European Review for Medical and Pharmacological Sciences 2019; 23: 397-401 Therapeutic uses of metronidazole 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 antibiotic widely used in different medical conditions such as trichomoniasis, amoebia- sis, and giardiasis among others. Its use has Metronidazole is a synthetic antibiotic derivat- been associated with toxicity; however, it is not ized from azomycin, a nitroimidazole 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 infection caused by the protozoan tigation in this field. MATERIALS AND METHODS: Relevant infor- Trichomonas vaginalis. Further, metronidazole has mation, original research articles, clinical tri- been effective against dysentery and liver abscess 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 Giardia 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 Trichomonas vaginalis; 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 infections caused forms of 250 or 500 mg are rapidly absorbed and by Bacteroides, Fusobacteria and Clostridia, ro- distributed almost to the entire body. The liver is the sacea, oral and dental infections, bone and joint main organ responsible for metabolizing metronida- infections, gynecologic infections, endocarditis, 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 nausea, abdominal trichomoniasis treatment; however, subsequent- pain, and diarrhea. 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 drugs 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 drug. 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 tetracycline 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 redox potential of their electron transport compo- with acid suppression regimens15-17. nents, which are responsible for nitro group re- duction and generate toxic metabolites. Clostridium Difficile These metabolites such as N-(2-hydroxyethyl) C. difficile colitis 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 Antiparasitic 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 bacteria (for example, Bacteroides fragilis) in Giardia lamblia, Entamoeba histolytica, Clostri- combination with other antibiotics such as cefa- dium difficile, Helicobacter pylori,among others1. zolin, cefuroxime, ceftriaxone, quinolone, cefta- zidime, cefepime, carbapenems, piperacillin or Amoebiasis tazobactam depending on the infection type. Me- Amoebiasis is an infection caused by the protozo- tronidazole dosage varies in anaerobic infections; an Entamoeba histolytica that can result in amebic however, 500 mg administered intravenously colitis or amebic liver abscess. 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 Bacterial Vaginosis postoperative anaerobic infections when is used Metronidazole is useful to treat some bacterial as a prophylactic treatment in appendicitis, 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 Gardnerella vaginalis. A gel Rosacea 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, peripheral neuropathy, and encephalopathy