Treatment and Screening of H. Explain theories for the high - - PDF document

1/12/2018 1 Treatment and Screening of H. pylori Infection in Alaskan Populations

Matthew F. Deraedt, Pharm.D. Lieutenant United States Public Health Service Alaska Native Medical Center Pharmacy Practice PGY-1 Resident

Learning Objectives – Pharmacist

• Explain theories for the high prevalence of H. pylori infection in

Alaskan populations.

• Discuss the risk factors for H. pylori Infection, appropriate screening,

and criteria for treatment.

• Outline the similarities and differences for H. pylori treatment using

the current American College of Gastroenterology treatment guidelines and the Alaska Native Medical Center statewide guidelines.

• Differentiate post treatment testing methodologies and patient

specific factors that predict H. pylori treatment success.

Learning Objectives – Technician

• Explain theories for the high prevalence of H. pylori infection in

Alaskan populations.

• Discuss the common signs and symptoms associated with H. pylori

infection.

• Recognize medication regimens for the treatment of H. pylori

infection.

No conflicts of interest to disclose.

Pre-learning Assessment

Which of the following symptoms are considered alert symptoms?

• a. early satiety
• b. post prandial belching
• c. unexplained weight loss
• d. dyspepsia

Pre-learning Assessment

Which of the following Alaskan patients would be candidates for endoscopy and possible H. pylori treatment?

• a. A 27 y/o male who presents with several weeks of dyspepsia

secondary to eating

• b. A 60 y/o male who has recent weight loss and complaints of

dyspepsia

• c. A 38 y/o male reports with several weeks of epigastric pain

secondary eating

• d. A 57 y/o female who has daily ibuprofen use for osteoarthritis

and reports dyspepsia

1/12/2018 2

Pre-learning Assessment

What specific factors influence the treatment of H. pylori treatment in Alaska versus the contiguous United States?

• a. > 60% prevalence among patient populations
• b. high rate of resistance
• c. injudicious use of antimicrobials
• d. crowded living considerations

Pre-learning Assessment

Which of the following are theories for the transmission of H. pylori?

• a. fecal-oral
• b. fomite associated
• c. bodily fluids
• d. oral-oral
• H. pylori
• Genus Helicobacter
• Gastric vs. Enterohepatic
• Helicobacter pylori
• Microaerophilic
• Gram negative
• Morphology
• Spiral shaped
• Rod
• Coccoids (viable?)
• Highly motile

http://ngm.nationalgeographic.com/2013/01/125-microbes/oeggerli-photography#/06-helicobacter-670.jpg

Kusters JG, et al. Clin MicroBiol Rev. 2006

• H. pylori
• Urease (+), Catalase (+), oxidase

(+)

• Cryptic plasmids – not resistance

associated

• Genetic heterogeneity
• Genetic rearrangement
• Rich G+C regions
• Lawn formation
• Poorly cultured
• H. pylori on blood agar

Kusters JG, et al. Clin MicroBiol Rev. 2006

Koch’s Postulates – Theory Meets Practice

• Warren observed spiral

bacteria in gastric biopsies

• Named them “Campylobacter

like organisms”

• In 1985, Marshall ingested

cultured bacteria and subsequently experienced gastritis

• Marshall and Warren

awarded The Nobel Prize in Physiology and Medicine in 2005

Kumar S. Textbook of Microbiology. 2012. Kusters JG, et al. Clin MicroBiol Rev. 2006 Marshall BJ, et al. Med J Aust. 1985

Virulence Factors Mediate Pathogenesis

Kao CY, et al. Biomed J. 2016 39:14-23

1/12/2018 3

• H. pylori intracellular modulation

Salama NR, et al. Nat Rev Microbiol. 2013;11(6):385-399.

Presentation

• Dyspepsia
• Epigastric pain
• Upper right or left quadrant
• Worsens with eating
• Post-prandial belching
• Early satiety
• Nausea
• Reflux
• Commonly associated with GERD

Kasper DL, et al. Harrison’s Principles of Internal Medicine. 19th Edition https://www.mayoclinic.org

Alarm Symptoms

Alarm Symptoms New onset dyspepsia in patient ≥ 60 y/o GI bleeding (hematemesis, melena, hematochezia, occult blood in stool) Anorexia Unexplained weight loss Dysphagia Odynophagia Vomiting GI cancer in 1st degree relative

Implications of Non-treatment

• International Agency for

Research on Cancer listed as a class I carcinogenic substance

• Peptic ulcer disease
• Chronic gastritis
• Mucosa-associated lymphoid

tissue (MALT) lymphoma

• Adenocarcinoma of the stomach

Mcmahon BJ, et al. Epidemiol Infect. 2016.144:225 – 223.

Gastric Cancer Risk in Alaska Native Patients

• 5th most diagnosed cancer in AN
• Mortality rate is three times

what is seen in contiguous U.S.

• Presence of anti-H. pylori

antibodies in patients with gastric cancer demonstrated a 2.63-fold increase in odds of cancer (P=0.01).

Keck JW, et al. Can J Gastroenterol Hepatol. 2014:28(6):305-10 https://www.nrcs.usda.gov

Helicobacter pylori infection and markers of gastric cancer risk in Alaska Native persons: A retrospective case-control study

Keck JW, et al. Can J Gastroenterol Hepatol. 2014:28(6):305-10

1/12/2018 4

Transmission…a work in progress

• Epidemiological data suggest
• ral-oral transmission or fecal-
• ral transmission
• Recent studies suggest an

environmental reservoir

• Possible a combination?
• Environmental risk factors?

J Adv Research 2015;4(6):539 - 547 Krueger WS, et al. Epidemiol Infect. 2015;143:2520-31 Leja M, et al. Heliconacter. 2016;21(1):3-7.

Transmission Hypothesis

• The fecal oral hypothesis
• Contaminated water sources
• H. pylori PCR studies
• Oral –Oral hypothesis
• Supported by higher rate in

cohabitation

• H. pylori may be linked to

hepatitis A infection (HAV)

• Conflicting studies

J Adv Research 2015;4(6):539 - 547 Krueger WS, et al. Epidemiol Infect. 2015;143:2520-31

Water as a reservoir?

• In Japan, Fujimura et al, compared three groups with different

drinking water sources

• River water vs. ground water
• Lower prevalence in ground water
• Insufficient N
• Mazari-Hiriart et al. utilized 16S rRNA and cagA sequencing to

comment on H. pylori presence in drinking water

• Detected DNA 16S rRNA 44% of sources and cagA gene 14% samples
• Positive PCR correlate to viable infectious matter?
• Further Studies conducted by Bockleman et al. unable to find positive

PCR samples in water samples from Spain, Italy and Belgium.

Fujimura S, et al. J Med Microbiol. 2008;57:909-10. Bocklemann u, et al. Appl Environ Microbiol. 2009;75:154-63. Mazari-Hiriart M, et al. Plos One. 2008;3:e2305.

Intermediate Hosts and Biofilm Formation

• Cellini et al. discovered a strain of
• H. pylori in zooplankton
• Reports of isolates producing

biofilms

• Metabolically inactive
• Possibly persist in protozoa
• intermediate host
• Reports of clinical strains producing
• rdered biofilms
• Biofilms demonstrated through

SEM in gastric mucosa samples

Capon M, et al. J Gastrointest Surg. 2006;10(5):712-17. Cellini L, et al. Appl Microbiol.2008;105:761-9. Giao MS, et al. Appl Eviron Microbiol. 2008.;74:5898-904. microbiologyonline.org http://ocean.si.edu

Environmental Risk Factors

• Higher prevalence among infected family members
• Acquisition rates are higher during childhood in developing countries

than developed countries

• Impoverished areas with overcrowding
• Variable infection rates between developed vs. developing world and

geographical regions

Krueger WS, et al. Epidemiol. Infect. (2015), 143, 2520–2531.

Krueger et al.

• National Health and Nutritional Examination Survey
• 1999 – 2000
• Examined for Environmental H. pylori risk factors weighted to

represent the U.S. population

• Multivariable linear regression estimated an adjusted odds ratio and

95% confidence interval

Krueger WS, et al. Epidemiol Infect. 2015;143:2520-31

1/12/2018 5

Krueger et al. conclusions

• Participants < 20 years of age
• Having well water (aOR 1.7, 95% CI 1.1–2.6) and living in a more crowded

home (aOR 2.3, 95% CI 1.5–3.7)

• Participants ≥ 20 years of age
• Adults in soil-related occupations had significantly higher odds of

seropositivity compared to those in non-soil-related occupations (aOR 1.9, 95% CI 1.2–2.9)

• Exposures to both well water and occupationally related soil increased the

effect size of adults’ odds of seropositivity compared to non-exposed adults (aOR 2.7, 95% CI 1.3-5.6)

Krueger WS, et al. Epidemiol Infect. 2015;143:2520-31

High Risk Patients

• Risk factors agreed upon in the

literature:

• Low socioeconomic status
• Increasing number of siblings
• Infected parent – especially

mother

• Men
• Alaska Native/American Indian

Krueger WS, et al. Epidemiol. Infect. (2015), 143, 2520–2531. Chey WD, et al. Am J Gastroenterology 2017 ;112:212-238.

Application to Alaska Populations

• Crowded living conditions
• More time spent indoors
• Limited access to clean

water

• Overuse of antibiotics in

remote areas

• Access to specialty services

http://www.alaskanative.net

• M. Bruce, et al. Public Health. 2016;137:5-12.

What else makes treatment of H. pylori unique in Alaska? High prevalence in AI/AN

• Seropositivity
• 40% worldwide for industrialized countries
• 80 - 90% in developing nations
• Alaska Natives
• 75% overall
• Ranges 64 – 81%, dependent on region
• Puts treated individuals at high risk for reinfection… more later

Tveit AH, et al. J Clin Microbiol. 2011;49(10):3638-43 Parkinson AJ, et al. Emerging Infectious Diseases. 2000;7:885-888

Rates of H. pylori infection in AN, 1980 - 1986

Tveit AH, et al. J Clin Microbiol. 2011;49(10):3638-43 Parkinson AJ, et al. Emerging Infectious Diseases. 2000;7:885-888

1/12/2018 6

Diagnosis – Endoscopy

• Invasive
• Gold standard
• Multiple methods
• Biopsy
• Urease testing (no PPI)
• Culture (rare)
• Histology

Kasper D, et al Harrison's Principles of Internal Medicine, 19e; 2015

Noninvasive Diagnosis

• Urea breath testing
• Consume carbon isotope
• Stool antigen testing
• Serology (IgA and IgG

ELISA)

• PCR
• 13C-urea assay

https://www.sgihealth.com/patients/digestive-health-library/h-pylori-breath-test/

Urea Breath Test

http://www.cddcfresno.com/urea-breath-test-ubt/

American College of Gastroenterology (ACG)Clinical Guidelines To treat or not to treat…

All patients with a positive test for an active infection should be offered treatment (strong recommendation)

Strong Recommendations

Patient Characteristic Quality of Evidence Active peptic ulcer disease (PUD) High Past history of PUD (except if previously eradicated High Mucosa-associated lymphoid tissue (MALT) lymphoma Low History of early gastric cancer resection Low Patients gastric biopsies should be evaluated for H. pylori High Patients with typical symptoms of GERD w/o a history of PUD – no testing recommended High Patients Initiating chronic treatment with NSAIDs Moderate

Chey WD, et al. Am J Gastroenterology 2017 ;112:212-238.

1/12/2018 7

Conditional Recommendations

Patient Characteristic Quality of Evidence < 60 y/o uninvestigated dyspepsia w/o alarm symptoms High for efficacy; Low for threshold Taking long term low dose ASA Moderate Patients already taking long term NSAIDs Low Unexplained iron deficiency anemia High Idiopathic thrombocytopenic purpura (TTP) Very low

Chey WD, et al. Am J Gastroenterology 2017 ;112:212-238.

ACG Suggested Treatment Regimens

Chey WD, et al. Am J Gastroenterology 2017 ;112:212-238. Chey WD, et al. Am J Gastroenterology 2017 ;112:212-238.

Management of H. pylori in high prevalence artic regions

Recommendations to follow

• Expert commentary
• Literature review:
• RCT’s and longitudinal cohort

studies

• Cross-sectional studies
• Three face to face meetings
• Clinical practice experience

McMahon et al, Epidemiol Infect. 2016;144(2):225-33.

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ACG Guidelines

• Developed for countries where H. pylori infection < 1/3 of

population

• Test-and-treat strategy
• Modest benefit
• Mixed results from RCT
• Endemic area’s defined as >60% prevalence

Chey WD, et al. Am J Gastroenterology 2017 ;112:212-238. McMahon et al, Epidemiol Infect. 2016;144(2):225-33.

Dyspepsia Weight loss, Fecal Blood Yes No Perform Upper Endoscopy Empiric Therapy: H2 blocker, PPI No improvement? Improvement Monitor treatment

• H. Pylori identified

from EGD sample or CLOtest

McMahon et al, Epidemiol Infect. 2016;144(2):225-33.

Positive H. pylori When should treatment be recommended?

Yes

Endoscopy result indicate:

• Duodenal ulcers
• Gastric ulcers
• MALT lymphoma
• Intestinal metaplasia

No

Many possible causes

• GERD
• IBS
• Mild/moderate

gastritis

• NSAID usage
• EtOH abuse
• Poor GI motility

McMahon et al, Epidemiol Infect. 2016;144(2):225-33.

Why is treatment not indicated? High reinfection rates post confirmed eradication

• Reinfection rates higher for urban and rural AI/AN (14.5% vs. 22.1%)

as well as for urban Alaska non-native patients (12.0%)

• Followed for 2 years post confirmed eradication
• Reinfection rate for U.S. is estimated to be < 5% at 2 years
• Rural AI/AN at highest risk for reinfection

Bruce MG, et al. Epidemiol. Infect 2015;143:1236 – 1246. McMahon et al, Epidemiol Infect. 2016;144(2):225-33

Colonized household members predictive for reinfection

Bruce MG, et al. Epidemiol. Infect 2015;143:1236 – 1246.

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Inconclusive benefit?

• Severe gastritis
• w/o anemia
• Not NSAID or EtOH induced
• Lack of RCT
• Gastric cancer prevention
• Lack of quality RCT
• More long-term follow up needed

http://www.pathologyoutlines.com/topic/stomachacutegastritis.html McMahon et al, Epidemiol Infect. 2016;144(2):225-33.

Lack of benefit?

• Many etiologies
• GERD
• IBD
• Gastric motility disorder
• Lack of symptomatic relief

McMahon et al, Epidemiol Infect. 2016;144(2):225-33.

Adult Empiric Therapy Recommendations in AN/AI

Indication Regimen Duration Preferred Therapy Metronidazole 500mg PO QID Amoxicillin 1000mg PO BID Omeprazole 20mg PO BID Bismuth Subsalicylate 524mg PO QID 14 days *PCN Allergy Metronidazole 500mg PO QID Doxycycline 100mg PO BID Omeprazole 20mg PO BID Bismuth Subsalicylate 524mg PO QID 14 days

*Anaphylactic reactions McMahon et al, Epidemiol Infect. 2016 Jan;144(2):225 Fallone et al, Gastroenterology 2016 Jul:151(51- 69. Carothers JJ et al, Clin Infect Dis. 2007 Jan 15;44(2):e5-8.

Resistance in H. pylori isolates from Alaska native persons

• Metronidazole
• 42% (222/531) isolates had resistance
• Varied from 30 % – 51 %, per year of study (not significant)
• Women exhibited statistically significant more resistance than men (OR: 2.6; P

< 0.0001)

• No difference in urban vs. rural populations
• Patients age 30 - 40 demonstrated the greatest resistance
• Amoxicillin
• 2% (10/531) overall resistance
• Varied year to year 0% - 4% (not significant)

Tveit AH, et al. J Clin Microbiol. 2011;49(10):3638-43

Alaskan isolates resistance continued

• Clarithromycin
• 30% (159/531) of isolates were resistant
• Statistically higher resistance in woman (37%) than men (24%) (OR: 1.7; P =

0.001)

• No statistical difference seen between age group, urban vs. rural, or referral

institution

• Levofloxacin
• 19% (30/155) of isolates are resistant
• Urban areas isolates were approximately 5 times more likely to have

resistance than rural areas

• 38% vs. 13% (OR: 4.2; P = 0.0005)
• No differences in age group, gender, or referring institution

Tveit AH, et al. J Clin Microbiol. 2011;49(10):3638-43

1/12/2018 10

Alaskan isolates resistance continued

• Multidrug resistance
• 15% (82/531) of isolates resistant to metronidazole and clarithromycin
• Patients with metronidazole isolates were at higher risk for clarithromycin isolates than

patients with metronidazole susceptible isolates (OR: 5.2; P= 0.002)

• Females are more likely to be infected with metronidazole and clarithromycin

resistant strains (OR: 2.4; P = 0.0004)

Tveit AH, et al. J Clin Microbiol. 2011;49(10):3638-43 Tveit AH, et al. J Clin Micrbiol. 2011;49(10):3638 - 43

Resistance in H. pylori isolates from Alaska native persons

Tveit AH, et al.J Clin Micrbiol. 2011;49(10):3638 - 43 Tveit AH, et al. J Clin Micrbiol. 2011;49(10):3638 - 43

Past treatments with fluoroquinolones correlate with H. pylori levofloxacin resistance

Carothers JJ, et al. Clin Infect Dis. 2007;44:e5-8

• H. Pylori resistance in North America

Chey WD, et al. Am J Gastroenterology 2017 ;112:212-238.

1/12/2018 11

• H. pylori cagA and vacA genotypes in Alaska

Miernyk K, et al. J Clin Microbiol. 2011;49(9):3114-21. Miernyk K, et al. J Clin Microbiol. 2011;49(9):3114-21.

Clinical presentation correlates to genotype

Miernyk K, et al. J Clin Microbiol. 2011;49(9):3114-21.

Symptomatic Treatment

• Adults
• Omeprazole 20 mg PO BID
• Ranitidine 150mg PO BID
• Pediatrics
• Ranitidine 5-10 mg/kg/day divided

into PO BID

Special Populations

• Pregnancy
• Delay treatment postpartum
• Tetracyclines
• Avoid in pregnancy
• Bismuth
• Avoid in pregnancy
• Breast feeding
• Avoid
• Metronidazole
• Bismuth
• Levofloxacin

www.healthline.com Mahadevan U, et al. Gastroenterology. 2006;131(1):283. Goldberg D, et al. Obstet Gynecol. 2007;110(3):695. Cardaropoli, et al. World J Gastroenterol. 2014; 20(3):654-664.

Recurrence/Treatment Failure

Medication Duration Metronidazole 500mg PO QID Doxycycline 100mg PO BID Omeprazole 20mg PO BID Bismuth subsalicylate 524mg PO QID 14 days Amoxicillin 1000mg PO BID Levofloxacin 500mg PO Daily Omeprazole 20mg PO BID 14 days

McMahon et al, Epidemiol Infect. 2016;144(2):225-33. Fallone et al, Gastroenterology 2016:151(51- 69. Carothers JJ, et al. Clin Infect Dis. 2007;44(2):e5-8.

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Treatment success predictors

• Adherence
• Resistance
• Cigarette smoking
• Diabetes

Treatment success confirmatory testing

• ACG recommends testing 4

weeks post treatment

• 1-2 weeks off PPI therapy
• No specific test preferred
• Urea breath test
• Fecal antigen test
• Endoscopic tests
• AI/AN
• ACG recommendations

Learning Assessment

Which of the following patient specific factors are predictive of successful H. pylori eradication?

• a. poor adherence to medication regimen
• b. low prevalence of H. pylori colonization
• c. diabetes
• d. cigarette smoker

Learning Assessment

Which of the following should be consideration when recommending an H. pylori eradication regimen?

• a. national antibiotic resistance
• b. patients poor adherence to medication regimens
• c. prevalence of H. pylori infection in your practice area
• d. patients past use of a PPI

Learning Assessment

Which of the following increase the risk of a patient becoming infected with H. pylori?

• a. poor social economic standing
• b. household crowding (>1.5 people/room)
• c. high prevalence of H.pylori
• e. age < 10y/o
• d. all of the above

Learning Assessment

Which of the following patients should be referred to a specialist for further evaluation?

• a. A 75 y/o male who presents with dyspepsia that he has been

experience on and off for several years.

• b. A 27 y/o male who presents with 2 days of N/V.
• c. A 62 y/o male who reports dyspepsia that started several

weeks prior. Patient states he has never experienced these symptoms before.

• d. A 52 y/o female who reports using high doses of ibuprofen for

treatment of her osteoarthritis