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European Review for Medical and Pharmacological Sciences 2019; 23: 397-401 Therapeutic uses of and its side effects: an update

A. HERNÁNDEZ CERUELOS, L.C. ROMERO-QUEZADA, J.C. RUVALCABA LEDEZMA, L. LÓPEZ CONTRERAS

Área Académica de Medicina, Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Circuito Ex Hacienda, Pachuca de Soto Hidalgo, México

Abstract. – OBJECTIVE: Metronidazole is Introduction an widely used in different medical conditions such as , amoebia- sis, and among others. Its use has Metronidazole is a synthetic antibiotic derivat- been associated with toxicity; however, it is not ized from azomycin, a produced well characterized. In this review, we discuss by the genera Actinobacteria and Proteobacteria. the different therapeutic uses of metronidazole In 1959, this compound was used for trichomonia- and its side effects in order to aid future inves- sis treatment, an caused by the protozoan tigation in this field. MATERIALS AND METHODS: Relevant infor- vaginalis. Further, metronidazole has mation, original research articles, clinical tri- been effective against and als, and reviews were collected from PubMed to produced by the intestinal protozoan parasite, En- know the state of the art of the different thera- tamoeba histolytica. It also was efficacious against peutic uses of metronidazole and the reported lamblia, another intestinal parasite that side effects. 1 RESULTS: causes malabsorption and epigastric pain . Metroni- Metronidazole was used by the dazole is available as orally, intravenously, vaginally first time in 1959, to treat an infection caused by ; subsequently, new ther- and rectally presentations, although the most clin- apeutic properties were discovered. Nowadays, ically used is the oral presentation. Its oral dosage Metronidazole is used to treat caused forms of 250 or 500 mg are rapidly absorbed and by , Fusobacteria and Clostridia, ro- distributed almost to the entire body. The liver is the sacea, oral and dental infections, and main organ responsible for metabolizing metronida- infections, gynecologic infections, , zole, where this is hydroxylated, acetylated and or septicemia, and respiratory tract infections. It al- conjugated with glucuronides. The metabolites are so can be used to treat Crohn´s disease or even 2-4 like prophylaxis, before surgical procedures. finally excreted mainly by the kidneys . Metronidazole is well tolerated with mild to mod- Metronidazole was introduced in 1959 for erate side effects such as , abdominal trichomoniasis treatment; however, subsequent- pain, and . Nevertheless, serious neu- ly, new pharmacological properties were uncov- rotoxicity, optic neuropathy, peripheral neurop- ered5. Due to the high cost and long time needed athy, and encephalopathy have been reported in for research and development of novel therapeutic rare cases. Their genotoxic effects observed in animal models are controversial in humans. molecules, exploring new uses of existing 6,7 CONCLUSIONS: The therapeutic use of metro- is a possible solution to treat infectious diseases . nidazole had increased worldwide. Even though In this review, we recapitulate the current clini- it is widely used, metronidazole has been asso- cal uses of metronidazole and discuss their side ciated with neurotoxicity and genotoxicity; how- effects. ever, its side effects are not well established. Conversely, its veterinary use is restricted in Pharmacodynamics some countries because of its tumor associa- tion. Subsequently, further studies are needed The mechanism of action of metronidazole to discover the secure use of metronidazole and has not been fully elucidated. However, its nitro describe new usages for this . group reduction by anaerobic organisms appears to be responsible for the cytotoxic and antimicro- Key Words: bial effects. The mechanism described for this Metronidazole, Therapeutic uses, Side effects. drug is summarized here:

Corresponding Author: Luilli López Contreras, Ph.D; e-mail: [email protected] 397 A. Hernández Ceruelos, L.C. Romero-Quezada, J.C. Ruvalcaba Ledezma, L. López Contreras

Metronidazole crosses the membrane of the cell in combination with bismuth and for target by passive diffusion; then, its nitro group is two weeks is highly effective for H. pylori era- reduced to nitro radicals by ferredoxin or flavodoxin. dication. Dosage may vary from 200 to 500 mg The selectivity of metronidazole for anaerobic three or five times daily. Metronidazole also has or microaerophilic microorganisms is due to the been combined with bismuth and amoxicillin or potential of their electron transport compo- with acid suppression regimens15-17. nents, which are responsible for nitro group re- duction and generate toxic metabolites. Difficile These metabolites such as N-(2-hydroxyethyl) C. difficile is a major cause of nosocomial oxamic acid and acetamide can react with DNA infections, causing morbidity and mortality in pa- and form adducts with guanosine1,5. tients. Its treatment is based on oral metronidazole, 500 mg three times a day for 10-14 days18-20. Antibiotic and Uses Metronidazole is usually, very effective to treat Anaerobic Infections infections caused by anaerobic or microaerophilic Metronidazole is also effective against anaero- microorganisms, such as Trichomonas vaginalis, bic (for example, Bacteroides fragilis) in Giardia lamblia, histolytica, Clostri- combination with other such as cefa- dium difficile, ,among others1. zolin, cefuroxime, , quinolone, cefta- zidime, cefepime, carbapenems, piperacillin or tazobactam depending on the infection type. Me- Amoebiasis is an infection caused by the protozo- tronidazole dosage varies in anaerobic infections; an that can result in amebic however, 500 mg administered intravenously colitis or amebic . Optimal treatment, every 8 h is the most common dose used13,21. usually effective for intestinal or hepatic infections by E. histolytica, includes three daily oral doses of Crohn’s Disease 750 mg of metronidazole for 5 or 10 days8-10. Crohn’s disease is a chronic inflammatory bowel disease, which has been hypothesized, is Giardiasis the result of an abnormal immune response to the Giardia lamblia is the most common intesti- gut microbiome in susceptible subjects. Metroni- nal parasite as the etiological agent of diarrheal dazole is used for the treatment of Crohn’s disease around the world; its treatment is based on 250 and its effectiveness has been evaluated in several mg of the drug thrice daily for 5 to 7 days11. clinical trials, suggesting that metronidazole has therapeutic benefits against the symptoms, such Trichomoniasis as perianal discharge and pain. However, control- Trichomonas vaginalis is a protozoan parasite led clinical trials are needed to establish the effi- responsible for one of the most sexually transmit- cacy of metronidazole for Crohn´s disease13,22. ted diseases, and its management includes a 2 g single dose of metronidazole. However, if the sin- Surgical Prophylaxis gle dose fails, the treatment can be administered Infections after surgical procedures contribu- during 7 days12,13. te to higher rates of mortality; however, a single dose of 500 mg metronidazole reduces the risk of postoperative anaerobic infections when is used Metronidazole is useful to treat some bacterial as a prophylactic treatment in , but infections. 500 mg are administered orally twice also is used in prophylactic treatment in surgical a day for a week. There is a second scheme con- procedures for the colon, head, and neck13,23-24. sisting of a single dose of 2 g of metronidazole, mainly used to treat . A gel presentation of 0.75% metronidazole, administe- Rosacea is a cutaneous disease of uncertain red intravaginally twice a day for five days is also etiology characterized by flushing, erythema, pa- effective for bacterial vaginosis13,14. pules, pustules and telangiectasia that affect the cheeks, nose, eyes, chin and forehead26. There Helicobacter Pylori are various treatments available for rosacea, but H. pylori causes peptic ulcers disease and it is topical metronidazole gel and azelaic acid appe- associated with stomach cancer. Metronidazole ar to be effective and safe according to multiple

398 Therapeutic uses of metronidazole and its side effects: an update clinical trials. 200 mg of metronidazole, admini- der metabolic activation39. Also, it has been re- stered orally twice a day for 12 weeks, is effica- ported, that metronidazole can induce an increase cious when tetracycline is not effective in rosacea in chromosomal aberrations and chromatid and treatment25-27. isochromatic breaks in the cell of patients treated with therapeutic doses of metronidazole40. Adverse Effects of Metronidazole In a study41 where patients were treated with me- Metronidazole is well tolerated with mild to mo- tronidazole 4 hours before surgery to remove colon derate side effects such as nausea, abdominal pain, tumors, a high concentration of the drug and its hy- and diarrhea. Serious neurotoxicity, optic neuro- droxyl metabolite were found inside the lesion and pathy, , and encephalopathy metastatic tumors, but not in healthy tissue. have been reported in rare cases. Metronidazole In carcinogenesis, its role is controversial be- neurotoxicity is not fully elucidated. Rao and col- cause metronidazole can induce genotoxic effects leagues suggested that the free radicals damage in human cells and in vivo; however, it nerves, while Alston, proposed the formation of a has been established with a carcinogenic role in thiamine analog derived from the metronidazole mice and rats. According to the IARC (Interna- that may result in a nutrition deficiency-like neu- tional Agency for Research on Cancer), there is ropathy. On the other hand, Scholars proposed that evidence to consider metronidazole as an animal the union of metronidazole and its metabolites to , but insufficient evidence in humans42. RNA provokes the inhibition of protein synthesis More studies are needed for clarifying the role of and axonal degeneration of nerve fiber13,28-31. metronidazole in human cancers. Peripheral neuropathy is uncommon with short term-use of metronidazole (4 weeks). Yet, the risk of peripheral neuropathy increases when the dose Conclusions is higher than 42 g; however, this effect is reversi- ble when discontinuing the drug therapy. Cerebel- Metronidazole was first described in 1959 as a lar dysfunction, visual impairment, vestibulotoxi- therapeutic agent to treat Trichomonas vaginalis city, cochleotoxicity, ataxic gait, dysarthria, and infection; over time, metronidazole has been used also have been reported when metroni- against Giardia lamblia, Entamoeba histolytica, dazole is used32-34. Clostridium difficile, Helicobacter pyloriand ana- erobic bacteria. Metronidazole is also used to tre- Genotoxicity of Metronidazole at Crohn´s disease, rosacea, and as a prophylactic Metronidazole induces single and double DNA after a surgical procedure. A lot of work must be strand breaks, especially in AT clusters. It also performed to elucidate new uses of metronidazo- forms adducts and GC-CG transversions. The le; however, some more studies are also needed to clastogenic effect is related to its hydroxylated find alternatives or variations of this drug because derivatives formed during its biotransformation of the increase of metronidazole-resistant micro- by cytochrome P45035-36. organisms. For the mouse micronucleus test and chromo- Metronidazole is widely used to treat a variety somal aberration in bone marrow cells, metroni- of infections due to its high efficacy compared dazole showed a dose-dependent effect, inducing with others drugs; however, their side effects cytogenetic damage in both models, but did not must be considered. Genotoxicity and neurotoxi- show alteration in the rate of polychromatic/ nor- city studies on humans should be done to clarify mochromic erythrocytes as a measure of its cyto- the role of metronidazole in human health. toxic effect37. In combination with , metronidazole was tested for its teratogenic ef- fect on mice, showing strong potentiation for the Conflict of Interest production of skeletal defects when administered The Authors declare that they have no conflict of interest. together38. Few studies have been done on human geno- toxicity; metronidazole and its analogues did not References induce sister chromatid exchanges in human lym- phocytes with or without S9 mixture, indicating 1) Samuelson J. Why metronidazole is active against that the drug only induced DNA minor ruptures both bacteria and parasites. Antimicrob Agents while its cytotoxic effect was observed only un- Chemother 1999; 43: 1533-1541.

399 A. Hernández Ceruelos, L.C. Romero-Quezada, J.C. Ruvalcaba Ledezma, L. López Contreras

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400 Therapeutic uses of metronidazole and its side effects: an update

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