Helicobacter pylori infects an estimated half of the world’s population and remains highly prevalent across the Eastern Mediterranean region. The bacterium colonizes the gastric mucosa, where it drives chronic inflammation and, in a subset of those infected, progresses to peptic ulcer disease, mucosa-associated lymphoid tissue lymphoma, or adenocarcinoma of the stomach. Eradicating the organism is therefore not merely a matter of relieving dyspepsia; it is a recognized cancer-prevention strategy. Yet the standard triple therapy that dominated H. pylori treatment for decades, a proton pump inhibitor combined with clarithromycin and amoxicillin, has been losing ground worldwide as clarithromycin resistance has climbed, and in Syria the decline has been compounded by antibiotic misuse, disrupted healthcare infrastructure, and limited access to diagnostic resources.

When clarithromycin-based regimens fail or cannot be relied upon, clinicians frequently turn to levofloxacin, a fluoroquinolone antibiotic, as the backbone of alternative combinations. Two such combinations were tested in this trial. The concomitant regimen delivers a proton pump inhibitor, levofloxacin, amoxicillin, and a fourth agent simultaneously for the full 14 days, so the patient takes all drugs at once throughout the treatment period. The sequential regimen splits the therapy into phases: one antibiotic pairing is given first, followed by a second pairing, with the theoretical rationale that an initial phase of amoxicillin reduces bacterial load and damages cell walls in a way that may improve the effectiveness of the subsequent phase while limiting the window in which resistance can emerge.

Sequential therapy has been promoted in some settings as a way to sidestep clarithromycin resistance, and it has been studied extensively in Europe and Asia, but it had never been formally evaluated in Syrian patients. The researchers, led by Marouf Alhalabi of Damascus Hospital together with colleagues at Ibn Al-Nafees Hospital and the Syrian Board in Gastroenterology, designed a single-center, prospective, open-label, randomized superiority trial to answer the question directly under local conditions. The trial was prospectively registered on ClinicalTrials.gov as NCT06065267 on October 3, 2023, and received ethics approval from the Damascus Hospital and Ibn Al-Nafees Ethics Committee under approval number 41/23.

The study enrolled 150 adults with histologically confirmed H. pylori infection, all of whom had never previously received eradication therapy. Participants were assigned equally, 75 to each arm, to either the concomitant or the sequential levofloxacin-based regimen, each lasting 14 days. The primary outcome was eradication success, confirmed by a negative stool antigen test performed six weeks after the completion of therapy, a timing chosen to allow residual bacterial antigen to clear and to avoid false-positive results. The analysis followed the intention-to-treat principle, meaning every randomized patient was counted in the group to which they were assigned regardless of whether they completed the full course, an approach that preserves the real-world validity of the comparison by accounting for dropouts and imperfect adherence.

The numbers told a story of near-equal performance. Concomitant therapy eradicated the infection in 63 of 75 patients, an intention-to-treat rate of 84 percent, while sequential therapy succeeded in 61 of 75, or 81.3 percent. The absolute risk difference was 2.7 percentage points, with a 95 percent confidence interval spanning from minus 9.4 to 14.8, and the comparison yielded a p value of 0.83 with an odds ratio of 1.20, corresponding to a confidence interval of 0.516 to 2.81. In plain terms, the data provide no evidence that one regimen outperforms the other, and the confidence interval is wide enough that a modest advantage in either direction cannot be excluded. The authors were careful to state that the absence of a statistically significant difference does not establish equivalence or non-inferiority, a distinction that matters in clinical trial interpretation: proving two treatments equal requires a trial designed and powered for that purpose, which this superiority trial was not.

Both regimens were generally well tolerated, an important consideration given that eradication therapy requires patients to take multiple medications daily for two weeks. Nausea was the most frequently reported adverse event in both groups, followed by anorexia, headache, a persistent bitter taste, and skin rash. There was no significant difference in the frequency of adverse events between the two arms, suggesting that the added complexity of the sequential schedule does not buy any tolerability advantage. Baseline characteristics of the two groups were comparable, reducing the likelihood that imbalances in age, sex, or disease profile skewed the outcome.

The findings arrive against a backdrop of genuine clinical constraint. In settings where culture and susceptibility testing are unavailable, clinicians must prescribe empirically, choosing regimens based on regional resistance data and local experience rather than on the resistance profile of an individual patient’s infection. Syria’s healthcare system has been strained by years of conflict and economic crisis, and the authors note that susceptibility-guided therapy and many of the internationally recommended first-line regimens may simply be unavailable. In that context, levofloxacin-based empirical therapy remains in use, and the question of which levofloxacin-based strategy to choose is not academic. The trial suggests that when such therapy is required, the simpler concomitant regimen may offer practical advantages: a single, uniform dosing schedule for 14 days is easier to explain, easier to follow, and less prone to the confusion that phased regimens can introduce, with no measurable cost in effectiveness.

The moderate eradication rates observed in both arms, in the low-to-mid 80 percent range, also serve as a reminder that levofloxacin resistance itself is a growing problem in many regions, and that no empirical regimen can be assumed to work indefinitely. The authors emphasize that these findings should be interpreted in light of local resistance patterns and healthcare limitations, and they call for further multi-center studies that incorporate antimicrobial susceptibility testing. Such studies would allow clinicians to match therapy to the actual resistance profile of circulating H. pylori strains, an approach that international guidelines increasingly favor but that remains aspirational in much of the Eastern Mediterranean.

For the broader field, the trial adds a data point from a population that is rarely represented in H. pylori treatment literature. Most eradication trials are conducted in East Asia, Europe, or North America, where resistance patterns, drug availability, and patient populations differ substantially from those in conflict-affected or resource-limited settings. Demonstrating that a straightforward four-drug concomitant regimen achieves roughly 84 percent eradication in treatment-naïve Syrian patients, and that a more complex sequential schedule offers nothing extra, gives local clinicians an evidence-based reason to favor simplicity. As antibiotic resistance continues to erode the effectiveness of legacy regimens worldwide, trials like this one, grounded in the realities of a specific healthcare environment rather than in idealized conditions, are becoming an essential complement to guideline committees’ recommendations.

Subject of Research: A randomized trial comparing levofloxacin-based concomitant and sequential therapies for Helicobacter pylori eradication in treatment-naïve Syrian patients.

Article Title: Levofloxacin-based concomitant versus sequential therapy for Helicobacter pylori eradication in treatment-naïve Syrian patients: a randomized trial showing no superiority of sequential therapy

Article References: Alhalabi, M., Alshiekh, H. A., Sheikh Alhara, A. A., Ismail, A. A., Shehab, W., & Osamah, W. (2026). Levofloxacin-based concomitant versus sequential therapy for Helicobacter pylori eradication in treatment-naïve Syrian patients: a randomized trial showing no superiority of sequential therapy. Gut Pathogens. https://doi.org/10.1186/s13099-026-00881-x

Image Credits: AI Generated

DOI: 10.1186/s13099-026-00881-x

Keywords: Helicobacter pylori, levofloxacin, concomitant therapy, sequential therapy, eradication therapy, antibiotic resistance, randomized clinical trial, Syria, gastroenterology, stool antigen test, fluoroquinolone, clinical trial

The study, led by Dmytro Butov of Kharkiv National Medical University together with Stefan Niemann and Viola Dreyer of the Research Center Borstel in Germany, enrolled 4,828 patients and successfully sequenced 4,162 isolates after quality-control exclusions. Participants were divided into two groups: a drug-resistant tuberculosis cohort of 3,112 patients with rifampicin-resistant, multidrug-resistant, pre-extensively drug-resistant, or extensively drug-resistant disease, and a comparator cohort of 1,050 patients with non-MDR or drug-susceptible tuberculosis. Within the drug-resistant group, 62.3 percent of isolates were classified as multidrug-resistant, nearly a third as pre-XDR, and 2.5 percent as extensively drug-resistant.

The population structure of the circulating bacteria tells a striking story. Fully 70.6 percent of all sequenced isolates belonged to Lineage 2, the so-called Beijing lineage, which predominates across Eastern Europe and is associated with enhanced transmissibility and a greater propensity to acquire resistance mutations. Among drug-resistant cases, Lineage 2 accounted for 83.7 percent of isolates, rising to 89.7 percent among extensively drug-resistant infections. By contrast, Lineage 4 Euro-American strains, which are more genetically diverse, dominated the comparator cohort, particularly among patients with drug-susceptible disease in western Ukraine.

Even more striking is how little diversity exists within the drug-resistant Lineage 2 population. More than 82 percent of MDR, pre-XDR, and XDR isolates belonged to just four previously described Beijing clades: the Europe/Russia W148 outbreak clone, which alone made up nearly 40 percent of the resistant cohort, the Ukraine outbreak clone, the Central Asia outbreak clone, and the broader Central Asia clade. Geospatial analysis showed Lineage 2 dominance in almost every participating region, with the highest proportions in the central, southern, northern, and eastern parts of the country, while Lineage 4 remained comparatively more common in the west.

Genomic clustering analysis, which identifies isolates separated by five or fewer allelic differences at 2,891 core-genome loci, revealed that nearly half of all isolates belonged to clusters, a signature of recent or ongoing transmission. Clustering was far more frequent in the drug-resistant cohort, affecting 55 percent of isolates, than in the comparator group at 28.9 percent. The three largest clusters, all exclusively Lineage 2, contained 671 drug-resistant isolates, over a fifth of that cohort. Cluster 1, assigned to the Ukraine outbreak clone, comprised 307 isolates, more than half of them pre-XDR or XDR. Cluster 2, the W148 clone, included 296 isolates, mostly MDR, and Cluster 3 contained 76 Central Asia outbreak isolates.

The resistance mutations embedded in these clusters indicate that resistance was largely fixed in common ancestors and propagated through clonal expansion rather than acquired independently. Canonical mutations such as KatG S315T and RpoB S450L, which confer resistance to isoniazid and rifampicin at low fitness cost, dominated all three major clusters. Fluoroquinolone resistance, present in roughly a third of drug-resistant isolates, was driven mainly by GyrA D94G and A90V substitutions, while bedaquiline and clofazimine resistance was linked primarily to loss-of-function variants in Rv0678, notably the 192_ins_g and 141_ins_c frameshift insertions.

Resistance to the newer Group A agents central to modern all-oral therapy remained uncommon, offering a measure of reassurance. WGS-inferred bedaquiline resistance was detected in only 90 isolates overall, about 2.8 percent of the drug-resistant cohort, and linezolid resistance in just 33 isolates, or 1.1 percent. Yet the researchers identified 11 isolates carrying variants associated with combined resistance to fluoroquinolones, bedaquiline, and linezolid, a combination that would compromise both BPaL and BPaLM regimens. Notably, seven bedaquiline-resistant XDR isolates carried atpE variants, six of them in Lineage 2 strains scattered across different clades, suggesting independent acquisition. Comparative analysis showed the Ukrainian atpE-mutant isolates were separated by at least 28 SNPs from publicly available Russian genomes, ruling out a single shared clone and pointing to a possible regional propensity for this resistance mechanism that the authors say warrants urgent investigation.

Temporal analysis across four consecutive 12-month intervals revealed significant declines in resistance to moxifloxacin and levofloxacin, each falling from around 41 percent in 2019–2020 to roughly 28 percent in 2022–2023, with pyrazinamide resistance also declining modestly. The fluoroquinolone trends held up in sensitivity analyses restricted to the 12 consistently sampled regions and within the pooled major genomic clusters. In parallel, recorded treatment success rose from 59.6 percent to 73.4 percent over the study period. The authors, however, caution strongly against causal interpretation: the trends coincided with changes in regional sampling after the February 2022 invasion, population displacement, diagnostic disruptions, evolving treatment policies, and the pandemic, and individual-level regimen data were unavailable.

The study also highlights the social epidemiology of the epidemic. Patients with drug-resistant disease were younger and more often male, and more frequently reported recurrent tuberculosis, previous treatment failure, homelessness, drug use, incarceration, HIV infection, and viral hepatitis. Lineage 2 infection was independently associated with rifampicin-resistant or MDR status, fluoroquinolone resistance, and genomic clustering in multivariable models adjusted for demographic, clinical, social, temporal, and regional factors.

The authors conclude that sustained genomic surveillance of drug-resistant tuberculosis in Ukraine and neighbouring countries is essential, particularly for dominant Lineage 2 clones and for resistance to fluoroquinolones, bedaquiline, and linezolid. They call for systematic fluoroquinolone testing before deployment of shorter all-oral regimens, targeted phenotypic confirmation of bedaquiline and linezolid susceptibility, integration of whole-genome sequencing into routine care, and cross-border data sharing to track tuberculosis among displaced, migrant, and refugee populations. As Ukraine continues to rebuild its health system amid ongoing conflict, the genomic record preserved in this cohort provides both a warning about the entrenched clones fuelling the epidemic and a template for surveillance elsewhere in Eastern Europe.

Subject of Research: Genomic surveillance of drug-resistant Mycobacterium tuberculosis in Ukraine from 2019 to 2023

Article Title: Drug-resistance profiles, population structure, genomic clustering, and temporal trends in drug resistance among Mycobacterium tuberculosis complex isolates in Ukraine, 2019–2023: a multicentre cohort study

Article References: Butov, D., Butova, T., Miasoiedov, V., Feshchenko, Y., Nakonechna, O., Kuzhko, M., Rosenthal, A., Grinev, A., Hoppes, D., Kilmnick, J., Levandovska, D., Hryhorieva, A., Vekshyn, V., Abramova, L., Niemann, S., & Dreyer, V. (2026). Drug-resistance profiles, population structure, genomic clustering, and temporal trends in drug resistance among Mycobacterium tuberculosis complex isolates in Ukraine, 2019–2023: a multicentre cohort study. The Lancet Regional Health – Europe, 70, Article 101865. https://doi.org/10.1016/j.lanepe.2026.101865

Image Credits: AI Generated

DOI: 10.1016/j.lanepe.2026.101865

Keywords: tuberculosis, drug resistance, whole-genome sequencing, Lineage 2 Beijing, MDR-TB, Ukraine, fluoroquinolone, bedaquiline, linezolid, genomic clustering, outbreak clones, public health surveillance