America’s Formula Shortages –The Bigger Picture

A recent article (The Dispatch, Scott Lincicome: America’s Infant Formula Crisis and the ‘Resiliency’ Mirage) explains that the reasons we are facing formula shortages go beyond the Abbott recall.

Excerpts:

The infant formula crisis isn’t simply another case of a one-off event causing pandemic-related supply chain pressures to boil over. Instead, U.S. policy has exacerbated the nation’s infant formula problem by depressing potential supply….all part of our government’s longstanding subsidization and protection of the politically powerful U.S. dairy industry…

[Additionally, there] are strict FDA labeling and nutritional standards that any formula producer wishing to sell here must meet….These regulatory barriers are probably well-intentioned, but that doesn’t make them any less misguided—especially for places like Europe, Canada, or New Zealand that have large dairy industries and strict food regulations

The combination of trade and regulatory barriers to imported infant formula all but ensures that our almost $2 billion U.S. market is effectively captured by a few domestic producers—despite strong demand for foreign brands. What German company, for example, is willing to spend the time and money meeting all the FDA requirements—registration, clinical trials, labeling and nutritional standards, inspections, etc.—only to then face high import taxes that make its product uncompetitive except during emergencies? The answer: almost none…

Meanwhile, Abbott is in full-on crisis mode and has turned to flying in formula produced at an FDA-registered Irish affiliate…

WIC program’s use of sole supplier contracts has created a problem specific to the current crisis because … the big FDA recall just happened to hit the very producer—Abbott—holding most of the WIC contracts. 

My take: This article explains why there is not a simple switch to flip to fix the current formula bottlenecks.

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Antimicrobial Stewardship for Helicobacter Pylori

Yesterday, this blog discussed what is needed to achieve high cure rates for H pylori. One of my microbiology colleagues informed me that until recently there have only been susceptibility standards for clarithromycin from the Clinical Laboratory Standards.  Now, the European Committee on Antimicrobial Susceptibility Testing has criteria for clarithromycin, tetracycline, amoxicillin, levofloxacin, metronidazole, and rifampin. Given the difficulty culturing H pylori, his view is that stool testing is the most promising avenue for susceptibility testing because we now have the genes that determine resistance delineated for all of these drugs.

A related issue is antimicrobial stewardship: DY Graham. J-M Liou. Clin Gastroenterol Hepatol 2022; 20: 973-983. Open Access: Primer for Development of Guidelines for Helicobacter pylori Therapy Using Antimicrobial Stewardship

Key points:

  • “Therapies that fail to achieve at least a 90% cure rate should be abandoned as unacceptable”
  • “Antibiotics in the access group have lower resistance potential … They should be widely available and affordable. Amoxicillin, tetracycline, and metronidazole are classified as the access group. In contrast, clarithromycin and levofloxacin have higher resistance potential and are classified as the watch group. They should be prioritized as key targets of stewardship program and monitoring”
  • “Therapies that contain antibiotics which do not contribute to outcome should be eliminated”
  • The “full antisecretory activity of PPIs requires 3–4 days. This makes the actual duration of effective therapy shorter than the days it is administered…However, pharmaceutical companies often have chosen to shorten the recommended duration of therapy to obtain a marketing advantage at the expense of reduced effectiveness”
  • “Currently most H pylori infections receive empiric therapy, and the clinician does not know or even have access to treatment guidance based on local or regional antimicrobial susceptibility patterns…few hospitals or clinics offer susceptibility testing”
  • Even without susceptibility testing, clinicians could achieve much better results if test of cure data were carefully collected and analyzed
  • “Metronidazole-containing bismuth quadruple therapy is unique in that it appears that metronidazole resistance can be partially or completely overcome by increasing the dose and duration of therapy…metronidazole resistance as assessed in vitro does not correlate well with its effectiveness in vivo, especially when used as a component of a triple or quadruple therapy”

H pylori is difficult to eradicate:

  • Location: “the organisms reside within the highly acid stomach, which is physically outside of the body and thus poorly accessible to blood-borne antibiotics and the immune system”
  • Inoculum effect: “H pylori is also typically present in vast numbers, resulting in an inoculum effect … the inoculum effect is largely responsible for the failure of dual therapy with PPIs clarithromycin, metronidazole, or levofloxacin, as their effectiveness is undermined by emergence of resistance during therapy”
  • Biofilm and intracellular: “A proportion of H pylori attach to the surface of gastric cells, leading to a biofilm phenomenon, and some are present intracellular by requiring the use of antibiotics capable of penetrating into cells”
  • Dormant state: “H pylori can become dormant in part because they can replicate only when the pH is approximately 6…this results in a persister effect”

My take: The lack of action on H pylori susceptibility despite the current tools is a bad look for the GI community. Would this still be the case if the treatment were relegated to our infectious disease colleagues? Antibiotic stewardship is coming for H pylori -children and adults with this infection should have higher cure rates and easier treatment regimens.

Related blog posts:

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How To Achieve Helicobacter Pylori Cure Rates of >95%

Related to yesterday’s blog, here is an SNL commercial for the “Koohl” toilet (also with Benedict Cumberbatch) in 2016: SNL Koohl Toilet

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DY Graham, SF Moss. Am J Gastroenterol 2022. 117: 524-528. Antimicrobial Susceptibility Testing for Helicobacter pylori Is Now Widely Available: When, How, Why

Key points:

  • Susceptibility testing for H pylori is widely available in the U.S. and should help optimize treatments to get success rates >95%. Testing is now available for the most common treatment antibiotics: amoxicillin, metronidazole, tetracycline, levofloxacin, clarithromycin, and rifabutin.
  • Handling/shipping specimens properly is important with susceptibility testing
  • The authors recommend a PPI which is minimally-affected by CYP2C19 metabolism, namely rabeprazole or esomeprazole.
  • Provide careful instructions to patient/family regarding treatment

Susceptibility Testing Labs (see Table 1):

A treatment algorithm is listed:

  • In the absence of highly effective empiric treatment or after treatment failure, the authors recommend susceptibility testing.
  • If clarithromycin susceptible, then a 14-day clarithromycin triple therapy course is recommended
  • If clarithromycin resistant but metronidazole susceptible, then 14-day metronidazole triple therapy
  • If resistant to both clarithromycin and metronidazole, then either a 14-day bismuth quadruple therapy, or a rifabutin triple therapy are preferred. However, if H pylori organisms are levofloxacin susceptible, then 14-day levofloxacin triple therapy may be a good option.
  • The authors recommend quinolone therapy only in the setting of susceptibility testing due to the FDA warnings about long-term adverse effects.

My take: Perhaps H pylori susceptibility testing availability needs to be a quality metric for hospitals and endoscopy centers.


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AAP Guidelines for Down Syndrome & Screening for Celiac Disease Plus One (How to Fix Diarrhea)

The AAP has updated recommendations for Down syndrome: MJ Bull et al. Pediatrics (2022) 149 (5): e2022057010. Open Access: Health Supervision for Children and Adolescents With Down Syndrome

For gastroenterologists, one area of concern is screening for celiac disease in this population due to a mildly increased risk.

Here is what is recommended in children after 1 year of age:

“For children on a diet that contains gluten, review for symptoms potentially related to celiac disease at each health supervision visit because children with Down syndrome are at increased risk. These symptoms include diarrhea or protracted constipation, slow growth, unexplained failure to thrive, anemia, abdominal pain or bloating, or refractory developmental or behavioral problems.9799  For those with symptoms, obtain a tissue transglutaminase immunoglobulin A (TTG IgA) concentration and simultaneous quantitative IgA. The quantitative IgA is important, because an IgA deficiency renders the TTG IgA unreliable. Refer patients with abnormal laboratory values for specialty assessment. Do not institute a gluten-free diet before confirmation of the diagnosis, because lack of gluten can make interpretation of endoscopic results difficult. There is no evidence that routine screening of asymptomatic individuals would be beneficial. There are neither data nor consensus that would indicate whether patients with persistent symptoms who had normal laboratory values on initial evaluation should have further laboratory tests.”

In addition to celiac disease, the AAP article has a ton of useful resources regarding Down syndrome for clinicians and families.

My take: Celiac disease is difficult to diagnose and is much more common in children with Down syndrome. It is worth noting that other Down syndrome groups, NICE and NASPGHAN have recommended screening for celiac in all children with Down syndrome. (Ref: M Pavlovic et al. World J Clin Cases. 2017 Jul 16; 5(7): 264–269. Open Access: Screening of celiac disease in Down syndrome – Old and new dilemmas)

Related blog posts:

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Also, a keen observation from Carlo Di Lorenzo’s twitter feed:

The corollary of this is how miraculous it is when a child who has not stooled for 3 weeks straight has no residual markers after swallowing a Sitz capsule.

Understanding Rapid COVID-19 Testing Compared to PCR Testing

VT Chu et al. JAMA Intern MedPublished online April 29, 2022. doi:10.1001/jamainternmed.2022.1827. Open Access: Comparison of Home Antigen Testing With RT-PCR and Viral Culture During the Course of SARS-CoV-2 Infection

Background: This was a prospective cohort study of 225 adults and children comparing reverse transcription–polymerase chain reaction (RT-PCR)–confirmed SARS-CoV-2 infection with antigen testing (QuickVue At-Home OTC COVID-19 Test) and viral culture (January to May 2021)

Key findings:

  • Rapid testing (antigen) sensitivity was 64% and viral culture sensitivity was 84% when compared with same-day RT-PCR and viral culture
  • Rapid testing (antigen) sensitivity peaked 4 days after illness onset (77%); a second test 1 to 2 days later showed improved sensitivity (81%-85%)

My take: This study shows that a single rapid test is NOT adequate to exclude SARS-CoV-2 infection, especially if they are symptomatic (need to recheck 1-2 days later if negative rapid test). The reliability/accuracy/sensitivity is likely to vary greatly between different rapid tests and may change significantly with different viral variants.

@MondayNightIBD and Acute Severe Ulcerative Colitis Algorithm

A summary of the discussion and more detailed information on this topic from Gastroenterology and Endoscopy News (4/20/22): Open Access: ASUC: A Medical and Surgical Emergency Requiring Comprehensive, Timely Multidisciplinary Care

Lab workup per article:

For infliximab salvage therapy, the article recommends re-dosing at 3-5 days after initial dose.

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  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

IBD Shorts: Pediatric Colonic CD, UC Colectomy Risk Factors, Ustekimumab for 5 years

TD Berger et al. JPGN 2022; 74: 258-266. Clinical Features and Outcomes of Paediatric Patients With Isolated Colonic Crohn Disease

This study focused on 94 with isolated colonic Crohn’s disease (L2). Key findings: Response to enteral nutrition (78.3%) was comparable to those with L1 disease (82.4%) (n=104). Skp lesions and granulomas, identified in 65% and 36% in those with L2 disease was similar to those with L1 disease.

JS Hyams et al. Inflamm Bowel Dis 2022; 28: 151-160. Open Access: Clinical and Host Biological Factors Predict Colectomy Risk in Children Newly Diagnosed With Ulcerative Colitis

Key findings:

  • 25/428 (6%) children with recently diagnosed UC underwent colectomy at ≤1 year, 33 (9%) at ≤2 years, and 35 (13%) at ≤3 years. 
  • An initial PUCAI ≥ 65 was highly associated with colectomy (P = 0.0001)
  • A  pretreatment rectal gene expression panel showed that patients who had colectomy had significantly higher values for this genetic signature in comparison with those who did not require colectomy

WJ Sandborn et al. Clin Gastroenterol Hepatol 2022; 20: 578-590. Open Access: Five-Year Efficacy and Safety of Ustekinumab Treatment in Crohn’s Disease: The IM-UNITI Trial

Key findings:

  • Using an intent-to-treat analysis of all patients randomized to ustekinumab at maintenance baseline, 34.4% of patients in the every-8-weeks group and 28.7% in the every-12-weeks group were in clinical remission at week 252. In the 8 week group in the long-term extension portion of the study the rate was 54.9%
  • Adverse effect profile (per 100 patient-years): generally were similar in the placebo and combined ustekinumab groups for all adverse events (440.3 vs 327.6), serious adverse events (19.3 vs 17.5), infections (99.8 vs 93.8), and serious infections (3.9 vs 3.4).
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“For Hospitalized Patients With ASUC, 5-ASA Adds No Value to Steroids”

From Gastroenterology and Endoscopy News (4/25/22): Open Access: For Hospitalized Patients With ASUC, 5-ASA Adds No Value to Steroids

In the first prospective randomized study, presented at the 2022 Crohn’s & Colitis Congress and published in Inflammatory Bowel Dis (S Ben-Horin et al 2022;28 [suppl 1]:S14 CORTICOSTEROIDS AND 5ASA VERSUS CORTICOSTEROIDS ALONE FOR ACUTE SEVERE ULCERATIVE COLITIS: A RANDOMIZED CONTROLLED TRIAL), investigators at 10 centers in six countries randomly assigned 149 patients hospitalized for ASUC to receive daily doses of 300 mg of hydrocortisone (or equivalent methylprednisolone) alone or in combination with 4 g of mesalamine.

Key findings:

  • 72.6% of patients receiving combination corticosteroids with 5-ASA responded to treatment at one week compared with 76.3% of responders in the group receiving corticosteroids alone
  • “There were no differences in hospital length of stay between groups (median, 10 vs. nine days for the combination and monotherapy groups, respectively), the proportion of patients whose C-reactive protein level normalized (34.2% vs. 34.3%, respectively), or the proportion requiring colectomy within 90 days (4.9% vs. 4.5%, respectively).”
  • While 5-ASAs did not alter the trajectory of acute colitis, one other finding was a lower rate of biologic use (27% vs 47%, P=.07) at 90 days in those who continued to receive 5-ASA therapy at 90 days.

My take: 5-ASAs do not appear to be helpful during hospitalization for ASUC but may be beneficial as a maintenance therapy in some patients.

Related blog posts:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  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

How Industry Manipulates Physicians For Product Promotion

As an homage to May 4th, I wanted to highlight an AAP report that reminded me of Yoda telling Luke Skywalker: “If once you start down the dark path, forever will it dominate your destiny, consume you it will, as it did Obi-Wan’s apprentice.”

DS Diekema. AAP Committee on Bioethics. Pediatrics 2022; 149: e2022056549. Open Access. Health Care Clinicians and Product Promotion by Industry.

Background:

  • “In 2016, pharmaceutical companies spent $29.9 billion on marketing, of which $20.3 billion (68%) was directed toward health care clinicians in the form of prescriber detailing ($5.6 billion), free samples ($13.5 billion), direct physician payments related to specific drugs ($979 million), and disease education ($59 million)”
  • “In 2019, 615 000 physicians received payments or investment interests worth $3.6 billion (an average of $5854 per physician recipient), and 1194 teaching hospitals accepted payments totaling $2.63 billion”
  • “Despite their own sense of invulnerability to persuasive techniques, physicians do consider other physicians to be vulnerable.125  This phenomenon is what social scientists refer to as the “bias blind spot.”147  As a general rule, individuals underestimate the degree to which they are influenced by cognitive and motivational bias and overestimate the degree to which others are influenced by the same things.147 

Key points:

“In his book, Influence: The Psychology of Persuasion, Cialdini summarizes this literature and describes 6 basic categories of effective persuasive techniques.57

  • Commitment and Consistency…Industry representatives are trained to get health care clinicians to make a verbal commitment to use their products…once the health care clinician has tried the drug on 5 patients, he or she is more likely to continue to use the drug.7 
  • Social Proof…When told that almost all of the physicians in the region are now using drug A to treat disease B, a health care clinician will be hard-pressed not to join the group”
  • Liking… Humans tend to be more responsive and receptive to individuals who are friendly, likeable, and attractive”
  • Appeals to Authority…The use of opinion leaders and experts to give lectures supporting the use of a product”
  • Scarcity…Opportunities to engage in consulting and speaking opportunities fall into this category”
  • Reciprocation…A sense of obligation to reciprocate accompanies the receipt of any favor, gift, or kindness. Gifts can take many forms and need not be valuable.”

Reciprocation Elaborated:

  • “Much cognitive activity occurs without conscious awareness, and the most effective marketing and persuasion strategies are designed to engage the subconscious aspects of decision making…Decision making appears to rely on dual systems within the brain, a socioemotional system” and the cognitive control system.
  • “The socioemotional system tends to involve rapid, automatic processing that is often reactive, intuitive, unconscious, and sensitive to social norms…Effective marketing strategies, including the use of incentives and gifts and the nurturing of relationships, are designed to engage the socioemotional decision-making areas of the brain”
  • “The cognitive control system, on the other hand, tends to be consciously controlled, reasoned, and analytic and requires more time and conscious effort”
  • “Most health care clinicians believe they cannot be bribed and that they would never trade a small gift for changing their prescribing behavior…Gifts may subtly and subconsciously affect the way the receiver of the gift evaluates the information provided by the gift giver, and these feelings of indebtedness may ultimately lead to changes in prescribing behavior”

“With regard to the receipt of gifts from the industry, the American Academy of Pediatrics (AAP) has endorsed the AMA guidelines, which do not prohibit gifts outright but offer the following basic principles for managing them:198 

  • Physicians should decline cash gifts in any amount from an entity that has a direct interest in physicians’ treatment recommendations.
  • Physicians should decline any gifts for which reciprocity is expected or implied.
  • Physicians should accept an in-kind gift for the physician’s practice only when the gift is of minimal value and will directly benefit patients, including patient education.
  • Academic institutions and residency and fellowship programs may accept special funding on behalf of trainees to support their participation in professional meetings, including educational meetings, provided the program identifies recipients based on independent institutional criteria and funds are distributed to recipients without specific attribution to sponsors”

As a final incentive,  “in late 2020, the Department of Health and Human Services Office of the Inspector General issued a special fraud alert highlighting concerns … in connection with speaker programs.” The Office of the Inspector General warned both companies and health care professionals that such arrangements may, under certain circumstances, violate antikickback statutes.”

My take (from the report): “At a minimum, health care clinicians should be cognizant of the techniques used to attempt to alter their behavior and guard against them.”

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