Infection

Course Communication and Logistics

• Instructor: D. Gerber, PharmD, BCGP, FASCP, FAzPA.

• Email Communication Policy: Students must use the Canvas Inbox for all course-related communication instead of the standard MWU email. It is requested that students use succinct subject lines, such as "Risks associated with Vitamin C dietary supplements?"

• Response Time: Every effort is made to respond to Canvas messages within 48 hours.

• Office Hours: These are held via Microsoft Teams on Wednesdays from 12:00 pm to 12:30 pm. Links are provided in the Canvas Announcements.

Learning Objectives and Competencies

By the end of this lecture and review of the materials, students should be able to:

1. Compare and contrast evidence for dietary supplements promoted for COVID-19.

2. Compare and contrast cranberry dietary supplements versus cranberry juice for UTI treatment.

3. Compare and contrast cranberry dietary supplements versus cranberry juice for UTI prevention.

4. Recognize the Echinacea species best supported by available literature.

5. Identify Echinacea’s effect on the CYP system.

6. Recognize the most serious possible adverse reactions and drug interactions associated with Panax ginseng.

7. Identify risks associated with American Ginseng.

8. Describe the production procedure for Oscillococcinum®.

9. Compare and contrast Vitamin C dietary supplements versus juice for cold treatment.

10. Compare and contrast Vitamin C dietary supplements versus juice for cold prevention.

11. Identify risks associated with Vitamin C dietary supplements.

12. Elucidate on the data regarding Vitamin C in the treatment of sepsis.

13. Distinguish the form of zinc associated with anosmia (loss of smell).

14. Discern how zinc affects medications and other vitamins/minerals.

15. Compare the adult tolerable upper intake limit (UL) of zinc to doses recommended by commercial products for cold treatment.

16. Identify risks and benefits of zinc in cold treatment.

17. Educate others on the 1999 FDA final rule regarding OTC Drug Products Containing Colloidal Silver.

COVID-19 and Dietary Supplements: NIH Guidelines

• Ascorbic Acid (Vitamin C) for Critically Ill Patients: The NIH COVID-19 Treatment Guidelines Panel states there is insufficient data to recommend for or against use. There are no completed controlled trials in COVID-19 patients, and observational data is sparse and inconclusive.

• Ascorbic Acid (Vitamin C) for Non-Critically Ill Patients: The Panel finds insufficient data for or against use. It notes there is no compelling reason to use it in this setting because patients not critically ill are less likely to experience severe inflammation or oxidative stress.

• Zinc for Treatment: Insufficient data to recommend for or against the use of zinc for COVID-19 treatment.

• Zinc for Prevention: The Panel recommends against using zinc supplementation above the Recommended Dietary Allowance (RDA) for the prevention of COVID-19.

Vitamin C (Ascorbic Acid)

• Properties: A water-soluble vitamin. Injectable Vitamin C is an FDA-approved prescription product.

• Cochrane Review Findings (Hemilä H, Chalker E, 2013):

  • Incidence: Regular ingestion of > 2\,g had no effect on common cold incidence in the ordinary population ($29$ trial comparisons, $11,306$ participants).

  • Prophylactic Duration: Regular supplementation showed a modest but consistent effect in reducing cold symptom duration ($31$ study comparisons, $9,745$ episodes).

  • Therapeutic Use: High doses administered after symptom onset showed no consistent effect on duration or severity.

• Vitamin C in Sepsis (The "Marik Protocol"):

  • Initial Study (Marik et al., Chest 2017): A retrospective before-after clinical study using IV Vitamin C, hydrocortisone, and thiamine ($n=47$ in both groups).

    • Mortality: $8.5\%$ in the treatment group vs. $40.4\%$ in the control group (P < .001).

    • Vasopressor Weaning: Mean of $18.3 \pm 9.8$ hours in the treatment group vs. $54.9 \pm 28.4$ hours in the control group (P < .001).

  • VITAMINS Trial (Fujii et al., JAMA 2020): A multicenter, open-label, randomized trial ($10$ ICUs in Australia, NZ, and Brazil).

    • Intervention: IV Vit C ($1.5\,g$ q6h), hydrocortisone ($50\,mg$ q6h), thiamine ($200\,mg$ q12h).

    • Results: No significant difference in time alive and vasopressor-free up to day 7 ($122.1$ hours for intervention vs. $124.6$ hours for control; $P = 0.83$).

    • Mortality (90-day): $28.6\%$ intervention vs. $24.5\%$ control ($P = 0.61$).

  • Conclusion: The combination does not lead to more rapid resolution of septic shock than hydrocortisone alone.

• Benefits: Helps body absorb iron; may reduce cold duration with regular use.

• Risks and Caveats:

  • GI Effects: $1-3\,g$ daily can increase diarrhea and heartburn.

  • Diagnostic Interference: High concentrations may affect point-of-care glucometer accuracy.

  • Contraindications: Avoid in patients with cirrhosis, gout, renal tubular acidosis, or paroxysmal nocturnal hemoglobinuria.

Zinc

• Overview: Essential trace element and co-factor in >300 enzymatic reactions. It is vital for immune function, DNA/protein synthesis, and wound healing.

• Deficiency Symptoms: Growth delay, impaired immunity, and hypogeusia (decreased taste).

• Clinical Evidence:

  • Common Cold: Reduces symptoms if started within 24 hours of onset; can reduce symptom duration by $24$ hours.

  • Wound Healing: Supports repair specifically in deficient patients.

• Safety and Toxicity:

  • Adult Tolerable Upper Intake Level (UL): $40\,mg/day$.

  • Commercial Products: Many lozenges exceed the UL (some reach $~80\,mg/day$).

  • Anosmia: Intranasal zinc products (e.g., Zicam) are linked to rapid, potentially permanent loss of smell. The FDA warns against intranasal use.

  • Chronic Dosing Risk: Chronic use (>2-3 weeks) or doses >40\,mg/day can cause copper deficiency, leading to anemia and neuropathy.

• Interactions: Zinc chelates with fluoroquinolones and tetracyclines (e.g., doxycycline). Patients must separate administration by $2-4$ hours.

Cranberry

• Historical Context: German scientists began researching the UTI link in 1840. The 1994 Ocean Spray study ($300\,mL$ daily) showed a significant reduction in recurrent UTI in elderly women.

• Theoretical Mechanisms: Altering hippuric acid levels or preventing bacterial adhesion to uroepithelial cells.

• Prevention vs. Treatment Evidence:

  • Cochrane 2012 Update: Added 14 studies; concluded cranberry juice is less effective than previously thought. The benefit for preventing UTI is considered small, and it is not recommended due to high dropout rates (acceptability issues).

  • JAMA 2016 (Nursing Home Women): $2$ capsules daily ($72\,mg$ total proanthocyanidins) vs. placebo. Result: No significant difference in the presence of bacteriuria plus pyuria over 1 year ($25.5\%$ treatment vs. $29.5\%$ control).

• Risks:

  • Drug Interactions: Possible interaction with Coumadin (CYP2C9 inhibition data is conflicting).

  • Side Effects: High juice consumption (>3\,L daily) causes GI upset and diarrhea.

  • Contraindications: History of kidney stones.

Echinacea

• Key Species: Echinacea purpurea (tablets/capsules, best research support), Echinacea pallida (tinctures), Echinacea angustifolia (teas).

• Efficacy: May modestly reduce cold severity and duration by $10\%$ to $30\%$. Cochrane 2014 noted overall evidence for clinically relevant effects is weak.

• Risks:

  • Contraindications: Autoimmune diseases and immunosuppressant therapy.

  • Allergies: Cross-allergenicity with ragweed.

  • Drug Metabolism: Possible inhibition of CYP 1A2 and induction of 3A4.

Ginseng

• Types: Panax ginseng (Asian), American ginseng (CVT-E002), and Siberian ginseng (not a "true" ginseng).

• Panax Ginseng Risks:

  • Cardiovascular: Short-term use can slightly increase the QT interval; theoretic additive effect with other QT-prolonging drugs.

  • Hormonal: Potential hormone-like effects; usage should be limited to less than 6 months.

  • Side Effects: Headaches, insomnia, sleep disturbances, and hypotension.

• American Ginseng Risks: May decrease the effectiveness of warfarin.

Oscillococcinum®

• Manufacturer: Boiron Laboratories (Homeopathic).

• Ingredients: Anas barbariae hepatis et cordis extractum 200CK HPUS.

• Production: Made from the heart and liver of a wild duck (believed to be a reservoir for flu).

• Preparation Process: Due to the 200CK homeopathic dilution process, there are virtually no original molecules of duck heart or liver in the final product.

• Evidence: Insufficient available data for both benefit and risk.

Colloidal Silver

• 1999 FDA Final Rule: FDA declared that all OTC drug products containing colloidal silver or silver salts are not recognized as safe and effective and are misbranded.

• FDA Stance: It is not safe or effective for treating any disease or condition.

• Argyria: A condition caused by silver accumulation resulting in a bluish-gray skin discoloration that is usually permanent.

Fraudulent and OTC Products

• Airborne® Facts: Contains $1000\,mg$ Vitamin C ($1667\%$ DV), $2000\,IU$ Vitamin A, $8\,mg$ Zinc, and a herbal blend including Echinacea and Ginger.

• FDA Warns on STD Products: FDA warns against bogus products (e.g., Medavir, Herpaflor, Viruxo) that claim to treat STDs. No non-prescription drugs or supplements can treat, cure, or prevent STDs.