When to test for H.pylori antibiotic sensitivity?

The success of standard treatment for H.pylori has steadily declined. Increased use of antibiotics in foods and medical therapy may have contributed to increasing H. pylori antibiotic resistance.1 While there are some benefits of gastric colonization by H. pylori infection, it is still recognized as a carcinogen by the World Health Organization (WHO) and most infected individuals opt to undergo further therapy for H. pylori. Many guidelines are available but it is estimated about 20 percent will fail to eradicate with currently recommended therapies despite well-devised algorithms for salvage therapy, many will undergo multiple courses without success. While it is standard to perform culture and sensitivity to ensure effective antibiotics are used in most other infectious diseases (e.g., UTI, pneumonia, etc.), this practice has not been adopted in the U.S. for H. pylori infection in part due to difficulty accessing H. pylori culture and sensitivity (Cx/Sensi) testing. Hence this perspective addresses this important clinical dilemma in the management of persistent H.pylori infection despite multiple courses of H.pylori therapies.

A few disclaimers are in order regarding the opinions presented here. There is generally a lack of clinical data in the U.S. for an evidence-based strategy to guide the next course of therapy and the strategies presented below are based mostly on experiences outside the U.S. Real-life U.S. experience that incorporates H.pylori culture and sensitivity in clinical practice is based on two single-center retrospective studies. Nevertheless, these available clinical data are helpful to better inform U.S. practicing physicians to select the best next treatment regardless of the availability of the antibiotic sensitivity profile of the patient’s H. pylori.

In 2010, we developed an in-house H. pylori culture protocol after several failed attempts to culture stomach biopsies at outside labs. We hypothesize that the delay of getting the biopsies to outside labs for culture may explain the low yield and had much better success when cultures were done in-house delivered to the microbiology lab within one hour. Tan et al. reported important lessons learned treating H. pylori over the past seven years.2 First, U.S. patients who failed two courses of H. pylori therapy (usually clarithromycin (CLAR)-based triple or bismuth-based quadruple therapies) are likely (greater than 70 percent) to have resistance to CLAR and metronidazole (MTZ) but not to amoxicillin (AMOX) and tetracycline (TCN). About 40 percent of them will have ciprofloxacin (CIPRO) resistance. Second, not all treatment failures are due to antibiotic resistance as about 50 percent of tailored therapy failed despite using sensitive antibiotics. Our multivariate analysis revealed BMI greater than 30 as a single most important predictor of tailored therapeutic failures. Bhakta et al. found similar rates of antibiotic resistance and tailored treatment success in Houston.3


Figure 1. Management algorithm for persistent H. pylori infection post therapies (abbreviations: Hp Cx/Sensi – H. pylori culture and sensitivity testing, R – resistance, CLAR –clarithromycin, MTZ – metronidazole, CIPRO – ciprofloxacin, AMOX – amoxicillin, TCN – tetracycline, PPI- proton pump inhibitor, PCN – penicillin).

Although the reason why high BMI may lead to treatment failures despite using sensitive antibiotics is unknown, it is possible that inadequate dosing and high acid diet may contribute to sub-therapeutic concentrations of the sensitive antibiotics to eradicate H.pylori. This is especially true for AMOX where BID dosing is used in standard triple therapy instead of TID dosing normally recommended for other indications. Indeed, Yang et al. demonstrated that high-dose dual (HDDT) with AMOX and proton pump inhibitor (PPI) was more than 90 percent effective as salvage therapy in Taiwanese population.4 Our preliminary experience using this similar HDDT was about 50 percent effective, but be aware that our patients have significantly higher BMI than the Taiwanese cohort.2 Yang et al. also demonstrated that, unlike other antibiotics, repeated exposure to AMOX does not lead to AMOX-resistance in H. pylori.4 Thus, due to the low rate of resistance, simple to use, and good side-effect profile of HDDT, empiric HDDT is an attractive option especially when H. pylori Cx/Sensi is not available. Personal communication with Dr. Yang noted the importance of strict low-acid diet (e.g., avoidance of spicy, acidic, fatty foods, pungent herbs and sodas), in using HDDT to achieve optimal results.

What if the patient has penicillin allergy as many do in the U.S. or have failed HDDT? The decision to pursue H. pylori Cx/Sensi depends on access to local centers where H. pylori can be cultured so that the next course of therapy can be tailored. To my knowledge, H. pylori Cx/Sensi is only available at the University of Michigan, Mayo Clinic, and Baylor College of Medicine. Send-out services are available but yield may be low due to sub-optimal transport conditions in route to the lab and may not include ciprofloxacin in their test panel. An organized effort by H. pylori experts in the U.S. is underway to push health care systems across the nation to include H. pylori Cx/Sensi service in their clinical microbiology lab. If available, our experience with tailored therapy is that bismuth-based quadruple therapy is superior to non-bismuth based therapy in metronidazole-resistant patients and high-dose bismuth regimen (e.g., bismuth 2 tabs QID, MTZ 500mg TID, AMOX 1gm QID, PPI TID) especially in patients with BMI greater than 30. The use of high-dose bismuth-based quadruple therapy has been shown to be effective in non-U.S. cohorts,5,6 but patient tolerance may limit its use.

The future promises a simpler regimen that is highly effective and well tolerated. To get there, it is important that H. pylori Cx/Sensi is widely available so we can better differentiate the true cause of treatment failure such as the relative contribution of bacterial factors (e.g., antibiotic resistance) or host factors (e.g., high BMI, high gastric acidity, diet). Available antibiotic resistance profile will also minimize unnecessary antibiotic use and its potential negative impact on the gut microbiota.

Dr. Kao has no conflicts to disclose. Dr. Kao is a member of the AGA International Committee.

References
1. Kaur, N., Chen, C.C., Luther, J., Kao, J.Y. Intestinal dysbiosis in inflammatory bowel disease. Gut Microbes. 2011; 2: 211-6.
2. Tan, B., Yang, J.C., Young, C.L. et al, Helicobacter pylori Antimicrobial Susceptibility Testing-Guided Salvage Therapy in the USA: A Real Life Experience. Dig Dis Sci. 2017; 63(2): 437-445.
3. Bhakta, D., Graham, D.Y., Chan, J., El-Serag, H. Lessons from Using Culture-Guided Treatment after Referral for Multiple Treatment Failures for Helicobacter pylori Infection. Clin Gastroenterol Hepatol. 2018; DOI: 10.1016/j.cgh.2017.12.040.
4. Yang, J.C., Lin, C.J., Wang, H.L. et al, High-dose dual therapy is superior to standard first-line or rescue therapy for Helicobacter pylori infection. Clin Gastroenterol Hepatol. 2015; 13: 895-905 e5.

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