Salvage Therapy and Standard Therapy for H pylori

A recent review (thanks to KT Park for reference) provides helpful resource for treating H pylori infection; this is becoming more important in this era of frequent antibiotic resistance. While this blog has reviewed expert recommendations for treatment, this article provides more insight into salvage treatments.  Table 1 reviews standard quadruple and triple regimens. Table 2 (below) provides dosing in adults for salvage therapy.

Thung, I., et al. (2015), Review article: the global emergence of Helicobacter pylori antibiotic resistance. Alimentary Pharmacology & Therapeutics. doi: 10.1111/apt.13497

Full link: Review article: the global emergence of Helicobacter pylori antibiotic resistance

 

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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.

Pet Peeves -Cough and Cold Medicines and Antibiotic Usage

Although upper respiratory illnesses are not a primary focus for pediatric gastroenterologists, due to their frequency, we see them quite a bit.  Even with my limited exposure, I frequently receive requests for medications to reduce the symptoms of cough and runny nose.

My approach has typically been to explain that I don’t believe that cough and cold medicines (CCMs) are effective and can be harmful, especially in young children.  This explanation is in agreement with efforts that both the pharmaceutical industry and the Food and Drug Administration (FDA) took in 2007 and 2008 to limit the use of over the counter (OTC) CCMs in young children.  The American Academy of Pediatrics has gone further and advised against their usage in children under age 6 years.  These recommendations came in part due to lack of efficacy of these agents but also due to the recognized potential for adverse effects, including fatalities.

Recently, a study (J Pediatr 2014; 165:1024-8) has shown that despite labeling changes on CCMs there has been virtually no impact on the use of OTC CCMs.  Using information from administrative databases, this study compared prescribing patterns 2005-2006 with 2009-2010 in children aged ≤ 12 years.  Results: There was an increase in use of OTC CCM used in ambulatory clinics (6.3% to 11.1%) but a decrease in the use of prescription CCMs 6.7% to 2.9%.  The OTC CCM use in children <2 years was essentially unchanged between the two timeframes (6.8% compared to 6.5%)

Bottomline: If parents and physicians want to do what is best for the children they care for, then more effort is needed to stop the widespread use of CCMs.  Prevention with influenza vaccination and proper hand hygiene are measures which can help.

A separate problem is the misuse of antibiotics for upper respiratory illnesses.  This is widespread as well.  While this blog has discussed antibiotic resistance and antimicrobial stewardship, a recent article (NEJM 2014; 371: 1761-63) provided a few new ideas on this subject.

  • First, the authors note that modern medicine is entirely dependent on antibiotics.  “Two major ways that modern medicine saves lives are through antibiotic treatment of severe infections and the performance of medical and surgical procedures under the protection of antibiotics.”
  • Second, the authors note that “as people in wealthier regions run out of effective antibiotics, they come to share the lot of people in poorer regions who can’t afford them to begin with.”
  • Third, the authors point out that antibiotic resistance was recognized in 1945 by Alexander Fleming and Howard Walter Florey when they accepted the Nobel Prize for the discovery of penicillin.

The authors then outline the areas that need to be addressed to diminish the prospects of ineffective antibiotics:

  • Prevention with vaccination and sanitation
  • Leadership to coordinate global surveillance and manage rewards for proper usage
  • Access to subsidized appropriate usage in poorer countries
  • Conservation of antibiotic usage –restrain use of antibiotics in agriculture/farming
  • Conservation through appropriate use of prescriptions

Related blog posts:

Understanding Resistance to Helicobacter pylori

An editorial (by Ben Gold -congratulations!) helps sort out the potential advantages of gene based testing for Helicobacter pylori in a commentary on a recent publication (JPGN 2014;  59: 6-9).

In the study, the authors used formalin=fixed biopsies in 38 H pylori--infected gastric biopsies.  These specimens were examined for 23S rRNA mutations associated with resistance to clarithromycin.  Overall, the authors (from Dallas, TX) noted H pylori in 4.5% of their biopsies.  The majority of these children, treated between 2010-2012, were given clarithromycin, amoxicillin, and a proton pump inhibitor (n=25).  Due to clarithromycin resistance, this is no longer considered a first-line treatment in the absence of clarithromycin susceptibility testing according to NASPGHAN guidelines (published in 2011).

The authors noted a cure rate of 62.5%, likely due to the use of clarithromycin-based triple therapy.  In addition, Dr. Gold notes that the authors identified a very high rate of clarithromycin resistance (50%): “greater than that reported by any of the previously published national surveys or single-center studies in the United States, Europe, or Japan.”

Take-home point from Dr. Gold: “Because the common mutations responsible for H pylori resistance to the other major antimicrobials used for eradication…have been described, the assay developed by Mittui et al could be modified to include a panel of antibiotics…to optimize therapy.”

Related blog posts:

What is Evidence-Based Medicine for Helicobacter Pylori?

Full article (Clin Gastroenterol Hepatol 2014; 12: 177-86): http://ow.ly/sPKbi 

My take on the most important parts of this Helicobacter pylori (HP) article:

  • Success defined: curing HP ≥95% =excellent, curing HP ≥90% =good, acceptable ≥85%, and unsatisfactory <85%.
  • “Because clarithromycin-containing triple therapy and 10-day sequential therapy are now only effective in special populations, they are considered obsolete.”
  • The “preferred choices for Western countries” are the following
  1. 14-day concomitant therapy: PPI, amoxicillin 1 g, clarithromycin 500 mg, metronidazole -all twice daily
  2. 14-day bismuth quadruple therapy: PPI BID, bismuth BID, tetracycline 500 mg QID, metronidazole 500 mg TID
  3. 14-day hybrid sequential-concomitant therapy: 7 days of PPI-amoxicillin 1 g, followed by amoxicillin 1 g, clarithromycin 500 mg, metronidazole 500 mg for 7 days-all BID

Other useful points:

  • Tetracycline is not available in many parts of the world and generally doxycycline is not an adequate substitute for tetracycline.
  • Triple therapies are extremely sensitive to resistance of the third drug (eg. clarithromycin and metronidazole).  The increase in resistance is making these regimens ineffective
  • An online calculator can help predict which therapy to choose: https://hp-therapy.biomed.org/tw/ (need to know local resistance)
  • Poor compliance is the other factor besides resistance that can undermine a well-constructed treatment regimen. Spending ample time educating patients about the need to  take all of their medicines is crucial.
  • Figure 1 on page 178 outlines the recommended treatment approach.  Unfortunately, availability of susceptibility testing has been quite limited.

Take-home message: The authors emphasize using regimens that work locally and using the evidence that we have to choose the best treatments.  However, given the resistance patterns, working on collaborating with laboratories to culture HP for susceptibility/resistance would be worthwhile to increase the likelihood of excellent outcomes.

Related blog links:

Also noted:  full text article online (from Kipp Ellsworth twitter feed): http://goo.gl/dD2ooF “Intestinal Transplantation: An Unexpected Journey”  This is a succinct overview of intestinal transplantation’s progress and potential.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  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.

Hospital-based Antimicrobial Stewardship

While there has been growing recognition of antibiotic resistance, the efforts to implement strategies to preserve the effectiveness of our current antibiotics have not been embraced by enough stakeholders.  A recent review provides insight into the antibiotic stewardship (AS) programs that are being implemented by pediatric hospitals (JAMA Pediatrics; 2013; 167: 859-66).  Thanks to Ben Gold for sharing this reference.

AS goals are to “optimize clinical outcomes while minimizing unintended consequences of antimicrobial use, including toxicity, the selection of pathogenic organisms, and the emergence of resistance.”  Five specific goals:

  • timely management of antimicrobial therapy -prompt initiation when indicated, avoid when not indicated (eg. viral illness)
  • appropriate antibiotic selection -minimize redundant antibiotic coverage
  • appropriate antibiotic administration and de-escalation of therapy -reassess after 48-72 hrs whether to discontinue antibiotics, monitor levels when needed
  • use of available expertise and resources at point of care
  • transparent monitoring of antimicrobial data usage

Adoption of AS programs has been accelerating in the past few years.  “A recent survey of 43 children’s hospitals showed that 16 institutions (37%) ..currently have an established AS  program supported by full-time equivalents for a pediatric infectious diseases physician and/or clinical pharmacist.”  Another 15 (35%) are in the preparatory stage of implementing an AS program.

Potential barriers for AS programs:

  • Lack of funding or time –these programs have been reported to yield cost savings
  • Lack of hospital leadership
  • Concerns about physician autonomy

Potential outcome variables to measure:

  • Reduction in adverse events
  • Improved (?) antibiotic resistance trends
  • Reduction (?) in C difficile rates

The authors note that on a national level that AS programs have not been mandated. However, multiple societies, including the Infectious Diseases Society and the Society for Healthcare Epidemiology of America, have recommended their widespread adoption.

Bottomline: Improving hospital antibiotic usage with the use of AS programs will help reduce antibiotic resistance, but it is the tip of the iceberg when it comes to addressing this issue (see related blog posts below).

Related blog entries:

High Rates of Helicobacter Pylori Resistance

While the development of antibacterial resistance has broad implications, in gastroenterology patients specific problems have emerged with Helicobacter pylori (H pylori) and this has led to changes in first-line therapy( ).  More data on the treatment resistant H pylori has been published (JPGN 2013; 56: 645-48).

77 consecutive strains of H pylori  from Brazilian children and adolescents were isolated from gastric biopsies and analyzed; this study took place between 2008-2009 and the mean age was 11.1 years.  In 71 strains, there were no previous attempts at eradication.

Results:

  • 40% of strains were resistant to metronidazole
  • 19.5% of strains were resistant to clarithromycin
  • 10.4% of strains were resistant to amoxicillin
  • All strains were susceptible to furazolidone and tetracycline
  • 14/77 (18.2%) patients had multiple resistances

Take-home point: Resistance to antibiotics is altering our approach to H pylori therapy.  Antibiotic susceptibility testing may be needed to improve antibiotic selection and eradication rates.

Related blog links:

Sugar-resistant bugs

“Evolution helps cockroaches lose their sweet tooth, increase survival”

An excerpt from the following link: Evolution helps cockroaches lose their sweet tooth, increase   summarizes a recent study from Science below.  The findings provide further evidence of how bugs (along with microbial bugs) adapt; in circumstances where glucose can be lethal, bugs that are sugar averse have a selective advantage.

Have you ever wished you could just turn off your sweet tooth to help you resist that third piece of pie? For people, the downside of the deliciousness of sugar is simply feeling really full or gaining weight, but for cockroaches, their sweet tooth can be deadly.

The poisoned baits people set to kill roaches in their homes lure the unsuspecting insects in with sugar. But it turns out that the selective pressure of delicious, deadly traps throughout the environment has led to the rapid evolution of cockroaches that avoid sugar. They turned the sweet tooth off—or rather redirected it so it now tastes bitter.

A team of researchers from North Carolina State University published research this week looking at how the German cockroach, Blattella germanica, was able to adapt so quickly when surrounded by tasty insecticide. Sweet baits became popular for roach control in the mid-1980s, but several years later scientists began noticing a new behavioral trait: aversion to glucose, the most common simple sugar. The trait is heritable, and cockroaches with it avoided the baits. In areas treated with these traps, the roaches without a sweet tooth had much better survival rates than the roaches that lacked this new adaptation.

Insects’ sense of taste comes from hair-like structures on the mouthparts that contain nerve cells called peripheral gustatory sensory neurons. Insects have four “tastes”—sweet, bitter, water, and salt. Typically, foods that trigger the sweet neurons led the insects to eat, while foods that trigger the bitter neurons cause them to avoid that food.

The scientists, Ayako Wada-Katsumata, Jules Silverman, and Coby Schal, suspected that a change in the bitter and sweet sensory systems led to the glucose aversion trait. When they compared the sugar and bitter sensitivities of the averse roaches with the wild type, they found that the glucose triggered the same neurons as caffeine — very bitter. However, both groups of roaches still ate fructose, another simple sugar molecule, at the same rates.

Sampling wild cockroaches, they found glucose-averse individuals in seven out of 19 populations. The sensory responses in the native cockroaches mimicked the lab experiments, with caffeine and fructose responses remaining normal and glucose triggering the bitter system instead of the sweet. This shows that a very similar glucose aversion mechanism arose in multiple populations.

What kind of mutation led to this adaptive behavior? The researchers suspect that one or more mutations modified the bitter sensing system to react to glucose. For populations surrounded by sweet poisons, this mutation offers a serious evolutionary advantage. However, growth and reproduction of the glucose-averse roaches is slower than the normal population, so the mutation only functions as an adaptation in the face of attempted pest control.

The more we try to poison the roaches, the greater the advantages of being a cockroach that thinks sugar tastes bitter, and the more common this mutation will become. We probably need to find a new type of insecticide.

Science, May 2013. DOI: 10.1126/science.1234854

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What is the risk with Rifaximin?

While no one knows how quickly resistance of gut microbes will develop in response to rifaximin, the likelihood of resistance is high and this should temper its usage (J Clin Gastroenterol 2013; 47: 205-11).

Rifaximin, along with other antibiotics, has been shown to relieve symptoms in certain cohorts of irritable bowel syndrome (IBS) patients.  Generally, the results of these studies have been modest (see below); however, because it is a “gut specific” antibiotic with minimal systemic absorption (<1%) and therefore minimal adverse effects, it has been considered a reasonable and safe treatment by many.  It has been useful as well for traveler’s diarrhea, hepatic encephalopathy, and colonic diverticular disease.  With regard to IBS, the major concern is that this is a chronic disorder and repeated usage will result in antimicrobial resistance.

Resistance to rifaximin could result in serious consequences if it provoked a class effect resistance.  Rifaximin belongs to the rifamycin class of antibiotics which treat numerous diseases including tuberculoses, meningococcal disease, Clostridium difficile, and methicillin-resistance Staphylococcus aureus.

Given the limited number of suitable alternatives and emerging resistance patterns, wise stewardship of our current antibiotics is essential, though unlikely.  It is not difficult to foresee a rise in mortality from some infectious problems that are easily treated currently.

Related references:

  • -JPGN 2011; 52: 382.  Double-blind, placebo-controlled study of rifaximin in children with RAP.  n=75.  Not effective in this study.
  • -NEJM 2011; 364: 22 (pg 81-editorial). About 10% improvement over placebo in pts with IBS-D. Effects lasted up to 3 months.
  • -DDW 2010, 475 abstract. Target 1 & Target 2. n=623, n=637. Relief of IBS in ~41% vs ~32% placebo. 550mg TID x 14days.

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Antibiotic resistance: doomed to repeat

“We’re doomed to repeat the past no matter what. That’s what it is to be alive. It’s pretty dense kids who haven’t figured that out by the time they’re ten.” Kurt Vonnegut, Bluebeard

“Those who don’t know history are destined to repeat it.” Edmund Burke

Antibiotic resistance has been occurring for billions of years and will keep on happening (NEJM 2013; 368: 299-301).  This commentary offers a different perspective and indicates that Kurt Vonnegut’s quote is more appropriate for this post.  Some key points:

  • “We live in a bacterial world where we will never be able to stay ahead of the mutation curve.” We will run out of targets to attack microbes.
  • Bacteria “invented” antibiotics billions of years ago, and “resistance is primarily the result of bacterial adaptation to eons of antibiotic exposure.” Thus, even with good antimicrobial stewardship, resistance will still occur.
  • Antibiotic resistance has been identified in bacteria found in underground caves that have been geologically isolated from the planet surface for four million years.
  • In 1945, Alexander Fleming called for stopping the overuse of penicillin to slow the development of resistance.
  • In 2009, three million kilograms of antibiotics were administered to humans and 13 million kilograms to animals.

Possible useful steps: more vaccines to prevent infections, smaller antibiotic clinical trials, use of rapid biomarkers to withhold antibiotics from those without bacterial infections, stopping antibiotics to help livestock growth, better waste-treatment of antibiotics, ‘self-cleaning’ hospital rooms, and better drug delivery to avoid foreign materials in intensive care patients.

Related blog entry: