Version May 2024
INTRODUCTION — Metronidazole is one of the mainstay drugs for the treatment of anaerobic infections [1,2]. It is approved by the US Food and Drug Administration for the treatment of anaerobic and protozoal infections. Metronidazole exerts its antimicrobial effects through the production of free radicals that are toxic to the microbe.
The use of metronidazole for treating specific infections is discussed separately. (See "Anaerobic bacterial infections" and "Clostridioides difficile infection in adults: Treatment and prevention" and "Intestinal Entamoeba histolytica amebiasis" and "Extraintestinal Entamoeba histolytica amebiasis" and "Trichomoniasis: Clinical manifestations and diagnosis".)
MECHANISM OF ACTION — Activity against most obligate anaerobes occurs through a four-step process:
●Entry into the microorganism – Metronidazole is a low molecular weight compound that diffuses across the cell membranes of anaerobic and aerobic microorganisms. However, antimicrobial activity is limited to anaerobes [3].
●Reductive activation by intracellular transport proteins – Metronidazole is reduced by the pyruvate:ferredoxin oxidoreductase system in obligate anaerobes, which alters its chemical structure. Pyruvate:ferredoxin oxidoreductase normally generates adenosine triphosphate (ATP) via oxidative decarboxylation of pyruvate. With metronidazole in the cellular environment, its nitro group acts as an electron sink, capturing electrons that would usually be transferred to hydrogen ions in this cycle. Reduction of metronidazole creates a concentration gradient that drives uptake of more drug and promotes formation of intermediate compounds and free radicals that are toxic to the cell [3-5].
●Reduced intermediate particle interacts with intracellular targets – Cytotoxic-intermediate particles interact with host cell deoxyribonucleic acid (DNA), resulting in DNA strand breakage and fatal destabilization of the DNA helix [6,7].
●Breakdown of cytotoxic-intermediate products – The toxic-intermediate particles decay into inactive end products [8].
Metronidazole is also cytotoxic to facultative anaerobic bacteria such as Helicobacter pylori and Gardnerella vaginalis, but the mechanism of this action is not well understood [3]. Metronidazole exerts rapid bactericidal effects against anaerobic bacteria with a killing rate proportional to the drug concentration [9,10]. Concentration-dependent killing has also been observed with Entamoeba histolytica and Trichomonas vaginalis [11,12]. Metronidazole kills Bacteroides fragilis and Clostridium perfringens more rapidly than clindamycin [13]. (See "Clindamycin: An overview".)
No apparent antagonism exists between metronidazole and other antimicrobial agents, such as clindamycin, rifampin, and ticarcillin, against strains of B. fragilis [14].
RESISTANCE — Despite extensive worldwide use, acquired resistance to metronidazole among anaerobic bacteria is rare.
Anaerobes — Surveys demonstrate that more than 95 percent of anaerobic isolates in the United States are susceptible to metronidazole [15,16]. Among Bacteroides spp, one large multicenter study of more than 4000 strains collected over a seven-year period in the 1990s revealed no isolates resistant to metronidazole [17]. A second survey during that time period also found no resistance in 542 bloodstream B. fragilis isolates from 12 United States medical centers [18]. Through 2007, only three metronidazole-resistant cases were reported in United States surveillance studies [19]. Subsequently, metronidazole-resistant B. fragilis infections in the United States have been described in several case reports [20-22]. The organisms were resistant to multiple other antibiotics in addition to metronidazole. Affected patients had either traveled or were hospitalized internationally, which may have contributed to acquisition of these resistant B. fragilis strains.
Outside the United States, metronidazole resistance among gram-negative anaerobes has been reported more frequently and appears to be rising in some countries such as India [23]. Resistance rates vary by country but are generally low in most countries. Predictions were made that the incidence of metronidazole resistance would rise with increased use of the drug for the treatment of antibiotic-associated colitis [24]. However, a study from France compared Clostridioides difficile isolates from 1991 and 1997 and found no increase in minimum inhibitory concentration (MIC) to metronidazole or vancomycin among these strains [25].
In Bacteroides species, resistance has been conferred by both plasmid- and chromosomally mediated mechanisms, although plasmid-mediated transfer of resistance to susceptible strains has been rare [26]. Multiple steps appear necessary for resistance to develop, which may explain why resistance is rare in the absence of long-term therapy [27]. Resistance is conferred through a reduction in pyruvate:ferredoxin oxidoreductase activity, which limits cellular uptake of metronidazole and subsequent activation. The level of susceptibility and rate of drug uptake varies with the level of pyruvate:ferredoxin oxidoreductase activity. Resistant bacteria compensate for reduced action of pyruvate:ferredoxin oxidoreductase by increasing lactate dehydrogenase activity [28].
Helicobacter pylori — Although development of resistance to metronidazole in anaerobic bacteria is rare, it has been reported more frequently with H. pylori [29,30]. A systematic review of 19 studies performed in the United States found that more than 30 percent of H. pylori isolates were resistant to metronidazole [31]. Data regarding the mechanism of resistance to metronidazole are evolving. Mutations in the rdxA gene, which encodes an enzyme that activates the drug, may result in resistant strains of H. pylori. Mutations in other redox genes such as frxA may also contribute to resistance synergistically in the presence of rdxA mutations [32]. Other mechanisms may also contribute to resistance, such as reduced uptake or efflux of metronidazole [33-35].
Several reports have documented the development of resistance and subsequent clinical failure among patients receiving metronidazole for H. pylori infections [36,37]. One study found that eradication rates among 196 patients with H. pylori infection were significantly lower for metronidazole-resistant strains than metronidazole-susceptible strains (67 versus 87 percent) [38]. A meta-analysis of 49 studies found that resistance to metronidazole decreased the efficacy of treatment by a mean of 38 percent, but there was significant heterogeneity in the results [39]. The outcome was more dramatic for clarithromycin resistance, although the number of studies available for analysis was fewer.
Trichomonas vaginalis — Resistant T. vaginalis strains have been isolated from patients with refractory trichomonal infections [40-42]. In these organisms, the pyruvate:ferredoxin oxidoreductase protein is contained in a hydrogenosome, since the organism lacks mitochondria [43]. Resistance to metronidazole is associated with reduced transcription activity of the ferredoxin gene that results in decreased intracellular levels of ferredoxin and reduced pyruvate:ferredoxin oxidoreductase activity. In addition, oxidation of pyruvate to lactate within hydrogenosomes is terminated and occurs instead in the cytosol via lactate dehydrogenase [44,45]. (See "Trichomoniasis: Clinical manifestations and diagnosis".)
Susceptibility testing — Susceptibility testing for anaerobic bacteria is not routinely performed in clinical laboratories since it is cumbersome and not well standardized. However, testing may be indicated for certain serious infections, including brain abscess, endocarditis, osteomyelitis, arthritis, prosthetic device or vascular graft infection, and refractory or recurrent bacteremia. Testing might also be useful for persistent infections, for infections in which medical rather than surgical therapy is chosen, and for those in which prolonged therapy is anticipated. The Clinical Laboratory Standards Institute (formerly called the National Committee for Clinical Laboratory Standards) has established for anaerobes a breakpoint of 8 mcg/mL for susceptibility, 16 mcg/mL for intermediate susceptibility, and ≥32 mcg/mL for resistance to metronidazole.
The primary benefit of susceptibility testing is not to document susceptibility but rather to demonstrate unexpected resistance to an antimicrobial that is normally useful. Many clinicians will request anaerobic susceptibility testing from a reference laboratory when a patient has not responded clinically to an appropriate regimen directed at anaerobes. While awaiting the results of this testing, the patient should be changed to a different empiric therapy.
The clinical relevance of documented bacterial resistance in the setting of mixed anaerobic infections remains unclear. Other factors, including surgical debridement and the presence of comorbidities, significantly affect treatment outcomes. One prospective multicenter study assessed mortality, clinical treatment failure, and microbiologic persistence in 128 patients with Bacteroides bacteremia; susceptibility testing was performed on all isolates [46]. All of the outcome measures were worse for patients who received drugs that were not active against the organism compared with those with susceptible isolates (45 versus 16 percent 30-day mortality; 82 versus 22 percent clinical failure; and 47 versus 12 percent microbiologic persistence). No isolates were resistant to metronidazole in this study.
SPECTRUM OF ACTIVITY — Metronidazole is active against a broad array of anaerobes, protozoa, and microaerophilic bacteria.
Anaerobes — Metronidazole exerts potent bactericidal activity against anaerobic gram-negative organisms such as Bacteroides spp, Prevotella spp, Porphyromonas spp, Fusobacterium spp, Bilophila wadsworthia, and Capnocytophaga [47-49]. Anaerobic cocci such as Peptostreptococcus and Veillonella species are also inhibited by metronidazole.
Metronidazole is active against the anaerobic gram-positive bacilli of Clostridium spp, although Clostridium ramosum may require higher concentrations of the drug for inhibition [50,51]. Among gram-positive anaerobic bacilli, metronidazole activity is generally lower or variable. Seventy-five percent of Actinomyces spp, Propionibacterium propionica, Cutibacterium (formerly Propionibacterium) acnes, and Lactobacillus species are resistant to metronidazole [48-52]. Susceptibility of Mobiluncus is variable; Mobiluncus curtisii is usually resistant to metronidazole, whereas Mobiluncus mulieris is often susceptible [53,54].
Other organisms — Metronidazole is also active against anaerobic protozoa such as T. vaginalis, E. histolytica, Giardia lamblia, Blastocystis hominis, and Balantidium coli. G. vaginalis and Actinobacillus actinomycetemcomitans are usually susceptible to the parent compound; the hydroxy metabolite of metronidazole is two to eight times more active against these organisms [55,56]. Activity of metronidazole against H. pylori varies. (See 'Helicobacter pylori' above.)
PHARMACOKINETICS — Two of the hallmarks of metronidazole are that the drug achieves high serum concentrations following oral administration and that its tissue penetration is excellent.
Systemic metronidazole — Metronidazole is well absorbed after oral administration and is virtually 100 percent bioavailable [57].
Metronidazole generally distributes well into body tissues and, unlike clindamycin, effectively penetrates the blood-brain barrier. In patients without meningeal inflammation, cerebrospinal fluid (CSF) levels approximate 45 percent of corresponding serum concentrations [58]. Patients with meningitis experience similar CSF and serum concentrations. Metronidazole exhibits excellent penetration into brain abscesses, where concentrations approximate that in serum [59]. Metronidazole also distributes well into muscle tissue of patients with sepsis or those undergoing surgery [60,61].
Metronidazole is minimally protein bound, with approximately 80 percent or more circulating as free drug. Concentrations sufficient for therapeutic activity are achieved in hepatic abscesses as well as alveolar bone. Among patients with common bile duct obstruction, metronidazole concentrations in the common bile duct following intravenous administration were reportedly 56 to 99 percent that of serum. Among patients with gallstones but preserved gallbladder function and among those with absent gallbladder function but a patent cystic duct, metronidazole concentrations in the gallbladder bile, common duct bile, and serum were similar. By contrast, little to no metronidazole was recovered from gallbladder bile among patients who had a stone blocking the cystic duct [62].
Metronidazole exhibits a dose-dependent metabolism and is metabolized in the liver to glucuronide-conjugated and oxidative products, including a hydroxy-metabolite, which has 30 to 65 percent of the activity of the parent compound [63]. Six to 18 percent of metronidazole is excreted unchanged in urine; the metabolites are also excreted in the urine.
The half-life of metronidazole in patients with normal renal function is six to nine hours and is unchanged in those with renal insufficiency. Some studies have demonstrated that elimination of metronidazole metabolites may be reduced among those with renal insufficiency, but there are no specific recommendations for dose reduction in this patient population [64]. Hemodialysis may increase the clearance of metronidazole by 100 percent or more, resulting in a shortened half-life of only 2.1 to 3.3 hours [64-67]. The wide therapeutic index of the drug may make dose supplementation necessary only in seriously ill patients. The pharmacokinetics of metronidazole and its metabolites are not appreciably affected by chronic ambulatory peritoneal dialysis, with peritoneal dialysis accounting for only 8.9 percent of total body clearance [68]. However, the half-life of the drug may be extended to 18 to 20 hours in those with hepatic failure [69-80]. The delay in elimination is directly related to the extent of liver impairment.
The wide therapeutic index and a half-life that approaches 12 hours of metronidazole have prompted some to question whether three times a day dosing for most anaerobic infections is necessary for optimal clinical outcomes. Although a few retrospective studies have demonstrated similar clinical outcomes with twice-daily dosing of metronidazole, further studies are needed to elucidate which patients and/or infections are suitable for lower metronidazole dosing. There are limited data for certain populations and infections so more frequent dosing is still commonly used in pediatrics, central nervous system infections, parasitic/amebic infections, and C. difficile infection.
In a retrospective, single-center pre- and postintervention study of 200 patients with indications for metronidazole, there were no differences in clinical cure (85 versus 85 percent), mean duration of antibiotic therapy (5.9 versus 5.8 days), or hospital length of stay (8.1 versus 6.7 days) in patients who received twice-daily dosing compared with thrice-daily dosing of metronidazole 500 mg [81]. Patients with C. difficile, parasitic, amebic, and central nervous system infections were excluded from the study, and more than 90 percent of participants received metronidazole empirically and did not appear to have a confirmed anaerobic infection. In another multi-center retrospective study of 85 patients with confirmed anaerobic bacteremia, there was no significant difference in mortality, length of stay, or escalation of therapy in patients receiving twice-daily dosing compared with thrice-daily dosing of metronidazole 500 mg [82]. In vitro studies similarly demonstrated that twice-daily dosing achieved the MICs for most anaerobic organisms (eg, Bacterioides fragilis) [76,83].
Among children and adolescents, the pharmacokinetics of metronidazole are similar to those of adults. However, metabolic elimination of metronidazole is significantly decreased among premature neonates, with clearance and half-life correlating with gestational age. Careful dose adjustments are thus recommended for this patient population [57,74,75].
Topically administered metronidazole — When applied to the face, metronidazole gel is absorbed systemically to a negligible degree [76]. When administered intravaginally, metronidazole gel is absorbed to varying degrees, depending upon formulation. The commercial 0.75% intravaginal gel produced peak serum concentrations of 0.2 to 0.3 mg/L, which are significantly less than those observed after a single 500 mg oral dose (8 to 13 mg/L) [76]. However, vaginal suppositories have produced slightly higher peak serum concentrations of 1.1 to 1.9 mg/L (approximately 10 percent of concentrations achieved with oral administration) than those with the commercial intravaginal gel [76].
TOXICITY — The most common adverse effects associated with systemic metronidazole therapy are gastrointestinal [77].
Gastrointestinal — Gastrointestinal symptoms such as nausea, anorexia, vomiting, diarrhea, abdominal cramping, and constipation have been associated with metronidazole. An unpleasant metallic taste is also often experienced by those taking metronidazole systemically. Furry tongue, glossitis, and stomatitis have also been experienced and are associated with candidal overgrowth. Although the drug is active against C. difficile, cases of C. difficile colitis have been reported rarely among patients receiving metronidazole [78].
Nervous system — Seizures, peripheral neuropathy, dizziness, vertigo, ataxia, confusion, encephalopathy, irritability, weakness, insomnia, headache, and tremors have been reported among patients receiving metronidazole, particularly among those receiving high doses of the drug [75,79,80,84-86]. In some patients, metronidazole neurotoxicity can be visualized on magnetic resonance imaging and is characterized by bilateral symmetric T2 hyperintense lesions that resolve after metronidazole cessation [87]. A randomized trial evaluating metronidazole (500 mg three times daily) for the treatment of pulmonary multidrug-resistant tuberculosis was stopped early due to a high rate of peripheral neuropathy with metronidazole compared with placebo (50 versus 12 percent) [88]. Treatment was stopped at a median of 31 days in 12 patients, and the neuropathies resolved in most patients a median of 1006 days after treatment had been started. There was no correlation between pharmacokinetic measures of metronidazole exposure and peripheral neuropathy. All patients were taking other antituberculosis medications, but these were not described in detail.
Allergic reactions — Hypersensitivity reactions have been reported among patients receiving metronidazole and may include urticaria, erythematous rash, flushing, bronchospasm, and serum sickness [89].
Genitourinary — Transient darkening of the urine to a deep red-brown color is common among patients receiving metronidazole. Dysuria, cystitis, incontinence, vaginal Candida overgrowth, and decreased libido have also been reported less commonly.
Disulfiram-like reactions — There have been case reports suggesting a possible disulfiram-like reaction when metronidazole is administered systemically or vaginally to patients drinking ethanol [90-93], but it remains unclear whether metronidazole causes this reaction. The typical disulfiram reaction causes flushing, tachycardia, palpitations, nausea, and vomiting. In a review of cases of disulfiram-like reactions in patients receiving metronidazole published between 1964 and 1999, eight cases were identified [91]. Four of the cases were serious, including one fatality. Reported reactions included flushing, sweating, headache, nausea, vomiting, dyspnea, skin pallor, acidosis, and death. However, the authors of the review noted that, in most of these cases, there were possible alternative explanations for the reactions that were not explored.
The mechanism of disulfiram-like reactions with metronidazole is unknown; unlike disulfiram, metronidazole does not inhibit alcohol metabolism in the liver and does not increase acetaldehyde production. In a study of 12 healthy volunteers, no apparent adverse effects or increase in blood acetaldehyde levels were observed when six individuals received metronidazole 200 mg three times a day for five days followed by a single dose of ethanol 0.4 g/kg (approximately half a standard drink) compared with six individuals who ingested ethanol and placebo [94]. A study reported that rats receiving metronidazole and ethanol concomitantly had an increase in intracolonic acetaldehyde concentrations but not blood acetaldehyde concentrations compared with rats receiving ethanol alone [95]. The investigators suggested that this may be explained by metronidazole's impact on intestinal flora, with conversion to alcohol dehydrogenase-containing anaerobes; the mechanism of the disulfiram-like reaction with metronidazole may therefore be related to changes in gut flora with exposure to this antibiotic. Other studies have suggested that histamine reactions have been associated with similar intracolonic acetaldehyde concentrations, and investigators hypothesize that this could possibly lead to the disulfiram-like reaction with metronidazole [94].
While clear evidence of a disulfiram-like reaction with metronidazole is lacking, the manufacturer's product information recommends avoiding alcohol ingestion during metronidazole therapy and for at least 48 hours afterwards. Without larger studies suggesting safe coadministration of metronidazole and ethanol, concomitant use should be avoided.
Other — Less common adverse reactions reported with use of metronidazole include joint pain and thrombophlebitis; hematologic effects such as reversible neutropenia and thrombocytopenia have rarely occurred [96,97]. Several case reports have also documented pancreatitis and hepatitis associated with use of metronidazole, although these events are rare [98,99].
There have been a few reports of QT interval prolongation with use of metronidazole [100-103]; this may be of particular concern in patients receiving other drugs that prolong the QT interval or when other risk factors are present, particularly congenital prolonged QT syndrome. (See 'Drug interactions' below.)
Metronidazole topical (dermatologic) gel — Systemic effects are rare with topical application of metronidazole gel, since very little metronidazole is absorbed systemically. Local effects including skin irritation, transient skin erythema, and mild dryness or burning of the skin are uncommon.
Metronidazole vaginal gel — Genitourinary effects include symptomatic Candida cervicitis/vaginitis, vaginal, perineal, or vulvar itching, vaginal discharge, and vulvar swelling. Cramps and abdominal or uterine pain have also been reported among women using metronidazole intravaginally. Nausea, metallic taste, constipation, diarrhea, decreased appetite, dizziness, and headache have been reported less commonly. Increased or decreased white blood counts and rash are rare.
DRUG INTERACTIONS — As mentioned above, ingestion of alcohol during metronidazole therapy can result in a disulfiram-like reaction (see 'Disulfiram-like reactions' above). Ethanol-containing medications such as elixirs as well as tipranavir capsules, intravenous (IV) trimethoprim-sulfamethoxazole, and many cough/cold syrups may also lead to a disulfiram-like reaction when ingested with metronidazole. In addition, use of metronidazole with disulfiram can result in an acute psychosis or confusional state [57]. Sudden deaths have been attributed to metronidazole/ethanol reactions [90,91].
Metronidazole can promote renal retention of lithium, resulting in increased lithium levels and lithium toxicity [104,105]. Metronidazole can also decrease elimination of ergot derivatives, so concomitant use of these agents is not recommended.
Most drug interactions with metronidazole occur in the liver, where metronidazole is metabolized. It has been suggested that metronidazole selectively inhibits aromatic oxidase reactions in the liver, a property that may explain its inhibition of phenytoin, warfarin, and carbamazepine metabolism. Metronidazole decreases the clearance of phenytoin approximately 15 percent and thus prolongs its elimination half-life [106]. This reduced elimination may result in increased serum concentrations of phenytoin. Caution should also be used when administering fosphenytoin and metronidazole concomitantly. Metronidazole can increase the anticoagulant effect of warfarin via its S(-)-warfarin stereoisomer [107]. Thus, patients receiving the two agents concomitantly should have prothrombin time monitored closely and warfarin doses adjusted accordingly. One case report of carbamazepine toxicity in a patient five days after initiation of metronidazole suggests a potential drug interaction may also exist between metronidazole and carbamazepine [108].
Torsades de pointes has been reported rarely when metronidazole has been used in combination with other drugs that prolong the QT interval or when other risk factors have been present [102,109,110]. As an example, a potential interaction between metronidazole and amiodarone in a 71-year-old female appeared to result in QTc prolongation and torsades de pointes [109]. Cytochrome P450-3A4 inhibition by metronidazole may have resulted in increased serum concentrations of amiodarone, leading to marked QT interval prolongation and torsades de pointes. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)
A few investigators have reported significant increases in cyclosporine and tacrolimus serum concentrations after patients were initiated on metronidazole therapy [111-113]. However, in a cohort study of 52 adult solid organ transplant recipients with C. difficile infection, there were similar mean elevations in dose-normalized tacrolimus trough levels in patients treated with either metronidazole or vancomycin [114]. The observed increase in tacrolimus levels may be related to the effect of C. difficile infection on enterocyte integrity, rather than to a specific drug interaction.
A small study reported interactions between metronidazole and busulfan. Patients who received oral metronidazole as graft-versus-host disease prophylaxis in the setting of hematopoietic cell transplantation had significantly higher levels of busulfan than controls who received busulfan alone [115]. More adverse events were noted in the group of subjects receiving metronidazole and busulfan together (multiorgan failure, venoocclusive disease, and hemorrhagic cystitis), so the authors recommend avoiding administration of these agents together.
Hepatic enzyme inducers such as barbiturates, phenytoin, and rifampin can significantly reduce plasma concentrations of metronidazole by increasing its clearance [116]. Prednisone may also enhance hepatic clearance of metronidazole [117]. These interactions can result in clinical failure of metronidazole therapy [116]. Cimetidine may increase serum metronidazole concentrations by inhibiting hepatic enzyme activity, but data regarding this interaction are conflicting [118]. Binding interactions with the gastrointestinal tract can also occur between metronidazole and aluminum- or magnesium-containing antacids, as well as cholestyramine. The interactions result in approximately 15 to 20 percent decreased bioavailability of metronidazole.
Coadministration of flavonoid extract of milk thistle, silymarin, can lead to increased clearance of metronidazole, possibly through silymarin induction of intestinal P-glycoprotein [119]. Thus, concomitant use of these agents should be avoided.
Additional information on drug interactions with metronidazole can be found in the Lexicomp drug information monographs included within UpToDate. (See "Metronidazole (systemic): Drug information" and "Metronidazole (systemic): Pediatric drug information" and "Metronidazole (topical): Drug information" and "Metronidazole (topical): Pediatric drug information".)
SPECIAL POPULATIONS
Pregnancy — The use of metronidazole in pregnancy is somewhat controversial. In general, use of metronidazole should be avoided, particularly during the first trimester [120]. It should only be used in pregnancy if treatment of infection is necessary and no safe alternative agents are available (eg, bacterial vaginosis, trichomoniasis) [121]. However, the United States Centers for Disease Control and Prevention suggests that treatment of bacterial vaginosis with short courses of metronidazole in pregnancy appears to pose a low risk of teratogenicity or mutagenic effects.
In general, some studies have shown a slightly increased risk of congenital abnormalities or preterm birth when mothers used metronidazole, although data are conflicting. Although animal data suggest increased carcinogenesis, data in humans have not supported this observation. Representative data, according to outcome, are summarized below.
●Congenital malformations – Metronidazole crosses the placenta and rapidly enters the fetal circulation. Well-controlled studies are limited, and available data are conflicting. Concern for congenital malformations (eg, congenital hydrocephalus, cleft lip/palate) with the use of metronidazole during pregnancy was raised by two population-wide case control studies from the Hungarian Congenital Abnormality Registry. One study found that mothers of infants born with cleft lip/palate had a slightly higher rate of metronidazole use in the first trimester compared with mothers of infants born without cleft lip/palate (0.66 versus 0.53 percent) [122]. In the other study, vaginal metronidazole use during first trimester of pregnancy was associated with a slightly increased absolute risk of congenital hydrocephalus in infants [123]. Both studies, however, had a high recall bias.
Subsequent cohort studies have not shown an increased risk of congenital malformations [124,125]. As an example, in a prospective cohort trial of 190 pregnant females exposed to metronidazole (86.2 percent during first trimester) compared with 575 who were not exposed, there was no difference in the rate of major malformations between the two groups (1.6 versus 1.4 percent) [125]. In another retrospective study of 2829 singleton/mother pairs, 348 of whom were treated with metronidazole during first trimester of pregnancy, there was no association found between metronidazole treatment and congenital abnormalities (odds ratio 0.86, 95 CI 0.3 to 2.45) [126].
●Childhood cancers – Although metronidazole is carcinogenic in rodents, studies in humans have not shown the same risk. In a retrospective cohort of 328,846 children under the age of five (8.1 percent of whom were exposed in utero to metronidazole), there was no difference in childhood cancers between the two groups [127]. However, the infrequent use of metronidazole in pregnancy and the rarity of childhood cancers makes it difficult to establish a causative effect.
●Preterm birth/low birth weight – Metronidazole use during pregnancy is unlikely to be associated with preterm births or low birth weight in infants. Although a prospective study of 190 females exposed to metronidazole in pregnancy demonstrated a lower newborn birth weight (independent of gestational age at delivery) compared with females who were not exposed to metronidazole [125], subsequent studies did not corroborate this finding. In a retrospective study of 2829 singleton/mother pairs, 922 of whom received metronidazole treatment during pregnancy, there was no association between metronidazole use and preterm birth or low birth weight [126]. Furthermore, in a blinded, randomized controlled trial of over 2000 pregnant individuals who were randomized to antibiotics (metronidazole plus erythromycin) at 24 weeks of pregnancy or placebo for the prevention of preterm births, there was no difference in mean gestational age at delivery, percentage of preterm births, or birthweight between the two groups [128].
Nursing — Metronidazole is excreted in the breast milk after systemic administration at concentrations similar to those in the serum. Its half-life in breast milk is approximately 9 to 10 hours. Thus, it is recommended that nursing be discontinued during and for three days after metronidazole therapy.
Hemodialysis/chronic ambulatory peritoneal dialysis — Although metronidazole is significantly removed by hemodialysis, no specific dose recommendations are made for this patient population. Dose modifications are not recommended for patients undergoing chronic ambulatory peritoneal dialysis.
Renal/hepatic dysfunction — No specific dose adjustments are recommended for patients with renal or hepatic dysfunction receiving metronidazole. However, since accumulation of the drug and its metabolites can occur in those with hepatic dysfunction, lower doses may be considered based upon severity of illness and patient tolerability. Doses of 500 mg intravenously once or twice daily have been recommended for patients with severe liver failure [27,67,129].
SUMMARY
●Spectrum of activity − Metronidazole is one of the mainstay drugs for the treatment of anaerobic infections. It is approved by the US Food and Drug Administration for the treatment of anaerobic and protozoal infections. (See 'Introduction' above and 'Spectrum of activity' above.)
●Mechanism of action − The mechanism of action of metronidazole against obligate anaerobes occurs through a four-step process that includes entry into the organism, reductive activation by intracellular transport proteins, interactions with intracellular targets, and breakdown of cytotoxic-intermediate products. Metronidazole is also cytotoxic to facultative anaerobic bacteria such as Helicobacter pylori and Gardnerella vaginalis, but the mechanism of action against these organisms is not well understood. (See 'Mechanism of action' above.)
●Resistance − Despite extensive worldwide use, acquired resistance to metronidazole among anaerobic bacteria is rare. Resistance to metronidazole has been reported more frequently with H. pylori. (See 'Resistance' above.)
●Pharmacokinetics − Two of the hallmarks of metronidazole are that the drug achieves high serum concentrations following oral administration and that its tissue penetration is excellent. Metronidazole generally distributes well into body tissues and, unlike clindamycin, effectively penetrates the blood-brain barrier. (See 'Pharmacokinetics' above.)
●Toxicity − The most common adverse effects associated with systemic metronidazole therapy are gastrointestinal (eg, nausea, anorexia, vomiting, diarrhea, abdominal cramping, constipation). Metronidazole can also cause nervous system effects (eg, peripheral neuropathy, confusion, dizziness). Metronidazole has also been associated with hypersensitivity reactions. (See 'Toxicity' above.)
●Drug interactions − Most drug interactions with metronidazole occur in the liver, where metronidazole is metabolized. It has been suggested that metronidazole selectively inhibits aromatic oxidase reactions in the liver, a property that may explain its inhibition of phenytoin, warfarin, and carbamazepine metabolism.
•Ingestion of alcohol during metronidazole therapy (administered orally or vaginally) can result in a disulfiram-like reaction characterized by flushing, tachycardia, palpitations, nausea, and vomiting. Ethanol-containing medications such as elixirs as well as tipranavir capsules, intravenous trimethoprim-sulfamethoxazole, and many cough/cold syrups can also lead to a disulfiram-like reaction when ingested with metronidazole.
•Metronidazole can promote renal retention of lithium, resulting in increased lithium levels and lithium toxicity.
•Metronidazole can also decrease elimination of ergot derivatives, so concomitant use of these agents is not recommended.
•Agents that induce hepatic enzymes, such as barbiturates, phenytoin, and rifampin, can reduce levels of metronidazole. These interactions have been associated with clinical failure of metronidazole.
●Use in pregnancy − Metronidazole should only be used during pregnancy if treatment of infection is necessary and no safe alternative agents are available (eg, bacterial vaginosis, trichomoniasis). (See 'Pregnancy' above.)
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