eyes should be avoided.183,214 If such contact occurs, the eyes may be irrigated with copious amounts of cool water.177,183,214

Convulsive seizures and peripheral neuropathy (characterized by numbness or paresthesia of an extremity) have been reported in patients receiving oral or IV metronidazole.183,214 If abnormal neurologic manifestations occur during intravaginal metronidazole therapy, the drug should be discontinued promptly.183,214 In addition, the vaginal gel should be used cautiously in patients with a history of CNS disease.183,214

Metronidazole topical1,180,184 or vaginal183,214 preparations are contraindicated in patients with known hypersensitivity to metronidazole, other nitroimidazole derivatives, parabens, or any other ingredient in the formulation.1,180,183,184,214

Pediatric Precautions

Safety and efficacy of topical1,180,184,207 preparations of metronidazole in pediatric patients have not been established.1,180,184

Safety and efficacy of metronidazole vaginal gel (Vandazole^®) in postmenarchal females have been established based on extrapolation of clinical trial data from adult women; safety and efficacy of this preparation in premenarchal females have not been established.214

Geriatric Precautions

While safety and efficacy of metronidazole 1% topical gel (MetroGel^®) in geriatric patients have not been established specifically, safety and efficacy of this preparation in the 66 patients 65 years of age or older included in the clinical studies were comparable to the study population.1

Clinical studies of metronidazole vaginal gel (Vandazole^®) did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger patients.214

Mutagenicity and Carcinogenicity

Metronidazole has shown mutagenic activity in several in vitro microbial studies,1,30,45,105,180,183,184,207 and has caused chromosomal aberrations in mammalian cells cultured with the drug under anaerobic conditions.47 In addition, dose-response increases in the frequency of micronuclei were observed in mice receiving intraperitoneal administration of metronidazole.1,180,184,207 There was no evidence of mutagenic effects in in vivo studies using metronidazole in mammals.30,45,183 No excess chromosomal aberrations were observed in circulating human lymphocytes in patients receiving metronidazole therapy for 8 months.1,180,207 However, increases in chromosomal aberrations have been reported in patients with Crohn's disease receiving 200-1200 mg of metronidazole daily for 1-24 months.1,180,184,207 Oral metronidazole was carcinogenic in mice and rats in chronic studies. In several long-term studies in mice, oral administration of metronidazole at dosages of 225 mg/m² daily or more (about 37 times the recommended human topical dosage on a mg/m² basis) was associated with increases in the incidence of pulmonary tumors and lymphomas.184 In other long-term studies, increases in the incidence of pulmonary tumors in male mice and lymphomas in female mice were observed in mice receiving oral metronidazole at dosages of 198 mg/m² daily or more (about 29-71 times the recommended human topical dosage on a mg/m² basis).207 In other long-term studies, statistically significant increases in the incidence of hepatic and mammary tumors were observed in rats receiving oral metronidazole at dosages exceeding 885 mg/m² daily (about 144 times the recommended human topical dosage).184 Similar studies in hamsters did not reveal evidence of carcinogenicity.30,45,105 In other studies, the incidence of hepatic and mammary tumors in female rats and the incidence of testicular tumors and pituitary adenomas in male rats was increased in those receiving oral metronidazole at dosages of 1593 mg/m² daily or greater (about 230-573 times the recommended human topical dosage on a mg/m² basis).207 In another study, mammary tumors were reported in rats receiving metronidazole by oral gavage at a dosage of 177 mg/m² daily (about 26-64 times the human topical dosage on a mg/m² basis).207 In addition, in studies in albino, hairless mice, intraperitoneal administration of metronidazole at dosages of 45 mg/m² daily (about 7 times the recommended human topical dosage on a mg/m² basis) was associated with increased incidence or enhancement (as demonstrated by a decreased latency period to the development of skin neoplasms) of ultraviolet radiation-induced skin carcinogenesis.184,207 However, one manufacturer states that concentration of metronidazole in the skin was not determined, and the study did not differentiate whether metronidazole must be present during ultraviolet radiation exposure to enhance tumor formation or might promote tumor formation from preexisting ultraviolet radiation-initiated cells.207 Carcinogenicity (including dermal or photocarcinogenicity) studies have not been performed using topical1,207 or intravaginal183 metronidazole. Although there is no evidence to date that long-term use of metronidazole in humans is associated with an increased risk of mutagenicity or carcinogenicity,10,17,56,57,58,105 some clinicians suggest that further studies with longer-term follow-up are necessary before the risks of chronic systemic or topical metronidazole therapy can be fully determined.47,105

Pregnancy, Fertility, and Lactation

Pregnancy

No fetotoxicity was observed in rats or mice receiving oral administration of metronidazole at dosages 200 or 20 times the usual dosage, respectively.184 In addition, reproduction studies in pregnant mice using oral metronidazole doses about 6 times the maximum recommended human dose (on a mg/m² basis) have not revealed evidence of fetotoxicity or teratogenicity;183 however, intrauterine deaths have occurred following intraperitoneal administration of the drug.30,45,183 The fetal risk, if any, with the use of topical1 or vaginal176,177,183 metronidazole gel in pregnant women currently is not known. Metronidazole crosses the placenta and is rapidly distributed into fetal circulation.183,184,207 There have been no adequate and controlled studies to date using oral,30 IV,45 topical,1,180,184,207 or intravaginal183 metronidazole in pregnant women. Because animal reproduction studies are not always predictive of human response and because oral metronidazole has been shown to be carcinogenic in some rodents, topical metronidazole preparations1,180,184,207 or the vaginal183,214 gel should be used in pregnant women only when clearly needed.

Screening and/or treatment for bacterial vaginosis in pregnant women as clinically indicated should be conducted during the first prenatal visit.109 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,206 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.109,195,200 For the treatment of bacterial vaginosis and reduction in the incidence of adverse pregnancy outcomes associated with bacterial vaginosis (e.g., preterm birth), particularly in pregnant women at high risk for complications of pregnancy, a 7-day regimen of oral metronidazole or a 7-day regimen of oral clindamycin is recommended.109

Fertility

Reproduction studies in mice using oral metronidazole doses about 6 times the maximum recommended human dose (on a mg/m² basis), have not revealed evidence of impaired fertility.183 Induced inhibition of spermatogenesis and severe testicular degeneration were observed in rats receiving oral metronidazole at a dosage of 1,770 mg/m² daily (about 255-637 times the human topical dose on a mg/m² basis).207 Conflicting results (either no effect or a similar effect to that in rats) were reported in 2 strains of mice (ICR and CF1).207

Lactation

Following oral administration, metronidazole is distributed into milk in concentrations similar to those attained in plasma.1,30,45,131,207 Although plasma concentrations of metronidazole following topical or intravaginal administration are lower than those achieved after oral administration of the drug,1,180,183,184,207 it is not known whether metronidazole distributes into milk following topical or intravaginal application.183 Therefore, because oral metronidazole has been shown to be carcinogenic in some rodents, a decision should be made whether to discontinue nursing or topical or intravaginal metronidazole, taking into account the importance of the drug to the woman.1,180,183,184,207

Because metronidazole can be absorbed systemically following intravaginal application,119,131,132,183,186 214 the possibility that drug interactions could occur with this route of administration should be considered.106,183 Small amounts of metronidazole may be absorbed systemically following topical application to the skin,1,2,9,10,21,47,207 but the likelihood of systemic interactions following topical administration of the drug is less than with oral or parenteral administration.

Coumarin Anticoagulants

Systemic metronidazole potentiates the effects of oral anticoagulants resulting in prolongation of the prothrombin time.1,30,45,92,93,94,95,96,183 While only small amounts of metronidazole are absorbed from topical preparations through the skin or mucous membranes during topical or intravaginal therapy at usual dosages, the possibility that anticoagulant effects may be potentiated should be considered when topical or intravaginal metronidazole is used in patients receiving oral anticoagulant therapy.183,214

Alcohol

Disulfiram-like reactions have occurred in some patients who ingested alcohol while receiving oral or IV metronidazole.21,30,45,92,98,183 A disulfiram-like reaction also has occurred in at least one patient who ingested alcohol while receiving intravaginal metronidazole.106 Although serum metronidazole concentrations are substantially lower with usual intravaginal doses of the 0.75% vaginal gel compared with usual oral doses, the possibility of an interaction with alcohol exists during intravaginal metronidazole therapy.106,115,119,183,214 Patients should be cautioned about the use of alcohol during therapy with the vaginal gel.183,214

These reactions have not been reported to date in patients receiving topical application of metronidazole to the skin.21,47,61,99

Disulfiram

Administration of disulfiram and oral metronidazole has been associated with acute psychoses in some patients;92,97,168,169,183 therefore, the drugs should not be used concomitantly.92,97 The manufacturers recommend that 2 weeks elapse following discontinuance of disulfiram prior to initiating therapy with metronidazole vaginal gel.183,214

Lithium

Initiation of short-term metronidazole therapy in patients stabilized on a relatively high dosages of lithium has been reported to increase serum lithium concentrations resulting in signs of lithium toxicity in several patients.30,181,183

Cimetidine

Concomitant use of cimetidine with oral or IV metronidazole may prolong the plasma half-life and decrease the plasma clearance of metronidazole.182,183 In a study in healthy individuals, pretreatment with cimetidine reportedly increased the plasma half-life and decreased total plasma clearance of metronidazole following a single IV dose of the anti-infective, possibly by inhibiting hepatic metabolism of metronidazole.182

Laboratory Test Interferences

Metronidazole interferes with serum AST (SGOT), ALT (SGPT), LDH, triglycerides, and glucose determinations when such determinations are based on the decrease in ultraviolet absorbance that occurs during oxidation of NADH to NAD.30,183 Metronidazole interferes with these assays because the drug has an absorbance peak of 322 nm at pH 7, which is close to the 340 nm absorbance peak of NADH; this causes an increase in absorbance at 340 nm resulting in falsely decreased values.30,183

Acute Toxicity

The manufacturers state that there currently is no experience with acute overdosage of metronidazole vaginal gel.183,214 However, intravaginally applied metronidazole 0.75% vaginal gel can be absorbed in sufficient amounts to produce systemic effects.183,214 Animal studies show no evidence of acute toxicity associated with oral administration of metronidazole vaginal gel; mild irritation in both the eye and the vagina were observed with application of the gel in these areas in animals.119

Mechanism of Action

Antimicrobial Effects

Metronidazole is bactericidal, amebicidal, and trichomonacidal in action.2,30,48,52,56 The exact mechanism of antimicrobial action of the drug has not been fully elucidated.48 Metronidazole is un-ionized at physiologic pH49 and is readily taken up by anaerobic organisms or cells.48,49,50,56,72 In susceptible organisms or cells, metronidazole is reduced by low-redox-potential electron transport proteins (e.g., nitroreductases such as ferredoxin) to unidentified polar product(s) that lack the nitro group.48,49,50,56,64,65,66,68,69,70,71,72 The reduction product(s) appears to be responsible for the cytotoxic and antimicrobial effects of the drug, which include disruption of DNA and inhibition of nucleic acid synthesis.48,56,63,64,65,66,67,68,70,71,72 Metronidazole is equally effective against dividing and nondividing cells.56

Anti-inflammatory and Immunosuppressive Effects

In vitro and in vivo studies indicate that metronidazole has direct anti-inflammatory effects2,14,17,21,28,180 and effects on neutrophil motility, lymphocyte transformation, and some aspects of cell-mediated immunity.2,10,32,33,34,35

In in vivo studies in rats given metronidazole in dosages of 2-4 mg/100 g of body weight, the drug reportedly inhibited the development of formalin-induced edema in the rat paw.14 In vitro in neutrophils, metronidazole has a dose-dependent inhibitory effect on generation of hydrogen peroxide and hydroxyl radicals, oxidants that may cause tissue injury at the site of inflammation.2,17,21,28 This antioxidant effect appears to be caused by a direct effect on neutrophil function28 and may contribute to the drug's anti-inflammatory effect in vivo.2,28

Results of in vitro studies using leukocytes obtained from patients with Crohn's disease indicate that exposing the cells to metronidazole concentrations of 10 or 50 mcg/mL improved both spontaneous and induced leukocyte migration in cells that previously exhibited reduced migration; the drug had no effect on leukocytes obtained from healthy adults or patients with Crohn's disease when the cells exhibited normal migration prior to exposure to the drug.33,34 This effect on leukocyte migration also was observed in vivo in adults with Crohn's disease who received a single 400-mg dose of metronidazole.33 It has been suggested that metronidazole may increase leukocyte migration by a direct effect on the leukocytes,33,34 possibly by causing the release of surface-bound immune complexes from the cell surface.34

In in vivo studies in mice, metronidazole given orally in a dosage of 20 or 200 mg/kg daily suppressed granuloma formation around Schistosoma mansoni eggs that had been injected IV into the lungs of the mice.35 In mice sensitized to S. mansoni eggs, oral metronidazole (20 mg/kg) inhibited the development of delayed hypersensitivity footpad reactions to soluble schistosome egg antigen.35 The drug, however, did not affect nonspecific inflammation around divinylbenzene copolymer beads injected in mice and did not suppress skin allograft rejection in mice.35

Effects on Rosacea

The mechanism(s) by which metronidazole reduces inflammatory lesions (papules and pustules) and erythema in patients with rosacea has not been elucidated,1,2,6,10,11,17,19,21,28,29,184,207 but these effects may result in part from the anti-inflammatory or immunosuppressive actions of the drug.1,2,3,10,17,28,29,207 Although metronidazole has antimicrobial effects,2,7,29,30,45,48,52,53,54,55,56 there currently is no evidence that suppression of skin bacteria is involved directly in the mechanism of action of the drug in the treatment of inflammatory lesions of rosacea.2,10,11,29 Metronidazole is inactive in vitro against Propionibacterium acnes ,2,4,5,48 staphylococci, and streptococci,2,48 and has no appreciable effects on the aerobic or anaerobic microflora of the skin of patients with rosacea.2,10,29 In addition, the mechanism of action of metronidazole on inflammatory papules and pustules of rosacea does not appear to result from a direct effect on Demodex folliculorum, a parasitic mite that may be present on the skin of patients with rosacea, since results of in vitro studies indicate that metronidazole probably is inactive against the mite.2,6,10,17,21,22,29 Further study is needed to determine whether the drug may reduce an inflammatory response elicited by this mite.2,11,91,107

Spectrum

In general, metronidazole is active against most obligately anaerobic bacteria2,7,29,30,45,48,53,56,64 and many protozoa.2,29,30,48,52,64 The drug also is toxic to other anoxic or hypoxic cells.48,51,56 Metronidazole is inactive against most aerobic or facultatively anaerobic bacteria2,7,30,45,48,73,74 and is inactive against fungi2,3,48 and viruses.48

Anaerobic Bacteria

Metronidazole is active in vitro against many anaerobic gram-negative bacilli including Bacteroides fragilis ,2,3,30,45,48,53,54,55,124,126,130 B. bivius ( Prevotella bivia ),53,124,126,128,129 B. disiens ( Prevotella disiens ),54,128 B. distasonis ,30,45,54,55,124 B. gingivalis ( Porphyromonas gingivalis ),7,124 B. intermedius ( Prevotella intermedia ),7,124 B. melaninogenicus ( Prevotella melaninogenica ),48,54,124,126,128,129 B. oralis ( Prevotella oralis ),54,124,126,129 B. ovatus ,30,45,55,124 B. thetaiotaomicron ,30,45,54,55,124 B. vulgatus ,30,45,54,55,124 B. asaccharolyticus ( Porphyromonas asaccharolytica ),124,129 B. ureolyticus ,124,126 Fusobacterium ,2,7,30,45,48,53,55 and Veillonella .7,54,55 Some strains of Mobiluncus (motile, anaerobic, curved rods) are inhibited in vitro by metronidazole;119,125,126,129,133,183 other strains are considered resistant to the drug.124,125,129,133 The drug also is active against many anaerobic gram-positive cocci including Clostridium ,2,30,45,48,53,55 C. difficile ,54,55 C. perfringens ,48,55 Eubacterium ,2,30,45,48,53,54 Peptococcus ,2,30,45,48,53,54,55 and Peptostreptococcus .2,7,30,45,48,53,55,124,128 Actinomyces , Lactobacillus ,48 Propionibacterium acnes ,2,4,5,48 P. avidum ,5 and P. granulosum 5 generally are resistant to metronidazole.

Other Organisms

In vitro, metronidazole is active against Campylobacter fetus .48 Most strains of Gardnerella vaginalis (formerly Haemophilus vaginalis ) are susceptible only to relatively high concentrations of metronidazole in vitro.119,126,129,135,140,141,142 However, the 2-hydroxy metabolite is approximately 4-8 times as active as the parent drug against this organism,129,130,142 and this metabolite may be principally responsible for the activity of metronidazole against G. vaginalis in vivo when the drug is administered systemically.129,130,142 In addition, at metronidazole concentrations readily achievable locally (750 mcg/mL) following intravaginal application of the commercially available 0.75% gel, approximately 90% of strains tested reportedly were inhibited by the parent drug in vitro.119,177

Standard methodology for susceptibility testing of G. vaginalis , Mobiluncus spp, or Mycoplasma hominis has not been defined.125,154,183

In vitro studies indicate that metronidazole is inactive against fungi, including dermatophytes.3 The drug is inactive against Trichophyton mentagrophytes , T. rubrum , Epidermophyton floccosum , Candida albicans , C. parapsilosis , Aspergillus fumigatus , A. niger , and Malassezia furfur ( Pityrosporum ovale ).3

In vitro, metronidazole appears to be inactive against Demodex folliculorum , a parasitic mite that may be present in human pilosebaceous follicles.6,22 Metronidazole solutions containing up to 1 mg/mL of the drug had no effect on survival of D. folliculorum obtained from hair follicles and scales of patients with rosacea.6,22 Further study is needed to determine whether any of metronidazole's metabolites16,22 or higher concentrations2 of the drug are active against the mite.6,22

Resistance

Natural and acquired resistances to metronidazole have been reported occasionally in some strains of Trichomonas vaginalis .48,52,75,76,77,78,79 Rarely, resistance to the drug also has been reported in Bacteroides fragilis and other anaerobic bacteria following long-term therapy.44,48 Resistance to metronidazole may result from poor cell penetration and/or decreased nitroreductase activity.48,75,77,78,79,207

Pharmacokinetics

Absorption

Topical Administration

Only small amounts of metronidazole are absorbed systemically following topical application to the skin; the extent of absorption varies depending on the topical formulation used.1,2,9,10,21,47,207

In adults with rosacea who received once-daily application to the face of metronidazole 1% topical cream in doses averaging 3.75 mg (range: 2.2-6.8 mg) for 1 month, serum concentrations of the drug ranged from undetectable to 45 ng/mL; traces of the drug were detectable in the serum of 20% of patients.9 In another study, following topical application of 1 g of metronidazole 1% topical cream in a limited number of healthy individuals, the drug was detectable in serum of about 44% of patients; mean serum metronidazole concentrations ranged from 20.3-34.9 ng/mL and peak serum concentrations were achieved within 8-12 hours after topical application of the cream.184

Following topical application of 1 g of metronidazole 0.75% lotion (7.5 mg of metronidazole) to the face of healthy individuals, the peak plasma concentration was 96 ng/mL and was about 80 times lower than peak plasma concentrations attained following oral administration of a single 250-mg dose of the drug; the drug was detectable in the plasma of all individuals.207

In in vitro studies using human skin and hydroalcoholic solutions containing approximately 3.1 mg of metronidazole per mL with propylene glycol, approximately 3-10% of the metronidazole dose is absorbed within 20 hours.24,26 Hydration of the skin by occlusion appears to increase percutaneous absorption of metronidazole following topical application of the drug in a hydroalcoholic solution containing propylene glycol.26

Intravaginal Administration

Metronidazole is absorbed systemically following intravaginal application of the drug as a vaginal gel,119,131,132,183 cream (not commercially available in the US),131,132,143 tablet131,132,144 (not commercially available in the US), or suppository (not commercially available in the US).131,143,145 The systemic bioavailability of intravaginally administered cream, tablet, or suppository is only about 20-25%;131,132,143,144,145,186 however, that of the commercially available vaginal gel (MetroGel^®) is increased substantially, averaging about 50-56% in healthy females.119,131,132,186 Despite the good systemic bioavailability of the vaginal gel, only small concentrations of the drug and its active 2-hydroxy metabolite are achieved systemically following application of usual intravaginal doses (e.g., 37.5 mg) relative to usual oral or parenteral doses (e.g., 500 mg).119,131,132,186 Following intravaginal administration of 5 g of metronidazole 0.75% vaginal gel (MetroGel^®; approximately 37.5 mg of the drug) in a limited number of healthy women, peak serum metronidazole concentrations 6-12 hours after administration averaged 237 ng/mL (range: 152-368 ng/mL).119,183,186 Following oral administration of a single 500-mg dose of the drug in these women, peak serum metronidazole concentrations 1-3 hours after administration averaged 12.8 mcg/mL (range: 10-17.4 mcg/mL).119,183,186 Thus, peak serum concentration of metronidazole after a single 37.5-mg intravaginal dose (5-g dose of the 0.75% vaginal gel MetroGel^®) was approximately 2% of that after a single 500-mg oral dose.119,132,183,186 Systemic bioavailability (as determined by area under the concentration-time curve [AUC]) of metronidazole after a single 37.5-mg intravaginal dose (5-g dose of the 0.75% vaginal gel) was approximately 4 and 53% of that after single 500- and 37.5-mg oral doses, respectively.119,183,186 Following intravaginal administration of single and multiple doses of 5 g of metronidazole 0.75% vaginal gel (MetroGel^®; approximately 37.5 mg of the drug) in several women with bacterial vaginosis, peak serum metronidazole concentrations approximately 6-12 hours after administration averaged 214 and 294 ng/mL (range: 228-349 ng/mL) on days 1 and 5 of therapy, respectively.119,177,183

Distribution

The distribution of metronidazole following topical application to the skin10 or intravaginal application176,177 has not been determined. Metronidazole is less than 20% bound to plasma proteins.30,45,56

The distribution of metronidazole across the placenta or into milk following topical application to the skin1 or intravaginal application183 is not known; however, the drug readily crosses the placenta and is rapidly distributed into fetal circulation, and it is distributed into milk following oral or IV administration.1,30,45,56,131,180,183,184

Elimination

The metabolic fate and elimination of metronidazole following topical application to the skin10 or intravaginal application176,177 have not been determined. Because anaerobic conditions do not exist in dermal cells of healthy individuals or patients with rosacea, it is unlikely that metronidazole is reduced following topical application to the skin.10 Metronidazole probably is absorbed percutaneously as unchanged drug, and any systemically absorbed drug is metabolized in the liver and excreted in urine.10,61

Chemistry and Stability

Chemistry

Metronidazole is a synthetic, nitroimidazole-derivative3 antibacterial and antiprotozoal agent.1,2,27,29,47,183,207 Metronidazole occurs as white to pale yellow, odorless crystals or crystalline powder,2,60,184 is slightly soluble in alcohol,2 and has a solubility in water of about 8.3, 8.8, or 11.4 mg/mL at 20, 26, or 30°C, respectively.27

For topical use, metronidazole is commercially available as a 0.75% emollient cream containing emulsifying wax, sorbitol, glycerin, isopropyl palmitate, benzyl alcohol, and lactic acid and/or sodium hydroxide to adjust pH;180 a 1% emollient cream containing micronized metronidazole in an aqueous base of stearic acid, glyceryl monostearate, glycerin, methylparaben, triethanolamine, and propylparaben;184 a 1% aqueous gel containing betadex, edetate disodium, methyl and propyl parabens, hydroxyethyl cellulose, niacinamide, phenoxyethanol, and propylene glycol;1 and a 0.75% lotion containing benzyl alcohol carbomer 941, cyclomethicone, glycerin, glyceryl stearate, light mineral oil, PEG-100 stearate, polyethylene glycol 400, potassium sorbate, purified water, steareth-21, stearyl alcohol, and sodium hydroxide and/or lactic acid to adjust pH.207

For vaginal use, metronidazole is commercially available as a 0.75% aqueous gel containing carbomer 934P or hypromellose, edetate disodium, methyl and propyl parabens, propylene glycol, and sodium hydroxide.183,214 Each gram of commercially available metronidazole 0.75% topical or vaginal gel or 0.75% topical lotion contains approximately 7.5 mg of metronidazole. The pH of the topical gel is 5.25 and that of the vaginal gel is 4.

Stability

Metronidazole 0.75% or 1% topical cream,180,184 1% topical gel,1 and 0.75% topical lotion207 should be stored at 20-25°C. The 1% topical gel may be exposed to temperatures ranging from 15-30°C;1 freezing of the lotion should be avoided.207

Metronidazole 0.75% vaginal gel (MetroGel^®) should be stored at 15-30°C;183 metronidazole 0.75% vaginal gel (Vandazole^®) should be stored at 20-25°C;214 freezing of the vaginal gels should be avoided.183,214 When stored as recommended, the commercially available vaginal gel is stable for 3 years following the date of manufacture.177

Metronidazole is stable in air but darkens on exposure to light.60

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Galderma. MetroGel^® (metronidazole) 1% topical gel prescribing information. Fort Worth, TX; 2005 Jul.

2. Curatek Pharmaceuticals. MetroGel^® (metronidazole) 0.75% topical gel product monograph. Elk Grove Village, IL; 1988 Nov.

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