AHFS Class:

• Nitroimidazole Derivatives, Miscellaneous 8:30.16.92

Generic Name(s):

• metroNIDAZOLE

• metroNIDAZOLE Hydrochloride

Metronidazole is a synthetic, nitroimidazole-derivative antibacterial and antiprotozoal agent.

Amebiasis

Metronidazole is used orally in the treatment of acute intestinal amebiasis and amebic liver abscess caused by Entamoeba histolytica .100,152,153,197,364,368,370

The regimen of choice for symptomatic intestinal amebiasis or extraintestinal disease (including liver abscess) is treatment with a nitroimidazole derivative (oral metronidazole or oral tinidazole) followed by treatment with a luminal amebicide (oral iodoquinol or oral paromomycin).100,153,364,368,370 The sequential use of these drugs ensures eradication of tissue-invading trophozoites as well as cysts in the intestinal lumen.100,364,368,370 In patients with severe disease who do not respond to or cannot tolerate these drugs, some clinicians suggest that a regimen of dehydroemetine (available in the US only from CDC) followed by a luminal amebicide be considered.100 Alternatively, hepatic abscess can be treated with a regimen of chloroquine phosphate and metronidazole (or tinidazole) or, if necessary, dehydroemetine followed by a therapeutic course of a luminal amebicide.100 However, these alternative regimens are associated with severe adverse effects and generally require hospitalization.364,368 Although some clinicians suggest use of oral tetracycline or oral erythromycin followed by a luminal amebicide for the treatment of mild or less severe colitis in patients who cannot tolerate metronidazole, this regimen will not eradicate trophozoites in the liver.364,368

Metronidazole and tinidazole are not recommended for treatment of asymptomatic cyst passers because of limited activity against encysted E. histolytica .100,153,364,368,370 Asymptomatic cyst passers should be treated with a luminal amebicide such as iodoquinol, paromomycin, or diloxanide furoate (not commercially available in the US).100,153,364,368,370 For information on treatment of asymptomatic amebiasis, see Iodoquinol 8:30.04.

Anaerobic and Mixed Aerobic-Anaerobic Bacterial Infections

Metronidazole is used orally or IV in the treatment of serious infections such as intra-abdominal infections (including peritonitis, intra-abdominal abscess, and liver abscess), gynecologic infections (including endometritis, endomyometritis, tubo-ovarian abscess, and postsurgical vaginal cuff infections), skin and skin structure infections, bone and joint infections, lower respiratory infections (including pneumonia, empyema, and lung abscess), CNS infections (including meningitis and brain abscess), septicemia, and endocarditis caused by susceptible anaerobic bacteria. Metronidazole has been effective in some B. fragilis infections which failed to respond to clindamycin, chloramphenicol, or penicillin. Prior to and during metronidazole therapy for bacterial infections, the causative organism should be cultured and in vitro susceptibility tests conducted, if possible. Because metronidazole is inactive against most aerobic bacteria, appropriate anti-infectives should be used in conjunction with metronidazole in the treatment of mixed aerobic-anaerobic bacterial infections. IV metronidazole is used in conjunction with cefepime for the treatment of complicated intra-abdominal infections caused by Escherichia coli , viridans streptococci, Ps. aeruginosa , Klebsiella pneumoniae , Enterobacter , or Bacteroides fragilis 456,457 and is used in conjunction with ciprofloxacin for the treatment of complicated intra-abdominal infections caused by E. coli , Ps. aeruginosa , P. mirabilis , K. pneumoniae , or B. fragilis .458 Because brain abscesses often are polymicrobial and can include aerobic bacteria and aerotolerant anaerobes, which usually are resistant to metronidazole, appropriate anti-infectives also should be used in conjunction with the drug in the treatment of this infection.454 In some studies, IV metronidazole was ineffective in a large percentage of patients when used alone in the treatment of bacterial lung abscess or necrotizing pneumonia; treatment failures in these patients were presumably due to the presence of aerobic bacteria. Use of metronidazole does not replace surgical procedures when indicated.

Bacterial Vaginosis

Metronidazole is used orally (as immediate-release tablets†152,199,292,297,302,341,365,366 or as extended-release tablets)430 or intravaginally (e.g., as a vaginal gel)199,204,288,289,291,295,297,301,302,341,365,366 for the treatment of bacterial vaginosis (formerly called Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, Corynebacterium vaginitis, or anaerobic vaginosis).298

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.287,293,295,297,299,302,303,341,365,366 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.287,300,302 Clinical diagnosis of the syndrome generally is established by characteristic vaginal manifestations rather than bacteriologic determinations.287,292,294,295,297,298,302,341,365,366 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”).287,292,294,295,297,298,302,303,341,365,366 The presence of clue cells on wet mount examination of vaginal secretions is one of the most reliable indicators of bacterial vaginosis.294,309

Gram stain results consistent with a diagnosis of bacterial vaginosis include markedly reduced or absent Lactobacillus morphology and predominance of Gardnerella morphotype.204,287,294 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.287,290,297,309 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.204,287,295,302,302 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,204 particularly since coinfection with these organisms may occur.287,309

Goals of treatment and recommended therapy for bacterial vaginosis differ for nonpregnant versus pregnant women.341 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.341

Nonpregnant Women

The principal goal in the treatment of bacterial vaginosis in nonpregnant women is to provide relief of vaginal symptoms and signs of infection. Other potential benefits include a reduction in other infectious complications, including human immunodeficiency virus (HIV) infection and other STDs.341 The CDC states that treatment of bacterial vaginosis is indicated in all nonpregnant women who are symptomatic.341 The CDC recommended regimens for 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.341 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.341 (See Uses: Bacterial Vaginosis in Metronidazole 84:04.04 or Clindamycin Phosphate 84:04.04.)

Intravaginal metronidazole results in clinical cure rates comparable to those reported with a 7-day oral metronidazole regimen; intravaginal clindamycin appears to be less effective than the metronidazole regimens.341 In 2 unpublished comparative studies conducted by the manufacturer of metronidazole extended-release tablets, nonpregnant women with bacterial vaginosis receiving oral metronidazole 750 mg daily (administered as extended-release tablets) for 7 consecutive days had similar (61 versus 59%) or higher (62 versus 43%) clinical cure rates at 28-32 days following completion of therapy than those receiving one applicatorful clindamycin phosphate (2% clindamycin) vaginal cream (100 mg of clindamycin) intravaginally once daily for 7 consecutive days.430 Regardless of the therapy chosen, relapse or recurrence of bacterial vaginosis is common,287,295,297,298,300,302,307,341,365 and some clinicians suggest that an alternative regimen (e.g., topical therapy when oral therapy was used initially) can be employed in such infections.297,341

A single 2-g dose of oral metronidazole also has been used for the treatment of bacterial vaginosis, and has been recommended for patients who might be noncompliant with multiple-dose regimens.120,122,199,292,297,302 Several comparative studies in women with bacterial vaginosis suggest that a single 2-g dose of oral metronidazole is as effective as 7-day oral regimens of the drug (400 or 500 mg twice daily) when patients are evaluated 7-10 days after completion of therapy.118,119,120,121,122,279 In addition, pooled analysis of data from several randomized, controlled studies indicates that neither efficacy nor recurrence rate differ significantly between the treatment regimens, although analysis of data for recurrence rate was limited by the smaller number of patients evaluated for recurrence of infection.292 However, efficacy data from several controlled studies indicate an overall cure rate of 84-86% for the single 2-g dose regimen compared with 94-95% for the standard 7-day regimen (500 mg twice daily)297,302 and there is some evidence that the recurrence rate several weeks after completion of oral therapy may be higher with the single-dose regimen.119,302 Therefore, the CDC states that a 2-g single dose of oral metronidazole is no longer a recommended or alternative regimen for the treatment of bacterial vaginosis.341

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,341,410,411,412,413,414 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.341,415 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.341,416,417

Because of the increased risk of adverse pregnancy outcomes associated with the presence of bacterial vaginosis, the CDC recommends that all symptomatic pregnant women be treated for bacterial vaginosis.341,415 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 of a premature infant) has reduced preterm delivery, some experts recommend that all women at high risk be screened and treated for bacterial vaginosis.341 The CDC recommends that screening for bacterial vaginosis (if conducted) should be performed at the first prenatal visit and treatment initiated if needed.341,415

The preferred regimens for the treatment of bacterial vaginosis in pregnant women are a 7-day course of oral metronidazole (500 mg twice daily or 250 mg 3 times daily) or a 7-day course of oral clindamycin (300 mg twice daily).341 (See Uses: Bacterial Vaginosis in Clindamycin 8:12.28.20.) Although some clinicians have recommended single-dose oral metronidazole as another alternative regimen for the treatment of bacterial vaginosis in pregnant women at high risk for complications of pregnancy, the safety and efficacy of this dosage schedule for the treatment of bacterial vaginosis in pregnant women have not been established and the manufacturer and other clinicians state that the single-dose regimen should not be used in pregnant women because it may result in slightly higher serum concentrations of the drug, which can reach the fetal circulation.152

Although some experts state that intravaginal metronidazole may be used solely for symptomatic relief (and not for prevention of adverse pregnancy outcomes) in women at low risk for preterm delivery,309 others 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.341,415,422 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.341,415

Although analysis of pooled data from case-control and cohort studies indicates that metronidazole therapy during pregnancy (including during the first trimester) is not associated with increased teratogenic risk or mutagenic effects in newborns,341,423,424 systemic therapy with metronidazole is contraindicated in the first trimester of pregnancy.152,297,302

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).295,296,297,302,341,365,366 A reduction in postoperative PID in women with bacterial vaginosis undergoing first-trimester elective abortion has been established in at least one study employing oral metronidazole,296,341 but further study is needed to determine the value of treating asymptomatic bacterial vaginosis in patients who are about to undergo other invasive procedures.297,309,366

HIV-Infected Women

Recommendations for treatment and preferred regimens for bacterial vaginosis in patients with concurrent HIV infection are the same as those for patients without HIV infection.341

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 appear to affect the clinical cure rate, including the risk of relapse or recurrence of the syndrome, in the woman.298,341,425,426,427,428 Therefore, routine treatment of male sexual contacts currently is not recommended.287,292,297,298,302,341 Further study is needed to elucidate the possible role, if any, of sexual transmission in bacterial vaginosis.287,295,300,302,425

Balantidiasis

Oral metronidazole is recommended as an alternative to tetracycline for the treatment of balantidiasis† caused by Balantidium coli .100,153

Blastocystis hominis Infections

Oral metronidazole has been used in the treatment of Blastocystis hominis infections†.100,153,368,371,372 However, the clinical importance of B. hominis as a cause of GI pathology is controversial100,153,368,371,372 and it is unclear when treatment of B. hominis infection is indicated.100,368,371 If B. hominis is identified in stool specimens from symptomatic patients, other causes should be considered before assuming that GI symptoms are related to the organism.100,371 Some clinicians suggest that treatment be reserved for certain individuals (e.g., immunocompromised patients) who are symptomatic and in whom no other pathogen or process is found to explain the patient's GI symptoms.100,368 Metronidazole, iodoquinol, co-trimoxazole, or nitazoxanide have been used,100,153 but metronidazole resistance may be common.153

Clostridium difficile-Associated Diarrhea and Colitis

Oral metronidazole has been used effectively for the treatment of Clostridium difficile -associated diarrhea and colitis† (CDAD; also known as antibiotic-associated diarrhea and colitis, C. difficile diarrhea, C. difficile colitis, and pseudomembranous colitis)100,125,126,127,128,129,131,132,312,313,314,315,316,344,345,443,444,445,446,447 and, along with oral vancomycin hydrochloride, is considered the drug of choice for the treatment of C. difficile -associated diarrhea and colitis.100,312,313,314,315,316 Most experts100,406,444,445,446,448 and clinicians126,127,312,313,314,315,316,322,323,443,447 state that in order to decrease the incidence of vancomycin-resistant enterococci (see Resistance and also Uses in Vancomycin 8:12.28.16), metronidazole therapy should be used first in patients with C. difficile -associated diarrhea and colitis, reserving vancomycin therapy for seriously ill patients (i.e. those with severe or potentially life-threatening colitis), patients in whom metronidazole-resistant C. difficile is suspected, patients in whom metronidazole therapy is contraindicated or not tolerated, or those who do not respond to metronidazole.100,126,127,312,313,314,315,316,322,323,406 Oral metronidazole therapy also generally is preferred because of cost considerations.100,126,127,312,313,314,315,316,322,323,443,444,445,446,447 Diarrhea generally remits gradually over 3-5 days after initiation of oral metronidazole therapy,125,126,314 although resolution occasionally may take a week or longer, probably because of persistent inflammation despite cessation of toxin production.127,312

Oral metronidazole appears to be as effective as oral vancomycin for the treatment of pseudomembranous colitis caused by C. difficile .126,127,312,313,314,315,316,321,322,323,345,443,444,445,446,447 However, the relative efficacy of oral metronidazole for severe, potentially life-threatening cases of pseudomembranous colitis remains unclear, and some clinicians continue to prefer vancomycin when anti-infective therapy is indicated for such cases (e.g., in critically ill patients).313,314,315,316,321,345,346,445,446

Oral therapy is always preferred for the treatment of C. difficile -associated diarrhea and colitis, but the oral route may not always be feasible;443,444,445,446,447 the drugs should never be administered IV simply for reasons of convenience.445 Metronidazole has been effective when given IV for the treatment of C. difficile -associated diarrhea and colitis in patients in whom oral therapy was not feasible.161,162,313,445,446,447 Although IV therapy with metronidazole may not be as reliable as oral therapy,445,447 higher intracolonic drug concentrations are more likely with IV metronidazole than with IV vancomycin,445,447 and some clinicians suggest that parenteral metronidazole is the preferred treatment for this disease if oral therapy cannot be used (e.g., in patients with severe ileus or recent surgery).161,313,344,445,446,447 Because treatment failures have been reported with both IV metronidazole and IV vancomycin alone, some clinicians have suggested that both drugs be used if IV therapy is considered necessary (i.e., IV metronidazole combined with IV, enteral, intracolonic, or rectal vancomycin).445,446,447 Alternative approaches have included administration of metronidazole or vancomycin via a nasogastric tube, enterally (e.g., via placement of a tube or pigtail catheter into the small intestine, directly via an ileostomy), intracolonically (e.g., via a pigtail catheter positioned during colonoscopy), or rectally (e.g., via enema).443,445,446,447 However, the comparative efficacy of these approaches, particularly relative to oral therapy, has not been established.446

Although oral metronidazole and intravaginal metronidazole have been associated rarely with causing antibiotic-associated diarrhea and colitis, including pseudomembranous colitis,125,126,127,128,129,131,132,133,159,445 most clinicians believe this should not discourage use of the drug in the treatment of C. difficile -induced diarrhea and/or colitis, especially if the clostridium strain is susceptible to the drug.125,126,127,128,129,131,132,133,314,344

Relapse, which usually is apparent within several weeks (occasionally up to several months) and probably is secondary to persistent germinating C. difficile spores or reinfection with the same or a different strain, occurs in about 10-35% of patients treated with an effective anti-infective but generally responds to additional therapy with the same or an alternative anti-infective; true treatment failures (i.e., secondary to resistant strains) are rare.127,312,313,314,321,344,345,346,443,444,445,446,447 Alternative anti-infectives (e.g., bacitracin, fusidic acid, teicoplanin) have been suggested for the treatment of relapses; however, because such relapses rarely are caused by resistant strains, and established evidence of superior efficacy with such alternatives is lacking, treatment with oral metronidazole or oral vancomycin is preferred even in patients who received the respective drug previously.445,446,447 Patients should be advised that while relapses may be common, they do not have a tendency to become more severe, even though they may cause more concern with each episode.445 Because return of a protective normal fecal flora may be one of the most important factors in preventing relapses, unnecessary use of anti-infectives for prophylaxis or treatment of infections, particularly minor ones, should be avoided for at least 2 months after treatment of an episode of C. difficile -associated diarrhea and colitis.445

No specific treatment regimen currently available in the US has been established through adequately designed studies to prevent multiple relapses of C. difficile -associated diarrhea and colitis, although standard anti-infective therapy (i.e., oral metronidazole or oral vancomycin) usually is effective in treating them even if it does not prevent further recurrences.443,445 Some clinicians have suggested that repeated relapses be treated with an intermittent regimen of oral metronidazole (or oral vancomycin when indicated) over several weeks or possibly months, followed by gradual tapering, or with low prophylactic doses of oral metronidazole given daily or on alternate days or weeks; however, while there may be anecdotal evidence of efficacy of such approaches, such positive findings may only have been coincidental rather than the result of the therapy.445 Anion-exchange resins such as cholestyramine (e.g., combined with the anti-infective regimen) also have been employed in an attempt to reduce the rate of relapse, but an established benefit of this approach is lacking, and these resins can bind to vancomycin in the colon and also can cause constipation and GI obstruction.445 Various other unproven measures (e.g.,, biotherapies such as Lactobacillus , nontoxigenic C. difficile , yogurt with live cultures, brewer's yeast) to restore the normal fecal flora also have been employed.443,445,446,447 One potentially promising approach has been administration of a live yeast preparation (i.e., Saccharomyces boulardii , which is different from the species in brewer's yeast) for about 4 weeks beginning several (e.g., 4) days after completion of appropriate anti-infective therapy.443,445,447,449,450 Combined oral vancomycin and rifampin also has been used for possible synergistic or other combined activity against the bacteria and/or its spores, but the role, if any, of this approach in the treatment of multiple relapses remains to be established.443,445,451

Oral metronidazole or oral vancomycin also has been used to prevent nosocomial outbreaks of C. difficile diarrhea and colitis in institutionalized patients who asymptomatically harbor the organism.329,330,331,332 However, current evidence suggests that the risks of such prophylactic therapy (e.g., in selecting potentially resistant organisms such as enterococci), particularly with vancomycin, outweigh any possible benefit.315,317,318,320,322,329,331,332,333 Most experts currently recommend that appropriate enteric and barrier precautions (e.g., isolation of patients, private bathroom facilities, strict hygiene) rather than prophylactic anti-infective therapy be implemented to prevent nosocomial transmission of such organisms.313,318,320,321,330,331,332,333,444,445

For additional information on C. difficile -associated diarrhea and colitis, see Cautions: GI Effects in Clindamycin 8:12.28.20.

Crohn's Disease

Oral metronidazole (used with467,468,471,475,476,477,485 or without ciprofloxacin);101,102,103,104,105,469,470,471,472,473,474,478,479,484,485,486 has been used for the induction of remission of mildly to moderately active Crohn's disease†;101,102,103,104,105,467,468,469,471,472,473,474,475,476,477,478,479,484 the drug also has been used for refractory perianal disease.102,104,105,470,471,474,478,479,485,486 It appears that the combination of metronidazole and ciprofloxacin is more effective than metronidazole alone.467 Because the intestinal flora appears to have an association with intestinal inflammation468,474,475,480,481 and because metronidazole has a direct anti-inflammatory effect,137,139,148,166,167 metronidazole may be useful in the management of Crohn's disease as an adjunct to conventional therapies.468,469,475,476

Reports on the efficacy of metronidazole in the management of active Crohn's disease have been equivocal.101,102,103,104,469,471,473,476,478,479 While results of several open-label,468,476 retrospective,467 comparative,475 and at least one placebo-controlled study469 indicate that metronidazole (with or without ciprofloxacin) can result in clinical response (e.g., improvement of clinical condition, clinical remission) in patients with mildly to moderately active Crohn's disease,468,469,475,476 results of other controlled and uncontrolled studies using metronidazole failed to show evidence of substantial beneficial effects on the clinical condition of the patients.472,473,482,484 In one double-blind, placebo-controlled study in patients with mildly to moderately active Crohn's disease, oral metronidazole, administered in dosages of 10 or 20 mg/kg daily for 16 weeks, was associated with substantial improvements in disease activity (measured by Crohn's Disease Activity Index [CDAI]); however, remission rates were similar to those reported with placebo.469,471,474,478,479 The CDAI score is based on subjective observations by the patient (e.g., the daily number of liquid or very soft stools, severity of abdominal pain, general well-being) and objective evidence (e.g., number of extraintestinal manifestations, presence of an abdominal mass, use or nonuse of antidiarrheal drugs, the hematocrit, body weight).483 Limited data indicate that metronidazole may be more effective in patients with ileocolitis or colitis rather than in those with ileitis.101,468,469,471,473,474,482

Results of a randomized, double-blind, 2-period cross-over trial in 78 patients with active Crohn's disease suggest that oral metronidazole (400 mg twice daily) is at least as effective as sulfasalazine (1.5 g twice daily).101,103,105,473 Disease activity in this study was monitored by CDAI and serum orosomucoid concentrations.101,103,105 In the first treatment period, there was no significant difference in decreases in CDAI scores between patients receiving metronidazole or sulfasalazine, although decreases in serum orosomucoid concentrations were substantially more pronounced in those receiving metronidazole.101,103,105 After crossover, patients who had responded to the first drug have continued to respond to the other drug.101,105 Further studies are needed to determine the long-term efficacy and safety of metronidazole and the role of the drug in the treatment of this condition.103,105 Some clinicians suggest that metronidazole be reserved for patients in whom sulfasalazine is ineffective or not tolerated.105

Safety and efficacy of concomitant use of metronidazole and ciprofloxacin have been evaluated in a 12-week comparative (versus methylprednisolone) study in 41 patients with active Crohn's disease (CDAI of more than 200 at the time of study entry).475 Patients were randomized to receive metronidazole 250 mg 4 times daily in conjunction with ciprofloxacin 500 mg twice daily (22 patients) or methylprednisolone (0.7-1 mg/kg daily initially, followed by variable tapering to 40 mg, and subsequent tapering of 4 mg weekly; 19 patients).475 At 12 weeks of therapy, clinical remission (defined as a CDAI of 150 points or less) has been reported in 63 or 46% of patients receiving the corticosteroid or the combination therapy, respectively.475 It has been suggested that such combination therapy could be an alternative to corticosteroids, although a high incidence of adverse effects (27% discontinued therapy because of such effects) was associated with the anti-infectives. 475 In addition, results of a multicenter, randomized study in patients with active Crohn's disease indicate that addition of combination therapy with ciprofloxacin and metronidazole to budesonide does not provide greater benefit than budesonide alone;482 however, it has been suggested that this anti-infective combination may improve outcome in patients with Crohn's disease involving the colon.482 Results of several small placebo-controlled trials in patients with active Crohn's disease have shown no treatment benefit with metronidazole when compared with placebo.472,473,484 It is not known whether metronidazole is useful for prevention of recurrent disease.105

Oral metronidazole has been used effectively for the treatment of refractory perineal Crohn's disease.103,104,105,471,474,478,479,485,486 Nonsuppurative perianal complications of the disease usually respond to metronidazole alone103,104,105,471,474,478,479,485 or when used in conjunction with ciprofloxacin.471 Results of an open-label trial in 21 adults with perineal Crohn's disease who had an inadequate response to conventional therapies (e.g., corticosteroids, sulfasalazine, antibiotics, antimetabolites) indicate that administration of oral metronidazole (20 mg/kg daily) for 5-21 months decreased pain and tenderness within 1-2 weeks of therapy in 90% (19 out of 21) of patients, while decreases in erythema, drainage, and swelling and beginning of epithelization of open wounds were observed within 2-4 months of therapy in 86% (18 out of 21) patients.104,105,485 Complete healing (e.g., epithelization of ulcerations, closure of draining fistulas) of perianal disease has been reported in about 48% (10 out of 21) of patients; in addition, about 24% (5 out of 21) patients experienced advanced, but not complete healing of the perineum.104,478,485 Results of a follow-up study indicate that discontinuance or dosage reduction of metronidazole has been associated with exacerbation of disease activity in all patients, although perineal manifestations of the disease healed promptly, when full dosage of metronidazole was reinstituted.102,103,474,485 Although about 28% of patients, who received metronidazole for up to 16 months and in whom metronidazole was gradually discontinued experienced no relapse of the disease,102,105,485 some clinicians state that continuous therapy is needed to prevent recurrence of perineal disease.471 Because safety471 and efficacy105 of long-term metronidazole therapy have not been established, further study is needed to determine the long-term safety and efficacy of the drug in this condition.105,471 It has been suggested that patients be monitored for nervous system effects (e.g., peripheral neuropathy) during long-term administration of the drug.471 Limited data indicate that short-term (8 weeks) combination therapy with metronidazole and ciprofloxacin given with, or followed by, azathioprine (up to about 20 weeks) in patients with perineal Crohn's disease may result in rapid reduction of fistula drainage (induced by the antibiotics) and beneficial maintenance (associated with the azathioprine).486

Although the manufacturers state that safe use of oral metronidazole in children for any indication except amebiasis has not been established, some clinicians state that children with mild perianal Crohn's disease† or those intolerant to sulfasalazine or mesalamine may receive oral metronidazole (10-20 mg/kg daily up to 1 g daily).487 In addition, although the manufacturers state that safe use of IV metronidazole in children for any indication have not been established, IV metronidazole has been used concomitantly with corticosteroids in children with moderately to severely active Crohn's disease† in whom infection or abscess was present.487

For further information on the management of Crohn's disease, see Uses; Crohn's Disease, in Mesalamine 56:36.

Dientamoeba fragilis Infections

Oral metronidazole is considered a drug of choice for the treatment of infections caused by Dientamoeba fragilis †.153 Many clinicians recommend iodoquinol, paromomycin, tetracycline, or metronidazole for the treatment of D. fragilis infections.153

Dracunculiasis

Oral metronidazole has been used in the treatment of dracunculiasis† caused by Dracunculus medinensis (guinea worm disease).153 Slow extraction of the worm and wound care is recommended by some clinicians as the treatment of choice.153 Although metronidazole therapy is not curative, it decreases inflammation and facilitates removal of the worm.153

Giardiasis

Oral metronidazole is used for the treatment of giardiasis† in adults and children.100,153,367,452

Drugs of choice for treatment of giardiasis are metronidazole, tinidazole, or nitazoxanide; alternative agents include paromomycin (especially in pregnant women), furazolidone (no longer commercially available in the US), or quinacrine (not commercially available in the US).100,153,367

Treatment of asymptomatic carriers of giardiasis is controversial.100,367 Although some clinicians suggest that asymptomatic carriers be treated if the risk of reinfection is low,367 the AAP states that treatment of asymptomatic carriers is not generally recommended, except possibly in patients with hypogammaglobulinemia or cystic fibrosis or in an attempt to prevent household transmission of the disease from toddlers to pregnant women.100 If asymptomatic carriers need to be treated, oral metronidazole may be used for such patients. Oral metronidazole also is used in patients with coexistent giardiasis and amebiasis. (See Giardiasis in Dosage and Administration: Dosage.)

Retreatment for recurrences of giardiasis, either from relapse or reinfection, depends on individual and epidemiologic circumstances.367 Retreatment with the same initial regimen generally is effective for reinfection; however, use of an alternative agent or combination therapy (e.g., metronidazole and quinacrine hydrochloride) may be necessary in patients who do not respond or relapse following initial therapy.367 Relapse is common in immunocompromised patients, and these patients may require prolonged therapy and/or use of a combination of agents.100,367

If an outbreak of giardiasis is suspected in a child-care center in the US, the AAP recommends that an epidemiologic investigation be undertaken to identify and treat all symptomatic children, child-care workers, and family members and that all individuals with diarrhea be excluded from the center until they become asymptomatic.100 The AAP states that treatment of asymptomatic carriers has not been shown to be effective in outbreak control and that exclusion of carriers from child care is not recommended.100

Helicobacter pylori Infection and Duodenal Ulcer Disease

Metronidazole is used in combination with tetracycline hydrochloride, bismuth subsalicylate, and an H₂-receptor antagonist for the treatment of Helicobacter pylori (formerly Campylobacter pylori or C. pyloridis ) infection in patients with an active duodenal ulcer.455 Metronidazole also has been used successfully in other multiple-drug regimens (with or without tetracycline hydrochloride, bismuth salts, and/or an H₂-receptor antagonist) for the treatment of H. pylori infection† in patients with peptic ulcer disease.207,208,209,212,213,214,215,216,217,218,219,220,237,242,243,244,270,347,374,376,378,379,380,381,382,383,384,385,386,387,388,389,390,391,399,400,401,402 Current epidemiologic and clinical evidence supports a strong association between gastric infection with H. pylori and the pathogenesis of duodenal and gastric ulcers;207,209,212,216,223,224,225,226,274,347,376,378,381,387,388,389,403,404 long-term H. pylori infection also has been implicated as a risk factor for gastric cancer.212,242,347,350,351,352,353,354,355,356,357,358,378 For additional information on the association of this infection with these and other GI conditions, see Helicobacter pylori Infection, under Uses, in Clarithromycin 8:12.12.92.

Conventional antiulcer therapy with H₂-receptor antagonists, proton-pump inhibitors, sucralfate, and/or antacids heals ulcers but generally is ineffective in eradicating H. pylori , and such therapy is associated with a high rate of ulcer recurrence (e.g., 60-100% per year).207,216,226,376,378,387,388 Several useful therapeutic regimens for H. pylori -associated peptic ulcer disease have been identified,207,208,212,214,217,218,219,220,241,242,243,244,255,257,260,261,262,263,347,376,380,383,387,388,389 and the American College of Gastroenterology (ACG), the National Institutes of Health (NIH), and most clinicians currently recommend that all patients with initial or recurrent duodenal or gastric ulcer and documente d H. pylori infection receive anti-infective therapy for treatment of the infection.360,376,387,388,389

The optimum regimen for treatment of H. pylori infection has not been established; however, combined therapy with 3 drugs that have activity against H. pylori (generally a bismuth salt, metronidazole, and tetracycline or amoxicillin) has been effective in eradicating the infection, resolving associated gastritis, healing peptic ulcer, and preventing ulcer recurrence in many patients with H. pylori -associated peptic ulcer disease.207,208,209,212,214,215,225,237,238,239,240,241,274,347,376,378,381,382,383,387,388,389,390,392,455 Although such 3-drug regimens typically have been administered for 10-14 days, current evidence principally from studies in Europe suggests that 1 week of such therapy provides H. pylori eradication rates comparable to those of longer treatment periods.376,388,389 Other regimens that combine one or more anti-infective agents (e.g., clarithromycin, amoxicillin) with a bismuth salt and/or an antisecretory agent (e.g., omeprazole, H₂-receptor antagonist) also have been used successfully for H. pylori eradication,207,208,215,219,220,240,242,243,244,245,347,374,376,378,379,383,384,385,386,387,388,389,391,393,394,395 and the choice of a particular regimen should be based on the rapidly evolving data on optimal therapy, including consideration of the patient's prior exposure to anti-infective agents, the local prevalence of resistance, patient compliance, and costs of therapy.360,376,377,378,388,392 Current data suggest that eradication of H. pylori infection using regimens consisting of 1 or 2 anti-infective agents with a bismuth salt and/or an H₂-receptor antagonist or proton-pump inhibitor (e.g., omeprazole, lansoprazole) is cost effective compared with intermittent or continuous maintenance therapy with an H₂-receptor antagonist (considering the costs associated with ulcer recurrence, including endoscopic or other diagnostic procedures, physician visits, and/or hospitalization).396,460,461,462,463,464

Although high eradication rates have been achieved with standard 3-drug, bismuth-based regimens (e.g., bismuth-metronidazole-tetracycline or bismuth-metronidazole-amoxicillin), such regimens typically involve administration of many tablets/capsules and have been associated with a relatively high (although variable) incidence of adverse effects.376,388,389,390 In addition, the efficacy of these regimens generally is unacceptable in patients with H. pylori strains resistant to the imidazole anti-infective (e.g., metronidazole) component.376,388,389,390,455 Current evidence suggests that inclusion of a proton-pump inhibitor (e.g., omeprazole, lansoprazole) in anti- H. pylori regimens containing 2 anti-infectives enhances effectiveness, and limited data suggest that such regimens retain good efficacy despite imidazole (e.g., metronidazole) resistance.376,388 Therefore, the ACG and many clinicians376,390,391 currently recommend 1 week of therapy with a proton-pump inhibitor and 2 anti-infective agents (usually clarithromycin and amoxicillin or metronidazole), or a 3-drug, bismuth-based regimen (e.g., bismuth-metronidazole-tetracycline) concomitantly with a proton-pump inhibitor, for treatment of H. pylori infection.376,388,391 Although few comparative studies have been performed, such regimens appear to provide high (e.g., 85-90%) H. pylori eradication rates, are well tolerated, and may be associated with better patient compliance than more prolonged therapy.376,391,464 The ACG states that in a cost-sensitive environment, an alternative regimen consisting of a bismuth salt, metronidazole, and tetracycline for 14 days is a reasonable choice in patients who are compliant and in whom there is a low expectation of metronidazole resistance (no prior exposure to the drug and a low regional prevalence of resistance).376

Rapid development of resistance by H. pylori to certain drugs (e.g., metronidazole, clarithromycin and other macrolides, quinolones) has occurred when these drugs were used as monotherapy or as the only anti-infective agent in anti- H. pylori regimens.208,209,252,347,373,387,459 Resistance commonly emerges during therapy with metronidazole or clarithromycin when eradication of H. pylori is not achieved; therefore, prior exposure to these anti-infectives predicts resistance in individual patients and should be considered when selecting anti- H. pylori treatment regimens.373,376,387,455 Regimens containing metronidazole or clarithromycin should not be used to treat H. pylori infection in patients with known or suspected metronidazole- or clarithromycin-resistant isolates because of reduced efficacy in such patients.373,376,455

For additional discussion of H. pylori infection, including details about the efficacy of various regimens and rationale for drug selection, see Helicobacter pylori Infection, under Uses, in Clarithromycin 8:12.12.92.

Nongonococcal Urethritis

Oral metronidazole is used for the treatment of recurrent and persistent urethritis† in patients with nongonococcal urethritis who have already been treated with a recommended regimen.341 The CDC currently recommends that nongonococcal urethritis in adults be treated with a single oral dose of azithromycin or a 7-day regimen of doxycycline; alternative regimens recommended by the CDC are a 7-day regimen of oral erythromycin base or ethylsuccinate or a 7-day regimen of oral ofloxacin or oral levofloxacin.341 Patients treated for nongonococcal urethritis should be instructed to abstain from sexual intercourse until 7 days after initiation of treatment and to return for evaluation if symptoms persist or recur after completion of therapy; symptoms alone (without documentation of signs or laboratory evidence of urethral inflammation) are not sufficient basis for retreatment.341 Patients with persistent or recurrent urethritis who were not compliant with the treatment regimen or were reexposed to untreated sexual partner(s) should be retreated with the initial regimen.341 If the patient has recurrent and persistent urethritis, was compliant with the regimen, and reexposure can be excluded, the CDC recommends a single 2-g dose of oral metronidazole or oral tinidazole given in conjunction with a single 1-g dose of oral azithromycin (if azithromycin was not used in the initial regimen).341

Pelvic Inflammatory Disease

IV or oral metronidazole is used in conjunction with other anti-infectives for the treatment of acute pelvic inflammatory disease (PID).199,341,496

When a parenteral regimen is indicated for the treatment of PID, the CDC and others generally recommend an initial regimen of IV cefoxitin or IV cefotetan given in conjunction with IV or oral doxycycline or a regimen of IV clindamycin given in conjunction with IV or IM gentamicin; parenteral therapy may be discontinued 24 hours after there is clinical improvement and a regimen of oral doxycycline continued to complete 14 days of therapy.199,341,496 However, if tubo-ovarian abscess is present, many clinicians recommend use of metronidazole or clindamycin with doxycycline for follow-up after the parenteral regimen (rather than doxycycline alone) to provide coverage against anaerobes.341

When an oral regimen is indicated for the treatment of PID, the CDC recommends a regimen consisting of a single IM dose of ceftriaxone, cefoxitin (with a single oral dose of probenecid), or other parenteral cephalosporin (e.g., cefotaxime) with a 14-day regimen of oral doxycycline with or without a 14-day regimen of oral metronidazole.341 If a parenteral cephalosporin is not feasible, a 14-day regimen of oral ofloxacin or oral levofloxacin with or without a 14-day regimen of oral metronidazole can be considered,199,341,496 provided the community prevalence and individual risk of gonorrhea is low.496

For further information on the treatment of PID, including regimens recommended by the CDC, see Uses: Pelvic Inflammatory Disease, in the Cephalosporins General Statement 8:12.06.

Rosacea

Oral metronidazole has been used with some success in the treatment of inflammatory lesions (papules and pustules) and erythema associated with rosacea† (acne rosacea)137,139,145,146,148,168,180,181 and has decreased total numbers of inflammatory lesions associated with the disease.145,146,168,180 Metronidazole also is effective in reducing the number of inflammatory lesions and improving erythema associated with rosacea when applied topically to the skin of patients with the disease.137,138,139,140,141,142,143,144,147,148,168,181 Although there are no studies to date comparing efficacy and safety of topical and oral metronidazole therapy in the treatment of rosacea, the topical preparation may be preferred.137,181 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.137,181 For information on rosacea and the use of topical metronidazole in the treatment of the disease, see Uses: Rosacea in Metronidazole 84:04.04 and for information on possible mechanism(s) by which metronidazole reduces inflammatory lesions and erythema in patients with rosacea, see Mechanism of Action: Effects on Rosacea in Metronidazole 84:04.04.

Tetanus

Metronidazole is used as an adjunct to tetanus immune globulin (TIG), tetanus toxoid adsorbed, sedatives, and muscle relaxants in the treatment of active tetanus infection caused by C. tetani .100,489 Anti-infective agents cannot neutralize toxin already formed and cannot eradicate C. tetani spores which may revert to toxin-producing vegetative forms.489 Treatment of a tetanus wound consists of surgical debridement and prevention of associated infections that could create an anaerobic environment and help proliferation of C. tetani .489

Trichomoniasis

Metronidazole is used orally in the treatment of symptomatic and asymptomatic trichomoniasis in men and women in whom T. vaginalis has been demonstrated by an appropriate diagnostic procedure (e.g., wet smear and/or culture, OSOM Trichomonas Rapid Test, Affirm^® VP III).100,152,153,197,199,297,298,302,337,338,339,341 Metronidazole also is used orally for the treatment of trichomoniasis in children and adolescents†.100,153

The nitroimidazole derivatives, metronidazole100,297,302,337,338,339,341 and tinidazole,466 are the only drugs currently commercially available drugs in the US that are effective in the treatment of this disease. The goal of treatment is to provide symptomatic relief, achieve microbiologic cure, reduce transmission, and prevent reinfection; to achieve this goal, both the index patient and sexual (particularly steady) partner(s) should be treated.297,302,339,341 Some evidence suggests an association between vaginal trichomoniasis and adverse pregnancy outcomes, particularly premature membrane rupture, preterm delivery, and low birthweight.297,334,338,341 Trichomoniasis also may be a cofactor for the transmission of human immunodeficiency virus (HIV).335

Most infected men are asymptomatic (although some may experience urethritis), while many women with trichomoniasis are symptomatic.297,302,341 T. vaginalis infection in women characteristically causes a diffuse, malodorous, yellow-green discharge accompanied by vulvar irritation.341 Because trichomoniasis is a sexually transmitted disease, the US Centers for Disease Control and Prevention (CDC) and other experts currently recommend that infected individuals and their sexual contacts be treated regardless of symptomatology;199,297,302,337,338,339 therefore, asymptomatic sexual contacts should be treated presumptively even when T. vaginalis has not been demonstrated. While trichomoniasis in males generally appears to be transient, some evidence indicates that a large proportion of relapse in females may result from reinfection from untreated male sexual partners; therefore, unless clear evidence accumulates that concomitant treatment of male partners is not beneficial, the current recommendation of concomitantly treating steady male sexual partners should be followed.302,339,341 This strategy is aimed at minimizing the risk of reinfection, curing any symptomatic disease in the male, and diminishing the pool of asymptomatic male carriers.297,302,339 Treatment of female sexual partners of lesbians with trichomoniasis also should be considered since transmission between such women has been reported.434

Trichomoniasis cure rates of about 90-95% are achieved with currently recommended metronidazole regimens (2-g single dose or 500 mg twice daily for 7 days);297,302,337,338,339,341 ensuring the treatment of sexual partners may increase the cure rate.341 Following treatment, test-of-cure is not necessary for females or males who become asymptomatic after treatment or for those who were initially asymptomatic.297,341 To minimize the risk of reinfection and transmission, patients should be advised to avoid sex until both the patient and partner(s) are considered cured; in the absence of microbiologic test-of-cure, cure is considered to have been achieved following completion of a recommended regimen and resolution of symptoms.297,341 When T. vaginalis is associated with endocervicitis, cervicitis, or cervical erosion, the organism may interfere with accurate assessment of cytology smears and additional smears should be obtained after eradication of the infection.152

Intravaginal † metronidazole as sole therapy for the treatment of trichomoniasis is not recommended because of substantially lower efficacy compared with systemic therapy.341,433

For information on the treatment of trichomoniasis during pregnancy and lactation, see Cautions: Pregnancy, Fertility, and Lactation.

Treatment Failure

Despite several decades of use of metronidazole for the treatment of trichomoniasis, resistance of T. vaginalis to the drug remains relatively uncommon.124,297,302,336,337,338,341 However, while resistance to metronidazole is not a recent phenomenon,124,336,337,341 its prevalence appears to be increasing.302,338 Most resistant strains exhibit either marginal or very low resistance to the drug.302,338 Recent estimates indicate that marginal resistance occurs in about 2% of cases, low to moderate resistance occurs in less than 1% of cases, and high-level resistance occurs rarely (e.g., in about 0.03-0.05% of cases).338

In most cases, infection with resistant strains of T. vaginalis is cured with repeat courses and/or increased metronidazole dosages.124,153,199,297,302,338,339,341 Approximately 85% of marginally resistant cases will be cured by a repeat course at usual dosage, particularly if retreatment is initiated soon after initial failure, when the organism burden is relatively low.302,338 If treatment failure occurs following an initial regimen (i.e., a single 2-g dose of oral metronidazole) and reinfection has been excluded, the CDC recommends that the patient be retreated with either oral metronidazole 500 mg twice daily for 7 days or a single 2-g dose of oral tinidazole; if retreatment fails, then the patient should receive oral metronidazole or oral tinidazole in a dosage of 2 g once daily for 5 days.341 If the multiple-dose regimen is ineffective, consultation with a specialist is recommended and in vitro susceptibility testing of T. vaginalis isolates may be indicated.297,341 Regimens specific for the level of resistance have been suggested;124,302,338 under aerobic conditions, strains of T. vaginalis exhibiting low-level metronidazole resistance (minimum lethal concentration [MLC] less than 100 mcg/mL) can be treated with 2 g daily for 3-5 days, those with moderate (intermediate) resistance (MLC of 100-200 mcg/mL) can be treated with 2-2.5 g daily for 7-10 days, and those with high-level resistance (MLC exceeding 200 mcg/mL) can be treated with 3-3.5 g daily for 14-21 days.124,302,338,340 However, because infection with strains exhibiting high-level resistance is difficult to treat,124,297,302,338,340 CDC currently recommends that patients with culture-documented infection who do not respond to repeat regimens and in whom the possibility of reinfection has been excluded should be managed in consultation with an expert;297,341 such consultation is available from CDC.341 In some such cases, short-course (to minimize the risk of adverse effects) IV metronidazole therapy (e.g., 2 g IV every 6-8 hours for 2-4 days) may be tolerable and effective; however, patients should be advised of the potential risks of such dosages.302,338

Tinidazole (e.g., 2 g daily for 7-14 days), has been effective in for the treatment of trichomoniasis in some patients who did not respond to metronidazole dosages of 3 g or more daily for 14 days.199,124,338 Resistant cases of vaginal trichomoniasis also have been treated in a limited number of patients with combined systemic and intravaginal metronidazole therapy302,338,339,340 (see Uses: Trichomoniasis, in Metronidazole 84:04.04) or with intravaginal paromomycin (not commercially available).436 While the choice of treatment of male sexual partners of females with metronidazole-resistant trichomoniasis is not clear, some clinicians treat such males with the same systemic regimen as the female unless the male is tested adequately (cultures of semen, prostatic secretions, and urethra) and shown to be infection free.124,302

Desensitization

Because effective alternatives to metronidazole for the treatment of trichomoniasis currently are not available in the US, CDC states that desensitization to the drug can be attempted in patients with metronidazole hypersensitivity†.341 If desensitization is attempted, the possibility that the procedure may be hazardous should be considered.435 Adequate procedures (e.g., established IV access, blood pressure monitoring) and therapies (e.g., epinephrine, corticosteroids, antihistamines, oxygen) for the management of an acute hypersensitivity reaction should be readily available.435 Pretreatment (e.g., with an antihistamine and/or corticosteroid) also should be considered.435 Desensitization has been performed in a limited number of women by administering increasing IV doses of metronidazole incrementally until a therapeutic dose was achieved, at which time oral dosing was initiated.435 In this regimen, metronidazole was administered IV beginning with 5 mcg and then the dose was increased at 15- to 20-minute intervals to 15, 50, 150, and 500 mcg and then to 1.5, 5, 15, 30, 60, and 125 mg.435 Once a dose of 125 mg was achieved IV, incremental increases were switched to oral dosing with 250, 500, and 2 g doses administered at 1-hour intervals.435 For trichomoniasis, dosing can be stopped after the 2-g dose has been achieved.435 Monitoring of the patient should continue for at least 4 hours after administration of the last dose (24 hours if there was any evidence of a reaction).435

Pediatric Infections

The American Academy of Pediatrics (AAP) and other clinicians recommend oral metronidazole for the treatment of trichomoniasis in children†.100,153 Because trichomoniasis principally is a sexually transmitted disease, its presence in a prepubertal child should raise the question of sexual abuse.100 T. vaginalis can be acquired by neonates during birth and causes a vaginal discharge in the first weeks of life.100

Perioperative Prophylaxis

IV metronidazole is used for perioperative prophylaxis to reduce the incidence of postoperative anaerobic bacterial infections in patients undergoing contaminated or potentially contaminated elective colorectal surgery.109,110,111,112,156,495 For perioperative prophylaxis in patients undergoing colorectal surgery, a regimen of IV cefoxitin alone, IV cefazolin and IV metronidazole, oral erythromycin and oral neomycin, or oral neomycin and oral metronidazole usually is recommended.110,112,490 Although many clinicians use both an oral and a parenteral regimen for perioperative prophylaxis in patients undergoing colorectal surgery;110,112,465,490,493 there is controversy about the benefits and risks of this strategy.110,112,493 There is some evidence that a combined oral and parenteral regimen may be more effective than use of an oral or parenteral regimen alone;110,490,493 however, the combined regimen may be associated with a higher incidence of adverse effects (e.g., nausea, vomiting, Clostridium difficile -associated diarrhea and colitis).491,492

Metronidazole has been given orally, IV, or rectally for perioperative prophylaxis in patients undergoing appendectomy†.109,111,112,113 For perioperative prophylaxis in patients undergoing appendectomy (nonperforated), a regimen of IV cefoxitin alone or IV cefazolin and IV metronidazole is recommended.110,111

Prophylaxis in Sexual Assault Victims

Oral metronidazole is used in conjunction with IM ceftriaxone and either oral azithromycin or oral doxycycline for empiric anti-infective prophylaxis in adolescent and adult victims of sexual assault†; postexposure hepatitis B vaccination also is recommended for susceptible victims.199,341 Many experts recommend routine empiric prophylactic therapy after a sexual assault, and use of such prophylaxis probably benefits most patients since follow-up of assault victims can be difficult and such prophylaxis allays the patient's concerns about possible infection.341 The CDC states that trichomoniasis, genital chlamydial infection, gonorrhea, and bacterial vaginosis are the sexually transmitted diseases (STDs) most commonly diagnosed in women following sexual assault; however, the prevalence of these infections is substantial among sexually active women and their presence after assault does not necessarily indicate that the infections were acquired during the assault.341 Chlamydial and gonococcal infections among females are of special concern because of the possibility of ascending infection.341

When empiric anti-infective prophylaxis is indicated in adolescent or adult sexual assault victims, the CDC recommends administration of a single 125-mg IM dose of ceftriaxone given in conjunction with a single 2-g oral dose of metronidazole and a single 1-g oral dose of azithromycin or a 7-day regimen of oral doxycycline (100 mg twice daily).341 This 3-drug regimen provides coverage against gonorrhea, chlamydia, trichomoniasis, and bacterial vaginosis, but efficacy in preventing these infections after sexual assault has not been specifically studied.341 Because of possible adverse GI effects with the 3-drug regimen, the CDC suggests that the patient be counseled regarding the possible benefits, as well as the possibility of toxicity of such prophylaxis.341 Alternative regimens may be required for some patients because of the likelihood of transmission of other STDs from the assailant.341 CDC states that a recommendation concerning the appropriateness of antiretroviral prophylaxis against HIV cannot be made based on currently available information, and the decision to offer such prophylaxis should be individualized taking into account the probability of HIV transmission from a single act of intercourse and the nature of the assault (e.g., extent and site of physical trauma and exposure to ejaculate).341 (See Guidelines for Use of Antiretroviral Agents: Antiretroviral Agents for Postexposure Prophylaxis in Sexual Assault Victims or Nonoccupational Exposure to HIV, in the Antiretroviral Agents General Statement 8:18.08.)

There are few data available to establish the risk of a child acquiring a sexually transmitted disease as a result of sexual assault or abuse.341 The risk is believed to be low in most circumstances, although documentation to support this position is inadequate.341 The CDC and AAP state that presumptive treatment for children who have been sexually assaulted or abused is not widely recommended because girls appear to be at lower risk for ascending infection than adolescent or adult women, and regular follow-up usually can be ensured.100,341 Even if the risk is perceived by the health-care provider to be low, some children or their parents or guardians may have concerns about the possibility of the child contracting a sexually transmitted disease as a result of the assault and these concerns may be an appropriate indication for presumptive treatment in some settings, but only after appropriate specimens for STD testing have been obtained.341

For topical and vaginal uses of metronidazole, see 84:04.04.

Reconstitution and Administration

Metronidazole is administered orally or by continuous or intermittent IV infusion; metronidazole hydrochloride is administered by continuous or intermittent IV infusion. Metronidazole has been administered rectally†,113,114,115 but this dosage form is not currently available in the US. The drug also is administered intravaginally157,158,159,163,204,288,289,290,291,295,297,301,302 or applied topically to the skin.137,138,139,140,141,142,143,144,147,148 (See Metronidazole 84:04.04.)

Parenteral Administration

Metronidazole and metronidazole hydrochloride should not be mixed with other drugs, and other IV infusions should be discontinued, if possible, while metronidazole or metronidazole hydrochloride is being infused.

Metronidazole injection does not need to be diluted or neutralized prior to IV administration. However, IV infusions of metronidazole hydrochloride must be prepared by reconstituting, diluting, and then neutralizing the commercially available powder for injection. Metronidazole hydrochloride powder for injection is reconstituted by adding 4.4 mL of sterile or bacteriostatic water for injection, 0.9% sodium chloride injection, or bacteriostatic sodium chloride injection to a vial labeled as containing 500 mg of metronidazole. The resultant solution contains approximately 100 mg of metronidazole per mL and must be further diluted with 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer's injection to a concentration of 8 mg or less of metronidazole per mL. The reconstituted and diluted metronidazole hydrochloride solution must then be neutralized by adding approximately 5 mEq of sodium bicarbonate injection for each 500 mg of metronidazole. The addition of sodium bicarbonate to the metronidazole hydrochloride solution may generate carbon dioxide gas and it may be necessary to remove gas pressure from the container.

When the commercially available IV infusion solution of metronidazole is used, the accompanying labeling should be consulted for proper methods of administration and associated precautions.

Oral Administration

While food does not affect the extent of absorption of metronidazole administered as capsules,197 it does increase the rate of absorption of the drug administered as extended-release tablets.430 To optimize the pharmacokinetic disposition of the extended-release oral preparation of metronidazole, the manufacturer recommends that metronidazole extended-release tablets be administered during the fasting state (i.e., at least 1 hour before or 2 hours after meals).430

An extemporaneously compounded oral liquid formulation of metronidazole containing 50 mg/mL has been prepared.98

Standardize 4 Safety

Standardized concentrations for an extemporaneously compounded oral liquid formulation of metronidazole have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 99Multidisciplinary expert panels were convened to determine recommended standard concentrations. 99Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. For additional information on S4S (including updates that may be available), see [Web].99

Dosage

Dosage of metronidazole hydrochloride is expressed in terms of metronidazole. Because the pharmacokinetics of metronidazole may be altered in geriatric individuals, monitoring of plasma metronidazole concentrations may be necessary to properly adjust dosage of the drug in such patients.

Amebiasis

For the treatment of acute intestinal amebiasis or extraintestinal disease caused by Entamoeba histolytica , metronidazole is administered orally and metronidazole therapy is followed by therapy with a luminal amebicide (iodoquinol, paromomycin).153,364,368,370 (See Uses: Amebiasis.)

The usual adult dosage of metronidazole for acute intestinal disease is 750 mg 3 times daily for 5-10 (usually 10) days.152,197,364,368,370 The usual adult dosage for amebic liver abscess is 500-750 mg 3 times daily for 5-10 (usually 10) days.152,197,364,368,370 Some clinicians recommend that adults receive 500-750 mg 3 times daily for 7-10 days for mild to moderate intestinal disease or 750 mg 3 times daily for 7-10 days for severe intestinal and extraintestinal disease.153 Alternatively, amebic liver abscess has been treated in adults with 2.4 g once daily for 1 or 2 days.364 When oral therapy could not be used, metronidazole has been administered IV in a dosage of 500 mg every 6 hours for 10 days.364

For the treatment of mild to moderate intestinal amebiasis, severe intestinal disease, or extraintestinal disease (including amebic liver abscess) in children, the usual dosage of metronidazole is 35-50 mg/kg given in 3 divided doses daily for 7-10 (usually 10) days.152,153,197,370

Anaerobic Bacteria Infections

For the treatment of serious infections caused by anaerobic bacteria, metronidazole or metronidazole hydrochloride is administered IV initially and oral metronidazole is substituted when the condition of the patient warrants. IV infusions are usually given over 1 hour. Adults should receive an initial IV loading dose of 15 mg/kg followed by IV maintenance doses of 7.5 mg/kg every 6 hours. The usual adult oral dosage is 7.5 mg/kg every 6 hours. The maximum daily adult IV or oral dose recommended by the manufacturers for the treatment of anaerobic bacterial infections is 4 g. The manufacturers state that the usual duration of therapy is 7-10 days; however, most serious anaerobic bacterial infections require 2-3 weeks of therapy.

Bacterial Vaginosis

For the treatment of bacterial vaginosis† in nonpregnant women and adolescents, the CDC, AAP, and others recommend an oral metronidazole dosage of 500 mg twice daily for 7 days.100,199,286,297,298,300,301,302,341,366 Although not recommended by the CDC, alternative regimens that have been used include a single 2-g dose of oral metronidazole (provides improved patient compliance and reduced risk of adverse effects)100,120,122,199,292,297,341 and 750 mg (as an extended-release tablet) once daily for 7 consecutive days.199,430

For the treatment of bacterial vaginosis in pregnant women, the CDC and other experts currently recommend an oral metronidazole dosage of 500 mg twice daily or 250 mg 3 times daily for 7 days.341,416,417 The manufacturer and some experts state that the single-dose regimen should not be used in pregnant women because it may result in slightly higher serum concentrations of the drug, which can reach the fetal circulation.152 Use of oral metronidazole administered as extended-release tablets for the treatment of bacterial vaginosis currently is being studied in pregnant women.430

AAP suggests that prepubertal children weighing less than 45 kg can receive oral metronidazole is a dosage of 15 mg/kg daily (up to 1 g) in 2 divided doses given for 7 days for the treatment of bacterial vaginosis.100

Balantidiasis

For the treatment of balantidiasis† caused by Balantidium coli , many clinicians recommend an oral metronidazole dosage of 750 mg 3 times daily for 5 days in adults and 35-50 mg/kg daily given in 3 divided doses for 5 days in children.153

Blastocystis hominis Infections

When used in the treatment of symptomatic Blastocystis hominis infections†, oral metronidazole has been given in a dosage of 750 mg 3 times daily for 10 days.153,372

Clostridium difficile-Associated Diarrhea and Colitis

For the treatment of Clostridium difficile -associated diarrhea and colitis† in adults, oral metronidazole dosages of 750 mg to 2 g daily given in 3 or 4 divided doses for 7-14 days have been used.125,126,129,131,132,133,313,314 While dose-ranging studies to determine comparative efficacy have not been performed, the most commonly employed oral metronidazole regimens in adults have been 250 mg 4 times daily or 500 mg 3 times daily for 10 days.443,444,445,446 An IV dosage of 500-750 mg every 6-8 hours has been used in adults when oral therapy was not feasible.134,161,162,313,342,343,445

Children have been given oral metronidazole dosages of 30-50 mg/kg daily given in 3 or 4 equally divided doses for 7-10 days, but not to exceed the adult dosage, for the treatment of C. difficile -associated diarrhea and colitis†.445,446 AAP recommends 30 mg/kg daily (up to 2 g daily) given in 4 divided doses for 7-10 days for initial treatment in most patients with colitis.100

Crohn's Disease

Optimum metronidazole dosage for the treatment of active Crohn's disease† has not been established,103 but an oral dosage of 400 mg twice daily101,103,105 or 1 g daily has been effective.467,472,473,475,476,482 For the treatment of refractory perineal disease, an oral dosage of 20 mg/kg (1-1.5 g) given in 3-5 divided doses daily has been employed.102,103,104,105,478,486

Dientamoeba fragilis Infections

For the treatment of infections caused by Dientamoeba fragilis †, adults should receive 500-750 mg 3 times daily for 10 days and children should receive 20-40 mg/kg daily given in 3 divided doses for 10 days.153

Dracunculiasis

For the treatment of dracunculiasis† caused by Dracunculus medinensis (guinea worm infection), adults have received oral metronidazole in a dosage of 250 mg 3 times daily for 10 days and children have received 25 mg/kg daily (maximum 750 mg daily) given in 3 divided doses for 10 days.153 Although not curative, this regimen may decrease inflammation and facilitate worm removal.153

Giardiasis

For the treatment of giardiasis†, the usual dosage of oral metronidazole for adults is 250 mg 3 times daily for 5-7 days.153,367,452 Adults have been treated successfully with a single daily dose of 2 g for 3 days. For adults with coexistent amebiasis, the usual dosage is 750 mg 3 times daily for 5-10 days.

Some clinicians recommend that children receive 15 mg/kg daily in 3 divided doses for 5-7 days.153,367,452

Helicobacter pylori Infection

For the treatment of Helicobacter pylori (formerly Campylobacter pylori or C. pyloridis ) infection† in adults with an active duodenal ulcer, the FDA-labeled dosage of metronidazole is 250 mg in combination with tetracycline hydrochloride (500 mg) and bismuth subsalicylate (525 mg) 4 times daily (at meals and at bedtime) for 14 days; these drugs should be given concomitantly with an H₂-receptor antagonist in recommended dosage.455 Metronidazole generally has been used in an oral dosage of 250-500 mg 3 times daily in combination with at least one other agent that has activity against H. pylori (e.g., bismuth subsalicylate, amoxicillin, tetracycline).207,208,216,240,241,255,257,261,263,267,273,274 (See Helicobacter pylori Infection, in Uses.)

In a limited number of children with H. pylori -associated peptic ulcer disease (e.g., gastritis, duodenitis/duodenal ulcer)†, oral metronidazole 15-20 mg/kg daily in 2 divided doses for 4 weeks has been administered as part of a 6-week multiple-drug regimen that included amoxicillin and/or bismuth subsalicylate.213,273 Further study is needed to establish an optimal drug regimen for the treatment of H. pylori infection in children.213,215,272,273

The minimum duration of therapy required to eradicate H. pylori infection in peptic ulcer disease has not been fully established.207,208,212,214 The American College of Gastroenterology (ACG) and many clinicians376,390,391 currently recommend 1 week of therapy with a proton-pump inhibitor and 2 anti-infective agents (usually clarithromycin and amoxicillin or metronidazole), or a 3-drug, bismuth-based regimen (e.g., bismuth-metronidazole-tetracycline) concomitantly with a proton-pump inhibitor, for treatment of H. pylori infection.376,388,391 However, the ACG states that in a cost-sensitive environment, an alternative regimen consisting of a bismuth salt, metronidazole, and tetracycline for 14 days is a reasonable choice in patients who are compliant and in whom there is a low expectation of metronidazole resistance (no prior exposure to the drug and a low regional prevalence of resistance).376 (See Helicobacter pylori Infection in Uses: GI Infections, in the Tetracyclines General Statement 8:12.24.)

Nongonococcal Urethritis

For the treatment of recurrent and persistent urethritis† in patients who have already received a regimen recommended for the treatment of nongonococcal urethritis (see Uses: Nongonococcal Urethritis), the CDC recommends a single 2-g dose of oral metronidazole in conjunction with a single 1-g dose of oral azithromycin (if azithromycin was not used in the initial regimen).341

Pelvic Inflammatory Disease

For the treatment of PID when an oral regimen is indicated, a single IM dose of ceftriaxone (250 mg) or a single IM dose of cefoxitin (2 g with oral probenecid 1 g) is given in conjunction with oral doxycycline (100 mg twice daily for 14 days) with or without oral metronidazole in a dosage of 500 mg twice daily for 14 days.341

Alternatively, when a parenteral cephalosporin is not feasible and the community prevalence and individual risk of gonorrhea is low,496 oral metronidazole is given in a dosage of 500 mg twice daily in conjunction with oral ofloxacin (400 mg twice daily) or oral levofloxacin (500 mg once daily) for 14 days.199,341,496

Tetanus

When used as an adjunct in the treatment of tetanus, some clinicians recommend that IV metronidazole be given in a dosage of 500 mg every 6 hours for 7-10 days.489 In children, oral or IV metronidazole has been given in a dosage of 30 mg/kg daily in 4 divided doses (maximum 4 g daily).100

Trichomoniasis

For the initial treatment of symptomatic and asymptomatic trichomoniasis caused by Trichomonas vaginalis , metronidazole is administered orally in a single-dose or 7-day regimen; treatment should be individualized. The dosages are the same for sexual contacts. The single-dose regimen can ensure compliance, especially if administered under supervision, in patients who cannot be relied upon to continue the 7-day regimen, and is currently considered the regimen of choice by the US Centers for Disease Control and Prevention (CDC) and other experts. However, the 7-day regimen may minimize reinfection of the woman long enough to treat sexual contacts, and there is some evidence that cure rates as determined by vaginal smears and symptoms may be higher after the 7-day regimen than after the single-dose regimen.

For the single-dose regimen, the dosage for adults and adolescents is 2 g administered as a single dose;100,153,199,341 alternatively, the dose can be divided and administered in 2 doses on the same day. For the 7-day regimen, the CDC and many clinicians currently recommend an adult dosage of 500 mg twice daily.100,153,199,341 Alternatively, the manufacturer and some clinicians state that a 375-mg metronidazole capsule can be given twice daily for 7 days; 153,199,197 however, this regimen is not included in current CDC guidelines for the treatment of trichomoniasis.341

Before repeat courses of therapy are given, the manufacturer states that the presence of the organism should be reconfirmed by wet smear and/or culture and an interval of 4-6 weeks should be allowed between courses of metronidazole.152,197 If treatment failure occurs following an initial metronidazole regimen of a single 2-g dose and reinfection has been excluded, the CDC recommends that the patient be retreated with an oral metronidazole regimen of 500 mg twice daily for 7 days or, alternatively, a single 2-g dose of oral tinidazole; if retreatment fails, then 2 g of metronidazole or tinidazole should be given once daily for 5 days.341 If the multiple-dose regimen is ineffective, consultation with a specialist is recommended and in vitro susceptibility testing of T. vaginalis isolates may be indicated.297,341 Some clinicians recommend retreatment with a metronidazole regimen of 2-4 g daily for 7-14 days if metronidazole-resistant strains are involved.153,199 If treatment of resistant infection is guided by in vitro susceptibility testing under aerobic conditions, some clinicians suggest that strains of T. vaginalis exhibiting low-level resistance (minimum lethal concentration [MLC] less than 100 mcg/mL) can be treated orally with 2 g daily for 3-5 days, those with moderate (intermediate) resistance (MLC of 100-200 mcg/mL) can be treated orally with 2-2.5 g daily for 7-10 days, and those with high-level resistance (MLC exceeding 200 mcg/mL) can be treated orally with 3-3.5 g daily for 14-21 days.124,302,338,340 However, because infection with strains exhibiting high-level resistance is difficult to treat,124,297,302,338,340 CDC currently recommends that patients with culture-documented infection who do not respond to repeat regimens at dosages up to 2 g daily for 3-5 days and in whom the possibility of reinfection has been excluded should be managed in consultation with an expert;297,341 such consultation is available from CDC.341

The AAP and others recommend that children weighing less than 45 kg with trichomoniasis receive 15 mg/kg daily in 3 divided doses (maximum 2 g daily) for 7 days.100,153

Perioperative Prophylaxis

When metronidazole is used for perioperative prophylaxis in patients undergoing contaminated or potentially contaminated colorectal surgery, the manufacturers recommend that adults receive 15 mg/kg by IV infusion over 30-60 minutes 1 hour prior to the procedure and, if necessary, 7.5 mg/kg by IV infusion over 30-60 minutes at 6 and 12 hours after the initial dose.156,495 The initial preoperative dose must be completely infused approximately 1 hour prior to surgery to ensure adequate serum and tissue concentrations of metronidazole at the time of incision.156 Prophylactic use of metronidazole should be limited to the day of surgery and should not be continued for more than 12 hours after surgery.156,495

Alternatively, if an oral regimen is used for perioperative prophylaxis in patients undergoing colorectal surgery, adults can receive 2 g of oral metronidazole and 2 g of oral neomycin sulfate at 7 p.m. and 11 p.m. on the day preceding surgery.110 The oral regimen is used in conjunction with an appropriate diet and catharsis; a minimum residue or clear liquid diet and catharsis usually is prescribed 1-3 days prior to colorectal surgery.110

Some clinicians recommend that adults undergoing colorectal surgery receive 0.5 g of metronidazole IV in conjunction with 1-2 g of IV cefazolin just prior to surgery.110

Prophylaxis in Sexual Assault Victims

If empiric anti-infective prophylaxis is indicated in adolescent or adult victims of sexual assault†, a single 2-g oral dose of metronidazole is given in conjunction with a single 125-mg IM dose of ceftriaxone and either a single 1-g oral dose of azithromycin or a 7-day regimen oral doxycycline given in a dosage of 100 mg twice daily has been recommended.100,341 Hepatitis B vaccination also should be initiated in susceptible individuals and completed according to the usual schedule.100,341

If empiric anti-infective prophylaxis is indicated in preadolescent children and use of oral metronidazole for prevention of trichomoniasis and bacterial vaginosis is considered in these children, AAP states that those weighing less than 45 kg can receive metronidazole in a dosage of 15 mg/kg daily given in 3 divided doses for 7 days and those weighing 45 kg or more can receive a single 2-g dose.100

Dosage in Hepatic Impairment

In patients with severe hepatic impairment, doses and/or frequency of administration of metronidazole should be modified in response to the degree of hepatic impairment and plasma concentrations of the drug should be monitored.152,156,160,197,430,495

GI Effects

The most frequent adverse reaction to oral metronidazole is nausea, which is sometimes accompanied by headache, anorexia, dry mouth, and a sharp, unpleasant metallic taste. Other occasional adverse GI effects of oral metronidazole include vomiting, diarrhea, epigastric distress, abdominal discomfort, and constipation. Nausea, vomiting, abdominal discomfort, a metallic taste, and diarrhea have also been reported with IV metronidazole. Antibiotic-associated pseudomembranous colitis, presumably caused by toxin-producing clostridia (e.g., C. difficile ) resistant to metronidazole, has been reported rarely following oral administration of the drug125,126,127,128,129,131,132,133,314 and has also been reported in at least one patient following intravaginal administration of metronidazole.159 Pancreatitis, which has improved following discontinuance of the drug but recurred upon subsequent rechallenge, has been reported rarely during oral metronidazole therapy.149,150,152,156

In clinical trials in which combined therapy with tetracycline hydrochloride, metronidazole, and bismuth subsalicylate was used for the treatment of H. pylori infection and associated duodenal ulcer, adverse effects generally were related to the GI tract, were reversible, and infrequently led to discontinuance of therapy.455 Adverse GI effects reported in at least 1% of patients receiving combined therapy with tetracycline hydrochloride, metronidazole, and bismuth subsalicylate (generally in conjunction with acid-suppression therapy) were nausea (10.2%) diarrhea (5.1%), abdominal pain (3%), melena (2.5%), anal discomfort (1.5%), anorexia (1.5%), vomiting (1.5%), and constipation (1%).455 Adverse GI effects reported in less than 1% of patients receiving combined therapy with tetracycline hydrochloride-metronidazole-bismuth subsalicylate in clinical trials were dry mouth, dyspepsia, dysphagia, flatulence, GI hemorrhage, glossitis, and stomatitis.455

Nervous System Effects

Peripheral neuropathy, characterized by numbness, tingling, or paresthesia of an extremity, and convulsive seizures have been reported rarely with oral or IV metronidazole. Peripheral neuropathy is usually reversible if metronidazole is discontinued but may persist in patients who receive prolonged therapy or higher than recommended dosage of the drug. Dizziness, vertigo, incoordination, ataxia, confusion, irritability, depression, weakness, insomnia, headache, syncope, tinnitus, and hearing loss have also occurred with metronidazole.108,156 Headache occurred in 18% of nonpregnant women receiving oral metronidazole (administered as extended-release tablets) for bacterial vaginosis, and among those reporting headache, 10% described it as severe.430

Dizziness or paresthesia was reported in 1.5% of patients receiving combined therapy with tetracycline hydrochloride, metronidazole, and bismuth subsalicylate (generally in conjunction with acid-suppression therapy) in clinical trials; asthenia or insomnia was reported in 1% of such patients.455 Nervousness, malaise, or syncope was reported in less than 1% of patients receiving tetracycline hydrochloride-metronidazole-bismuth subsalicylate therapy in clinical trials.455

Hematologic Effects

Mild, transient leukopenia and thrombocytopenia have been reported rarely in patients receiving metronidazole,152,156,197,430,495 and bone marrow aplasia has been reported in at least 1 patient.

Genitourinary Effects

Urethral burning or discomfort, dysuria, cystitis, polyuria, incontinence, a sense of pelvic pressure, dryness of the vagina or vulva, dyspareunia, and decreased libido have been reported with oral metronidazole. Urine may be dark or reddish-brown in color following oral or IV administration of metronidazole due to the presence of water-soluble pigments which result from metabolism of the drug. Vulvovaginal candidiasis (or yeast vaginitis) was reported in 15% of nonpregnant women receiving oral metronidazole (administered as extended-release tablets) and in 12% of those receiving clindamycin phosphate (2% clindamycin) vaginal cream in a comparative study for the treatment of bacterial vaginosis.430 Although a definite causal relationship to the drug has not been established, genital pruritus, dysmenorrhea, and urinary tract infection have been reported in 5, 3, and 2%, respectively, of nonpregnant women receiving oral metronidazole (administered as extended-release tablets) for the treatment of bacterial vaginosis.430

Sensitivity Reactions

Hypersensitivity reactions including urticaria, pruritus, erythematous rash, flushing, nasal congestion, fever, and fleeting joint pains sometimes resembling serum sickness have been reported in patients receiving oral metronidazole. Erythematous rash and pruritus have been reported in patients receiving IV metronidazole. Aseptic meningitis, that appeared to be a hypersensitivity reaction, has occurred in at least one patient after administration of oral metronidazole.369 The reaction consisted of severe headache, fever, arthralgia, myalgia, stiff neck, nausea, and vomiting.369

Photosensitivity reaction or rash was reported in less than 1% of patients receiving combined therapy with tetracycline hydrochloride, metronidazole, and bismuth subsalicylate (generally in conjunction with acid-suppression therapy) in clinical trials.455

Respiratory Effects

Upper respiratory tract infection, rhinitis, sinusitis, and pharyngitis were each reported in less than 5% of nonpregnant women receiving oral metronidazole (administered as extended-release tablets) for the treatment of bacterial vaginosis.430

Other Adverse Effects

Furry tongue, glossitis, and stomatitis have been reported with oral metronidazole and may be due to overgrowth of Candida which may occur during metronidazole therapy. Candidiasis was reported in 3% of nonpregnant women receiving oral metronidazole (administered as extended-release tablets) for the treatment of bacterial vaginosis.430

Flattening of the T-wave has been reported rarely in ECG tracings of patients receiving oral metronidazole.

Thrombophlebitis has been reported after IV infusion of metronidazole. The manufacturers state that thrombophlebitis may be minimized or avoided by avoiding prolonged use of indwelling IV catheters.

Although a definite causal relationship to the drug has not been established, bacterial infection and flu-like symptoms have been reported in 7 and 6%, respectively, of nonpregnant women receiving oral metronidazole (administered as extended-release tablets) for the treatment of bacterial vaginosis.430 Myopia in a woman receiving metronidazole for trichomoniasis also has been associated with, but not causally related to, the drug.437

Pain or upper respiratory tract infection was reported in 1% of patients receiving combined therapy with tetracycline hydrochloride, metronidazole, and bismuth subsalicylate (generally in conjunction with acid-suppression therapy) in clinical trials, while hypertension, myocardial infarction, or rheumatoid arthritis was reported in less than 1% of such patients.455

Precautions and Contraindications

When the commercially available combination preparation containing tetracycline hydrochloride, metronidazole, and bismuth subsalicylate (Helidac^® Therapy) is used for the treatment of Helicobacter pylori infection and associated duodenal ulcer disease, the cautions, precautions, and contraindications associated with tetracycline hydrochloride and bismuth subsalicylate must be considered in addition to those associated with metronidazole.

If abnormal neurologic symptoms occur during oral or IV metronidazole therapy, such therapy should be discontinued promptly.152,157,430,455 Metronidazole should be used with caution in patients with CNS diseases.152,157,430,455

The manufacturers state that metronidazole should be used with caution in patients with evidence or a history of blood dyscrasias, and total and differential leukocyte counts should be performed before and after treatment with the drug, especially when repeated courses of therapy are necessary.

Patients should be advised to avoid concurrent use of metronidazole and alcoholic beverages.152,156,197,430,455,495 (See Drug Interactions: Alcohol.)

The use of oral or IV metronidazole may result in oral, vaginal, or intestinal candidiasis. If suprainfection or superinfection occurs, appropriate therapy should be instituted.

Metronidazole should be used with caution and in reduced dosage in patients with severe hepatic impairment. The manufacturers recommend that plasma metronidazole concentrations be monitored in patients with severe hepatic impairment. The manufacturers state that commercially available metronidazole injection should be used with caution in patients receiving corticosteroids and in patients predisposed to edema because the injection contains 28 mEq of sodium per gram of metronidazole.

To reduce development of drug-resistant bacteria and maintain effectiveness of metronidazole and other antibacterials, the drug should be used only for the treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.152,197,430,495 When selecting or modifying anti-infective therapy, results of culture and in vitro susceptibility testing should be used.152,197,430,495 In the absence of such data, local epidemiology and susceptibility patterns should be considered when selecting anti-infectives for empiric therapy.152,197,430,495 Patients should be advised that antibacterials (including metronidazole) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).152,197,430,495 Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with metronidazole or other antibacterials in the future.152,197,430,495

Metronidazole is contraindicated in individuals with a history of hypersensitivity to the drug or other nitroimidazole derivatives. However, cautious desensitization has been employed in some hypersensitive patients in whom metronidazole therapy was considered necessary.341,436 (See Trichomoniasis: Desensitization, in Uses.)

Pregnancy, Fertility, and Lactation

Pregnancy

There was no evidence of fetotoxicity when metronidazole was administered orally at a dosage of 20 mg/kg daily (approximately 1.5 times the usual human dosage based on mg/kg of body weight) or at a dosage of 60 mg/m² daily (approximately 10% of the usual human dosage) to pregnant mice; however, fetotoxicity did occur when the drug was administered intraperitoneally to pregnant mice at doses approximately equal to the usual human dose.152,156,197,430,455 There are no adequate or well-controlled studies to date using metronidazole in pregnant women, and the drug should be used during pregnancy only when clearly needed.152,197,430,442,455 The manufacturers, the CDC, and other experts100,152,197,341,430,442 state that use of the drug during the first trimester of pregnancy is contraindicated. Although evidence from case-controlled studies, pooled analysis of cohort and case-controlled studies, and other information, including some experience during first-trimester exposure, suggests that metronidazole is not associated with a clinically important teratogenic or fetotoxic risk,438,439,440,441,442 conflicting evidence potentially implicating an association between the drug and certain fetal effects (e.g., cleft palate) also has been reported.442 Because of conflicting data and theoretical concerns regarding the mutagenic and carcinogenic potentials of the drug, use of metronidazole during the first trimester remains controversial442,446 and is considered contraindicated by the manufacturers and others.100,152,197,341,430,442

Because no therapy other than metronidazole currently has been shown to produce adequate response in the treatment of trichomoniasis, the manufacturers, CDC, and other experts state that oral metronidazole should be used to treat this infection in pregnant women only when severe symptoms cannot be controlled with local palliative treatment and only during the second or third trimester. In addition, the manufacturers state that because the single-dose regimen may result in slightly higher serum concentrations of the drug, the 7-day regimen (see Dosage and Administration: Dosage) should be used to treat trichomoniasis during pregnancy. However, the CDC suggests the single-dose regimen when therapy with the drug is considered necessary.341 It has been suggested that 100 mg of clotrimazole administered intravaginally at bedtime for 7 days may produce symptomatic improvement but only occasionally cures in pregnant women with trichomoniasis; therefore, such therapy generally should be considered palliative.302,338

Screening and/or treatment for bacterial vaginosis in pregnant women as clinically indicated (see Bacterial Vaginosis: Pregnant Women, in Uses) should be conducted early in the pregnancy (i.e., first prenatal visit for women at high-risk).341,415 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 currently is preferred.341,416,417 the manufacturer and some experts state that the single-dose regimen of metronidazole should not be used in pregnant women because it may result in slightly higher serum concentrations of the drug, which can reach the fetal circulation.152 The safety and efficacy of oral metronidazole administered as extended-release tablets for the treatment of bacterial vaginosis have not been established in pregnant women.430

Fertility

Metronidazole in dosages up to 400 mg/kg daily (approximately 3.5 times the maximum recommended human dosage on a mg/m² basis) for 28 days failed to produce any adverse effects on fertility and testicular function in male rats.455 Reproduction studies in mice using metronidazole doses up to 6 times the human dose on a mg/m² basis have not revealed evidence of impaired fertility.152,197,430,442,455

Lactation

Metronidazole is distributed into milk. Because of the tumorigenic potential of metronidazole in mice and rats, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. The AAP states that, if a single 2-g dose of oral metronidazole is indicated in the mother, breast-feeding should be interrupted for 12-24 hours following the dose.100

Coumarin Anticoagulants

Oral or IV metronidazole potentiates the effects of oral anticoagulants resulting in prolongation of the prothrombin time, and concurrent administration should be avoided if possible.147,152,156,191,192,193,194,195,197,430,495 If metronidazole is used in patients receiving an oral anticoagulant, prothrombin times should be monitored and dosage of the anticoagulant adjusted accordingly.191,192,193,194,195

Alcohol

Metronidazole appears to inhibit alcohol dehydrogenase and other alcohol oxidizing enzymes. Mild disulfiram-like reactions including flushing, headache, nausea, vomiting, abdominal cramps, and sweating have occurred in some patients who ingested alcohol while receiving oral or IV metronidazole.139,152,156,157,187,196,197,430,495 A disulfiram-like reaction also occurred in one patient who ingested alcohol while receiving intravaginal metronidazole.157 Patients receiving metronidazole should be warned that this reaction may occur. Studies that investigated the use of metronidazole as an alcohol deterrent in the treatment of chronic alcoholism indicate that these reactions are unpredictable and relatively uncommon. The manufacturers recommend that alcohol not be consumed during or for at least 1 day (or at least 3 days with the oral capsules or extended-release oral tablets) following completion of metronidazole therapy.152,156,197,430,495

Disulfiram

Administration of disulfiram and metronidazole has been associated with acute psychoses and confusion in some patients; therefore, the drugs should not be used concomitantly and 2 weeks should elapse following discontinuance of disulfiram prior to initiating metronidazole therapy.152,156,197,430,495

Phenobarbital

Concomitant use of metronidazole and phenobarbital appears to decrease the serum half-life of metronidazole, presumably by increasing metabolism of the anti-infective.116,117,152,197,430,495 Serum concentrations of metronidazole have been decreased and serum concentrations of 2-hydroxymethyl metronidazole increased in patients receiving phenobarbital.116,117

Lithium

Initiation of short-term metronidazole therapy in patients stabilized on a relatively high dosage of lithium has been reported to increase serum lithium concentrations, resulting in signs of lithium toxicity in several patients;151,152,155,197,430,495 in some cases, signs of renal damage (e.g., persistent elevations in serum creatinine concentration, hypernatremia, abnormally dilute urine) were present.151 Pending further accumulation of data, caution should be exercised and frequent monitoring of serum lithium and creatinine concentrations should be performed when metronidazole and lithium are administered concurrently.151,152,155,197,430,495

Terfenadine and Astemizole

Metronidazole may interact with astemizole (no longer commercially available in the US) and terfenadine (no longer commercially available in the US), resulting in potentially serious adverse cardiovascular effects. Prolongation of the QT interval and QT interval corrected for rate (QT_c) and, rarely, serious cardiovascular effects, including arrhythmias (e.g., ventricular tachycardia, atypical ventricular tachycardia [torsades de pointes], ventricular fibrillation), cardiac arrest, palpitations, hypotension, dizziness, syncope, and death, have been reported in patients receiving the structurally similar antifungal ketoconazole concomitantly with usual dosages of terfenadine or astemizole. Ketoconazole can markedly inhibit the metabolism of astemizole or terfenadine, probably via inhibition of the cytochrome P-450 enzyme system, resulting in increased plasma concentrations of unchanged drug (to measurable levels) and reduced clearance of the active desmethyl or carboxylic acid metabolite, respectively. Such alterations in the pharmacokinetics of these antihistamines may be associated with prolongation of the QT and QT_c intervals. Similar alterations in the pharmacokinetics of these antihistamines and/or adverse cardiac effects have been reported in patients receiving the drugs concomitantly with another structurally related antifungal, itraconazole, although in vitro data suggest that itraconazole may have a less pronounced effect than ketoconazole on the pharmacokinetics of astemizole. Therefore, while astemizole and terfenadine were commercially available in the US, these antihistamines were contraindicated in patients receiving ketoconazole or itraconazole. In addition, it has been recommended that astemizole and terfenadine not be used in patients receiving drugs that are structurally related to itraconazole and ketoconazole, including nitroimidazoles such as metronidazole, imidazoles such as miconazole (systemic form no longer commercially available in the US), and triazoles such as fluconazole. For additional information, see Cautions: Cardiovascular Effects and Precautions and Contraindications, in the Antihistamines General Statement 4:00.

Other Drugs

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.106,152,156,197,430,495 Although further documentation is needed, the possibility of increased adverse effects of metronidazole should be considered if the drugs are administered concomitantly.106,107

Laboratory Test Interferences

Metronidazole interferes with serum AST (SGOT), ALT (SGPT), LDH, triglycerides, or glucose determinations when these determinations are based on the decrease in ultraviolet absorbance which occurs when NADH is oxidized to NAD.152,156,197,430,495 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.152,156,197,430,495

Mechanism of Action

Antimicrobial Effects

Metronidazole is bactericidal, amebicidal, and trichomonacidal in action. The exact mechanism of action of the drug has not been fully elucidated. Metronidazole is un-ionized at physiologic pH and is readily taken up by anaerobic organisms or cells. 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) which lack the nitro group. 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. Metronidazole is equally effective against dividing and nondividing cells.

Metronidazole is referred to as both a luminal or contact amebicide and a tissue amebicide because the drug is active against trophozoites in the intestinal lumen, intestinal wall, and at extraintestinal sites such as the liver and lungs following oral administration. However, because metronidazole is well absorbed from the GI tract, the drug usually has greater activity systemically than locally following oral administration.

Anti-inflammatory and Immunosuppressive Effects

In vitro and in vivo studies indicate that metronidazole has direct anti-inflammatory effects137,139,148,166,167 and effects on neutrophil motility, lymphocyte transformation, and some aspects of cell-mediated immunity.148,168,169,170,171,172

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.166 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.137,139,148,167 This antioxidant effect appears to be caused by a direct effect on neutrophil function167 and may contribute to the drug's anti-inflammatory effect in vivo.148,167

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.170,171 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.170 It has been suggested that metronidazole may increase leukocyte migration by a direct effect on the leukocytes,170,171 possibly by causing the release of surface-bound immune complexes from the cell surface.171

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.172 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.172 The drug, however, did not affect nonspecific inflammation around divinylbenzene copolymer beads injected in mice and did not suppress skin allograft rejection in mice.172

Spectrum

In general, metronidazole is active against most obligately anaerobic bacteria and many protozoa. The drug also is toxic to other anoxic or hypoxic cells. Metronidazole is inactive against fungi, viruses, and most aerobic or facultatively anaerobic bacteria.

When dilution susceptibility testing procedures (e.g., agar or broth dilution) are used to test susceptibility of bacteria to metronidazole, the manufacturer suggests that organisms with an MIC of 8 mcg/mL or less be considered susceptible to metronidazole and those with an MIC of 32 mcg/mL or greater be considered resistant to the drug.197,430

Anaerobic Bacteria

Metronidazole is active in vitro against many anaerobic gram-negative bacilli including Bacteroides fragilis ,148,152,156,164,173,174,175,176,275,277,280 B. distasonis ,152,156,175,176,275 B. ovatus ,152,156,176,275 B. thetaiotaomicron ,152,156,175,176,275 B. ureolyticus ,275,277 B. vulgatus ,152,156,175,176,275 Porphyromonas asaccharolytica ,275,279 P. gingivalis ,177,275 Prevotella bivia ,174,275,277,278,279 P. disiens ,175,278 P. intermedia ,177,275 P. melaninogenica ,164,175,275,277,278,279 P. oralis ,175,275,277,279 Fusobacterium ,148,152,156,164,174,176,177 and Veillonella .175,176,177 Some strains of Mobiluncus (motile, anaerobic, curved rods) are inhibited in vitro by metronidazole;204,276,277,279,281 other strains are considered resistant to the drug.275,276,279,281 The drug also is active against many anaerobic gram-positive cocci including Clostridium ,148,152,156,164,174,176 C. difficile ,175,176 C. perfringens ,164,176 Eubacterium ,148,152,156,164,174,175 Peptococcus ,148,152,156,164,174,175,176 and Peptostreptococcus .148,152,156,164,174,176,177,275,278 In vitro, the MIC₉₀ (minimum inhibitory concentration of the drug at which 90% of strains tested are inhibited) of metronidazole reported for susceptible gram-negative and gram-positive anaerobic bacteria is 0.125-6.25 mcg/mL.164,174,175,176,177 Actinomyces ,164,177 Lactobacillus ,164 Propionibacterium acnes ,148,164,178,179 P. avidum ,179 and P. granulosum 179 generally are resistant to metronidazole.

Other Bacteria

Most strains of Gardnerella vaginalis (formerly Haemophilus vaginalis ) are susceptible only to relatively high concentrations of metronidazole in vitro.277,279,282,283,284,285 However, the 2-hydroxy metabolite is approximately 4-8 times as active as the parent drug against this organism,279,280,284 and this metabolite may be principally responsible for the activity of metronidazole against G. vaginalis in vivo when the drug is administered systemically.279,280,284 Metronidazole has minimal activity against Lactobacillus species or other aerobic microorganisms commonly isolated from the vaginal tract.430

Metronidazole has some activity in vitro against Campylobacter fetus , an organism that can be microaerophilic or anaerobic.164 In vitro, the MIC₅₀ and MIC₉₀ of metronidazole reported for C. fetus are 3.1 and 25 mcg/mL, respectively.164

Limited data indicate that the MIC₉₀ of metronidazole for Helicobacter pylori (formerly Campylobacter pylori or C. pyloridis ) is 2-4 mcg/mL, although reported MICs of metronidazole for this organism have varied considerably205,206 and resistance develops rapidly when the drug is used alone for H. pylori infections.207,208,209,210 The combination of metronidazole and its hydroxy metabolite, or either compound plus tetracycline hydrochloride or amoxicillin, has demonstrated synergism in vitro against H. pylori .211

Protozoa

Metronidazole is active in vitro and in vivo against Entamoeba histolytica , Trichomonas vaginalis , Giardia lamblia , and Balantidium coli . In vitro, most strains of E. histolytica and T. vaginalis are inhibited by metronidazole concentrations less than 3 mcg/mL and most strains of G. lamblia are inhibited by metronidazole concentrations of 0.8-32 mcg/mL. Metronidazole acts primarily against the trophozoite forms of E. histolytica and has limited activity against the encysted forms.

Metronidazole is believed to exert an anthelmintic effect against the nematode Dracunculus medinensis (guinea worm), although this has not been proven to date.

Resistance

Natural and acquired resistances to metronidazole have been reported occasionally in some strains of Trichomonas vaginalis . Although the clinical importance is unclear, in vitro studies indicate that while some T. vaginalis isolates with reduced susceptibility to metronidazole also have reduced susceptibility to tinidazole, the minimum lethal concentration (MLC) of tinidazole for these strains may be lower than the MLC of metronidazole.488

Rarely, resistance to the drug also has been reported in Bacteroides fragilis and other anaerobic bacteria following long-term therapy. There has been at least one report of a strain of metronidazole-resistant B. fragilis that was cross-resistant in vitro to amoxicillin and clavulanate potassium, imipenem, and tetracycline; the strain was susceptible to chloramphenicol and clindamycin in vitro.136

Resistance to metronidazole may be due to poor cell penetration and/or decreased nitroreductase activity.

Pharmacokinetics

Absorption

At least 80% of an oral dose of metronidazole is absorbed from the GI tract. Following oral administration of a single 250-mg, 500-mg, or 2-g dose of metronidazole as immediate-release (conventional) preparations in healthy, fasting adults, peak plasma concentrations of unchanged drug and active metabolites are attained within 1-3 hours and average 4.6-6.5 mcg/mL, 11.5-13 mcg/mL, and 30-45 mcg/mL, respectively. When a single 750-mg dose of metronidazole is administered as two 375-mg capsules or three 250-mg conventional tablets in healthy, fasting adult women, average peak plasma concentrations of unchanged drug and active metabolites of 20.4-21.4 mcg/mL are attained in an average of 1.4-1.6 hours; metronidazole capsules and conventional tablets are bioequivalent at a single dose of 750 mg.197 The rate of absorption and peak plasma concentrations of metronidazole are decreased when conventional tablets or capsules of the drug197 are administered with food; however, the total amount of drug absorbed is not affected.

Following oral administration of metronidazole 750 mg once daily as the extended-release tablet for 7 consecutive days in healthy, adult women, steady-state peak plasma concentrations average 12.5 mcg/mL and are attained an average of 6.8 hours after the dose when the drug is given under fasting conditions; when the drug is given at the same dosage under nonfasting conditions, steady-state peak plasma concentrations average 19.4 mcg/mL and are attained an average of 4.6 hours after the dose.430 Administration of metronidazole extended-release tablets with food increases the rate of absorption and peak plasma concentrations of the drug.430 According to the manufacturer, metronidazole extended-release and conventional tablets are bioequivalent at a dose of 750 mg given under fasting conditions.430

After IV infusion over 1 hour of a loading dose of 15 mg/kg of metronidazole as the hydrochloride followed by IV infusion over 1 hour of 7.5-mg/kg doses every 6 hours in healthy adults, peak steady-state plasma concentrations of unchanged metronidazole average 26 mcg/mL and trough steady-state plasma concentrations of the drug average 18 mcg/mL. In one crossover study in adults, areas under the concentration-time curves (AUCs) were not significantly different following a single 500-mg oral dose of metronidazole as tablets or a single 500-mg IV dose of the drug as metronidazole hydrochloride given over 20 minutes. Small amounts of metronidazole are absorbed systemically when the drug is administered intravaginally.157,198

Distribution

Metronidazole is widely distributed into most body tissues and fluids including bone, bile, saliva, pleural fluid, peritoneal fluid, vaginal secretions, seminal fluid, CSF, and cerebral and hepatic abscesses. Distribution is similar whether the drug is administered orally or by IV infusion. Concentrations of metronidazole in CSF are reported to be 43% of concurrent plasma concentrations in patients with uninflamed meninges and equal to or greater than concurrent plasma concentrations of the drug in patients with inflamed meninges. The drug also distributes into erythrocytes.154 Limited data suggest that the volume of distribution of metronidazole may be reduced in geriatric individuals as compared with younger individuals, perhaps as a result of decreased erythrocyte uptake of the drug in such patients.154

Metronidazole is less than 20% bound to plasma proteins.

Metronidazole readily crosses the placenta. Metronidazole is distributed into milk in concentrations equal to concurrent plasma concentrations of the drug.

Elimination

The plasma half-life of metronidazole is reported to be 6-8 hours in adults with normal renal and hepatic function. In one study using radiolabeled metronidazole hydrochloride, the half-life of unchanged metronidazole averaged 7.7 hours and the half-life of total radioactivity averaged 11.9 hours. The plasma half-life of metronidazole is not affected by changes in renal function; however, the half-life may be prolonged in patients with impaired hepatic function. In one study in adults with alcoholic liver disease and impaired hepatic function, half-life of metronidazole averaged 18.3 hours (range: 10.3-29.5 hours).160

Approximately 30-60% of an oral or IV dose of metronidazole is metabolized in the liver by hydroxylation, side-chain oxidation, and glucuronide conjugation. The major metabolite, 2-hydroxy metronidazole, has some antibacterial and antiprotozoal activity. In a group of healthy adults, 19% of a single oral dose of 750-mg of radiolabeled metronidazole was excreted in urine and 3% in feces as unchanged drug and metabolites within 24 hours; 77% of the dose was excreted in urine and 14% in feces as unchanged drug and metabolites within 5 days. Limited data suggest that urinary excretion of unchanged drug and metabolites is decreased in geriatric individuals as compared with younger individuals.154 Urine may be dark or reddish-brown in color following oral or IV administration of metronidazole or metronidazole hydrochloride due to the presence of water-soluble pigments which result from metabolism of the drug. Metronidazole is removed by hemodialysis but not by peritoneal dialysis.

Chemistry and Stability

Chemistry

Metronidazole is a synthetic, nitroimidazole-derivative antibacterial and antiprotozoal agent. Metronidazole is commercially available as the base and the hydrochloride salt.

The base occurs as white to pale yellow crystals or crystalline powder, is sparingly soluble in water and in alcohol, and has a pK_a of 2.6. Metronidazole injection is a clear, colorless, isotonic solution that has a pH of 4.5-7, an osmolarity of 297-314 mOsm/L,156,201,202,203,495 and contains sodium phosphate, citric acid, and sodium chloride. As a result of the excipients, the injection contains 27-28 mEq of sodium per gram of metronidazole, depending on the specific preparation.

Metronidazole hydrochloride is very soluble in water, soluble in alcohol, and is commercially available as an off-white, lyophilized powder for injection which contains mannitol.

Stability

Metronidazole and metronidazole hydrochloride are stable in air but darken following prolonged exposure to light. Metronidazole conventional tablets should be stored in well-closed, light-resistant containers at less than 25°C.152 Metronidazole capsules should be stored in tight containers at 15-25°C.197 Metronidazole extended-release tablets should be stored in well-closed containers at approximately 25°C; temporary exposure to temperatures of 15-30°C is acceptable.430

Metronidazole hydrochloride powder for injection should be protected from light and stored at less than 30°C.156 Metronidazole injection should be protected from light and freezing and stored at 15-30°C.156 The manufacturer (Baxter) of commercially available metronidazole injection RTU^® states that this injection has an expiration date of 24 months following the date of manufacture.201

Following reconstitution of metronidazole hydrochloride powder for injection with sterile or bacteriostatic water for injection, 0.9% sodium chloride injection, or bacteriostatic sodium chloride injection, solutions containing approximately 100 mg of metronidazole per mL are clear, pale yellow to yellow-green in color, have a pH of 0.5-2, and are chemically stable for 96 hours in room light at less than 30°C. Solutions of metronidazole hydrochloride that have been diluted with 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer's injection to a concentration of 8 mg or less of metronidazole per mL and then neutralized with 5 mEq of sodium bicarbonate injection for each 500 mg of metronidazole have a pH of approximately 6-7 and should be stored at room temperature and used within 24 hours. Metronidazole and metronidazole hydrochloride should not be mixed with other drugs.

Because reconstituted metronidazole hydrochloride solution has a low pH, the solution may interact with aluminum resulting in a reddish-brown discoloration of the solution. Therefore, aluminum hub needles should not be used to reconstitute the drug or to transfer the reconstituted solution to the diluting fluid. Metronidazole hydrochloride that has been reconstituted, diluted, and neutralized and metronidazole injection do not interact with aluminum when administered over the time period specified by the manufacturers; however, some discoloration of these solutions may occur when they are in contact with aluminum for periods of 6 hours or longer.

Some commercially available injections of metronidazole (e.g., Baxter's Viaflex^® Plus, McGaw's PAB^®, Abbott's LifeCare^®) are provided in plastic containers.156,202,203,495 Water can permeate from inside of some plastic containers into the overwrap in amounts insufficient to substantially affect the solutions.156,202,495 Solutions in contact with the plastic containers can leach out some chemical components in very small amounts (e.g., bis(2-ethylhexyl)phthalate [BEHP, DEHP] in up to 5 ppm) within the expiration period of the injections; however, safety of the plastics has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.156,202,203,495

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.

Only references cited for selected revisions after 1984 are available electronically.

98. Allen LV Jr, Erickson MA 3rd. Stability of ketoconazole, metolazone, metronidazole, procainamide hydrochloride, and spironolactone in extemporaneously compounded oral liquids. Am J Health Syst Pharm. 1996 Sep 1;53(17):2073-8. doi: 10.1093/ajhp/53.17.2073. PMID: 8870895.

99. ASHP. Standardize 4 Safety: compounded oral liquid standards. Updated 2024 Mar. From ASHP website. Updates may be available at ASHP website. [Web]

100. American Academy of Pediatrics. 2006 Red Book: Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006.

101. Ursing B, Alm T, Barany F et al. A comparative study of metronidazole and sulfasalazine for active Crohn's disease: The Cooperative Crohn's Disease Study in Sweden. Gastroenterology . 1982; 83:550-62. [PubMed 6124474]

102. Brandt LJ, Bernstein LH, Boley SJ et al. Metronidazole therapy for perineal Crohn's disease: a follow-up study. Gastroenterology . 1982; 83:383-7. [PubMed 7084615]

103. Gilat T. Metronidazole in Crohn's disease. Gastroenterology . 1982; 83:702-4. [PubMed 6124478]

104. Bernstein LH, Frank MS, Brandt LJ et al. Healing of perineal Crohn's disease with metronidazole, Gastroenterology . 1980; 79:357-65. (IDIS 119497)

105. Sack DM, Peppercorn MA. Drug therapy of inflammatory bowel disease. Pharmacotherapy . 1983; 3:158-76. [PubMed 6136027]

106. Gugler R, Jensen JC. Interaction between cimetidine and metronidazole. N Engl J Med . 1983; 309:1518-9. [PubMed 6646177]

107. Hansten PD. Metronidazole and cimetidine. Drug Interact Newsl . 1984; 4:7.

108. Lawford R, Sorrell TC. Amebic abscess of the spleen complicated by metronidazole-induced neurotoxicity: a case report. Clin Infect Dis . 1994; 19:346-8. [PubMed 7986915]

109. Guglielmo BJ, Hohn DC, Koo PJ et al. Antibiotic prophylaxis in surgical procedures: a critical analysis of the literature. Arch Surg . 1983; 118:943-55. [PubMed 6347124]

110. Anon. Antimicrobial prophylaxis for surgery. Treat Guidel Med Lett . 2004; 2:27-32. [PubMed 15529111]

111. Burnakis TG. Surgical antimicrobial prophylaxis: principles and guidelines. Pharmacotherapy . 1984; 4:248-71. [PubMed 6438611]

112. American Society of Health-System Pharmacists. ASHP therapeutic guidelines on antimicrobial prophylaxis in surgery. Am J Health-Syst Pharm . 1999; 56:1839-88. [PubMed 10511234]

113. McLean A, Somogyi A, Ioannides-Demos L et al. Successful substitution of rectal metronidazole administration for intravenous use. Lancet . 1983; 1:41-3. [PubMed 6129377]

114. Giamarellou HJ, Daikos GK. Rectal administration of metronidazole. N Engl J Med . 1982; 307:121-2. [PubMed 7088042]

115. Barker EM, Aitchison JM, Cridland JS et al. Rectal administration of metronidazole in severely ill patients. BMJ . 1983; 287:311-3. [PubMed 6409287]

116. Mead PB, Gibson M, Schentag JJ et al. Possible alteration of metronidazole metabolism by phenobarbital. N Engl J Med . 1982; 306:1490. [PubMed 7078600]

117. Gupte S. Phenobarbital and metabolism of metronidazole. N Engl J Med . 1983; 308:529. [PubMed 6823276]

118. Blackwell AL, Phillips I, Fox AR et al. Anaerobic vaginosis (non-specific vaginitis): clinical, microbiological, and therapeutic findings. Lancet . 1983; 2:1379-82. [PubMed 6140492]

119. Swedberg J, Steiner JF, Deiss F et al. Comparison of single-dose vs one-week course of metronidazole for symptomatic bacterial vaginosis. JAMA . 1985; 254:1046-9. [PubMed 3894707]

120. Purdon A, Hanna JH, Morse PL et al. An evaluation of single-dose metronidazole treatment for Gardnerella vaginalis vaginitis. Obstet Gynecol . 1984; 64:271-4. [PubMed 6377153]

121. Mindowski WL, Baker CJ, Alleyne D et al. Single oral dose metronidazole therapy for Gardnerella vaginalis vaginitis in adolescent females. J Adolesc Health Care . 1983; 4:113-6. [PubMed 6345494]

122. Alawattegama AB, Jones BM, Kinghorn GR et al. Single dose versus seven day metronidazole in Gardnerella vaginalis associated non-specific vaginitis. Lancet . 1984; 1:1355. [PubMed 6145055]

124. Lossick JG, Müller M, Gorrell TE. In vitro susceptibility and doses of metronidazole required for cure in cases of refractory vaginal trichomoniasis. J Infect Dis . 1986; 153:948-55. [PubMed 3486237]

125. Cherry RD, Portnoy D, Jabbari M et al. Metronidazole: an alternate therapy for antibiotic-associated colitis. Gastroenterology . 1982; 82:849-51. [PubMed 7060906]

126. Teasley DG, Gerding DN, Olson MM et al. Prospective randomised trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhoea and colitis. Lancet . 1983; 2:1043-6. [PubMed 6138597]

127. Talbot RW, Walker RC, Beart RW Jr. Changing epidemiology, diagnosis, and treatment of Clostridium difficile toxin-associated colitis. Br J Surg . 1986; 73:457-60. [PubMed 3719271]

128. Bartlett JG. Treatment of antibiotic-associated pseudomembranous colitis. Rev Infect Dis . 1984; 6(Suppl 1):S235-41.

129. Fekety R, Silva J, Buggy B et al. Treatment of antibiotic-associated colitis with vancomycin. J Antimicrob Chemother . 1984; 14(Suppl D):97-102. [PubMed 6520070]

131. Alldredge BK, Barriere SL. Medical treatment for antibiotic colitis. Drug Intell Clin Pharm . 1985; 19:28.

132. Bartlett JG. Treatment of Clostridium difficile colitis. Gastroenterology . 1985; 89:1192-5. [PubMed 3899842]

133. Burnakis TG. Metronidazole versus vancomycin for antimicrobial-associated pseudomembranous colitis: the question of cost-effectiveness. Hosp Pharm . 1985; 20:742-4,747.

134. Gross MH. Management of antibiotic-associated pseudomembranous colitis. Clin Pharm . 1985; 4:304-10. [PubMed 3891202]

135. Travenol Laboratories, Inc. Descriptive information on premixed Mini-Bag^® container frozen products. Travenol Laboratories, Inc: Deerfield, IL; 1987 Jun.

136. Turner P, Edwards R, Weston V et al. Simultaneous resistance to metronidazole, co-amoxiclav, and imipenem in clinical isolate of Bacteroides fragilis . Lancet . 1995; 345:1275-7. [PubMed 7746059]

137. Bleicher PA, Charles JH, Sober AJ. Topical metronidazole therapy for rosacea. Arch Dermatol . 1987; 123:609-14. [PubMed 2953312]

138. Eriksson G, Nord CE. Impact of topical metronidazole on the skin and colon microflora in patients with rosacea. Infection . 1987; 15:8-10. [PubMed 2952597]

139. Aronson IK, Rumsfield JA, West DP et al. Evaluation of topical metronidazole gel in acne rosacea. Drug Intell Clin Pharm . 1987; 21:346-51. [PubMed 2952478]

140. Veien NK, Christiansen JV, Hjorth N et al. Topical metronidazole in the treatment of rosacea. Cutis . 1986; 38:209-10. [PubMed 2945705]

141. Nielsen PG. A double-blind study of I% metronidazole cream versus systemic oxytetracycline therapy for rosacea. Br J Dermatol . 1983; 109:63-5. [PubMed 6222756]

142. Dupont C. Metronidazole suspension applied topically for rosacea. Br J Dermatol . 1984; 111:499. [PubMed 6237665]

143. Nielsen PG. The relapse rate for rosacea after treatment with either oral tetracycline or metronidazole cream. Br J Dermatol . 1983; 109:122. [PubMed 6222753]

144. Nielsen PG. Treatment of rosacea with I% metronidazole cream: a double-blind study. Br J Dermatol . 1983; 108:327-32. [PubMed 6219689]

145. Saihan EM, Burton JL. A double-blind trial of metronidazole versus oxytetracycline therapy for rosacea. Br J Dermatol . 1980; 102:443-5. [PubMed 6446314]

146. Pye RJ, Burton JL. Treatment of rosacea by metronidazole. Lancet . 1976; 1:1211-2. [PubMed 58258]

147. Galderma Laboratories. Metrogel^® (metronidazole) 0.75% topical gel for topical use only (not for ophthalmic use) prescribing information. In: Physician's desk reference. 49th ed. Montvale, NJ: Medical Economics Company Inc; 1995:1055.

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

149. Plotnick BH, Cohen I, Tsang T et al. Metronidazole-induced pancreatitis. Ann Intern Med . 1985; 103:891-2. [PubMed 2415031]

150. Sanford KA, Mayle JE, Dean HA et al. Metronidazole-associated pancreatitis. Ann Intern Med . 1988; 109:756-7. [PubMed 3263823]

151. Teicher MH, Altesman RI, Cole JO et al. Possible nephrotoxic interaction of lithium and metronidazole. JAMA . 1987; 257:3365-6. [PubMed 3586264]

152. Pharmacia. Flagyl^® (metronidazole tablets) prescribing information. Chicago, IL; 2004 Jan.

153. Anon. Drugs for parasitic infections. Med Lett Drugs Ther . Aug 2004. From the Medical Letter web site. [Web]

154. Ludwig E, Csiba A, Magyar T et al. Age-associated pharmacokinetic changes of metronidazole. Int J Clin Pharmacol Ther Toxicol . 1983; 21:87-91. [PubMed 6840930]

155. Ayd FA Jr. Metronidazole-induced lithium intoxication. Int Drug Ther Newsl . 1982; 17:15-6.

156. SCS Pharmaceuticals. Flagyl^® IV and Flagyl^® I.V. RTU^® (metronidazole hydrochloride) prescribing information (dated 1997 Apr 16). In: Physicians' desk reference. 48th ed. Montvale, NJ: Medical Economics Company Inc; 1998:2563-5.

157. Plosker GL. Possible interaction between ethanol and vaginally administered metronidazole. Clin Pharm . 1987; 6:189-93. [PubMed 3665375]

158. Almodovar ER. Local application of metronidazole in vaginal ovules for treatment of trichomoniasis. Am J Obstet Gynecol . 1984; 149:807.

159. de Dios Garcia Diaz J, Moreno Sanchez D, Campos Canter R et al. Metronidazole: pseudomembranous colitis following intravaginal administration. J Medicina Clinica . 1987; 88:652.

160. Lau AH, Evans R, Chang CW et al. Pharmacokinetics of metronidazole in patients with alcoholic liver disease. Antimicrob Agents Chemother . 1987; 31:1662-4. [PubMed 3435113]

161. Kleinfeld DI, Sharpe RJ, Donta ST. Parenteral therapy for antibiotic-associated pseudomembranous colitis. J Infect Dis . 1988; 157:389. [PubMed 3335816]

162. Price EH, Wright VM, Walker-Smith JA et al. Clostridium difficile and acute enterocolitis. Arch Dis Child . 1988; 63:543-5. [PubMed 3389873]

163. Carver PL, Colburn P. Treatment of metronidazole-resistant cases of vaginal trichomoniasis. Clin Pharm . 1988; 7:718-9.

164. Lorian V, ed. Antibiotics in laboratory medicine. 2nd ed. Baltimore, MD: Williams & Wilkins; 1986:285-93,1016-33,1094.

165. Herman J. Metronidazole for a malodorous pressure sore. Practitioner . 1983; 227:1595-6. [PubMed 6634628]

166. Tanga MR, Antani JA, Kabade SS. Clinical evaluation of metronidazole as an anti-inflammatory agent. Int Surg . 1975; 60:75-6. [PubMed 1090554]

167. Miyachi Y, Imamura S, Niwa Y. Anti-oxidant action of metronidazole: a possible mechanism of action in rosacea. Br J Dermatol . 1986; 114:231-4. [PubMed 2936372]

168. Gamborg Nielsen P. Metronidazole treatment of rosacea. Int J Dermatol . 1988; 27:1-5. [PubMed 2964423]

169. Bahr V, Ullmann U. The influence of metronidazole and its two main metabolites on murine in vitro lymphocyte transformation. Eur J Clin Microbiol . 1983; 2:568-70. [PubMed 6667682]

170. Gnarpe H, Persson S, Belsheim J. Influence of metronidazole and tinidazole on leukocyte chemotaxis in Crohn's disease. Infection . 1978; 6(Suppl 1):S107-9.

171. Gnarpe H, Belsheim J, Persson S. Influence of nitroimidazole derivatives on leukocyte migration. Scand J Infect Dis . 1981; 26:68-71.

172. Grove DI, Mahmoud AA, Warren KS. Suppression of cell-mediated immunity by metronidazole. Int Arch Allergy Appl Immunol . 1977; 54:422-7. [PubMed 328408]

173. Gamborg Nielsen P. In vitro antifungal effect of metronidazole on Pityrosporum ovale . Mykosen . 1984; 27:475-6. [PubMed 6504071]

174. Heard ML, Bawdon RE, Hemsell DL et al. Susceptibility profiles of potential aerobic and anaerobic pathogens isolated from hysterectomy patients. Am J Obstet Gynecol . 1984; 149:133-43. [PubMed 6562855]

175. Rolfe RD, Finegold SM. Comparative in vitro activity of new beta-lactam antibiotics against anaerobic bacteria. Antimicrob Agents Chemother . 1981; 20:600-9. [PubMed 7325628]

176. Kesado T, Watanabe K, Asahi Y et al. Susceptibilities of anaerobic bacteria to N-formimidoyl thienamycin (MK0787) and to other antibiotics. Antimicrob Agents Chemother . 1982; 21:1016-22. [PubMed 6956247]

177. Wade WG, Addy M. Comparison of in vitro activity of niridazole, metronidazole and tetracycline against subgingival bacteria in chronic periodontitis. J Appl Bacteriol . 1987; 63:455-7. [PubMed 3440767]

178. Denys GA, Jerris RC, Swenson JM et al. Susceptibility of Propionibacterium acnes clinical isolates to 22 antimicrobial agents. Antimicrob Agents Chemother . 1983; 23:335-7. [PubMed 6838191]

179. Hoffler U, Niederau W, Pulverer G. Susceptibility of cutaneous Propionibacteria to newer antibiotics. Chemotherapy . 1980; 26:7-11. [PubMed 7353441]

180. Kurkcuoglu N, Atakan N. Metronidazole in the treatment of rosacea. Arch Dermatol . 1984; 120:837. [PubMed 6233939]

181. Anon. Topical metronidazole for rosacea. Med Lett Drugs Ther . 1989; 31:75-6. [PubMed 2526918]

182. Baker PG, Haig G. Metronidazole in the treatment of chronic pressure sores and ulcers: a comparison with standard treatments in general practice. Practitioner . 1981; 225:569-73. [PubMed 7024971]

183. Ashford RFU, Plant GT, Maher J et al. Metronidazole in smelly tumours. Lancet . 1980; 1:874-5. [PubMed 6103225]

184. Doll DC, Doll KJ. Malodorous tumors and metronidazole. Ann Intern Med . 1981; 94:139-40.

185. Sparrow G, Monton M, Rubens RD et al. Metronidazole in smelly tumours. Lancet . 1980; 1:1185. [PubMed 6103999]

186. Koch RL, Beaulieu BB, Chrystal EJT et al. A metronidazole metabolite in human urine and its risk. Science . 1981; 211:398-9. [PubMed 7221546]

187. Ethanol/metronidazole. In: Tatro DS, Olin BR, eds. Drug interaction facts. St. Louis: JB Lippincott Co; 1988:335.

188. Shank WA Jr, Amerson AB. Metronidazole: an update of its expanding role in clinical medicine. Hosp Formul . 1981; 16:283-97.

189. Beard CM, Kenneth MP, Noller L et al. Lack of evidence for cancer due to use of metronidazole. N Engl J Med . 1979; 301:519-22. [PubMed 460304]

190. Friedman GD. Cancer after metronidazole. N Engl J Med . 1980; 302:519-20. [PubMed 7351980]

191. Hansten PD. Drug interactions. 5th ed. Philadelphia: Lea & Febiger; 1985:96.

192. Anticoagulants, oral/metronidazole. In: Tatro DS, Olin BR, eds. Drug interaction facts. St. Louis: JB Lippincott Co; 1988:82.

193. O'Reilly RA. The stereoselective interaction of warfarin and metronidazole in man. N Engl J Med . 1976; 295:354. [PubMed 934223]

194. Kazmier FJ. A significant interaction between metronidazole and warfarin. Mayo Clin Proc . 1976; 51:782. [PubMed 994556]

195. Dean RP, Talbert RL. Bleeding associated with concurrent warfarin and metronidazole therapy. Drug Intell Clin Pharm . 1980; 14:864-6.

196. Hansten PD. Drug interactions. 5th ed. Philadelphia: Lea & Febiger; 1985:234.

197. Pharmacia. Flagyl^® 375 (metronidazole capsules) prescribing information. Chicago, IL; 2005 Apr.

198. Alper MM, Barwin BN, McLean WM et al. Systemic absorption of metronidazole by the vaginal route. Obstet Gynecol . 1985; 65:781-4. [PubMed 4000568]

199. Anon. Drugs for sexually transmitted infections. Treat Guidel Med Lett . 2004; 2:67-74. [PubMed 15529116]

200. The United States Pharmacopeia, 22nd rev, and The national formulary, 17th ed. Rockville, MD; The United States Pharmacopeial Convention, Inc; 1990:890-2.

201. Baxter Healthcare Corporation. Descriptive information on premixed liquid products. Baxter Healthcare Corporation; Deerfield, IL: 1994 Feb.

202. Abbott Laboratories. Metronidazole injection, USP (single-dose, flexible container) prescribing information. North Chicago, IL; 1990 Feb.

203. McGaw. Metro IV^® (sterile metronidazole injection USP). Irvine, CA; 1993 Jan.

204. 3M Pharmaceuticals. MetroGel-Vaginal^® (metronidazole 0.75% vaginal gel) prescribing information. Northridge, CA; 1997 May.

205. Loo VG, Sherman P, Matlow AG. Helicobacter pylori infection in a pediatric population: in vitro susceptibilities to omeprazole and eight antimicrobial agents. Antimicrob Agents Chemother . 1992; 36:1133-5. [PubMed 1510406]

206. Knapp CC, Ludwig MD, Washington JA. In vitro activity of metronidazole against Helicobacter pylori as determined by agar dilution and agar diffusion. Antimicrob Agents Chemother . 1991; 35:1230-1. [PubMed 1929268]

207. Ateshkadi A, Lam NP, Johnson CA. Helicobacter pylori and peptic ulcer disease. Clin Pharm . 1993; 12:34-48. [PubMed 8428432]

208. Marshall BJ. Treatment strategies for Helicobacter pylori infection. Gastroenterol Clin North Am . 1993; 22:183-98. [PubMed 8449566]

209. Murray DM, DuPont HL, Cooperstock M et al. Evaluation of new anti-infective drugs for the treatment of gastritis and peptic ulcer disease associated with infection by Helicobacter pylori . Clin Infect Dis . 1992; 15(Suppl 1):S268-73.

210. Becx MCJM, Janssen AJHM, Clasener HAL et al. Metronidazole-resistant Helicobacter pylori . Lancet . 1990; 335:539-40.

211. Pavicic MJ, Namavar F, Verboom T et al. In vitro susceptibility of Helicobacter pylori to several antimicrobial combinations. Antimicrob Agents Chemother . 1993; 37:1184-6. [PubMed 8517712]

212. Blaser MJ. Helicobacter pylori : its role in disease. Clin Infect Dis . 1992; 15:386-91. [PubMed 1520782]

213. Israel DM, Hassall E. Treatment and long-term follow-up of Helicobacter pylori -associated duodenal ulcer disease in children. J Pediatr . 1993; 123:53-8. [PubMed 8320625]

214. Chiba N, Rao BV, Rademaker JW et al. Meta-analysis of the efficacy of antibiotic therapy in eradicating Helicobacter pylori . Am J Gastroenterol . 1992; 87:1716-27. [PubMed 1449132]

215. Glassman MS. Helicobacter pylori infection in children. A clinical overview. Clin Pediatr (Phila) . 1992; 31:481-7. [PubMed 1643767]

216. Peterson WL. Helicobacter pylori and peptic ulcer disease. N Engl J Med . 1991; 324:1043-8. [PubMed 2005942]

217. Logan RP, Gummett PA, Misiewicz JJ et al. One week eradication regimen for Helicobacter pylori . Lancet . 1991; 338:1249-52. [PubMed 1682653]

218. Burette A, Glupczynski Y. On: The who's and when's of therapy for Helicobacter pylori . Am J Gastroenterol . 1991; 86:924-5. [PubMed 2058644]

219. Malfertheiner P. Compliance, adverse events and antibiotic resistance in Helicobacter pylori treatment. Scand J Gastroenterol Suppl . 1993; 196:34-7. [PubMed 8341989]

220. Bell GD, Powell U. Eradication of Helicobacter pylori and its effect in peptic ulcer disease. Scand J Gastroenterol Suppl . 1993; 196:7-11. [PubMed 8341990]

221. Graham DY, Go MF. Evaluation of new antiinfective drugs for Helicobacter pylori infection: revisited and updated. Clin Infect Dis . 1993; 17:293-4. [PubMed 8399892]

222. Murray DM, DuPont HL. Reply. (Evaluation of new antiinfective drugs for Helicobacter pylori infection: revisited and updated.) Clin Infect Dis . 1993; 17:294- 5.

223. George LL, Borody TJ, Andrews P et al. Cure of duodenal ulcer after eradication of H. pylori . Med J Aust . 1990; 153:145-9. [PubMed 1974027]

224. Farrell MK. Dr. Apley meets Helicobacter pylori . J Pediatr Gastroenterol Nutr . 1993; 16:118-9. [PubMed 8450375]

225. Fiocca R, Solcia E, Santoro B. Duodenal ulcer relapse after eradication of Helicobacter pylori . Lancet . 1991; 337:1614. [PubMed 1675746]

226. Marshall BJ. Campylobacter pylori : Its link to gastritis and peptic ulcer disease. Clin Infect Dis . 1990; 12(Suppl 1):S87-93.

227. Nomura A, Stemmermann GN, Chyou PH et al. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med . 1991; 325:1132-6. [PubMed 1891021]

228. Parsonnet J, Friedman GD, Vandersteen DP et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med . 1991; 325:1127-31. [PubMed 1891020]

229. The EUROGAST Study Group.. An international association between Helicobacter pylori infection and gastric cancer. Lancet . 1993; 341:1359-62. [PubMed 8098787]

230. Talley NJ, Zinsmeister AR, Weaver A et al. Gastric adenocarcinoma and Helicobacter pylori infection. J Natl Cancer Inst . 1991; 83:1734-9. [PubMed 1770552]

231. Forman D, Newell DG, Fullerton F et al. Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation. BMJ . 1991; 302:1302-5. [PubMed 2059685]

232. Forman D. Helicobacter pylori infection: a novel risk factor in the etiology of gastric cancer. J Natl Cancer Inst . 1991; 83:1702-3. [PubMed 1770545]

233. Parsonnet J. Helicobacter pylori and gastric cancer. Gastroenterol Clin North Am . 1993; 22:89-104. [PubMed 8449573]

234. Correa P. Is gastric carcinoma an infectious disease? N Engl J Med . 1991; 325:1170-1.

235. Isaacson PG, Spencer J. Is gastric lymphoma an infectious disease? Hum Pathol . 1993; 24:569-70.

236. Oderda G, Forni M, Dell'Olio D et al. Cure of peptic ulcer associated with eradication of Helicobacter pylori . Lancet . 1990; 335:1599.

237. Bianchi Porro G, Parente F, Lazzaroni M. Short and long term outcome of Helicobacter pylori positive resistant duodenal ulcers treated with colloidal bismuth subcitrate plus antibiotics or sucralfate alone. Gut . 1993; 34:466-9. [PubMed 8491391]

238. Borody T, Andrews P, Mancuso N et al. Helicobacter pylori reinfection 4 years post-eradication. Lancet . 1992;339:1295. Letter. [PubMed 1349686]

239. Hixson LJ, Kelley CL, Jones WN et al. Current trends in the pharmacotherapy for peptic ulcer disease. Arch Intern Med . 1992; 152:726-32. [PubMed 1558429]

240. Rauws EAJ, Tytgat GNJ. Cure of duodenal ulcer with eradication of Helicobacter pylori . Lancet . 1990; 335:1233-5. [PubMed 1971318]

241. Hentschel E, Brandst:atter G, Dragosics B et al. Effect of ranitidine and amoxicillin plus metronidazole on the eradication of Helicobacter pylori and the recurrence of duodenal ulcer. N Engl J Med . 1993; 328:308-12. [PubMed 8419816]

242. Bayerdorffer E, Mannes GA, Sommer A et al. Long-term follow-up after eradication of Helicobacter pylori with a combination of omeprazole and amoxycillin. Scand J Gastroenterol Suppl . 1993; 196:19-25. [PubMed 8341987]

243. Unge P, Ekstrom P. Effects of combination therapy with omeprazole and an antibiotic on H. pylori and duodenal ulcer disease. Scand J Gastroenterol Suppl . 1993; 196:17-8.

244. Hunt RH. Hp and pH: implications for the eradication of Helicobacter pylori . Scand J Gastroenterol Suppl . 1993; 196:12-6. [PubMed 8341986]

245. Hunt RH. pH and Hp—gastric acid secretion and Helicobacter pylori : implications for ulcer healing and eradication of the organism. Am J Gastroenterol . 1993; 88:481-3. [PubMed 8470623]

246. Goodwin CS. Duodenal ulcer, Campylobacter pylori, and the “leaking roof” concept. Lancet . 1988; 2:1467-9. [PubMed 2904580]

247. Blaser MJ. Epidemiology and pathophysiology of Campylobacter pylori infections. Clin Infect Dis . 1990; 12(Suppl 1):S99-106.

248. Barthel JS, Everett ED. Diagnosis of Campylobacter pylori infections: The “gold standard” and the alternatives. Clin Infect Dis . 1990; 12(Suppl 1):S107-4.

249. Plebani M, Di Mario F, Stanghellini V et al. Serological tests to monitor treatment of Helicobacter pylori . Lancet . 1992; 340:51-2. [PubMed 1351624]

250. Bell GD. Anti- Helicobacter pylori therapy: clearance, elimination, or eradication? Lancet . 1991; 337:310-1. Letter.

251. Logan RP, Polson RJ, Baron JH et al. Follow-up after anti- Helicobacter pylori treatment. Lancet . 1991; 337:562-3. [PubMed 1671932]

252. Graham DY, Borsch GM. The who's and when's of therapy for Helicobacter pylori . Am J Gastroenterol . 1990; 85:1552-5. [PubMed 2252013]

253. Yeung CK, Fu KH, Yuen KY et al. Helicobacter pylori and associated duodenal ulcer. Arch Dis Child . 1990; 65:1212-6. [PubMed 2248531]

254. Oderda G, Dell'Olio D, Morra I et al. Campylobacter pylori gastritis: long term results of treatment with amoxycillin. Arch Dis Child . 1989; 64:326-9. [PubMed 2495776]

255. Graham DY, Lew GM, Klein PD et al. Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer. A randomized, controlled study. Ann Intern Med . 1992; 116:705-8. [PubMed 1558340]

256. Axon AT. Helicobacter pylori therapy: effect on peptic ulcer disease. J Gastroenterol Hepatol . 1991; 6:131-7. [PubMed 1912418]

257. Cutler AF, Schubert TT. Patient factors affecting Helicobacter pylori eradication with triple therapy. Am J Gastroenterol . 1993; 88:505-9. [PubMed 8470629]

258. Rautelin H, Sepp:al:a K, Renkonen OV et al. Role of metronidazole resistance in therapy of Helicobacter pylori infections. Antimicrob Agents Chemother . 1992; 36:163-6. [PubMed 1590683]

259. Weil J, Bell GD, Powell K et al. Helicobacter pylori and metronidazole resistance. Lancet . 1990; 336:1445. [PubMed 1978897]

260. Logan RP, Gummett PA, Hegarty BT et al. Clarithromycin and omeprazole for Helicobacter pylori . Lancet . 1992; 25:340:239.

261. Graham DY. Treatment of peptic ulcers caused by Helicobacter pylori . N Engl J Med . 1993; 328:349-50. [PubMed 8419823]

262. Hosking SW, Ling TK, Yung MY et al. Randomised controlled trial of short term treatment to eradicate Helicobacter pylori in patients with duodenal ulcer. BMJ . 1992; 305:502-4. [PubMed 1392995]

263. Bell GD, Powell K, Burridge SM et al. Experience with ”triple' anti- Helicobacter pylori eradication therapy: side effects and the importance of testing the pre-treatment bacterial isolate for metronidazole resistance. Aliment Pharmacol Ther . 1992; 6:427-35. [PubMed 1420735]

264. Sloane R, Cohen H. Common-sense management of Helicobacter pylori -associated gastroduodenal disease. Personal views. Gastroenterol Clin North Am . 1993; 22:199-206. [PubMed 8449567]

265. Katelaris P. Eradicating Helicobacter pylori . Lancet . 1992; 339:54. [PubMed 1345965]

266. O'Morain C, Gilvarry J. Eradication of Helicobacter pylori in patients with non-ulcer dyspepsia. Scand J Gastroenterol Suppl . 1993; 196:30- 3. [PubMed 8102009]

267. Patchett S, Beattie S, Leen E et al. Eradicating Helicobacter pylori and symptoms of non-ulcer dyspepsia. BMJ . 1991; 303:1238-40. [PubMed 1747644]

268. Talley NJ. The role of Helicobacter pylori in nonulcer dyspepsia. A debate—against. Gastroenterol Clin North Am . 1993; 22(1):153-67. [PubMed 8449564]

269. Eberhardt R, Kasper G. Effect of oral bismuth subsalicylate on Campylobacter pylori and on healing and relapse rate of peptic ulcer. Clin Infect Dis . 1990; 12(Suppl 1):S115-9.

270. Adamek RJ, Wegener M, Opferkuch W et al. Successful Helicobacter pylori eradication: a systemic effect of antibiotics? Am J Gastroenterol . 1993; 88:792-3. Letter.

271. Drumm B. Helicobacter pylori . Arch Dis Child . 1990; 65:1278-82. [PubMed 2248546]

272. Rosioru C, Glassman MS, Halata MS et al. Esophagitis and Helicobacter pylori in children: incidence and therapeutic implications. Am J Gastroenterol . 1993; 88:510-3. [PubMed 8470630]

273. Reviewers' comments (personal observations).

274. Graham DY, Lew GM, Evans DG et al. Effect of triple therapy (antibiotics plus bismuth) on duodenal ulcer healing. A randomized controlled trial. Ann Intern Med . 1991; 115:266-9. [PubMed 1854110]

275. Goldstein EJC, Citron DM, Cherubin CE et al. Comparative susceptibility of the Bacteroides fragilis group species and other anaerobic bacteria to meropenem, imipenem, piperacillin, cefoxitin, ampicillin/sulbactam, clindamycin, and metronidazole. J Antimicrob Chemother . 1993; 31:363-72. [PubMed 8486570]

276. Spiegel CA. Susceptibility of Mobiluncus species to 23 antimicrobial agents and 15 other compounds. Antimicrob Agents Chemother . 1987; 31:249-52. [PubMed 3566250]

277. Jones BM, Geary I, Lee ME et al. Comparison of the in vitro activities of fenticonazole, other imidazoles, metronidazole, and tetracycline against organisms associated with bacterial vaginosis and skin infections. Antimicrob Agents Chemother . 1989; 33:970-2. [PubMed 2764547]

278. Ohm-Smith MJ, Sweet RL, Hadley WK. In vitro activity of cefbuperazone and other antimicrobial agents against isolates from the female genital tract. Antimicrob Agents Chemother . 1985; 27:958-60. [PubMed 4026268]

279. Jones BM, Geary I, Alawattegama AB et al. In-vitro and in-vivo activity of metronidazole against Gardnerella vaginalis , Bacteroides spp. and Mobiluncus spp. in bacterial vaginosis. J Antimicrob Chemother . 1985; 16:189-97. [PubMed 3905748]

280. Ralph ED, Amatnieks YE. Relative susceptibilities of Gardnerella vaginalis ( Haemophilus vaginalis ), Neisseria gonorrhoeae , and Bacteroides fragilis to metronidazole and its two major metabolites. Sex Transm Dis . 1980; 7:157-60. [PubMed 6779387]

281. Spiegel CA, Eschenbach DA, Amsel R et al. Curved anaerobic bacteria in bacterial (nonspecific) vaginosis and their response to antimicrobial therapy. J Infect Dis . 1983; 148:817-22. [PubMed 6631073]

282. Ralph ED, Amatnieks YE. Metronidazole in treatment against Haemophilus vaginalis ( Corynebacterium vaginale ). Antimicrob Agents Chemother . 1980; 18:101-4. [PubMed 6968175]

283. Ralph ED, Austin TW, Pattison FL et al. Inhibition of Haemophilus vaginalis ( Corynebacterium vaginale ) by metronidazole, tetracycline, and ampicillin. Sex Transm Dis . 1979; 6:199-202. [PubMed 388682]

284. Ralph ED. Comparative antimicrobial activity of metronidazole and the hydroxy metabolite against Gardnerella vaginalis . Scand J Infect Dis Suppl . 1983; 40:115-20. [PubMed 6607518]

285. Greaves WL, Chungafung J, Morris B et al. Clindamycin versus metronidazole in the treatment of bacterial vaginosis. Obstet Gynecol . 1988; 72:799-802. [PubMed 3050654]

286. Sobel JD. Bacterial vaginosis. Br J Clin Pract Symp Suppl . 1990; 71:65-9. [PubMed 2091736]

287. Hillier S, Holmes KK. Bacterial vaginosis. In: Holmes KK, Mardh PA, Sparling PF et al, eds. Sexually transmitted diseases. 2nd ed. New York: McGraw-Hill; 1990:547-59.

288. Hillier SL, Lipinski C, Briselden AM et al. Efficacy of intravaginal 0.75% metronidazole gel for the treatment of bacterial vaginosis. Obstet Gynecol . 1993; 81:963-7. [PubMed 8497364]

289. Livengood CH 3rd, McGregor JA, Soper DE et al. Bacterial vaginosis: efficacy and safety of intravaginal metronidazole treatment. Am J Obstet Gynecol . 1994; 170:759-64. [PubMed 8141197]

290. Hillier SL. Diagnostic microbiology of bacterial vaginosis. Am J Obstet Gynecol . 1993; 169:455-9. [PubMed 8357044]

291. Anon. Topical treatment for bacterial vaginosis. Med Lett Drugs Ther . 1992 Nov 27; 34:109.

292. Lugo-Miro VI, Green M, Mazur L. Comparison of different metronidazole therapeutic regimens for bacterial vaginosis: a meta-analysis. JAMA . 1992; 268:92-5. [PubMed 1535108]

293. Mardh PA. The vaginal ecosystem. Am J Obstet Gynecol . 1991; 165:1163-8. [PubMed 1951571]

294. Thomason JL, Gelbart SM, Anderson RJ et al. Statistical evaluation of diagnostic criteria for bacterial vaginosis. Am J Obstet Gynecol . 1990; 162:155-60. [PubMed 1689107]

295. Thomason JL, Gelbart SM, Scaglione NJ. Bacterial vaginosis: current review with indications for asymptomatic therapy. Am J Obstet Gynecol . 1991; 165:1210-7. [PubMed 1951577]

296. Larsson PG, Platz-Christensen JJ, Thejls H et al. Incidence of pelvic inflammatory disease after first-trimester legal abortion in women with bacterial vaginosis after treatment with metronidazole: a double-blind, randomized study. Am J Obstet Gynecol . 1992; 166:100-3. [PubMed 1733176]

297. Centers for Disease Control and Prevention, Atlanta, GA: Personal communication.

298. American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin: Vaginitis. Number 72. Washington, DC: American College of Obstetricians and Gynecologists; 2006 May.

299. Hill GB. The microbiology of bacterial vaginosis. Am J Obstet Gynecol . 1993; 169:450-4. [PubMed 8357043]

300. Thomason JL, Gelbart SM, Broekhuizen FF. Advances in the understanding of bacterial vaginosis. J Reprod Med . 1989; 34(Suppl):581-7. [PubMed 2677362]

301. Sweet RL. New approaches for the treatment of bacterial vaginosis. Am J Obstet Gynecol . 1993; 169:479-82. [PubMed 8357050]

302. Lossick JG. Treatment of sexually transmitted vaginosis/vaginitis. Clin Infect Dis . 1990; 12(Suppl 6):S665-81.

303. Amsel R, Totten PA, Spiegel CA et al. Nonspecific vaginitis. Diagnostic criteria and microbial and epidemiologic associations. Am J Med . 1983; 74:14-22. [PubMed 6600371]

304. Schmitt C, Sobel JD, Meriwether C. Bacterial vaginosis: treatment with clindamycin cream versus oral metronidazole. Obstet Gynecol . 1992; 79:1020-3. [PubMed 1579299]

305. Sobel JD, Schmitt C, Meriwether C. Long-term follow-up of patients with bacterial vaginosis treated with oral metronidazole and topical clindamycin. J Infect Dis . 1993; 167:783-4. [PubMed 8440952]

306. Andres FJ, Parker R, Hosein I et al. Clindamycin vaginal cream versus oral metronidazole in the treatment of bacterial vaginosis: a prospective double-blind clinical trial. South Med J . 1992; 85:1077-80. [PubMed 1439943]

307. Depew CC. Manufacturer letter regarding the use of Cleocin^® vaginal cream for bacterial vaginosis. Kalamazoo, MI: The Upjohn Company; 1992 Nov 25.

308. Higuera F, Hidalgo H, Sanchez CJ et al. Bacterial vaginosis: a comparative, double-blind study of clindamycin vaginal cream versus oral metronidazole. Curr Ther Res . 1993; 54:98-110.

309. Reviewers' comments (personal observations).

310. Bump RC, Zuspan FP, Buesching WJ III et al. The prevalence, six-month persistence, and predictive values of laboratory indicators of bacterial vaginosis (nonspecific vaginitis) in asymptomatic women. Am J Obstet Gynecol . 1984; 150:917-24. [PubMed 6391177]

311. Borody TJ, George LL, Brandl S et al. Helicobacter pylori eradication with doxycycline-metronidazole-bismuth subcitrate triple therapy. Scand J Gastroenterol . 1992; 27:281-4. [PubMed 1589705]

312. Fekety R, Shah AB. Diagnosis and treatment of Clostridium difficile colitis. JAMA . 1993; 269:71-5. [PubMed 8416409]

313. Bartlett JG. Antibiotic-associated diarrhea. Clin Infect Dis . 1992; 15:573-81. [PubMed 1420669]

314. Gross MH. Management of antibiotic-associated pseudomembranous colitis. Clin Pharm . 1985; 4:304-10. [PubMed 3891202]

315. Caputo GM, Weitekamp MR. The treatment of Clostridium difficile colitis. JAMA . 1993; 269:2088. [PubMed 8468761]

316. Spera RV, Farber BF. The treatment of Clostridium difficile colitis. JAMA . 1993; 269:2088.

317. Rubin LG, Tucci V, Cercenado E et al. Vancomycin-resistant Enterococcus faecium in hospitalized children. Infect Control Hosp Epidemiol . 1992; 13:700-5. [PubMed 1289397]

318. Goldmann DA. Vancomycin-resistant Enterococcus faecium : headline news. Infect Control Hosp Epidemiol . 1992; 13:695-9. [PubMed 1289396]

319. Schaberg D. Major trends in the microbial etiology of nosocomial infection. Am J Med . 1991; 91:72-5.

320. Vemuri RK, Zervos MJ. Enterococcal infections. The increasing threat of nosocomial spread and drug resistance. Postgrad Med . 93:121-4,127-8.

321. Wilcox MH, Spencer RC. Clostridium difficile infection: responses, relapses, and reinfections. J Hosp Infect . 1992; 22:85-92. [PubMed 1358964]

322. Spera RV, Farber BF. Multiply-resistant Enterococcus faecium : the nosocomial pathogen of the 1990s. JAMA . 1992; 268:2563-4. [PubMed 1308665]

323. Oh T, Mostes de Oca G, Osorno RJ. Antiobiotic-associated pseudomembranous colitis. Am J Dis Child . 1990; 144:526. [PubMed 2330918]

324. Courvalin P. Resistance of enterococci to glycopeptides. Antimicrob Agents Chemother . 1990; 34:2291-6. [PubMed 2088183]

325. Handwerger S, Perlman DC, Altarac D et al. Concomitant high-level vancomycin and penicillin resistance in clinical isolates of enterococci. Clin Infect Dis . 1992; 14:655-61. [PubMed 1562656]

326. Livornese LL, Dias S, Samel C et al. Hospital-acquired infection with vancomycin-resistant Enterococcus faecium transmitted by electronic thermometers. Ann Intern Med . 1992; 117:112-6. [PubMed 1605425]

327. Landman D, Mobarakai NK, Quale JM. Novel antibiotic regimens against Enterococcus faecium resistant to ampicillin, vancomycin, and gentamicin. Antimicrob Agents Chemother . 1993; 37:1904-8. [PubMed 8239604]

328. Centers for Disease Control and Prevention. Nosocomial enterococci resistant to vancomycin-United States, 1989-1993. MMWR Morb Mortal Wkly Rep . 1993; 42:597-9. [PubMed 8336690]

329. Johnson S, Homann SR, Gettin KM et al. Treatment of asymptomatic Clostridium difficile carriers (fecal excretors) with vancomycin or metronidazole. Ann Intern Med . 1992; 117:297-302. [PubMed 1322075]

330. Delmee M, Vandercam B, Avesani V et al. Epidemiology and prevention of Clostridium difficile infections in a leukemia unit. Eur J Clin Microbiol . 1987; 6:623-7. [PubMed 3440454]

331. Aronsson B, Barany P, Nord CE et al. Clostridium difficile -associated diarrhoea in uremic patients. Eur J Clin Microbiol . 1987; 6:352-6. [PubMed 3622506]

332. Bender BS, Bennett R, Laughon BE et al. Is Clostridium difficile endemic in chronic-care facilities? Lancet . 1986; 2:11-3.

333. Handwerger S, Raucher B, Altarac D et al. Nosocomial outbreak due to Enterococcus faecium highly resistant to vancomycin, penicillin, and gentamicin. Clin Infect Dis . 1993; 16:750-5. [PubMed 8329505]

334. Gotch MM. Carriage of Trichomonas vaginalis is associated with adverse pregnancy outcome. Proceedings of ICAAC Atlanta 1990. Abstract.

335. Laga M, Manoka A, Kivuvu M et al. Non-ulcerative sexually transmitted diseases as risk factors for HIV-1 transmission in women: results from a cohort study. AIDS . 1993; 7:95-102. [PubMed 8442924]

336. Müller M, Meingassner JG, Miller WA et al. Three metronidazole-resistant strains of Trichomonas vaginalis from the United States. Am J Obstet Gynecol . 1980; 138:808-12. [PubMed 7004190]

337. Lossick JG. Treatment of Trichomonas vaginalis infections. Rev Infect Dis . 1982; 4(Suppl):S801-18.

338. Lossick JG, Kent HL. Trichomoniasis: trends in diagnosis and management. Am J Obstet Gynecol . 1991; 165:1217-22. [PubMed 1951578]

339. Heine P, McGregor JA. Trichomonas vaginalis : a reemerging pathogen. Clin Obstet Gynecol . 1993; 36:137-44. [PubMed 8435938]

340. Seligman SA. Trichomonal vaginitis refractory to conventional treatment. Genitourin Med . 1989; 65:200-1. [PubMed 2759616]

341. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep . 2006; 55(No. RR-11):1-95.

342. Oliva SL, Guglielmo BJ, Jacobs R et al. Failure of intravenous vancomycin and intravenous metronidazole to prevent or treat antibiotic-associated pseudomembranous colitis. J Infect Dis . 1989; 159:1154-5. [PubMed 2491408]

343. Kleinfeld D, Donta ST. Failure of intravenous vancomycin and intravenous metronidazole to prevent or treat antibiotic-associated pseudomembranous colitis. J Infect Dis . 1989; 159:1155.

344. Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile colitis. N Engl J Med . 1994; 330:257-62. [PubMed 8043060]

345. Fekety R, Shah AB. Diagnosis and treatment of Clostridium difficile colitis. JAMA . 1993; 269:71-5. [PubMed 8416409]

346. Bartlett JG. Antibiotic-associated diarrhea. Clin Infect Dis . 1992; 15:573-81. [PubMed 1420669]

347. Marshall BJ. Helicobacter pylori . Am J Gastroenterol . 1994; 89(Suppl 8):S116-28.

348. Blaser MJ. Helicobacter pylori : its role in disease. Clin Infect Dis . 1992; 15:386-91. [PubMed 1520782]

349. Farrell MK. Dr. Apley meets Helicobacter pylori . J Pediatr Gastroenterol Nutr . 1993; 16:118-9. [PubMed 8450375]

350. Nomura A, Stemmermann GN, Chyou PH et al. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med . 1991; 325:1132-6. [PubMed 1891021]

351. Parsonnet J, Friedman GD, Vandersteen DP et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med . 1991; 352:1127-31.

352. The EUROGAST Study Group. An international association between Helicobacter pylori infection and gastric cancer. Lancet . 1993; 341:1359-62. [PubMed 8098787]

353. Talley NJ, Zinsmeister AR, Weaver A et al. Gastric adenocarcinoma and Helicobacter pylori infection. J Natl Cancer Inst . 1991; 83:1734-9. [PubMed 1770552]

354. Forman D, Newell DG, Fullerton F et al. Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation. BMJ . 1991; 302:1302-5. [PubMed 2059685]

355. Forman D. Helicobacter pylori infection: a novel risk factor in the etiology of gastric cancer. J Natl Cancer Inst . 1991; 83:1702-3. [PubMed 1770545]

356. Parsonnet J. Helicobacter pylori and gastric cancer. Gastroenterol Clin North Am . 1993; 22:89-104. [PubMed 8449573]

357. Correa P. Is gastric carcinoma an infectious disease? N Engl J Med . 1991; 325:1170-1.

358. Isaacson PG, Spencer J. Is gastric lymphoma an infectious disease? Hum Pathol . 1993; 24:569-70.

359. Reviewers' comments (personal observations) on the Aminopenicillins General Statement (Uses: Helicobacter pylori infections).

360. NIH Consensus Development Panel on. Helicobacter pylori in Peptic Ulcer Disease. JAMA . 1994; 272:65-9. [PubMed 8007082]

361. Feldman M. The acid test. Making clinical sense of the consensus conference on Helicobacter pylori . JAMA . 1994; 272:70-1. [PubMed 8007084]

362. Peura DA, Graham DY. Helicobacter pylori: consensus reached: peptic ulcer is on the way to becoming an historic disease. Am J Gastroenterol . 1994; 89:1137-9. [PubMed 8053422]

363. Cotton P. NIH consensus panel urges antimicrobials for ulcer patients, skeptics concur with caveats. JAMA . 1994; 271:808-9. [PubMed 8114221]

364. Ravdin JI. Amebiasis. Clin Infect Dis . 1995; 20:1453-66. [PubMed 7548493]

365. Schlicht JR. Treatment of bacterial vaginosis. Ann Pharmacother . 1994; 28:483-7. [PubMed 8038475]

366. Joesoef MR, Schmid GP. Bacterial vaginosis: review of treatment options and potential clinical indications for therapy. Clin Infect Dis . 1995; 20(Suppl 1):S72-9.

367. Hill DR. Giardiasis: issues in diagnosis and management. Infect Dis Clin North Am . 1993; 7:503-25. [PubMed 8254157]

368. Aucott JN, Ravdin JI. Amebiasis and “nonpathogenic” intestinal protozoa. Infect Dis Clin North Am . 1993; 7:467-85. [PubMed 8254155]

369. Corson AP, Chretien JH. Metronidazole-associated aseptic meningitis. Clin Infect Dis . 1994; 19:974. [PubMed 7893894]

370. Reed SL. Amebiasis: an update. Clin Infect Dis . 1992; 14:385-93. [PubMed 1554822]

371. Miller RA, Minshew BH. Blastocystis hominis : an organism in search of a disease. Rev Infect Dis . 1988; 10:930-8. [PubMed 3055191]

372. Grossman I, Weiss LM, Simon D et al. Blastocystis hominis in hospital employees. Am J Gastroenterol . 1992; 87:729-32. [PubMed 1590309]

373. Abbott Laboratories. Biaxin^® (clarithromycin) Filmtab^® tablets and granules for oral suspension prescribing information. Abbott Park, IL; 1998 Jul.

374. Markham A, McTavish D. Clarithromycin and omeprazole: as Helicobacter pylori eradication therapy in patients with H. pylori-associated gastric disorders. Drugs . 1996; 51:161-78. [PubMed 8741237]

375. Sung JJY, Chung SCS, Ling TKW et al. Dual therapy versus triple therapy for Helicobacter pylori -associated duodenal ulcers. Dig Dis Sci . 1996; 41:453-7. [PubMed 8617114]

376. Soll AH. Medical treatment of peptic ulcer disease. JAMA . 1996; 275:622-9. [PubMed 8594244]

377. Soll AH. Practice guidelines for treatment of peptic ulcer disease. JAMA . 1996; 276:1136-7.

378. Reviewers' comments (personal observations) on the Aminopenicillins General Statement 8:12.16.

379. Labenz J, Gyenes E, Rühl GH et al. Amoxicillin plus omeprazole versus triple therapy for eradication of Helicobacter pylori in duodenal ulcer disease: a prospective, randomized, and controlled study. Gut . 1993; 34:1167-70. [PubMed 8406147]

380. Bell GD, Powell KU, Burridge SM et al. Helicobacter pylori eradication: efficacy and side effect profile of a combination of omeprazole, amoxycillin and metronidazole compared with four alternative regimens. Q J Med . 1993; 86:743-50. [PubMed 8265776]

381. Labenz J, Börsch G. Highly significant change of the clinical course of relapsing and complicated peptic ulcer disease after cure of Helicobacter pylori infection. Am J Gastroenterol . 1994; 89:1785-8. [PubMed 7942667]

382. Wang WM, Chen CY, Jan CM et al. Long-term follow-up and serological study after triple therapy of Helicobacter pylori -associated duodenal ulcer. Am J Gastroenterol . 1994; 89:1793-6. [PubMed 7942669]

383. Anon. Drugs for treatment of peptic ulcer. Med Lett Drugs Ther . 1994; 36:65-7. [PubMed 7912812]

384. Freston JW. Emerging strategies for managing peptic ulcer disease. Scand J Gastroenterol . 1994; 29(Suppl 201):49-54.

385. Axon ATR. The role of acid inhibition in the treatment of Helicobacter pylori infection. Scand J Gastroenterol . 1994; 29(Suppl 201):16-23.

386. Labenz J, Rühl GH, Bertrams J et al. Medium- or high-dose omeprazole plus amoxicillin eradicates Helicobacter pylori in gastric ulcer disease. Am J Gastroenterol . 1994; 89:726-30. [PubMed 8172146]

387. Walsh JH, Peterson WL. The treatment of Helicobacter pylori infection in the management of peptic ulcer disease. N Engl J Med . 1995; 333:984-91. [PubMed 7666920]

388. Hackelsberger A, Malfertheiner P. A risk-benefit assessment of drugs used in the eradication of Helicobacter pylori infection. Drug Saf . 1996; 15:30-52. [PubMed 8862962]

389. Rauws EAJ, van der Hulst RWM. Current guidelines for the eradication of Helicobacter pylori in peptic ulcer disease. Drugs . 1995; 6:984-90.

390. van der Hulst RWM, Keller JJ, Rauws EAJ et al. Treatment of Helicobacter pylori infection: a review of the world literature. Helicobacter . 1996; 1:6-19. [PubMed 9398908]

391. Lind T, Veldhuyzen van Zanten S, Unge P et al. Eradication of Helicobacter pylori using one-week triple therapies combining omeprazole with two antimicrobials: the MACH I study. Helicobacter . 1996; 1:138-44. [PubMed 9398894]

392. Fennerty MB. Practice guidelines for treatment of peptic ulcer disease. JAMA . 1996; 276:1135. [PubMed 8827957]

393. Labenz J, Borsch G. Evidence for the essential role of Helicobacter pylori in gastric ulcer disease. Gut . 1994; 35:19-22. [PubMed 8307443]

394. Fennerty MB. Helicobacter pylori . Ann Intern Med . 1994; 154:721-7.

395. Adamek RJ, Wegener M, Labenz J et al. Medium-term results of oral and intravenous omeprazole/amoxicillin Helicobacter pylori eradication therapy. Am J Gastroenterol . 1994; 89:39-42. [PubMed 8273795]

396. Fennerty MB. “Cure” of Helicobacter pylori: clinically indicated and economically wise! Arch Intern Med . 1995; 155:1929-31. Editorial.

397. Graham KS, Malaty H, el-Zimaity HM et al. Variability with omeprazole-amoxicillin combinations for treatment of Helicobacter pylori infection. Am J Gastroenterol . 1995; 90:1415-8. [PubMed 7661160]

398. Borody TJ, Andrews J, Shortis NP et al. Optimal H.pylori [sic] (HP) therapy—a combination of omeprazole and triple therapy (TT). Gastroenterology . 1994; 106:A55.

399. Labenz J, Gyenes E, Rühl GH et al. Omeprazole plus amoxicillin: efficacy of various treatment regimens to eradicate Helicobacter pylori . Am J Gastroenterol . 1993; 88:491-5. [PubMed 8470626]

400. Labenz J, Rühl GH, Bertrams J et al. Medium- and high-dose omeprazole plus amoxicillin for eradication of Helicobacter pylori in duodenal ulcer disease. Dig Dis Sci . 1994; 39:1483-7. [PubMed 8026260]

401. Savarino V, Mela GS, Zentilin P et al. Acid inhibition and amoxicillin activity against Helicobacter pylori . Am J Gastroenterol . 1993; 88:1975-6. [PubMed 8237959]

402. Labenz J, Börsch G. Response to Savarino et al . Am J Gastroenterol . 1993; 88:1976. [PubMed 8292199]

403. Graham DY, Go MF. Evaluation of new antiinfective drugs for Helicobacter pylori infection: revisited and updated. Clin Infect Dis . 1993; 17:293-4. [PubMed 8399892]

404. Murray DM, DuPont HL. Reply. (Evaluation of new antiinfective drugs for Helicobacter pylori infection: revisited and updated.) Clin Infect Dis . 1993; 17: 294-5.

405. George LL, Borody TJ, Andrews P et al. Cure of duodenal ulcer after eradication of H. pylori . Med J Aust . 1990; 153:145-9. [PubMed 1974027]

406. Anon. The choice of antibacterial drugs. Med Lett Drugs Ther . 2001; 43:69-78. [PubMed 11518876]

407. G.D. Searle & Co. Flagyl^® ER (metronidazole extended release tablets) product information. Chicago, IL; 1998 Feb 10.

408. Sobel JD. Vaginitis. N Engl J Med . 1997; 337:1896-903. [PubMed 9407158]

409. Ferris DG, Litaker MS, Woodward L et al. Treatment of bacterial vaginosis: a comparison of oral metronidazole, metronidazole vaginal gel, and clindamycin vaginal cream. J Fam Pract . 1995; 41:443-9. [PubMed 7595261]

410. Newton ER, Piper J, Peairs W. Bacterial vaginosis and intraamniotic infection. Am J Obstet Gynecol . 1997; 176:672-7. [PubMed 9077627]

411. McGregor JA, French JI, Seo K. Premature rupture of membranes and bacterial vaginosis. Am J Obstet Gynecol . 1993; 169:463-6. [PubMed 8357046]

412. Hay PE, Lamont RF, Taylor-Robinson D et al. Abnormal bacterial colonisation of the genital tract and subsequent preterm delivery and late miscarriage. BMJ . 1994; 308:295-8. [PubMed 8124116]

413. Meis PJ, Goldenberg RL, Mercer B et al. The preterm prediction study: significance of vaginal infections. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol . 1995; 173:1231-5. [PubMed 7485327]

414. Hillier SL, Nugent RP, Eschenbach DA et al. Association between bacterial vaginosis and preterm delivery of a low-birth-weight infant. The Vaginal Infections and Prematurity Study Group. N Engl J Med . 1995; 333:1737-42. [PubMed 7491137]

415. Ferris DG. Management of bacterial vaginosis during pregnancy. Am Fam Physician . 1998; 57:1215-8. [PubMed 9531904]

416. Morales WJ, Schorr S, Albritton J. Effect of metronidazole in patients with preterm birth in preceding pregnancy and bacterial vaginosis: a placebo-controlled, double-blind study. Am J Obstet Gynecol . 1994; 171:345-7. [PubMed 8059811]

417. Hauth JC, Goldenberg RL, Andrews WW et al. Reduced incidence of preterm delivery with metronidazole and erythromycin in women with bacterial vaginosis. N Engl J Med . 1995; 333:1732-6. [PubMed 7491136]

418. McGregor JA, French JI. Bacterial vaginosis and preterm birth. N Engl J Med . 1996; 334:1337-8. [PubMed 8609962]

419. Hauth JC, Hillier SL. Bacterial vaginosis and preterm birth. N Engl J Med . 1996; 334:1338-9. [PubMed 8609963]

420. Hack M, Merkatz IR. Preterm delivery and low birth weight—a dire legacy. N Engl J Med . 1995; 333:1772-4. [PubMed 7491144]

421. McGregor JA, French JI, Parker R et al. Prevention of premature birth by screening and treatment for common genital tract infections: results of a prospective controlled evaluation. Am J Obstet Gynecol . 1995; 173:157-67. [PubMed 7631673]

422. Peipert JF, Montagno AB, Cooper AS et al. Bacterial vaginosis as a risk factor for upper genital tract infection. Am J Obstet Gynecol . 1997; 177:1184-7. [PubMed 9396917]

423. Caro-Paton T, Carvajal A, Martin de Diego I et al. Is metronidazole teratogenic? A meta-analysis. Br J Clin Pharmacol . 1997; 44:179-82. [PubMed 9278206]

424. Burtin P, Taddio A, Ariburnu O et al. Safety of metronidazole in pregnancy: a meta-analysis. Am J Obstet Gynecol . 1995; 172:525-9. [PubMed 7856680]

425. Moi H, Erkkola R, Jerve F et al. Should male consorts of women with bacterial vaginosis be treated? Genitourin Med . 1989; 65:263-8.

426. Vejtorp M, Bollerup AC, Vejtorp L et al. Bacterial vaginosis: a double-blind randomized trial of the effect of treatment of the sexual partner. Br J Obstet Gynaecol . 1988; 95:920-6. [PubMed 3056506]

427. Mengel MB, Berg AO, Weaver CH et al. The effectiveness of single-dose metronidazole therapy for patients and their partners with bacterial vaginosis. J Fam Pract . 1989; 28:163-71. [PubMed 2644391]

428. Colli E, Landoni M, Parazzini F. Treatment of male partners and recurrence of bacterial vaginosis: a randomised trial. Genitourin Med . 1997; 73:267-70. [PubMed 9389947]

429. Goldenberg RL, Rouse DJ. Prevention of premature birth. N Engl J Med . 1998; 339:313-20. [PubMed 9682045]

430. Pharmacia. Flagyl^® ER (metronidazole extended release tablets) prescribing information. Chicago, IL; 2003 Aug.

431. Janssen Pharmaceutica. Hismanal^® (astemizole) tablets prescribing information. Titusville, NJ; 1998 Feb.

432. Klausner MA. Dear doctor letter regarding important drug warning of Hismanal^® (astemizole). Titusville, NJ: Janssen Pharmaceutica; 1998 Feb.

433. duBouchet L, McGregor JA, Ismail M et al. A pilot study of metronidazole gel versus oral metronidazole for the tretament of Trichomoniasis vaginalis vaginitis. Sex Transm Dis . 1998; 25:176-9. [PubMed 9524997]

434. Kellock D, O'Mahony CP. Sexually acquired metronidazole-resistant trichomoniasis in a lesbian couple. Genitourinary Med . 1996; 72:60-1.

435. Pearlman MD, Yashar C, Ernst S et al. An incremental dosing protocol for women with severe vaginal trichomoniasis and adverse reactions to metronidazole. Am J obstet Gynecol . 1996; 174:934-6. [PubMed 8633672]

436. Coelho DD. Metronidazole resistant trichomoniasis successfully treated with paromomycin. Genitourin Med . 1997; 73:397-8. [PubMed 9534753]

437. Grinbaum A, Ashkenazi I, Avni I. Drug induced myopia associated with treatment for gynecologic problems. Eur J Ophtalmol . 1995; 5:136-8.

438. Czeizel AE, Rockenbauer M. A population based case-control teratologic study of oral metronidazole treatment during pregnancy. Br J Obstet Gynaecol . 1998; 105:322-7. [PubMed 9532994]

439. Caro-Paton T, Carvajal A, Martin de Diego I et al. Is metronidazole teratogenic? A meta-analysis. Br J Clin Pharmacol . 1997; 44:179-82. [PubMed 9278206]

440. Burtin P, Taddio A, Ariburnu O et al. Safety of metronidazole in pregnancy: a meta-analysis. Am J obstet Gynecol . 1995; 172(2 Part 1):525-9. [PubMed 7856680]

441. Schwebke JR. Metronidazole: utilization in the obstetric and gynecologic patient. Sex Transm Dis . 1995; 22:370-6. [PubMed 8578410]

442. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and lactation. 5th ed. Baltimore, MD: Williams & Wilkins; 1998:722-6.

443. Johnson S, Gerding DN. Clostridium difficile -associated diarrhea. Clin Infect Dis . 1998; 26:1027-36. [PubMed 9597221]

444. Gerding DN, Johnson S, Peterson LR et al for the Society for Healthcare Epidemiology of America. Position paper on Clostridium difficile -associated diarrhea and colitis. Infect Control Hosp Epidemiol . 1995; 16:459-77. [PubMed 7594392]

445. Fekety R for the American College of Gastroenterology Practice Parameters Committee. Guidelines for the diagnosis and management of Clostridium difficile -associated diarrhea and colitis. Am J Gastroenterol . 1997; 92:739-50. [PubMed 9149180]

446. American Society of Health-System Pharmacists Commission on Therapeutics. ASHP therapeutic position statement on the preferential use of metronidazole for the treatment of Clostridium difficile -associated disease. Am J Health-Syst Pharm . 1998; 55:1407-11. [PubMed 9659970]

447. Wilcox MH. Treatment of Clostridium difficile infection. J Antimicrob Chemother . 1998; 41(Suppl C):41-6. [PubMed 9630373]

448. Centers for Disease Control and Prevention Hospital Infection Control Practices Advisory Committee. Recommendations for preventing the spread of vancomycin resistance. Infect Control Hosp Epidemiol . 1995; 16:105-13. [PubMed 7759811]

449. McFarland LV, Surawicz CM, Fekety R et al. A randomized controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA . 1994; 271:1913-8. [PubMed 8201735]

450. McFarland LV. Saccharomyces boulardii is not Saccharomyces cerevisiae . Clin Infect Dis . 1996; 22:200-1. [PubMed 8825013]

451. Buggy BP, Fekety R, Silva J. Therapy of relapsing Clostridium difficile -associated diarrhea with a combination of vancomycin and rifampin. J Clin Gastroenterol . 1987; 9:155-9. [PubMed 3571889]

452. Ortega YR, Adam RD. Giardia : overview and update. Clin Infect Dis . 1997; 25:545-50. [PubMed 9314441]

454. Mathisen GE, Johnson JP. Brain abscess. Clin Infect Dis . 1997; 25:763-81. [PubMed 9356788]

455. Prometheus Laboratories. Helidac^® therapy (bismuth subsalicylate 262.4-mg chewable tablets, metronidazole 250-mg tablets, and tetracycline hydrochloride 500-mg capsules) prescribing information. San Diego, CA; 2004 Feb.

456. Bristol-Myers Squibb. Maxipime^® (cefepime hydrochloride) for injection for intravenous or intramuscular use prescribing information. Princetone, NJ; 1998 May.

457. Barie PS, Vogel SB, Dellinger EP et al. A randomized, double-blind clinical trial comparing cefepime plus metronidazole with imipenem-cilastatin in the treatment of complicated intra-abdominal infections. Arch Surg . 1997; 132:1294-302. [PubMed 9403533]

458. Bayer. Cipro^® I.V. (ciprofloxacin) for intravenous infusion prescribing information. West Haven, CT; 1998 Jul.

459. Reviewers' comments (personal observations) on clarithromycin 8:12.12.

460. O'Brien B, Goeree R, Mohamed AH et al. Cost-effectiveness of Helicobacter pylori eradication for the long-term management of duodenal ulcer in Canada. Arch Intern Med . 1995; 155:1958-64. [PubMed 7575049]

461. Imperiale TF, Speroff T, Cebul RD et al. A cost analysis of alternative treatments for duodenal ulcer. Ann Intern Med . 1995; 123:665-72. [PubMed 7574221]

462. Vakil N, Fennerty MB. Cost-effectiveness of treatment regimens for the eradication of Helicobacter pylori in duodenal ulcer. Am J Gastroenterol . 1996; 91:239-45. [PubMed 8607487]

463. Sonnenberg A, Townsend WF. Costs of duodenal ulcer therapy with antibiotics. Arch Intern Med . 1995; 155:922-8. [PubMed 7726700]

464. Langtry HD, Wilde MI. Lansoprazole: an update of its pharmacological properties and clinical efficacy in the management of acid-related disorders. Drugs . 1997; 54:473-500. [PubMed 9279507]

465. Nichols RI, Smith JW, Garcia RY et al. Current practices of preoperative bowel preparation among North American colorectal surgeons. Clin Infect Dis . 1997; 24:609-19. [PubMed 9145734]

466. Presutti Laboratories.Tindamax (tinidazole) tablets prescribing information. Arlington Heights, IL; 2004 May 14.

467. Prantera C, Berto E, Scribano ML et al. Use of antibiotics in the treatment of active Crohn's disease: experience with metronidazole and ciprofloxacin. Ital J Gastroenterol Hepatol . 1998; 30:602-6. [PubMed 10076781]

468. Greenbloom SL, Steinhart AH, Greenberg GR. Combination ciprofloxacin and metronidazole for active Crohn's disease. Can J Gastroenterol . 1998; 12:53-6. [PubMed 9544412]

469. Sutherland L, Singleton J, Sessions J et al. Double blind, placebo controlled trial of metronidazole in Crohn's disease. Gut . 1991; 32:1071-5. [PubMed 1916494]

470. Bernstein LH, Frank MS, Brandt LJ et al. Healing of perineal Crohn's disease with metronidazole. Gastroenterology . 1980; 79:599. [PubMed 7429123]

471. Hanauer SB, Sandborn W, and the Practice Parameters Committee of the American College of Gastroenterology. Management of Crohn's disease in adults: Practice Guidelines. Am J Gastroenterol . 2001; 96:635-43. [PubMed 11280528]

472. Blichfeldt P, Blomhoff JP, Myhre E et al. Metronidazole in Crohn's disease: a doubleblind cross-over clinical trial. Scand J Gastroenterol . 1978; 13:123-7. [PubMed 345410]

473. Sandborn WJ, Feagan BG. Review article: mild to moderate Crohn's disease defining the basis for a new treatment algorithm. Aliment Pharmacol Ther . 2003; 18:263-77. [PubMed 12895211]

474. Scribano M, Pantera C. Review article: medical treatment of moderate to severe Crohn's disease. Aliment Pharmacol Ther . 2003; 17(Suppl. 2):23-30. [PubMed 12786609]

475. Prantera C, Zannoni F, Scribano ML et al. An antibiotic regimen for the treatment of active Crohn's disease: a randomized, controlled clinical trial of metronidazole plus ciprofloxin. Am J Gastroenterol . 1996; 91:328-32. [PubMed 8607501]

476. Prantera C, Kohn A, Zannoni F et al. Metronidazole plus ciprofloxacin in the treatment of active, refractory Crohn's disease: results of an open study. J Clin Gastroenterol . 1994; 19:79-80. [PubMed 7930441]

477. Ishikawa T, Okamura S, Oshimoto H et al. Metronidazole plus ciprofloxin therapy for active Crohn's disease. Intern Med . 2003;42:318-21. [PubMed 12729319]

478. Hanauer SB, Preemt DH. The state of the art in the management of inflammatory bowel disease. Rev Gastroenterol Disord. 2003; 3:81-92. Selby WS. Current issues in Crohn's disease. Rev Gastroenetrol Disord . 2003; 3:81-92.

479. Hanauer SB. Inflammatory bowel disease. N Engl J Med . 1996; 334:841-8. [PubMed 8596552]

480. Colombel JF, Lémann M, Cassagnou M et al and Groupe d'Etudes Therapeutiques des Affections Inflammatoires Digestives (GETAID). A controlled trial comparing ciprofloxacin with mesalazine for the treatment of active Crohn's disease. Am J Gastroenterol . 1999; 94:674-8. [PubMed 10086650]

481. Arnold GL, Beaves MR, Pryjdun VO et al. Preliminary study of ciprofloxin in active Crohn's disease. Inflamm Bowel Dis . 2002; 8:10-5. [PubMed 11837933]

482. Steinhart AH, Feagan BG, Wong CJ et al. Combined budesonide and antibiotic therapy for active Crohn's disease: a randomized controlled trial. Gastroenterolology . 2002; 123:33-40.

483. Best WR, Becktel JM, Singleton JW et al. Development of a Crohn's disease activity index: National Cooperative Crohn's Disease Study. Gastroenterology . 1976; 70:439-44. [PubMed 1248701]

484. Ambrose NS, Allan RN, Keighley MR et al. Antibiotic therapy for treatment in relapse of intestinal Crohn's disease: a prospective randomized study. Dis Colon Rectum . 1985; 28:81-5. [PubMed 3882364]

485. Rutgeerts P. Treatment of perianal fistulizing Crohn's disease. Aliment Pharmacol Ther . 2004; 20(Suppl 4):106-10. [PubMed 15352905]

486. Dejaco C, Harrer M, Waldhoer T etal. Antibiotics and azathioprine for the treatment of perianal fistulas in Crohn's disease. Aliment Pharmacol Ther . 2003; 18:1113-20. [PubMed 14653831]

487. Kirschner BS. Differences in the management of inflammatory bowel disease in children and adolescents compared to adults. Neth J Med . 1998;53 :S13-8. [PubMed 9883009]

488. Crowell AL, Sanders-Lewis KA, Secor WE. In vitro metronidazole and tinidazole activities against metronidazole-resistant strains of Trichomonas vaginalis. Antimicrob Agents Chemother . 2003;47:1407-9. [PubMed 12654679]

489. Bleck T. Clostridium tetani (tetanus). In: Mandell GL, Bennett JE, Dolan R, eds. Mandell, Douglas, and Bennett's Principles and practices of infectious diseases. 5th ed. New York: Churchill Livingstone; 2000:2537-43.

490. Bratzler DW, Houck PM. Antimicrobial prophylaxis for surgery: an advisory statement from the national surgical infection prevention project. Clin Infect Dis . 2004; 38:1706-15. [PubMed 15227616]

491. Espin-Basany E, Sanchez-Garcia JL, Lopez-Cano M et al. Prospective, randomized study on antibiotic prophylaxis in colorectal surgery. Is it really necessary to use oral antibiotics? Int J Colorectal Dis . 2005; 20:542-6.

492. Wren SM, Ahmed N, Jamal A et al. Preoperative oral antibiotics in colorectal surgery increase the rate of Clostridium difficile colitis. Arch Surg . 2005; 140:752-6. [PubMed 16103284]

493. Lewis RT. Oral versus systemic antibiotic prophylaxis in elective colon surgery: a randomized study and meta-analysis send a message from the 1990s. Can J Surg . 2002; 45:173-80. [PubMed 12067168]

494. Kucers A, Crowe S, Grayson ML et al, eds. The use of antibiotics. A clinical review of antibacterial, antifungal, and antiviral drugs. 5th ed. Jordan Hill, Oxford: Butterworth-Heinemann; 1997: 936-58.

496. Centers for Disease Control and Prevention. Updated recommended treatment regimens for gonococcal infections and associated conditions—United States, April 2007. From CDC website. Accessed 2007 May 8. [Web]

495. Baxter. Metronidazole Injection, USP RTU^® prescribing information. Deerfield, IL; 2003 Jun.