Uses
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Amebiasis
Metronidazole is used orally in the treatment of acute intestinal amebiasis and amebic liver abscess caused by Entamoeba histolytica.
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). The sequential use of these drugs ensures eradication of tissue-invading trophozoites as well as cysts in the intestinal lumen. 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. 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. However, these alternative regimens are associated with severe adverse effects and generally require hospitalization. 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.
Metronidazole and tinidazole are not recommended for treatment of asymptomatic cyst passers because of limited activity against encysted E. histolytica. Asymptomatic cyst passers should be treated with a luminal amebicide such as iodoquinol, paromomycin, or diloxanide furoate (not commercially available in the US). For information on treatment of asymptomatic amebiasis, .
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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 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. 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. 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.
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Bacterial Vaginosis
Metronidazole is used orally (as immediate-release tablets or as extended-release tablets) or intravaginally (e.g., as a vaginal gel) for the treatment of bacterial vaginosis (formerly called Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, Corynebacterium vaginitis, or anaerobic vaginosis).
Bacterial vaginosis is a noninflammatory vaginal syndrome characterized by replacement of the normal vaginal flora (predominantly hydrogen peroxide-producing Lactobacillus) with a mixed flora including Gardnerella vaginalis, anaerobes (e.g., Bacteroides ureolyticus, Prevotella, Porphyromonas, Peptostreptococcus, Mobiluncus), and Mycoplasma hominis; vaginal discharge may be an unreliable indicator of infection since many women are asymptomatic. While Gardnerella previously was thought to be the sole causative agent of this syndrome, it currently is thought that bacterial vaginosis is a polymicrobial condition in which Gardnerella acts synergistically with anaerobic bacteria and genital mycoplasmas. Clinical diagnosis of the syndrome generally is established by characteristic vaginal manifestations rather than bacteriologic determinations. The presence of at least 3 of the following manifestations is considered diagnostic for bacterial vaginosis: a nonirritating, odoriferous, thin, homogeneous, grayish-white, noninflammatory vaginal discharge that smoothly coats the vaginal walls; a vaginal pH exceeding 4.5; the elaboration of malodorous amines (''fishy'' odor) from discharge fluid after alkalinization with potassium hydroxide 10% (''whiff test''); and/or microscopic smears containing small coccobacillary organisms adherent to epithelial cells (''clue cells''). The presence of clue cells on wet mount examination of vaginal secretions is one of the most reliable indicators of bacterial vaginosis.
Gram stain results consistent with a diagnosis of bacterial vaginosis include markedly reduced or absent Lactobacillus morphology and predominance of Gardnerella morphotype. Although Gram stain of vaginal secretions also has been employed as a diagnostic test for bacterial vaginosis, accuracy of this method depends on evaluation by an experienced microbiologist; thus, this technique is used more often in research and hospital settings whereas diagnosis by clinical criteria typically is performed in an office setting.Gardnerella can be isolated from vaginal cultures in a large proportion of healthy women; because of this lack of specificity, culture for the organism is not recommended as a diagnostic method for bacterial vaginosis, and it is not used to guide therapy. The possibility of other pathogens commonly associated with vulvovaginitis or cervicitis (e.g., Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, Candida albicans, herpes simplex viruses) generally should be ruled out, particularly since coinfection with these organisms may occur.
Goals of treatment and recommended therapy for bacterial vaginosis differ for nonpregnant versus pregnant women. However, relief of signs and symptoms of infection is a principal goal of therapy, and all women with symptomatic bacterial vaginosis should be treated regardless of pregnancy status.
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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. The CDC states that treatment of bacterial vaginosis is indicated in all nonpregnant women who are symptomatic. 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. 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. or
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. 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. Regardless of the therapy chosen, relapse or recurrence of bacterial vaginosis is common, and some clinicians suggest that an alternative regimen (e.g., topical therapy when oral therapy was used initially) can be employed in such infections.
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. 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. 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. 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) and there is some evidence that the recurrence rate several weeks after completion of oral therapy may be higher with the single-dose regimen. 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.
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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, and the organisms found in increased concentrations in the genital flora of women with bacterial vaginosis are frequently found in patients with postpartum or postcesarean endometritis. Evidence from randomized, controlled trials indicates that systemic treatment of bacterial vaginosis reduces the rate of preterm birth in pregnant women at high risk for complications of pregnancy.
Because of 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. 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. The CDC recommends that screening for bacterial vaginosis (if conducted) should be performed at the first prenatal visit and treatment initiated if needed.
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). 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.
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, 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. 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.
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, systemic therapy with metronidazole is contraindicated in the first trimester of pregnancy.
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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). 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, but further study is needed to determine the value of treating asymptomatic bacterial vaginosis in patients who are about to undergo other invasive procedures.
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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.
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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. Therefore, routine treatment of male sexual contacts currently is not recommended. Further study is needed to elucidate the possible role, if any, of sexual transmission in bacterial vaginosis.
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Balantidiasis
Oral metronidazole is recommended as an alternative to tetracycline for the treatment of balantidiasis caused by Balantidium coli.
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Blastocystis hominis Infections
Oral metronidazole has been used in the treatment of Blastocystis hominis infections. However, the clinical importance of B. hominis as a cause of GI pathology is controversial and it is unclear when treatment of B. hominis infection is indicated. 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. 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. Metronidazole, iodoquinol, co-trimoxazole, or nitazoxanide have been used, but metronidazole resistance may be common.
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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) and, along with oral vancomycin hydrochloride, is considered the drug of choice for the treatment of C. difficile-associated diarrhea and colitis. Most experts and clinicians state that in order to decrease the incidence of vancomycin-resistant enterococci , 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. Oral metronidazole therapy also generally is preferred because of cost considerations. Diarrhea generally remits gradually over 3-5 days after initiation of oral metronidazole therapy, although resolution occasionally may take a week or longer, probably because of persistent inflammation despite cessation of toxin production.
Oral metronidazole appears to be as effective as oral vancomycin for the treatment of pseudomembranous colitis caused by C. difficile. 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).
Oral therapy is always preferred for the treatment of C. difficile-associated diarrhea and colitis, but the oral route may not always be feasible; the drugs should never be administered IV simply for reasons of convenience. 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. Although IV therapy with metronidazole may not be as reliable as oral therapy, higher intracolonic drug concentrations are more likely with IV metronidazole than with IV vancomycin, 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). 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). 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). However, the comparative efficacy of these approaches, particularly relative to oral therapy, has not been established.
Although oral metronidazole and intravaginal metronidazole have been associated rarely with causing antibiotic-associated diarrhea and colitis, including pseudomembranous colitis, 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.
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. 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. 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. 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.
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. 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. 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. 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. 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. 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.
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. 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. 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.
For additional information on C. difficile-associated diarrhea and colitis, .
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Crohn's Disease
Oral metronidazole (used with or without ciprofloxacin); has been used for the induction of remission of mildly to moderately active Crohn's disease; the drug also has been used for refractory perianal disease. It appears that the combination of metronidazole and ciprofloxacin is more effective than metronidazole alone. Because the intestinal flora appears to have an association with intestinal inflammation and because metronidazole has a direct anti-inflammatory effect, metronidazole may be useful in the management of Crohn's disease as an adjunct to conventional therapies.
Reports on the efficacy of metronidazole in the management of active Crohn's disease have been equivocal. While results of several open-label, retrospective, comparative, and at least one placebo-controlled study 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, results of other controlled and uncontrolled studies using metronidazole failed to show evidence of substantial beneficial effects on the clinical condition of the patients. 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. 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). Limited data indicate that metronidazole may be more effective in patients with ileocolitis or colitis rather than in those with ileitis.
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). Disease activity in this study was monitored by CDAI and serum orosomucoid concentrations. 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. After crossover, patients who had responded to the first drug have continued to respond to the other drug. 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. Some clinicians suggest that metronidazole be reserved for patients in whom sulfasalazine is ineffective or not tolerated.
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). 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). 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. 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. 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; however, it has been suggested that this anti-infective combination may improve outcome in patients with Crohn's disease involving the colon. 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. It is not known whether metronidazole is useful for prevention of recurrent disease.
Oral metronidazole has been used effectively for the treatment of refractory perineal Crohn's disease. Nonsuppurative perianal complications of the disease usually respond to metronidazole alone or when used in conjunction with ciprofloxacin. 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. 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. 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. 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, some clinicians state that continuous therapy is needed to prevent recurrence of perineal disease. Because safety and efficacy 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. It has been suggested that patients be monitored for nervous system effects (e.g., peripheral neuropathy) during long-term administration of the drug. 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).
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). 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.
For further information on the management of Crohn's disease,
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Dientamoeba fragilis Infections
Oral metronidazole is considered a drug of choice for the treatment of infections caused by Dientamoeba fragilis. Many clinicians recommend iodoquinol, paromomycin, tetracycline, or metronidazole for the treatment of D. fragilis infections.
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Dracunculiasis
Oral metronidazole has been used in the treatment of dracunculiasis caused by Dracunculus medinensis (guinea worm disease). Slow extraction of the worm and wound care is recommended by some clinicians as the treatment of choice. Although metronidazole therapy is not curative, it decreases inflammation and facilitates removal of the worm.
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Giardiasis
Oral metronidazole is used for the treatment of giardiasis in adults and children.
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).
Treatment of asymptomatic carriers of giardiasis is controversial. Although some clinicians suggest that asymptomatic carriers be treated if the risk of reinfection is low, 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. 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. 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. Relapse is common in immunocompromised patients, and these patients may require prolonged therapy and/or use of a combination of agents.
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. 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.
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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. 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. Current epidemiologic and clinical evidence supports a strong association between gastric infection with H. pylori and the pathogenesis of duodenal and gastric ulcers; long-term H. pylori infection also has been implicated as a risk factor for gastric cancer. For additional information on the association of this infection with these and other GI conditions,
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). Several useful therapeutic regimens for H. pylori-associated peptic ulcer disease have been identified, 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 dH. pylori infection receive anti-infective therapy for treatment of the infection.
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. 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. 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, 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. 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).
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. 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. 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. Therefore, the ACG and many clinicians 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. 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. 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).
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. 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. 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.
For additional discussion of H. pylori infection, including details about the efficacy of various regimens and rationale for drug selection,
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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. 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. 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. 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. 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).
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Pelvic Inflammatory Disease
IV or oral metronidazole is used in conjunction with other anti-infectives for the treatment of acute pelvic inflammatory disease (PID).
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. 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.
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. 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, provided the community prevalence and individual risk of gonorrhea is low.
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.
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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) and has decreased total numbers of inflammatory lesions associated with the disease. 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. 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. 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. For information on rosacea and the use of topical metronidazole in the treatment of the disease, and for information on possible mechanism(s) by which metronidazole reduces inflammatory lesions and erythema in patients with rosacea,
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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. Anti-infective agents cannot neutralize toxin already formed and cannot eradicate C. tetani spores which may revert to toxin-producing vegetative forms. 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.
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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). Metronidazole also is used orally for the treatment of trichomoniasis in children and adolescents.
The nitroimidazole derivatives, metronidazole and tinidazole, 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. Some evidence suggests an association between vaginal trichomoniasis and adverse pregnancy outcomes, particularly premature membrane rupture, preterm delivery, and low birthweight. Trichomoniasis also may be a cofactor for the transmission of human immunodeficiency virus (HIV).
Most infected men are asymptomatic (although some may experience urethritis), while many women with trichomoniasis are symptomatic.T. vaginalis infection in women characteristically causes a diffuse, malodorous, yellow-green discharge accompanied by vulvar irritation. 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; 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. 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. Treatment of female sexual partners of lesbians with trichomoniasis also should be considered since transmission between such women has been reported.
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); ensuring the treatment of sexual partners may increase the cure rate. Following treatment, test-of-cure is not necessary for females or males who become asymptomatic after treatment or for those who were initially asymptomatic. 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. 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.
Intravaginal metronidazole as sole therapy for the treatment of trichomoniasis is not recommended because of substantially lower efficacy compared with systemic therapy.
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. However, while resistance to metronidazole is not a recent phenomenon, its prevalence appears to be increasing. Most resistant strains exhibit either marginal or very low resistance to the drug. 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).
In most cases, infection with resistant strains of T. vaginalis is cured with repeat courses and/or increased metronidazole dosages. 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. 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. 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. Regimens specific for the level of resistance have been suggested; 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. However, because infection with strains exhibiting high-level resistance is difficult to treat, 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; such consultation is available from CDC. 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.
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. Resistant cases of vaginal trichomoniasis also have been treated in a limited number of patients with combined systemic and intravaginal metronidazole therapy or with intravaginal paromomycin (not commercially available). 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.
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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. If desensitization is attempted, the possibility that the procedure may be hazardous should be considered. 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. Pretreatment (e.g., with an antihistamine and/or corticosteroid) also should be considered.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. 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. 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. For trichomoniasis, dosing can be stopped after the 2-g dose has been achieved. 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).
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Pediatric Infections
The American Academy of Pediatrics (AAP) and other clinicians recommend oral metronidazole for the treatment of trichomoniasis in children. Because trichomoniasis principally is a sexually transmitted disease, its presence in a prepubertal child should raise the question of sexual abuse.T. vaginalis can be acquired by neonates during birth and causes a vaginal discharge in the first weeks of life.
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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. 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. Although many clinicians use both an oral and a parenteral regimen for perioperative prophylaxis in patients undergoing colorectal surgery; there is controversy about the benefits and risks of this strategy. There is some evidence that a combined oral and parenteral regimen may be more effective than use of an oral or parenteral regimen alone; however, the combined regimen may be associated with a higher incidence of adverse effects (e.g., nausea, vomiting, Clostridium difficile-associated diarrhea and colitis).
Metronidazole has been given orally, IV, or rectally for perioperative prophylaxis in patients undergoing appendectomy. For perioperative prophylaxis in patients undergoing appendectomy (nonperforated), a regimen of IV cefoxitin alone or IV cefazolin and IV metronidazole is recommended.
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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. 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. 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. Chlamydial and gonococcal infections among females are of special concern because of the possibility of ascending infection.
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). 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. 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. Alternative regimens may be required for some patients because of the likelihood of transmission of other STDs from the assailant. 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).
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. The risk is believed to be low in most circumstances, although documentation to support this position is inadequate. 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. 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.
For topical and vaginal uses of metronidazole,
