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Protocol development in integrative medicine is not typically a simple process. Individuals require individualized care, and what works for one patient may not work for another.

To establish these protocols, we first developed a Rating Scale that could be used to discern the rigor of evidence supporting a specific nutrient’s therapeutic effect.

The following protocols were developed using only A through C-quality evidence.

Class
Qualifying studies
Minimum requirements
A
Systematic review or meta-analysis of human trials
 
B
RDBPC human trials
2+ studies and/or 1 study with 50 + subjects
C
RDBPC human trials
1 study

Antibiotic resistance is caused by the proliferation of intergenerational bacteria possessing genetic mutations that reduce the effectiveness of specific antibiotic treatments. It is possible for pathogenic bacteria to develop resistance to nearly any antibiotic. (33) Antibiotic resistance can also be horizontally distributed between existing microbes by genetic conjugation, transformation, transduction, and transfer mechanisms. (34) Particular attention has been given to antibiotic-resistant bacteria that can escape eradication by many antibiotics, known commonly by the acronym ‘ESKAPE’, which include: 

  • Enterococcus faecium
  • Staphylococcus aureus
  • Klebsiella pneumoniae
  • Acinetobacter baumannii
  • Pseudomonas aeruginosa
  • Enterobacterspecies (37)

Helicobacter pylori is another microbe demonstrating increasing rates of resistance to many antibiotics, leading to increased failure of eradication protocols with standard antibiotic therapies. (11)

Clinical management may now require combination therapies to support the eradication of bacterial infections. Though they may not directly kill antibiotic-resistant bacteria, many alternative therapies may assist in supporting the immune system or concurrent antibiotic treatment in bacterial eradication. These alternative therapies include those that:

  • Increase bacterial membrane permeability 
  • Inhibit kinase activity and intrinsic resistance
  • Disrupt genetic regulators
  • Induce the anti-quorum sensing system
  • Reduce bacterial adhesion and motility
  • Increase anti-toxins and secretion systems  (37)

A number of factors may contribute to the rising prevalence of antibiotic resistance, including: 

  • Antibiotic overuse and inappropriate prescribing (e.g., clinical misdiagnosis, prescribing incentives, etc.)
  • Antibiotic misuse (e.g., use past the expiration date, use after inappropriate storage, etc.)
  • Antibiotics use in the food chain
  • Prolonged hospital stays
  • Poor hygiene or sanitation (5)(33)

Please note that the following ingredient protocols provide details on case-specific uses that may not necessarily apply as a combined protocol.

Probiotics

7-25 billion CFU containing strains of Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus reuteri, Lactobacillus rhamnosus, and/or Bifidobacterium animalis subsp. lactis during antibiotic administration for bacterial eradication to adults for 7-14 days (4)(24)(25)(39)

3-4 billion CFU containing Lactobacillus rhamnosus or Streptococcus (salivarius or oralis) strains to infants and children for 3-12 weeks (22)(26)(31)

  • Reduced rates of microbial infection and associated conditions, as well as surgical infection and sepsis (4)(12)(14)(20)(22)(24)(25)(26)(27)(31)(39) 
  • Reduced hospitalization stay and duration of antibiotic use, which can lead to reduced risk of antibiotic resistance (14)(26) 
  • Increased eradication rates of H. pylori regardless of the presence antibiotic-resistant bacteria, as supplements or in yogurt (4)(22)(25)(27)
  • Increased eradication rate or prevented rises in vancomycin-resistant enterococci, as supplements or in yogurt as early as within one week (20)(24)(31)(39)
  • Reduced proportion of nasal and gastrointestinal methicillin-resistant Staphylococcus aureus (MRSA) compared with baseline (39)
  • Reduced colonization of antibiotic-resistant bacteria in infants (12)(31)
Probiotics (adults) in the Fullscript catalog

120-500 mg cranberry extract capsules or tablets (containing 3-60 mg proanthocyanidins), twice per day, ongoing for 2-12 months (2)(3)(9)(17)(21)(29)(30)(35)(36)

  • Reduced incidence of UTI, especially recurrent UTIs, and need for antibiotics, reducing the risk of emergence of antibiotic-resistant bacteria; particularly effective in women and children when capsules are consumed twice per day (as anti-adhesive effects on bacteria last approximately eight hours) or when consumed as juice (assists with hydration) (7)(19)(29)(30)(35)(36)
  • Not as effective as trimethoprim or trimethoprim-sulfamethoxazole for preventing recurrent UTIs, but had much lower risk of development of trimethoprim-sulfamethoxazole-, trimethoprim-, amoxicillin-, and ciprofloxacin-resistance in E. coli, C. difficile, or fungi (2)(21)
  • Reduced incidence of clinically defined UTI in high-risk older adults in long-term care facilities, in adults with spinal cord injury and neurogenic bladder (especially in patients with higher glomerular filtration rate), and in adolescents (3)(9)(17)
  • Within hours, proanthocyanidins dose-dependently reduced bacterial adhesiveness biofilm and bacterial growth regardless of antibiotic-resistance and E. coli virulence, without damaging vaginal microbiota in women when consumed as capsules or in juice (6)(10)(13)(16)(29)
Vaccinium macrocarpon in the Fullscript catalog

Garlic (Allium sativum)

~ 40 mg of allicin per day for two weeks during standard proton pump inhibitor and antibiotic therapy, and 400 mg garlic extract with 1-2 mg garlic oil twice per day for up to seven years after (8)(15)(18)(28)(38

  • Allicin combined with standard therapies (proton pump inhibitor (PPI)-amoxicillin-clarithromycin, PPI-bismuth-tinidazole-clarithromycin, or PPI-amoxicillin-furazolidone therapies) increased eradication rate of H. pylori infection, peptic ulcer healing, and remission rates compared with standard therapy alone (15)(28)
  • Long-term garlic therapy maintained higher rates of H. pylori-free patients and reduced the associated incidence of gastric cancer mortality for more than 22 years compared with placebo (8)(18)(38) 
  • Long-term garlic therapy increased serum folate levels, which are associated with H. pylori eradication (38)
  • Raw garlic consumption reduced H. pylori activity (41)
  • Proposed H. pylori inhibition mechanisms for garlic’s systemic anti-inflammatory and anti-ulcer properties included inhibition of IL-6, IL-8, and TNF-α; modulation and activation of γδ-T and NK immune cells; improvement of oxidative stress parameters including reduced MDA and MPO, and increased in GSH and SOD; and improvement of endothelial biomarkers including increased nitric oxide synthase activity, and reduced hsCRP, plasminogen activator inhibitor 1, and LDL-C (1)(23)(28)(32)(40)(42)
Garlic in the Fullscript catalog

Disclaimer

The Fullscript Integrative Medical Advisory team has developed or collected these protocols from practitioners and supplier partners to help health care practitioners make decisions when building treatment plans. By adding this protocol to your Fullscript template library, you understand and accept that the recommendations in the protocol are for initial guidance and may not be appropriate for every patient.

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References
  1. Avci, A., Atli, T., Ergüder, I. B., Varli, M., Devrim, E., Aras, S., & Durak, I. (2008). Effects of garlic consumption on plasma and erythrocyte antioxidant parameters in elderly subjects. Gerontology, 54(3), 173–176. https://www.ncbi.nlm.nih.gov/pubmed/18463427 (D)
  2. Beerepoot, M. A. J., ter Riet, G., Nys, S., van der Wal, W. M., de Borgie, C. A. J. M., de Reijke, T. M., Prins, J. M., Koeijers, J., Verbon, A., Stobberingh, E., & Geerlings, S. E. (2011). Cranberries vs antibiotics to prevent urinary tract infections: A randomized double-blind noninferiority trial in premenopausal women. Archives of Internal Medicine, 171(14), 1270–1278. https://www.ncbi.nlm.nih.gov/pubmed/21788542 (B)
  3. Caljouw, M. A. A., van den Hout, W. B., Putter, H., Achterberg, W. P., Cools, H. J. M., & Gussekloo, J. (2014). Effectiveness of cranberry capsules to prevent urinary tract infections in vulnerable older persons: A double-blind randomized placebo-controlled trial in long-term care facilities. Journal of the American Geriatrics Society, 62(1), 103–110. https://www.ncbi.nlm.nih.gov/pubmed/25180378 (B)
  4. Çekin, A. H., Şahintürk, Y., Akbay Harmandar, F., Uyar, S., Yolcular, B. O., & Çekin, Y. (2017). Use of probiotics as an adjuvant to sequential H. pylori eradication therapy: Impact on eradication rates, treatment resistance, treatment-related side effects, and patient compliance. The Turkish Journal of Gastroenterology, 28(1), 3–11. https://www.ncbi.nlm.nih.gov/pubmed/28007678 (B)
  5. Chokshi, A., Sifri, Z., Cennimo, D., & Horng, H. (2019). Global contributors to antibiotic resistance. Journal of Global Infectious Diseases, 11(1), 36–42. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380099/ (A)
  6. Di Martino, P., Agniel, R., David, K., Templer, C., Gaillard, J. L., Denys, P., & Botto, H. (2006). Reduction of Escherichia coli adherence to uroepithelial bladder cells after consumption of cranberry juice: A double-blind randomized placebo-controlled cross-over trial. World Journal of Urology, 24(1), 21–27.  https://www.ncbi.nlm.nih.gov/pubmed/16397814 (C)
  7. Fu, Z., Liska, D., Talan, D., & Chung, M. (2017). Cranberry reduces the risk of urinary tract infection recurrence in otherwise healthy women: A systematic review and meta-analysis. The Journal of Nutrition, 147(12), 2282–2288. https://www.ncbi.nlm.nih.gov/pubmed/29046404 (A)
  8. Gail, M. H., & You, W.-C. (2006). A factorial trial including garlic supplements assesses effect in reducing precancerous gastric lesions. The Journal of Nutrition, 136(3 Suppl), 813S – 815S. https://www.ncbi.nlm.nih.gov/pubmed/16484571 (B)
  9. Hess, M. J., Hess, P. E., Sullivan, M. R., Nee, M., & Yalla, S. V. (2008). Evaluation of cranberry tablets for the prevention of urinary tract infections in spinal cord injured patients with neurogenic bladder. Spinal Cord, 46(9), 622–626. https://www.ncbi.nlm.nih.gov/pubmed/18392039 (C)
  10. Howell, A. B., Botto, H., Combescure, C., Blanc-Potard, A.-B., Gausa, L., Matsumoto, T., Tenke, P., Sotto, A., & Lavigne, J.-P. (2010). Dosage effect on uropathogenic Escherichia coli anti-adhesion activity in urine following consumption of cranberry powder standardized for proanthocyanidin content: A multicentric randomized double blind study. BMC Infectious Diseases, 10, 94. https://www.ncbi.nlm.nih.gov/pubmed/20398248 (C)
  11. Hu, Y., Zhu, Y., & Lu, N.-H. (2017). Novel and effective therapeutic regimens for Helicobacter pylori in an era of increasing antibiotic resistance. Frontiers in Cellular and Infection Microbiology, 7, 168. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418237/ (F)
  12. Hua X.-T., Tang J., & Mu D.-Z. (2014). [Effect of oral administration of probiotics on intestinal colonization with drug-resistant bacteria in preterm infants]. Chinese Journal of Contemporary Pediatrics, 16(6), 606–609. https://www.ncbi.nlm.nih.gov/pubmed/24927436 (B)
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  14. Kasatpibal, N., Whitney, J. D., Saokaew, S., Kengkla, K., Heitkemper, M. M., & Apisarnthanarak, A. (2017). Effectiveness of probiotic, prebiotic, and synbiotic therapies in reducing postoperative complications: A systematic review and network meta-analysis. Clinical Infectious Diseases, 64(suppl_2), S153–S160. https://www.ncbi.nlm.nih.gov/pubmed/28475793 (A)
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  16. Lavigne, J.-P., Bourg, G., Combescure, C., Botto, H., & Sotto, A. (2008). In-vitro and in-vivo evidence of dose-dependent decrease of uropathogenic Escherichia coli virulence after consumption of commercial Vaccinium macrocarpon (cranberry) capsules. Clinical Microbiology and Infection, 14(4), 350–355. https://www.ncbi.nlm.nih.gov/pubmed/18190583 (C)
  17. Ledda, A., Belcaro, G., Dugall, M., Riva, A., Togni, S., Eggenhoffner, R., & Giacomelli, L. (2017). Highly standardized cranberry extract supplementation (Anthocran®) as prophylaxis in young healthy subjects with recurrent urinary tract infections. European Review for Medical and Pharmacological Sciences, 21(2), 389–393. https://www.ncbi.nlm.nih.gov/pubmed/28165546 (C)
  18. Li, W.-Q., Zhang, J.-Y., Ma, J.-L., Li, Z.-X., Zhang, L., Zhang, Y., Guo, Y., Zhou, T., Li, J.-Y., Shen, L., Liu, W.-D., Han, Z.-X., Blot, W. J., Gail, M. H., Pan, K.-F., & You, W.-C. (2019). Effects of Helicobacter pylori treatment and vitamin and garlic supplementation on gastric cancer incidence and mortality: Follow-up of a randomized intervention trial. BMJ , 366, l5016. https://www.ncbi.nlm.nih.gov/pubmed/31511230 (B)
  19. Luís, Â., Domingues, F., & Pereira, L. (2017). Can cranberries contribute to reduce the incidence of urinary tract infections? A systematic review with meta-analysis and trial sequential analysis of clinical trials. The Journal of Urology, 198(3), 614–621. https://www.ncbi.nlm.nih.gov/pubmed/28288837 (A)
  20. Manley, K. J., Fraenkel, M. B., Mayall, B. C., & Power, D. A. (2007). Probiotic treatment of vancomycin-resistant enterococci: A randomised controlled trial. The Medical Journal of Australia, 186(9), 454–457. https://www.ncbi.nlm.nih.gov/pubmed/17484706 (C)
  21. McMurdo, M. E. T., Argo, I., Phillips, G., Daly, F., & Davey, P. (2009). Cranberry or trimethoprim for the prevention of recurrent urinary tract infections? A randomized controlled trial in older women. The Journal of Antimicrobial Chemotherapy, 63(2), 389–395. https://www.ncbi.nlm.nih.gov/pubmed/19042940 (C)
  22. Paoluzi, O. A., Del Vecchio Blanco, G., Visconti, E., Coppola, M., Fontana, C., Favaro, M., & Pallone, F. (2015). Low efficacy of levofloxacin-doxycycline-based third-line triple therapy for Helicobacter pylori eradication in Italy. World Journal of Gastroenterology, 21(21), 6698–6705. https://www.ncbi.nlm.nih.gov/pubmed/26074708 (C)
  23. Percival, S. S. (2016). Aged garlic extract modifies human immunity. The Journal of Nutrition, 146(2), 433S – 436S. https://www.ncbi.nlm.nih.gov/pubmed/26764332 (B)
  24. Plummer, S. F., Garaiova, I., Sarvotham, T., Cottrell, S. L., Le Scouiller, S., Weaver, M. A., Tang, J., Dee, P., & Hunter, J. (2005). Effects of probiotics on the composition of the intestinal microbiota following antibiotic therapy. International Journal of Antimicrobial Agents, 26(1), 69–74. https://www.ncbi.nlm.nih.gov/pubmed/15967639 (B)
  25. Poonyam, P., Chotivitayatarakorn, P., & Vilaichone, R.-K. (2019). High effective of 14-day high-dose PPI- bismuth-containing quadruple therapy with probiotics supplement for Helicobacter pylori eradication: A double blinded-randomized placebo-controlled study. Asian Pacific Journal of Cancer Prevention, 20(9), 2859–2864. https://www.ncbi.nlm.nih.gov/pubmed/31554388 (B)
  26. Scott, A. M., Clark, J., Julien, B., Islam, F., Roos, K., Grimwood, K., Little, P., & Del Mar, C. B. (2019). Probiotics for preventing acute otitis media in children. Cochrane Database of Systematic Reviews, 6, CD012941. https://www.ncbi.nlm.nih.gov/pubmed/31210358 (A)
  27. Sheu, B.-S., Cheng, H.-C., Kao, A.-W., Wang, S.-T., Yang, Y.-J., Yang, H.-B., & Wu, J.-J. (2006). Pretreatment with Lactobacillus- and Bifidobacterium-containing yogurt can improve the efficacy of quadruple therapy in eradicating residual Helicobacter pylori infection after failed triple therapy. The American Journal of Clinical Nutrition, 83(4), 864–869. https://pubmed.ncbi.nlm.nih.gov/16600940/ (C)
  28. Si, X.-B., Zhang, X.-M., Wang, S., Lan, Y., Zhang, S., & Huo, L.-Y. (2019). Allicin as add-on therapy for Helicobacter pylori infection: A systematic review and meta-analysis. World Journal of Gastroenterology, 25(39), 6025–6040. https://www.ncbi.nlm.nih.gov/pubmed/31660038 (A)
  29. Singh, I., Gautam, L. K., & Kaur, I. R. (2016). Effect of oral cranberry extract (standardized proanthocyanidin-A) in patients with recurrent UTI by pathogenic E. coli: A randomized placebo-controlled clinical research study. International Urology and Nephrology, 48(9), 1379–1386. https://www.ncbi.nlm.nih.gov/pubmed/27314247 (C)
  30. Stothers, L. (2002). A randomized trial to evaluate effectiveness and cost effectiveness of naturopathic cranberry products as prophylaxis against urinary tract infection in women. The Canadian Journal of Urology, 9(3), 1558–1562. https://pubmed.ncbi.nlm.nih.gov/12121581/ (B)
  31. Szachta, P., Ignyś, I., & Cichy, W. (2011). An evaluation of the ability of the probiotic strain Lactobacillus rhamnosus GG to eliminate the gastrointestinal carrier state of vancomycin-resistant enterococci in colonized children. Journal of Clinical Gastroenterology, 45(10), 872–877. https://www.ncbi.nlm.nih.gov/pubmed/21814146 (C)
  32. Szulińska, M., Kręgielska-Narożna, M., Świątek, J., Styś, P., Kuźnar-Kamińska, B., Jakubowski, H., Walkowiak, J., & Bogdański, P. (2018). Garlic extract favorably modifies markers of endothelial function in obese patients -randomized double blind placebo-controlled nutritional intervention. Biomedicine & Pharmacotherapy, 102, 792–797. https://www.ncbi.nlm.nih.gov/pubmed/29604599 (B)
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  35. Vostalova, J., Vidlar, A., Simanek, V., Galandakova, A., Kosina, P., Vacek, J., Vrbkova, J., Zimmermann, B. F., Ulrichova, J., & Student, V. (2015). Are high proanthocyanidins key to cranberry efficacy in the prevention of recurrent urinary tract infection? Phytotherapy Research, 29(10), 1559–1567. https://www.ncbi.nlm.nih.gov/pubmed/26268913 (B)
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  37. Wang, C.-H., Hsieh, Y.-H., Powers, Z. M., & Kao, C.-Y. (2020). Defeating antibiotic-resistant bacteria: Exploring alternative therapies for a post-antibiotic era. International Journal of Molecular Sciences, 21(3). https://www.ncbi.nlm.nih.gov/pubmed/32033477 (F)
  38. Wang, Y., Zhang, L., Moslehi, R., Ma, J., Pan, K., Zhou, T., Liu, W., Brown, L. M., Hu, Y., Pee, D., Gail, M. H., & You, W. (2009). Long-term garlic or micronutrient supplementation, but not anti-Helicobacter pylori therapy, increases serum folate or glutathione without affecting serum vitamin B-12 or homocysteine in a rural Chinese population. The Journal of Nutrition, 139(1), 106–112. https://www.ncbi.nlm.nih.gov/pubmed/19056661 (B)
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  41. Zardast, M., Namakin, K., Esmaelian Kaho, J., & Hashemi, S. S. (2016). Assessment of antibacterial effect of garlic in patients infected with Helicobacter pylori using urease breath test. Avicenna Journal of Phytomedicine, 6(5), 495–501. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052411/ (D)
  42. Zhong, J., Xian, D., Xiong, X., & Liu, J. (2017). Therapeutic Hotline. Oral allicin in the treatment of Behcet’s disease through attenuating oxidative stress: A pilot study in 20 patients with mucocutaneous lesions. Dermatologic Therapy, 30(1). https://www.ncbi.nlm.nih.gov/pubmed/27723197 (C)

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