Diminishing Efficacy of Second-Line Levofloxacin-Based Quadruple Therapy in Helicobacter pylori Eradication: A Prospective Real-World Study in Vietnam Amid Rising Antibiotic Resistance

<b>Background/Objectives:</b><i>Helicobacter pylori</i> (<i>H. pylori</i>) infection remains highly prevalent in Vietnam, associated with chronic gastritis, peptic ulcers, and gastric cancer. This study aimed to evaluate the real-world eradication rate of levofloxacin-based bismuth quadruple therapy (PALB) as second-line treatment, assess adherence, and identify associated factors with treatment success. <b>Methods:</b> We conducted a prospective cohort study including 225 patients with confirmed failure of classical bismuth-based quadruple therapy. All received a 14-day PALB regimen. <i>H. pylori</i> eradication was assessed using 13C-urea breath test and/or rapid urease test 4-12 weeks after treatment. <b>Results:</b> Eradication rates were 78.2% (mITT) and 78.6% (PP), with 95% CIs overlapping the 80% benchmark. Adherence was high (91.6%) and significantly associated with success (OR = 2.93; 95% CI: 1.11-7.74; <i>p</i> = 0.039). No other factors were significantly associated. <b>Conclusions:</b> While PALB remains a valid second-line therapy, its efficacy may be declining, though not statistically inferior to 80%. Improving adherence and strengthening stewardship are essential.