AHFS Drug Information

Transcription

Metronidazole, Metronidazole Hydrochloride
Drug Nomenclature
Generic Name: Metronidazole
CAS Number: 443-48-1
Drug Nomenclature
Generic Name: Metronidazole Hydrochloride
CAS Number: 69198-10-3
Synonyms: Flagyl; Flagystatin; Florazole; Metrocream; Metrogel; Metrolotion;
Metronidazole; Nidagel; Noritate; Rosasol; Trikacide
Introduction
Metronidazole is a synthetic, nitroimidazole-derivative antibacterial and antiprotozoal
agent.
Uses
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 intraabdominal 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 fragilis456 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 lowbirthweight 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 7day 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 singledose 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 difficileassociated 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 lifethreatening 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 lifethreatening 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. difficileassociated 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. difficileassociated 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. pyloriassociated 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 documentedH. 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, H2receptor 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, bismuthbased regimens (e.g., bismuth-metronidazole-tetracycline or bismuth-metronidazoleamoxicillin), 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., bismuthmetronidazole-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-ofcure, 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.435Desensitization 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 1hour 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.
Dosage and Administration
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.)
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 extendedrelease 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
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.
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 singledose 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 7day 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
Cautions
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 antiinfectives 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.)
Pediatric Precautions
The manufacturers state that safe use of IV metronidazole in children for any indication
and safe use of oral metronidazole in children for any indication except amebiasis have
not been established; however, oral metronidazole has been used in children for
indications other than amebiasis (e.g., trichomoniasis, giardiasis) without unusual
adverse effects. The AAP and other clinicians recommend that children with
trichomoniasis be treated with oral metronidazole.100 153
Geriatric Precautions
Because of the greater frequency of decreased hepatic function in geriatric patients, the
possibility that adjustment of metronidazole dosage may be necessary in this age group
should be considered.152 197 430 (See Dosage and Administration: Dosage in Hepatic
Impairment.)
Mutagenicity and Carcinogenicity
In at least 6 different studies in mice, including one in which the animals received
metronidazole intermittently (every 4 weeks), the prominent effect of the drug was
promotion of pulmonary tumorigenesis.152 197 430 At doses of 1500 mg/m2 (about 3 times
the recommended human dose), there was also a statistically significant increase in the
incidence of malignant liver tumors in male mice.197 430 In addition, in one study in mice
who received lifetime feedings with metronidazole, there was an increase in the
incidence of malignant lymphomas as well as pulmonary neoplasms.152 In long-term
studies in rats receiving oral metronidazole, there was a statistically significant increase
in the incidence of various neoplasms in the females, particularly mammary and hepatic
tumors. Breast and colon cancer have been reported in patients with Crohn’s disease
who have been treated with high dosages of metronidazole for prolonged periods;
however, a direct causal relationship with the drug has not been established and
patients with Crohn’s disease are known to have an increased incidence of GI and
certain extraintestinal cancers.152 156
Metronidazole has shown mutagenic activity in several in vitro studies; however, in vivo
studies in mammals failed to demonstrate mutagenic effects.
Oral metronidazole was carcinogenic in mice and rats in chronic studies, but similar
studies in hamsters were negative. Long-term, controlled studies are needed to evaluate
the carcinogenic and mutagenic effects of metronidazole in humans. The manufacturers
state that unnecessary use of metronidazole should be avoided, and the drug should be
used only in serious infections where the potential benefit outweighs the possible risk.
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 singledose 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 extendedrelease 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
Drug Interactions
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 (QTc) 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 QTc 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
Acute Toxicity
The acute lethal dose of metronidazole in humans is not known. Neurotoxic effects,
including seizures and peripheral neuropathy, have occurred in individuals who received
6–10.4 g of metronidazole orally every other day for 5–7 days for the treatment of
malignant tumors.152 156 197 430 455 Nausea, vomiting, and ataxia without serious resultant
toxicity have been reported in individuals who ingested up to 15 g of metronidazole in a
single dose.152 197 430 The oral LD50 of metronidazole exceeds 5 g/kg in albino rats.147
If acute overdosage of metronidazole occurs, symptomatic and supportive treatment
should be initiated.152 156 197 430 455
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 unionized 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 antiinflammatory 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. granulosum179 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 extendedrelease 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 pKa 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 wellclosed, 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
Preparations
Excipients in commercially available drug preparations may have clinically important
effects in some individuals; consult specific product labeling for details.
Metronidazole
Routes
Dosage
Forms
Brand
Strengths Names
Manufacturer
Oral
Capsules
375 mg
Flagyl® 375
Pfizer
Tablets
250 mg*
Metronidazole
Tablets
Routes
Dosage
Forms
Brand
Strengths Names
500 mg*
Manufacturer
Metronidazole
Tablets
Tablets,
750 mg
extendedrelease,
filmcoated
Flagyl® ER
Pfizer
Tablets,
filmcoated
250 mg*
Flagyl®
Pfizer
500 mg*
Flagyl®
Pfizer
Parenteral Injection, 5 mg/mL* Flagyl® I.V.
for IV
RTU®
infusion
(Viaflex®
only
[Baxter])
SCS
Pharmaceuticals
Metronidazole Various
Injection
Manufacturers
®
(PAB
[Braun])
Metronidazole Abbott
Injection
(available in
LifeCare® and
glass
containers)
Metronidazole Various
Injection
Manufacturers
®
RTU
(Viaflex®
[Baxter])
* available from one or more manufacturer, distributor, and/or repackager by generic
(nonproprietary) name
Metronidazole Combinations
Dosage
Routes Forms Strengths
Kit
4 Capsules,
Tetracycline
Brand
Names
Helidac®
Therapy
Manufacturer
Prometheus
Dosage
Routes Forms Strengths
Hydrochloride
500 mg
4 Tablets,
Metronidazole,
250 mg, (with
povidone)
Brand
Names
Manufacturer
(available
as 14
blister
cards)
8 Tablets,
chewable,
Bismuth
Subsalicylate,
262.4 mg, (with
povidone)
Metronidazole Hydrochloride
Routes
Dosage
Forms
Strengths
Parenteral For
500 mg (of
injection, metronidazole)
for IV
infusion
only
Brand
Names
Manufacturer
Flagyl
SCS
®
I.V.
Pharmaceuticals
(with
mannitol
415 mg)
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This
pricing information was updated 03/2011. For the most current and up-to-date pricing
information, please visit www.drugstore.com. Actual costs to patients will vary
depending on the use of specific retail or mail-order locations and health insurance
copays.
Flagyl 250MG Tablets (PFIZER U.S.): 30/$99.99 or 90/$275.98
Flagyl 375MG Capsules (PFIZER U.S.): 30/$136 or 90/$390.97
Flagyl 500MG Tablets (PFIZER U.S.): 30/$180 or 90/$510
Flagyl ER 750MG 24-hr Tablets (PFIZER U.S.): 30/$365.98 or 90/$1066.01
MetroNIDAZOLE 250MG Tablets (TEVA PHARMACEUTICALS USA): 90/$15.98 or
180/$17.97
MetroNIDAZOLE 500MG Tablets (TEVA PHARMACEUTICALS USA): 30/$12.99 or
90/$27.97
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions June 2007.
American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue,
Bethesda, Maryland 20814.
† Use is not currently included in the labeling approved by the US Food and Drug
Administration.
References
Only references cited for selected revisions after 1984 are available electronically.
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