Chaochen Wang$^1$, Yingsong Lin$^1$, Masumi Okuda$^2$, Shogo Kikuchi$^1$
1.Aichi Medical University School of Medicine 2.Hyogo College of Medicine
Metronidazole (MNZ) has been broadly prescribed as therapy for \(H. pylori\) eradication worldwide.
Second line regimen using MNZ is covered under national health insurance in Japan.
Eradication rate :1
60.5% for PPI + AMPC + CLA (PAC) | 98.3% for PPI + AMPC + MNZ (PAM)
Resistance rate of CLA in Japanese children is reported to be more than 40%.2
MNZ \(\Longrightarrow\) Possibly carcinogenic to human (2B)
by International Agency for Research on Cancer, IARC in 1987
1: Unpublished data, Mabe et al.; 2: Kato and Fujimura 2010
Related literature (published until April. 2016) were reviewed.
(("Drug-Related Side Effects and Adverse Reactions"[Mesh]) AND "Metronidazole"[Mesh]) OR ("Metronidazole/adverse effects"[Mesh] OR "Metronidazole/toxicity"[Mesh]) OR (("Metronidazole"[Mesh]) AND "Carcinogenicity Tests"[Mesh])
Oral exposure of MNZ has shown carcinogenic activity in mice and rats.
|Pulmonary||\(\uparrow\)||1972||Rustia and Shubik|
|\(\uparrow\)||1983||Cavaliere et al.|
|Liver||\(\uparrow\)||1979||Rustia and Shubik|
|Lymphomas||\(\uparrow\)||1972||Rustia and Shubik|
|Mammary-gland||\(\uparrow\)||1979||Rustia and Shubik|
|\(\uparrow\)||1984||Cavaliere et al.|
|Pituitary-gland||\(\uparrow\)||1979||Rustia and Shubik|
|Genetic damage||Negative||2000||Touati et al|
|\(\downarrow\)||2013||Kumari and Singh|
Lack of evidence for cancer due to use of metronidazole. N Engl J Med. 1979;301:519–522. ヒトでの追跡研究
Data on MNZ carcinogenecity for humans is still not sufficient.
No increased cancer risk in 12,000 users of MNZ.1 \(\Longrightarrow\) Only followed for 2.5 years. (A letter to JAMA)
No association between short-term exposure to MNZ and cancer in human were found in 5,222 MNZ user/nonuser pairs (RR 0.98; 95% CI, 0.80$-$1.20)2
Another retrospective study3 of children (\(<\) 5 \(y.\), n \(=\) 328,846) who had been exposed to MNZ in utero also reported negative results (RR 0.81; 95% CI, 0.41$-$1.59) on cancer incidence of all sites.
1. Hari et al. 2013; 2. Farmakiotis et al. 2016; 3. Khan et al., 2007;4. Ohnishi et al. 2014;5. Kumar et al. 2013;6. O’Halloran et al. 2010.
Recommended regimens in UK (イギリスの小児除菌推奨レジメ)
|Age Range (\(y.\))||Oral dose (mg per day)
with omeprazole (PPI)
|AMPC||\(1\sim 6\)||250, twice||CLA|
|125, 3 times||MNZ|
|\(6\sim 12\)||500, twice||CLA|
|250, 3 times||MNZ|
|500, 3 times||MNZ|
|CLA||\(1\sim12\)||7.5 mg/kg (max. 500), twice||MNZ/AMPC|
|MNZ||\(1\sim 6\)||100, twice||CLA|
|100, 3 times||AMPC|
|\(6\sim 12\)||200, twice||CLA|
|200, 3 times||AMPC|
|400, 3 times||AMPC|
Abbreviations: AMPC, amoxicillin; CLA, clarithromycin; MNZ, metronidazole.
Evidence-based guidelines from ESPGHAN and NASPGHAN for Helicobacter pylori infection in children. J Pediatr Gastroenterol Nutr. 2011;53:230–243.
So far, there is no convincing evidence that short-term exposure to metronidazole would increase the risk of any cancer in human.
Considering the high resistance rate of clarithromycin in Japanese children, first-line therapy of PPI + amoxicillin + metronidazole would be an alternative option.