Susceptibility of Helicobacter pylori to Levofloxacin and Rifampicin in Israel

Introduction

Resistance of Helicobacter pylori to antibiotic agents is a challenging phenomenon that physicians face in eradication of the microorganism, while patients are forced to undergo repetitive treatment cycles. The current treatment success rate of first-line combination consisting of clarithromycin, metronidazole, amoxicillin, and a proton pump inhibitor is rather low, and there is a trend among physicians to switch to combinations containing alternative antibiotic agents. In 2013, the British Society for Antimicrobial Chemotherapy (BSAC) published a set of standards establishing the microorganism's degree of susceptibility to rifampicin and levofloxacin. Before this publication, the only susceptibility standards that were available to the microbiology laboratory were for amoxicillin, clarithromycin, tetracycline, and metronidazole.

Levofloxacin is a fluoroquinolone antibiotic with a wide spectrum of activity against gram-positive and gram-negative flora, most widely used in eradication of H. pylori as a second-line treatment; however, it has not yet been approved for use in the pediatric population.^5,14 Prolonged treatment with fluoroquinolones may result in inflammation of connective tissue (cartilage). ¹⁵ Successful treatment with levofloxacin has been reported in 70–90% of cases, making it popular with physicians who tend to prefer it over other agents as a first-line treatment modality,^7,8,11 compared to, for instance, rifampicin that is used less frequently in H. pylori infections as a third-line rescue therapy in those patients who are allergic to penicillin. ¹² Among all antibiotic agents that are currently used in H. pylori infection treatment, rifampicin is an antitubercular agent to which the bacterium exhibits the lowest resistance. ⁹ Although in countries where the tuberculosis-associated morbidity rate is high and rifampicin is widely used, the treatment failure rate is high in those instances where rifampicin is used in H. pylori infections.^2,4,10 It is worth noting that in countries where prudent use of this medication to treat H. pylori infections is not commonly practiced, there is an increase of resistant mycobacteria; therefore, it is important to opt for an alternative antibiotic for H. pylori eradication.

Antibiotic stewardship in treating H. pylori infections in the light of increasing resistance of the microorganism makes it imperative to return to culturing the microorganism from biopsies of stomach tissue and assessing its susceptibility to available antibiotic agents in accordance with established standards, in place of various alternative techniques such as the breath test, presence of antigen in stool samples, antibodies in blood, histology, or the quick urease test for stomach tissue biopsy samples.

The purpose of this study was to assess the resistance level of H. pylori isolates to levofloxacin and rifampicin from samples collected from pediatric and adult Israeli patients from 2012 to 2013 in accordance with the new standards published by the BSAC.

Materials and Methods

Results

Out of 117 isolates, 105 (89.7%, CI 82.8–94.6) were found susceptible and 12 (10.3%) were resistant to levofloxacin with 50/50% distribution among the adult and pediatric population (6 children and 6 adults). Mean MIC values were 0.20 mg/L for the susceptible isolates and 2.0 mg/L for the resistant isolates.

As for rifampicin, 104 (88.9%, CI 81.7–93.9) out of 117 isolates were found susceptible and 13 (11.1%) were resistant. Mean MIC values were 0.106 mg/L for the susceptible isolates and 2.38 mg/L for the resistant isolates (Fig. 1).

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FIG. 1.

Minimum inhibitory concentration (MIC) for levofloxacin and rifampicin.

Five (38.4%) isolates were from children and 8 (61.6%) from adults (Table 1). Importantly, double resistance to both antibiotics was not found.

When we examined the history of antibiotic susceptibility of the isolates that were resistant to levofloxacin and rifampicin, we found for levofloxacin that six isolates were also resistant to clarithromycin and metronidazole (50%), two isolates were also resistant to clarithromycin and amoxicillin (8.3%), one isolate was also resistant to clarithromycin and tetracycline, and three isolates were also resistant to clarithromycin but sensitive to the other antibiotics (25%). For rifampicin, we found that eight isolates were also resistant to clarithromycin and metronidazole (61.5%), two isolates were also resistant to clarithromycin, metronidazole, and amoxicillin (15.38%), two isolates were also resistant only to clarithromycin (15.38%), and one isolate was resistant only to metronidazole (7.7%) (Table 2).

Discussion

H. pylori resistance to antibiotic treatment presents clinicians with a challenge, more so in view of a worldwide increase in the number of resistant isolates. ⁶ Widespread use of antibiotics, especially clarithromycin and metronidazole, has led to the emergence of resistant strains, giving birth to a new reality forcing physicians to explore the use of alternative antimicrobial agents such as rifampicin and levofloxacin. These medications were expected to fulfill the need for an effective medication. However, due to the current inability of the microbiology laboratory to provide susceptibility data by means of MIC estimation for resistant versus sensitive isolates, inference of successful treatment outcome largely depends on the clinical history of remission of complaints or breath test results upon completion of treatment cycle.

It is worth noting that the practice of culturing H. pylori from stomach tissue biopsy samples with subsequent submission for the susceptibility test is not widely recognized, making isolation and identification of resistant strains rather problematic.

In Israel, an estimate of resistant H. pylori strains is not clear cut. With the exception of a limited number of small-scale studies, comprehensive regional data that could provide an evidence basis for effective empiric treatment protocol are not available. ¹

The present study examined 117 isolates of H. pylori, collected in Israel between 2012 and 2013, in compliance with BSAC standards established for levofloxacin and rifampicin. Fifty-four isolates were obtained from adult patients and 63 from pediatric patients.

Study results estimate an alarming resistance rate, despite the preference, in the last few years, of alternative antibiotics, levofloxacin and rifampicin, over well-established antimicrobial agents. This reiterates the need for prudent use of alternative antibiotics to prevent further spread of resistant strains.

Another worrying item in the study is that the isolates that were resistant to rifampicin or levofloxacin were resistant to at least one more antibiotic and in some cases to two antibiotics that were part of the alternative treatment for the bacteria.

By the same token, we suggest subjecting cultures and antimicrobial tests or PCR from biopsy samples to susceptibility testing for the purpose of identification of strains resistant to levofloxacin and rifampicin among other antibiotic agents. This will allow for successful monitoring of microbial resistance and will assure prudent use of antimicrobial modalities. ¹³

Likewise, we advise reserving the use of levofloxacin and rifampicin as a last resort for all those instances when administration of antibiotics such as metronidazole, amoxicillin, and clarithromycin proves ineffective in eradication of H. pylori.