Next-Generation Treatment for H Pylori

KG Hulten, et al. Gastroenterol 2021; 11: 1433-1442. Open Access: Comparison of Culture With Antibiogram to Next-Generation Sequencing Using Bacterial Isolates and Formalin-Fixed, Paraffin-Embedded Gastric Biopsies

Background: “The general unavailability of culture-based susceptibility testing for H pylori has resulted in the almost universal reliance on hopeful (empiric) therapy and a high proportion of treatment failures.” Besides the lack of availability of culture-based susceptibility testing, the global increase in prevalence of antimicrobial resistance contributes to the poor cure rates obtained with empiric use of the currently most popular triple therapies for H pylori infection.

Methods: H pylori isolates (n=170) (clinical isolates and formalin-fixed, paraffin-embedded) were tested for susceptibility to amoxicillin, clarithromycin, metronidazole, levofloxacin, tetracycline, and rifabutin using agar dilution and NGS targeted to 23S rRNAgyrA16S rRNApbp1rpoB and rdxA. Agreement was quantified using κ statistics.

Key findings:

  • Agreement between agar dilution and NGS from culture isolates was very good for clarithromycin (κ = 0.90012), good for levofloxacin (κ = 0.78161) and fair for metronidazole (κ = 0.55880), and amoxicillin (κ = 0.21400)
  • Comparison of NGS from tissue blocks and agar dilution from isolates from the same stomachs demonstrated good accuracy to predict resistance for clarithromycin (94.1%), amoxicillin (95.9%), metronidazole (77%), levofloxacin (87.7%), and tetracycline (98.2%)

Associated editorial: F Megraud et al. Gastroenterol 2021; 11: 1367-1369. Open Access: Molecular Diagnosis for Helicobacter pylori . . . at Last

Excerpts from editorial:

  • “By targeting all of the genes responsible for antibiotic resistance, it is possible to obtain genotypic susceptibility data for all of the antibiotics of potential use, without the need to perform” culture and antibiotic susceptibility testing
  • “Hulten et al show not only that they obtained comparable results with the reference method (phenotypic) for most of the antibiotics, but also that NGS can also be performed on both culture isolates and stored histologic preparations. This result is important because it avoids the need for extra biopsies and culture”
  • “NGS could also be applied on stools. In this particular environment where H pylori DNA is found in a low amount, excellent DNA extraction methods are mandatory and progress is being made in this field”

My take: NGS can bring H pylori treatment to a new era (like almost all other infections). “Molecular methods can potentially augment or even replace the current in vitro methods for susceptibility testing, which are cumbersome, technically challenging, and time-consuming.”

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Why Is There Low Adherence to H pylori Guidelines?

S Bonilla et al. JPGN 2021; 73: 178-183. Low Adherence to Society Guidelines for the Management of Helicobacter Pylori Among Pediatric Gastroenterologists

This retrospective study with 250 patients determined that clinicians at this large center (Boston Children’s) have a low rate of adherence to the NASPGHAN/ESPGHAN H pylori guidelines (JPGN 2017; 64: 991-1003).

Key findings:

  • Patient outcomes: 107/186 (58%) had resolution of symptoms after treatment; abdominal pain was the most common presenting symptom (67%)
  • 131 (62%) had documented followup visit and an eradication test
  • First-line treatment was most commonly amoxicillin, clarithromycin, and PPI (69%) (in those without sensitivity information, amoxicillin, metronidazole, and PPI are recommended in the guidelines)
  • Biopsy culture was sent in 3% of patients

In their discussion, the authors make a number of points:

  • Both pediatricians and gastroenterologists “are utilizing a ‘test and treat’ strategy rather than endoscopy-based diagnostic testing.” This along with low followup and low biopsy culture deviate from NASPGHAN guideline.
  • 77 of 256 patients had non-invasive testing prior to referral and in this subset, more than two-thirds of patients received a clarithromycin-based triple therapy before being referred; “this has a high likelihood of failure.”
  • The authors advocate endoscopy over empiric treatment but acknowledge some reasons why families may want to avoid endoscopy (interestingly the authors do not mention the cost of the procedure). They also note that H pylori culture is not widely available.

My take: There are several reasons why there is low adherence to NASPGHAN/ESPGHAN guidelines

  1. Treatment recommendations for initial triple therapy does not align with adult guidelines for quadruple therapy. Even the “rescue” therapies (Table 5), these pediatric guidelines do not recommend quadruple therapy. Yet, there is no indication that H pylori is more susceptible to treatment in children.
  2. Recommendations for susceptibility/antibiotic resistance testing (Table 1, #11) makes no sense if susceptibility testing is not available. Fortunately, PCR-based assays are making this easier recently.
  3. The absence of susceptibility testing and cost would favor empiric treatment over endoscopy as a first-line approach in those who have a reliable non-invasive test indicating infection along with symptoms suggestive of H pylori infection.

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Adult Guidelines:

Other related posts

This is the treatment approach per pediatric guidelines; these recommendations
do NOT align with treatment recommendations in adults

Helicobacter Pylori 2019 Review

A recent review (SE Crowe. NEJM 2019; 1158-65) provides a succinct summary of current H pylori management.

A couple of key points:

  • It is essential to test for cure after treatment 1 month afterwards
  • If retreatment is needed, use an alternative regimen
  • In the discussion of treatment, Dr. Crowe does NOT emphasize quadruple therapy except in individuals with a clarithromycin resistance probability of >25% (based on geographic incidence rates) or prior macrolide use.  She notes that in some populations that clarithromycin-based triple therapy had similar effectiveness as bismuth-based quadruple-based therapy.  Table 2 lists the 7 ACG approved treatment regimens.
  • It is noted that U.S. clarithromycin-resistance is between 21-30%.

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

It is Getting Harder to Treat H pylori -Here’s Why

In a recent study (A Savoldi et al. Gastroenterol 2018; 155: 1372-82, editorial pg 1287), the authors conducted a systematic review and meta-analysis to examine the prevalence of antibiotic resistance to Helicobacter pylori. The authors identified 178 studies with 66,142 H pylori isolates. Tables 2 & 3 provide comprehensive data.

Key points:

  • In the Americas region, primary resistance to clarithromycin, metronidazole, levofloxacin and amoxicillin was 10%, 23%, 15%, and 10% respectively.
  • In the European region, primary resistance to clarithromycin, metronidazole, levofloxacin and amoxicillin was 18%, 32%, 11%, and 0% respectively.

Antibiotic resistance is increasing: 

  • In the Americas region, resistance in 2006-2008 compared to 2012-201 for clarithromycin, & metronidazole: 11%–>20%, 26%–>29% respectively.
  • In the European region, resistance in 2006-2008 compared to 2012-201 for clarithromycin, & metronidazole: 28%–>28%, 38%–>46% respectively.
  • “The resistance rates to clarithromycin, metronidazole, and levofloxacin have increased over time in all WHO regions.”  Other regions with data in study included Eastern Mediterranean, Southeast Asia, and Western Pacific.
  • In the study, the authors also “describe a clear significant association between antibiotic resistance and treatment failure.”

In their discussion, the authors note that the incidence of gastric cancer is higher in areas with increased antibiotic resistance.  Though there has been a decline in gastric cancer, “based on our data, we can hypothesize that this trend in reduction is expected to revert soon because available treatment can no longer guarantee a satisfactory eradication rate.”

From editorial:

  • H pylori is not one of those bacteria in which resistance develops as an epidemic by horizonatal transfer of mobile genetic elements…Resistance in H pylori only occurs unevenly by mutations…Fortunately, resistance occurs “very seldomly for …amoxicillin and tetracycline.”
  • Treatment failure is “almost 7 times greater (6.97) when the strain is clarithromycin resistant and even greater (8.18) when the strain is levofloxacin resistant.” Resistance to metronidazole confers a lesser degree of treatment failure risk: OR 2.52.

My take: This study provides some sobering news about H pylori prevalence and how it is becoming more difficult to treat.

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Pooled Prevalence of resistance to clarithromycin (2006-2016). This is from Figure 2. Sections B & C (not shown) provide similar graphic info for metronidazole and levofloxacin

Hard-to-Treat Shigella Infections

From the CDC (4/2/15): Multidrug-resistant Shigellosis Spreading in the U.S.

International travelers are bringing a multidrug-resistant intestinal illness to the United States and spreading it to others who have not traveled, according to a report released today by the Centers for Disease Control and Prevention (CDC). Shigella sonnei bacteria resistant to the antibiotic ciprofloxacin sickened 243 people in 32 states and Puerto Rico between May 2014 and February 2015…

In the United States, most Shigella is already resistant to the antibiotics ampicillin and trimethoprim/sulfamethoxazole. Globally, Shigella resistance to Cipro is increasing…

Until recently, Cipro resistance has occurred in just 2 percent of Shigella infections tested in the United States, but was found in 90 percent of samples tested in the recent clusters.

Because Cipro-resistant Shigella is spreading, CDC recommends doctors use lab tests to determine which antibiotics will effectively treat shigellosis. Doctors and patients should consider carefully whether an infection requires antibiotics at all…

For more information on Shigella, please visit: www.cdc.gov/shigella.

Travelers can learn more about food and water precautions to prevent Shigella at: http://wwwnc.cdc.gov/travel/yellowbook/2014/chapter-2-the-pre-travel-consultation/food-and-water-precautions.

To view the full MMWR report, please click here.

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Sandy Springs

Sandy Springs

Preventing lethal antibiotic resistant outbreaks

Establishing “rigorous infection-control procedures” remain the main tool to reign in these lethal outbreaks (NEJM 2012; 367:   2168-70).

While that message has been said before, the referenced article concisely discusses issues regarding multidrug-resistant gram-negative rods (MDR-GNRs) which are now much “more menacing” than methicillin-resistant Staphylococcus aureus (MRSA).  The reason: there are no effective drugs available to treat some life-threatening MDR-GNR infections.

With resistance to cephalosporins increasing, clinicians have turned to carbapenems; as a consequence, resistance is emerging to these agents as well.  Multidrug-resistant organisms (MDROs) are increasing; in addition, resistance that develops in one place of the world can quickly spread as shown by the MDR-GNRs with the New Delhi metallo-beta-lactamase 1.

Key points:

  • MDROs are transmitted mainly on the hands of caregivers.  The most effective aspect of “rigorous infection-control procedures” remains hand washing.
  • Some infections survive for prolonged periods on surfaces.  For example, during an NIH outbreak of a MDR-GNR Klebsiella pneumoniae, klebsiella survived on a ventilator that had been cleaned three times with two different disinfectants.
  • Antimicrobial stewardship is an important aspect of decreasing resistance. This includes sending cultures prior to antibiotics to tailor regimens, specifying the indication, documenting the expected duration of treatment, and assessing at 72 hours whether an ongoing antibiotic course is needed.
  • If we adhere to established practices, infections due to invasive devices which are the source of most ICU infections can be minimized.  For example, incorporating evidence-based “bundles” of care have been effective in reducing central line infections.

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