Reply to letter to the editor: “The dosage of rifabutin in H. pylori eradication regimen should be appropriately determined in each area of the world”

We appreciate the interest of Losurdo et al.1 in our paper entitled “Rifabutin-based 10-day and 14-day triple therapy as a third-line and fourth-line regimen for Helicobacter pylori eradication: A pilot study. ”2 We agree with them in terms of the importance of confirming tuberculosis status before starting rifabutin therapy, including the regimen, and the assurance of empirical rescue regimens especially in third- or fourth-line treatment. Losurdo et al.1 raised concerns regarding the accuracy of the eradication rates we reported (83.3% in the 10-day group and 94.1% in the 14-day group with intention to treat) because recent studies show lower success rates (60%–80%) in relation to drug dose and treatment duration. There are few reports of rifabutin-containing regimen from Asia, while most of the reports are from Europe.3 Meanwhile, Wong et al.4 showed a 91% eradication rate and a 58% adverse-events rate with a rifabutin-containing regimen in China.4 Both of the Asian eradication rates are higher than those in previous reports.3 Rifabutin is metabolized and eliminated mainly by the CYP3A pathway and is a moderate inducer of CYP3A4 activity.5 Yamaori et al.6 revealed the difference between Japanese and Caucasian populations in the expression levels of messenger RNA (mRNA) for CYP3A4. Thus, we should determine the appropriate dosage of rifabutin because 300 mg per day may be a very high dose for Asian patients. Although Losurdo et al.1 described rifabutin 150 mg b.i. d. as low dose in their quadruple therapy, the daily dose was the same as that in our clinical trial (300 mg q.d.). 2 Furthermore, Perri et al.7 also showed that the triple therapy (pantoprazole 40 mg b.i.d., amoxicillin 1 g b.i.d., and rifabutin 300 mg q.d. for 10 days) was more effective and well tolerated than the quadruple therapy (pantoprazole 40 mg b.i.d., metronidazole 250 mg t.i.d., bismuth citrate 240 mg b.i.d., and tetracycline 500 mg q.i.d. for 10 days) (eradication rates: 86.6% vs. 66.6%, respectively). Therefore, it could not be determined whether the quadruple therapy is better than the rifabutin plus amoxicillin triple therapy. Losurdo et al.1 indicated that the amoxicillin resistance rate of our study (55%) is higher than the global rate.8 Although a broad international consensus has been formed about the cut-off points for antimicrobial resistance of clarithromycin and metronidazole, the cut-off point of amoxicillin has not been determined. In addition, the cut-off point of amoxicillin differs in each report (minimum inhibitory concentration (MIC) range 0.06–8 µg/ml). 8–10 Therefore, the amoxicillin resistance rate of our clinical data is simply not designated as high because most of the MICs of amoxicillin in our report were less than 1 µg/ml.2 We previously reported about the enhancement of amoxicillin resistance after unsuccessful eradication.11 Therefore, we can partially understand the opinion of Losurdo et al.1 that it would be reasonable to avoid drugs that have already been used in previously unsuccessful regimens.