This is the first prospective randomized trial to show that antofloxacin is effective in eradication of H. pylori infection. The data clearly demonstrated that ACLA therapy had a markedly higher eradication rate than of LCLA therapy, whether using ITT (93.8% vs. 86.2%) or PP analysis (97.8% vs. 92.6%). Among the antibiotics- resistant and antibiotics-susceptible strains, the ACLA group achieved a higher eradication rate. A treatment success rate ≥ 90% is generally desirable for bacterial infections, and ACLA therapy started with an excellent eradication rate.
Moreover, our study also gathered a full set of baseline information such as demographic data and clinical characteristics, antibiotic resistance rates and CYP2C19 polymorphisms to improve the reliability of our findings. We observed no resistance of H. pylori to antofloxacin, suggesting that this agent may be ideal for the first phase of bismuth quadruple therapy. As we known, quinolones have been widely used in clinical practice for decades, and many patients are likely to have used this kind of drug before H. pylori eradication therapy because of their efficient and broad-spectrum antibacterial activity. However, the high rate of resistance to quinolone manifests that quinolone-based regimens may not be a good choice. At present, the drug resistance rate of levofloxacin has reached 20%-50% in China.19, 20 Although the levofloxacin-based bismuth quadruple therapy can surmount the drug resistance to a degree, 9 the high rate of drug resistance will inevitably reduce the eradication rate. Antofloxacin, new-generation quinolones, is an improved version of LEV with an extra-NH2 group in the C-5 position which was invented in China in the late 1990s and approved in 2009.21 Antofloxacin have been continuously and intensively studied to remedy this situation and develop antibiotics exhibiting high potency, long half-lives of elimination, few adverse effects, and low risk of drug resistance.22 Our findings verify the previously reported, satisfactory results without the serious problem of resistance as levofloxacin.
In our study, the PP and ITT eradication rates for LCLA therapy were 92.6% and 86.2%, respectively. Subgroup analysis showed that the cure rate for levofloxacin-resistant strains in LCLA therapy was only 80.5% (33/41), but the eradication rate for levofloxacin-susceptible strains in LCLA therapy was 97.9% (92/94) in a satisfactory level. We found that 30.3% of H. pylori isolates showed some degrees of resistance to levofloxacin, similar to the results of other studies indicating that the primary resistance rate to levofloxacin is 20%-50% in China.10 Antibiotic resistance is the main factor that contributes to the failure of LCLA therapy to adequately eradicate H. pylori. To increase the eradication rate of initial treatment as much as possible, the international consensus also does not recommend using the levofloxacin-containing regimen as an initial treatment.2, 10, 23
We analyzed CYP2C19 polymorphism to characterize PPIs metabolism. PPIs not only result in more stable acid-sensitive antibiotics but also possess direct anti-H. pylori activity. 24 PPIs are commonly metabolized by hepatic cytochrome P450 enzymes, especially the CYP2C19 genotype which is polymorphic, and various mutations. 25 Several previous studies have showed that a significant difference in the H. pylori eradication rate has been reported between HetEM and HomEM (OR = 1.90; 95% CI, 1.38–2.60; P < 0.0001) but not between PM and HetEM. The CYP2C19 homEM genotype was an independent factor for eradication failure in first-line H. pylori eradication therapy. 26−28 In our study, multiple regression analyses showed that the eradication rates of two therapies were not significantly affected by CYP2C19 polymorphism. One reason is that patients were assigned to receive lansoprazole-containing therapy, the eradication rates were not significantly different between PM and HomEM with rabeprazole and lansoprazole therapy reported in previous studies24.
A meta-analysis has reported that smoking is a vital factor underlying the successful treatment of H. pylori infections. Smoking might decrease blood perfusion and mucus secession of stomach, which could reduce the delivery of antibiotics to the gastric mucosa. In addition, smoking causes excessive gastric acid secretion which could lead to failure of treatment.29 Multiple regression analyses in our study showed that the eradication rates of two therapies were not significantly affected by smoking. The reason for this might be that patients were told in advance to quit smoking during treatment. The previous study showed that smoking cessation during H. pylori therapy increased 8.4% eradication rates among smokers, treatment achieved similar results between smokers who gave up smoking during eradication therapy and nonsmokers.30
Our findings suggest that ACLA and LCLA therapies were well tolerated and shared comparable drug compliance. In addition, the ACLA therapy exhibited lower rates of overall adverse events than LCLA therapy (33.8% vs. 42.0%), but the difference was not statistically significant (p = 0. 159). Bismuth is considered safe as the doses of bismuth used in the quadruple regimen are relatively low and are administered for a short time period. 31 The incidences of side effects were not statistically significant when comparing a triple therapy with or without the addition of bismuth. 9 The common adverse events in patients receiving antofloxacin included nausea, vomiting, headache, diarrhea, anorexia, abdominal distension and pain. Photosensitivity caused by levofloxacin has not occurred in ACLA therapy. Previous study found that antofloxacin relatively had more photostable and a weaker photosensitizer compared with levofloxacin.21 The severities of adverse events in all the patients receiving ACLA and LCLA therapy were mild to moderate. There were rare severe adverse events in the ACLA group except that 2 patients had severe adverse events of headache and vomiting.
This study had several novel findings. First, this is the first randomized trial to show that ACLA therapy was more effective than LCLA therapy. Second, we assessed the antibiotic susceptibility in 290 patients within this randomized trial, estimation of eradication rates in these subgroups of resistant subjects may achieve a more reliable conclusion. Third, we used multivariate logistic regression analysis to assess some factors such as gender, smoking, alcohol, and CYP2C19 polymorphism which may influence the successful treatment of H. pylori infections. Finally, we found that the frequencies of adverse effects were lower in patients treated with ACLA therapy than in those treated with LCLA therapy, though there was no statistical difference.
This study has some limitations. First, this trial was not a double-blind placebo-controlled trial so that it was at risk for detection bias. Second, this trial was conducted in a single center. Third, the antofloxacin is not widely available in other countries and the regimens that we used were somewhat unconventional. Therefore, larger studies on larger groups of patients are needed to confirm the results.
In conclusion, the present results could state that antofloxacin is safe and effective in eradication of H. pylori. Antofloxacin-based bismuth quadruple therapy might be considered as an alternative for the eradication of H. pylori treatment, since it attained a successful eradication rate of 90% which was superior than LCLA therapy.