Amsterdam Rotation Protocols Dr H Training

Rotation of Antibiotics and Integrative/Herbal Protocols in the Difficult-to-Treat Lyme Patient Amsterdam June 19th 2019 Dr. Richard Horowitz, Medical Director HVHAC, Hyde Park, N.Y. Board Certified Internal Medicine Member, HHS Tick-Borne Disease Working Group 2017-2019 Co-chair, HHS Other Tick-borne Diseases and Co-infections, 2017-2019

Healing: Compassionate Empathetic Attuned Presence: Matt Liotta PhD Decety, J. Why empathy has a beneficial impact on others in medicine: unifying theories. Front Behav Neurosci, 2014;8:457

7 Point Action Plan for Lyme-MSIDS: ◼

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How Can I Get Better? St Martin’s Press 2017 Rule One: Symptoms Drive Diagnosis and Treatment Rule Two: Lower Inflammation Rule Three: Detoxify, Detoxify, Detoxify Rule Four: Repair the Damage Rule Five: Provide Internal Balance: Cytokines, Hormones, Microbiome Rule Six: Master the Big Three: Sleep, Food, and Exercise Rule Seven: Heal Your Emotional Wounds

16 Point MSIDS Map: Evaluate all of the Sources of Inflammation ◼

Primary Sources:

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Downstream effects:

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1) Chronic infections 2) G.I.: Dysbiosis of intestinal bacteria 3) G.I. : Leaky gut w/ Food allergies and sensitivities 4) Sleep disorders:↑ IL-6 5) Environmental toxins (heavy metals, mold…)

6) Nutritional Deficiencies

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7) Endocrine disorders: low T, low adrenal (f) 8, 9) Neurological, Psychological dysfunction 10) POTS/dysautonomia 11) Mitochondrial Dys(f) 11) Pain Syndromes 12) Liver Dysfunction 13) Autoimmune phen.

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Initial History & Physical ◼

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Initial visit: fill out the Horowitz MSIDS questionnaire (HMQ) to determine the probability of Lyme and associated tick-borne disease Do a complete History and Physical with the chief complaints, past medical history, & current symptoms, defining severity and frequency Social history, Family history Environmental history (? Mold ? Chem exposure) Review of Systems & Physical examination Differential Diagnosis and Testing

Empirical Validation of the Horowitz MSIDS Questionnaire for Suspected Lyme Disease Citera M, Freeman PR, Horowitz RI. International Journal of General Medicine 2017:10 249–273. http://www.ncbi.nlm.nih.gov/pubmed/28919803

Step 1: Prioritize Likely Abnormalities on the 16 point MSIDS Map Based on an H and P ◼

History: HMQ score > 63? (c/w Lyme), Migratory pain?

(Lyme, other Borrelia spp.), questions 1/22 + (sweats) ?

(Babesia). Perform differential diagnostic work-up based on history. Focus on key questions: ? Multiple tick-bites (↑ risk co-inf’s) ? Pain bottom feet (? Bart), ? New onset seizure d/o (Bart, POWV), ? Dizziness standing (POTS)

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Physical: ? Rashes (EM), striae (Bartonella), granulomas (Bartonella), other rashes (BMD, STARI, RMSF..), large LN’s (? Bart), Bells palsy (? Lyme), evidence of PNP (? Lyme, Bartonella, heavy metals, DM, hypothyroidism, CTS…), √ sitting/standing BP/pulse (POTS), dermatographism(MCAD)

Step 1: Prioritize the Most Important Abnormalities on the 16 point MSIDS Map ◼

Other Important History: Timing of the illness:

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? After being in woods, or highly endemic area (TBD) ? After being in a mold exposed building (Mold S) ? Recent renovations or chemical exposure (VOC’s, formaldehyde…). ? Feel better out of the house (MCS, Mold) ? Recent travel inside US, or outside the country (↑ risk malaria, dengue, chikungunya, parasites..) ? Recent trauma, i.e., physical, emotional (PTSD component, with concomitant adrenal stress) Do full H+ P, ROS to evaluate all major organ systems

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Step 1: Prioritize the Most Important Abnormalities on the 16 point MSIDS Map ◼ ◼

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Other Important History: Past Medical & Social History: Other inflammatory or AI disease? (RA, SLE, UC/IBD, MS…). On immunosuppressive medications?

History of gluten sensitivity/celiac: ? Compliant w/ diet History of CVID, CIDP? (20% + Lyme patients have immune deficiencies, interfering with treatment) ? Smoking/ETOH history (? Risk ASHD, cirrhosis, liver abN) ? Psych history: new sudden onset psychiatric illness without a clear trigger (schizophrenia post tick-bite), or not responding to classical therapies, wrong age for illness

Step 1: Prioritize the Most Important Abnormalities on the 16 point MSIDS Map ◼ ◼

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Other Important History: Past Medical & Social History: Recent long term antibiotic use for TBD’s (? Candida issue, ? Mitochondrial dysfunction). Sx worse w/carbs?

History of itching, wheezing, sneezing, anaphylactic reactions (? Food allergies/? leaky gut/? mast cell activation/? alpha gal allergy…apart from prior allergic rhinitis/asthma history..)

Are you sensitive to all meds/herbs/diet? (MCS, trauma) Change in symptoms? Do you crash after exercise? (mitochondrial dys(f), adrenal fatigue, deconditioning..)

Step 1: Prioritize the Most Important Abnormalities on the 16 point MSIDS Map ◼ ◼

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Other Important History: Change in symptoms, what makes it better or worse? ? Feel better or worse with antibiotics or herbs (Lyme, coinf’s, Herxheimer reactions) ? Feel better or worse with detoxification, i.e., GSH, CSM, charcoal/clay (Detoxification issues) ? Feel better or worse with methylation (Detox issues) ? Change in symptoms based on hormonal cycles (women with Lyme disease tend to flare around the menses) ? Change in diet w/ ↑ carbs, w/ mid am +/or aft fatigue that is sudden, profound (hypoglycemia, Candida)

Step 2: Evaluate Potential Medication Side Effects ◼ ◼

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Psychiatric medication: can cause drowsiness/fatigue Sleep medication: ? Hangover effect with sleep walking/eating/driving, ↓ memory/conc… (Benadryl and other anti-H1’s like Atarax, Ambien, Lunesta, Sonata..)

Stimulants: caffeine, chocolate, Vyvanse: ? Interfering with sleep, and increasing anxiety due to long ½ life Hormonal imbalance: ? Too much thyroid medication causing jitteriness, anxiety; too little thyroid medication (? Needs to be in upper 1/3 of normal range), ? not enough adrenal support..

Check PDR for SE’s/interactions of all medications!

Step 3: Create A Differential Diagnosis For Every Symptom ◼ ◼

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Every symptom should have several differential diagnoses See pages 50-64 “How Can I Get Better?” for a list of extensive differentials to be considered. Often more than 1 etiology is ↑ symptoms in the Lyme-MSIDS patient Ex: Neuropathy symptoms: seen in up to 94% of all Lyme patients. Differential includes: Borreliosis, Bartonella, Autoimmune disorders (MS), carpal and cubital tunnel syndrome, or any nerve entrapment (thoracic outlet), DM, hypothyroidism, heavy metals (Hg, Pb, As), other environmental toxins (TCE, mold), vitamin deficiencies (B vit’s, B12, folate, MMA, HC), immune deficiency (CVID), mitochondrial dys(f), hx CVA, pregnancy, hyperventilation..

Differential Diagnosis Pain ◼

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Pain syndromes associated with Lyme Disease and associated co-infections (ie., Bart, Mycoplasma): Chronic fatigue syndrome/ Fibromyalgia w/ widespread pain Autoimmune diseases (RA/SLE/MS) with inflammation Neurologic: headaches/migraines, neuropathy, radiculopathy, encephalopathy, cranial nerve palsies, carpal tunnel/ulnar nerve

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GI/GU: IBS/IBD, interstitial cystitis (Lyme, Bart) GYN: pain syndromes: dysparaneuria, neuralgia (Lyme, Bart) Cardiac: chest pain (costochondritis, pericarditis..), palpitations..

Psych: depression, psychosis, OCD, anxiety→↑pain (Lyme, Bart) Ophthalmology: painful eye syndromes (conjunctivitis, uveitis, retinitis, optic neuritis..). If unresponsive to NSAIDS, narcotics, neuroleptic medication, ? Underlying source(s) of infection..

Establish a Differential Diagnosis: Table 2.1: Symptoms and Associated Medical Conditions on the MSIDS Map Possible Medical Laboratory Testing Symptoms Unexplained fevers, sweats, chills, or flushing

Conditions

to Consider

• Lyme disease (chronic and

• CBC with a white cell count

other bacterial, viral, parasitic, and fungal infections)

• CMP with liver functions • Giemsa stain and malarial smears

• Babesiosis • Malaria

• Babesia IFA

•Brucellosis • Hyperthyroidism • Hormonal failure (early menopause) • Tuberculosis* • Non- Hodgkin’s lymphoma* • Panic disorders • Autoimmune disorders • Inflammation

• Babesia WA- 1/duncani titers • Babesia FISH and PCR • Thyroid function tests (TFT’s) • Sex hormone levels • Chest X-ray/PPD • ANA, RF • Erythrocyte sedimentation rate (ESR),C-reactive protein (CRP) • Cytokine panel

Step 4: Address Inflammation To Heal ◼

1. Block NFKappa-B and Activate Nrf2 with antioxidants (curcurmin, green tea, resveratrol) and phytochemicals (sulforaphane..)

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2. Block Activation of Glial cells in the brain: LDN: Blocks NFKappa-B and TLR4 signaling (decreasing glial cell activation) and shifts immune responses from TH2 to TH1

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3. Do an Anti-inflammatory diet: ↑ omega 3, ↓ omega 6 FA (Medit diet)→ ↓ arachidonic acid, avoid allergic/sensitive foods, reduce simple sugars, red meat, eggs, dairy, gluten, ? histamine

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4. Replace minerals (zinc, copper, magnesium) 5. Get proper sleep and exercise (insomnia:↑ IL-6)

Address Inflammation To Heal ◼

6. Treat the Infections causing inflammation, immune dysfunction (The 3 I’s): antibiotics and natural therapies

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7. Detoxification: Remove chemicals and inflammatory cytokines causing inflammation

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8. Balance the hormones, cytokines, & the microbiome 9. Heal the Damage to the Body: Repair the mitochondrial damage from free radicals and oxidative stress (may improve energy; neuro/card)

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10. Heal the Damage to the Mind/Emotions: role of

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meditation, love and compassion Annie Hopper, Dynamic Limbic Neural Retraining (DNRS)

Commonly Seen Obstacles to Healing ◼

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The most difficult to treat, sensitive patients usually have certain things in common: 1. Often they suffer from MCS and detoxification problems 2. They often have GI issues: with disruption of the microbiome, +/- SIBO, gluten sensitivity, leaky gut, parasites, +/- enzyme deficiencies…

3. MCAD is often present, triggered by infections like Lyme (PIMCAD) and/or environmental toxins like mold

Commonly Seen Obstacles to Healing ◼

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4. Multiple chronic infections are often present: Bacteria we have seen persist: Borrelia spp and Bartonella spp. are on the top of the list, with Mycoplasma spp., tularemia, & brucella right behind. We have only seen a rare case of a chronic rickettsial infection (Q-fever)

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Parasites we have seen persist: Babesia spp. persist despite most rotations of anti-malarial medications/herbs

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Viruses we have seen persist: HHV6 reactivation was seen in our practice, w/ 4x ↑ titers and + PCR’s. EBV PCR+ was occ. found. Also, chronic candidiasis possible…

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Horowitz, R.I.; Freeman, P.R. Precision Medicine: retrospective chart review and data analysis of 200 patients on dapsone combination therapy for chronic Lyme disease/post-treatment Lyme disease syndrome: part 1. International Journal of General Medicine 2019:12 101–119

Commonly Seen Obstacles to Healing ◼

5. There is immune deficiency: over 20% of our practice had immunoglobulin deficiencies & subclass deficiencies

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6. There is immune overactivation: autoimmune markers and inflammatory markers were elevated in up to 70% of our sickest patients

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7. There are disrupted sleep patterns: including DSPS, circadian rhythm disorders and insomnia/hypersomn

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8. There is a history of emotional trauma, with PTSD & unresolved issues of abuse

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Horowitz, R.I.; Freeman, P.R. Precision Medicine: The Role of the MSIDS Model in Defining, Diagnosing, and Treating Chronic Lyme Disease/Post Treatment Lyme Disease Syndrome and Other Chronic Illness: Part 2. Healthcare 2018, 6, 129.

Commonly Seen Obstacles to Healing ◼

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9. There is resistant POTS/dysautonomia with severe autonomic dysfunction 10. There is mitochondrial dysfunction w/the cell danger response (CDR). Difficult to find a safe environment without continuous exposure to toxins 11. Whatever underlying medical problems are present (including endotoxemia from dental/GI sources), they are not well controlled, & contribute to the burden of illness, w/ genetic predispositions Horowitz, R.I.; Freeman, P.R. Precision Medicine: The Role of the MSIDS Model in Defining, Diagnosing, and Treating Chronic Lyme Disease/Post Treatment Lyme Disease Syndrome and Other Chronic Illness: Part 2. Healthcare 2018, 6, 129.

Use Of Compounded Medications In This Patient Populations is Essential ◼

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Compounded Medications Provide Some Solutions for this sensitive patient population: Compounded medications provide flexible dosing (LDN, DMSA, hormones), liposomal formulations (GSH, oregano oil), dye/excipient free compounds (MCS), medications otherwise unavailable (methylene blue for Dapsone, Bartonella) Compounders: Ex’s: Infuserve America (Fla), Hopkinton Drug (Mass), Fallon Pharmacy..

Liposomes and Drug Delivery ◼

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Liposomes localize preferentially to sites of inflammation and infection → ideal for targeting biofilms (liposomal oregano oil). Compounders can make liposomal formulas Liposomes are able to concentrate antimicrobial agents at biofilm interfaces.

Liposomes can carry both hydrophobic/hydrophilic and lipophilic drugs over long periods of time and changes the pharmacokinetics of antimicrobial agents, increasing the circulation time and reducing the toxic side effects

Compounded Liposomal Herbal Preparations/Medications ◼

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Compounded pain creams (neuropathy: ketoprofen (NSAID), local anesthetic, gabapentin, amitriptyline) Compounded hormones: thyroid, sex hormones Liposomal formulations (Artemesia, Curcurmin, oregano oil) for Babesia, inflammation, biofilms Compounded antibiotics (dye, excipient free) for those with Environmental Illness/Chem Sensitivity Yadav, et al. Immunomodulatory effects of curcurmin. Immunopharmacol Immunotox. 2005;27 (3):485-97 Feng J, et al. Front. Med, 11 October 2017

I. Multiple Chemical Sensitivity (MCS) ◼

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Avoidance of chemicals: #1, + Measure body burden of mold, metals, VOC’s, pesticides..(DD, PacTox..)

Air and water purifiers, + fresh, clean food…? EMF free Evaluate detoxification pathways (Genova, Great Plains..)

Support detoxification: Skin (FIR saunas), GI (fiber, flax, binders [clay/charcoal], pre/probiotics, saccharomyces..), liver (phase I and II support: NAC, ALA, DIM, sulforaphane glucosinolate [Oncoplex ES] , GSH, methylation, MedCaps DPO…), kidney (> 2 L fluid/day) + remove mold, metals..

Mental detox: Annie Hopper’s Dynamic Limbic Retraining ? Low dose Keppra (250 mg +) HS Kakisaka, Y. et al. Levetiracetam improves symptoms of multiple chemical sensitivity: Case report. J Med Invest. 2017;64(3.4):296-298.

Mycotoxin testing: Positive in Many Patients With Mold Exposure

II. Gastrointestinal Issues ◼

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Testing: upper GI: H. pylori (titer, breath test), ?

Achlorhydria (Heidelberg gastric analysis test), + test pancreatic enzymes (amylase, lipase), Liver (NH3, LFT’s) Lower GI: CDSA: Genova, DD, Diagnos-Tech: (microbiome eval [Prevotella spp., Clostridium spp, O+P..], ? Candida overgrowth, ? adequate enzyme levels, ? Fat in stool [malabsorption], pH, inflammatory markers [Eosinophil protein X, calprotectin, lactoferrin, SCFA’s/butyrate levels] Breath testing (SIBO, leaky gut, fructose intolerance) Zonulin levels, IgE & IgG food profile, sIga (? Leaky gut) Antigliadin/TTG levels for gluten/celiac ? Cyrex lab Check for Mast Cell Activation Syndrome! If resistant sx

III. MCAS: Affects Different Disease Processes Slide thanks to Bob Miller, ISEAI, 2019

MCAS: ↑ Inflammatory Mediators (ASD) Slide thanks to Bob Miller, ISEAI, 2019

III. Mast Cell Activation Syndrome ◼

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May involve 1/5-10 people: check tryptase, histamine, chromogranin A, PGD2 (blood,urine), mold in sinuses, urine Also: urinary N-methyl histamine, leukotriene E4, biopsy with CD 117 staining. Triggers: mold, inf’s, trauma (MIT) Rapid reaction to anything PO (food, liquid)→ think MCAS ↑ Sensitivities: if sensitivity is increased to chemicals (MCS), food, touch, smell, light, EMF → think MCAS Symptoms: pruritis, wheezing, sneezing, sinus congestion, laryngitis, n. drip.. G.I.: after eating: sweating, flushing, palpitations, N+, V+, diarrhea, bloating, gas, pain, headache migraines, potentially anaphylaxis, + dermatographism Skin: rashes of every type (itching, flushing, hives), paresth.

CV: POTS, palpit’s, arrythmias, lightheadedness, vertigo

III. Mast Cell Activation Syndrome ◼ ◼

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Gen Symptoms: malaise, fatigue, temp dysreg, wt loss/gain Pelvic: bladder pain, cystitis. Neuro Psych: tics, seizures, brain fog, ANS dysregulation!! + mood/sleep d/o’s (labile) Triggers: Mold and mycotoxins, infections(PIMCAS), trauma Mast cells coordinate the immune response to infectious agents and toxins. Treat mold, inf’s, trauma (DNRS)…(MIT) Treatments: Mold: PC 3 g PO BID, GSH 1 g BID, NAC 600 BID, ALA 600 BID, N-butyrate 500 mg BID, binders (charcoal/bentonite clay, CSM), dose is based on tolerance.

Intranasal Therapy : Amphot B, itraconazole, Nystatin + biofilm agents (colloidal Ag, EDTA); Bactroban synergistic Mekori, Y. et al. Integrating innate and adaptive immune cells: Mast cells as crossroads between regulatory and effector B and T cells. C Eur J Pharmacol (2015)

III. Mast Cell Activation Syndrome ◼

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Systemic Antifungals: itraconazole (not well absorbed with Zantac or PPI’s), voriconazole, posaconazole, isavuconazole Consider limbic retraining program if reactivity is prominent & limiting symptom w/ MCAD/mold sensitivity Treat inf’s (Lyme, co-inf’s) and use Mast cell stabilizers: MCAD: H1 and H2 blockers (Zyrtec 10 mg + Zantac 150 mg QD-BID, or Claritin 10 mg + Pepcid [famotidine] 10-20 mg, vs fexofenadine [Allegra] 180 mg/day w/ H2 blocker) Mast cell stabilizers: Cromolyn Na (Gastrocrom…) + Ketotifen: compounded: 0.5mg cap’s HS, then AC Diet: Low histamine diet Molderings, G. et al. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Hematol Oncol 2011; 4: 10

IV. Multiple Chronic Infections ◼

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Bacteria: goal is to treat multiple IC pathogens at once, and address different forms of borrelia during the treatment course, following the clinical response to each drug/botanical as its added, personalizing treatment Cell wall forms: penicillins, cephalosporins (Ceftin 500 BID) Round body/cystic forms: Plaquenil 200 BID, GSE 2 PO BID (Pure Encap’s), occ Flagyl/Tindamax (body wt), Alinia Intracellular location: tetracyclines, macrolides, quinolones, rifampin, rifampicin, sulfa (dapsone), PZA. Extracell: Gent Biofilm/persister forms: dapsone, PZA, + add on treatment for Bartonella (? methylene blue, clotrimazole, berberine) + add on treatment for Babesia (malarone, herbs, rotations)

New Bartonella “Persister” Drugs ◼

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Bartonella has been shown to have stationary persister forms, like borrelia. Methylene blue, Gent, daptomycin & clotrimazole were among the most active agents.? Berberine 7 azole drugs including had high activity vs stationary phase Bh. Best: clotrimazole (also anti-malarial prop’s) Daptomycin: 21% residual viability (IV, expensive, SE’s) Methylene blue: 25% residual viability (used with dapsone) Gent (not IC)/?Nitrofurantoin: MIC values of 0.31–0.63 μg/mL Rifampin was the most effective against growing Bh (doxy/zithro/quinolones also useful for growing forms) Li, T. et al. Identification of FDA-Approved Drugs with Activity against Stationary Phase Bartonella henselae. Antibiotics 2019, 8(2), 50;

Basic Antibiotic Approaches for LD ◼

Create a personalized AB protocol:

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? Allergies to any antibiotics. If sulfa sensitive, to what extent? (most people with a sulfa sensitivity can tolerate dapsone, as long as the reaction was not one of anaphylaxis, or severe dermatitis, i.e., Stevens Johnson syndrome). ? Use Zyrtec 10 mg + Zantac 150 mg before ? Are there strong Herxheimer reactions with certain medications. A strong Herx with an intracellular drug (tetra, macrolide, quinolone, rifampin, PZA, dapsone) or a significant benefit, implies that the load of bacterial inf’s making the patient sick are inside the cell Personalize treatment based on responses to medication

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Lyme 101: Simply Follow the Reaction To the AB’s, Personalize Treatment ◼

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Feels better with a cell wall drug? (Amox 875 2-3 BID; Augmentin 1 g BID, Bicillin inj’s 1.2 mil U TIW, Ceftin 500 mg BID, cefdinir (Omnicef) 300 mg BID, IV Rocephin 2 g QD, IV Teflaro: then there are actively growing/log phase Can use probenecid 500 mg BID in adults to ↑ levels of penicillins or cephalosporins for better CNS penetration, but may ↑ levels of other medications (i.e., dapsone…)

Can check peak and trough levels Can pulse cell wall drugs, ? Benefit in some patients Usually combined with Plaquenil, Zithromax, Nystatin Same logic applies to how the patient feels w/other meds

Lyme 101: Simply Follow the Reaction To the AB’s, Personalize Therapy ◼

Feels better or worse with a cystic drug? (atypical forms, round bodies, S-forms, L-forms, CWD forms), ie:

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Plaquenil, GSE: usually mild reactions if any. Plaquenil alkalizes IC compartment (Coxiella), affects DNA Gyrase and round bodies, modulates immunity (AI reactions). GSE has an effect on round bodies, ? Effect on Candida

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Flagyl (metronidazole), Tindamax (tinidazole), Alinia (nitoxazide): often w/ stronger reactions. ? Killing of round body forms, flare from Candida…Flagyl and Tindamax have excellent CNS penetration, but careful with neuropathy/Candida! (add B complex) + no ETOH!

Lyme 101: Simply Follow the Reaction To the AB’s, Personalize Therapy ◼

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Feels better or worse with an intracellular drug? → implies active IC inf’s (borrelia, Bartonella, Mycoplasma, tularemia, brucella..). How to proceed?

Personalize treatment: ? Good Herx or bad Herx. Good Herx = feels better after days/weeks of ongoing ↑ symptoms. Continue med. Bad Herx= no improvement after stopping the IC drug, back to baseline. Rotate IC med Mix IC drugs for maximum effect, ↓ any potential resistance (not seen for borrelia, present w/ mycobact) Clues apart from clinical symptoms that an IC pathogen is present: ↑ VEGF (Bart), ↑ 1,25/25 OH Vit D ratio, rise in AB titers (Bart, Mycopl, Brucella), ? False + tularemia/Bruc

Lyme 101: Simply Follow the Reaction To the Herbs, Personalize Therapy ◼ ◼

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Feels better or worse with an biofilm agent? → implies stationary forms in biofilms Biofilm agents: Commonly used at HVHAC: Work up dose: Stevia (Nutramedix, 15 drops BID), Biocidin 2-3 pumps of liposomal form BID, oregano oil (60 mg) ? Liposomal BID Others: Serrapeptase 1-2 BID, Lauricidin (monolaurin, up to 1 scoop/d, rarely BID); Some MD’s use EDTA, Boluke..

Also: peppermint oil, clove oil, cinnamon oil…Mix biofilm agents & Personalize treatment: if flaring, lower dose or use different agent? Try and push through flare Effective killing of Borrelia burgdorferi in vitro with novel herbal compounds Kati Karvonen* and Leona Gilbert, Gen Med Open, 2018, Volume 2(6): 1-4

Dapsone Combination Therapy ◼

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DDS CT: Plaquenil 200 BID, doxycycline (100-200 mg) BID, rifampin 300 mg BID (empty stomach, or rifabutin 150 mg BID with a full stomach), dapsone (from 25 mg QOD, to 25 mg QD, to 50/25 QOD, to 50 mg/d, max usual dose 100 mg/day), Nystatin 500,000 U tabs, 2 BID, Leucovorin 25 mg BID, Folafy-ER (L-methylfolate) 15 mg QD or BID (increase doses of folic acid based on anemia), triple probiotics *(Ultraflora DF BID, Theralac BID, saccharomyces boulardii BID) with 3 biofilm agents, including oregano oil cap’s BID, Stevia (NutramediX) 15 drops BID, Biocidin 2 sprays BID (work up doses of biofilm agents according to Herxing).

Future: Double dose dapsone study secondary to success Works well long term if no active co-infections (Bab, Bart)

Monitoring on Dapsone Combination Therapy ◼

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Initial G6PD levels must be normal. Rule out and treat any underlying anemia (Fe deficiency, B12..) before treatment with DDS CT Monitor CBC, CMP, methemoglobin levels: frequency depends on the dose of dapsone (q wk, w/ ↑ doses) Make sure women report any unusually heavy periods/clots where the risk of anemia rises. Stop dapsone if any heavy bleeding, and ↑ folic acid (? > 100 mg/day) Stop dapsone if methemoglobin levels ↑> 8-10% despite methylene blue 50 BID and 1000 mg liposomal GSH BID, NAC 600 BID, ALA 600 mg BID, esp. if symptomatic. Lower DDS dose to previously tolerated, helpful dose

Add on Babesia/Bartonella Therapy to DDS CT if Symptoms/Inf’s Persist ◼

Add for Bartonella: Zithro (can be pulsed 4 days in a row per week, i.e. Zithro BID, Mon-Thurs) + PZA (body weight), methylene blue 50 BID (aver), clotrimazole QID. Avoid mixing QT drugs if on a macrolide, quinolone, SSRI’s, Coartem, Quinine…Follow Bart titers, PCR, FISH, VEGF w tx

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Add for Babesia: Clinda + macrolide (or quinine), +/Mepron (1-2 tsp BID) or malarone (2 BID) + artemisinin (?

Liposomal), cryptolepis (1 tsp BID to TID), CSA…Consider 3 day rotation of Coartem 4 BID + Daraprim 25, 2 QD, sulfadiazine 1 g QID, followed by 11 days Primaquine 26.3 mg 2 QD X 4 cycles. Follow symptoms, titers, PCR, FISH…

What About Other Persister Drugs? ◼

IV Daptomycin: dose by body weight: based on research

by Dr Zhang at JHU. Tried his protocol at the HVHAC, using doxycycline, Rocephin and IV Dapto in 3 patients: Herxed+++ without significant improvement post stopping meds

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Disulfuram (Antabuse) 250 mg, up to 2 day: based on

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Kim Lewis’s work at Northeastern. We are presently evaluating the effects compared to dapsone (sulfa drug with less SE’s) Continue persister drugs/biofilm agents for adequate time

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Saki Miyaue et al. Bacterial Memory of Persisters: Bacterial Persister Cells Can Retain Their Phenotype for Days or Weeks After Withdrawal From Colony–Biofilm Culture. Front. Microbiol., 26 June 2018

HVHAC Clinical Trial: Disulfiram vs Dapsone Combination Therapy

Add Herbal/Integrative Therapies: Solo, Combination Treatments ◼ ◼ ◼

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Buhner protocol (Samento, Andrographis, J K..)

Zhang protocol (TCM→Coptis, HH, Allicin, Circ P) Homeopathy: Ledum, syphilitic, malarial nosodes..

Byron White protocol (A-L, A-Bab, A-Bart) Cowden protocol (Samento, Banderol, Cumunda..)

Beyond Balance (MC Bab 2, Bab 1, BB-1..)

Others: Biocidin, Lauricidin, Liposomal Vitamin C, Rife, Coil machines, Bionic 880, heat therapy, stem cells, Acupuncture, oxidative stress tx (ozone)…

Silver Enhances Antibiotic Activity Against Gram-Negative Bacteria. Jose Ruben Morones-Ramirez et al.

Sci Transl Med 5, 190ra81 (2013);

V. Treat Immune Deficiency ◼

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IV: Gammaguard, Gammaplex most commonly used. Dose by body wt/level of immunoglobulins, and response (follow small fiber nerve biopsies, neuropsychiatric symptoms if AI encephalopathy w o without PANS/PANDAS) Use Benadryl, other H1 and H2 blockers, fluids, Tylenol to prevent reactions. Glutathione may help SQ: Cuvitru, Hizentra most commonly used.

Follow immunoglobulin levels and subclasses, clinical response

VI. Treat An Overstimulated Immune System ◼

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Remove and treat offending agent(s) whether infectious (borrelia, bartonella, mycoplasma..) +/-or toxins (mold, metals) driving AI phenomenon. Support detox pathways!

Treat leaky gut, food allergies, MCAS, microbiome imbalance, Vit D deficiency: major cause of inflammation Balance hormones (adrenal, thyroid, sex hormones, post pituitary: VIP, MSH, ADH) Address ↑ cytokines: LDN 4.5 HS (microglial activation), Nrf2 activators (curcuplex, Oncoplex, resveratrin, green tea extract), Medit diet/gluten + allergen free/sugar-yeast free DMARDS (Plaquenil + ? Mino), IVIG, SQIG, Smilax (BLT)

VII. Disrupted Sleep Patterns ◼

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Differential diagnosis: Lyme, other co-inf’s (Babesia w/sweats), LA stimulants (medication like Vyvanse, Adderall, caffeine, chocolate), BPH, menopause, adrenal + thyroid hormone dys(f), anxiety/depression, OSA, narcolepsy, RLS, SWS, EMF’s, environmental noise levels Sleep study (in home: Accusom/Novasom) if resistant sx Treat underlying etiologies (as above) & treat symptoms: Get into stage III/IV non-REM sleep: avoid benzo’s, Ambien, Lunesta when possible. Use: Tradazone (50-200 mg HS), Gabitril (4-20 mg), Remeron (7.5-15 mg), pregabalin (Lyrica, 50-200 HS), occ gabapentin (300 mg+), doxepin 10 HS, Flexeril 5 HS (1/3 Amrix cap), Atarax 10-25

Commonly Used Botanicals For Sleep ◼

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Melatonin: 1-10 mg (↓ IL-17). Watch for hangover Cerenity PM: Designs For Health: 2 HS Herbsom: TCM (Zhang): 2 HS Valerian Root: Xymogen’s SynovX Calm: 2 HS Kavinase: 2 HS Honokiol: 2 HS (also for Candida, neuromodulation) GABA-L theanine (cream [Xymogen], oral version=Relax Max [Xymogen or L-theanine cap’s]) Magnesium: Optimag Neuro (Xymogen): 1 scoop Lingmei Sun, et al. Honokiol induces reactive oxygen species mediated apoptosis in Candida albicans through mitochondrial dysfunction. PLoS ONE 12(2): e0172228; Woodbury, A., et al.

Neuromodulating effects of Honkiol: A review. Front in Neurology, Sept 2013

VIII. Emotional Trauma/PTSD With Extreme Hypersensitivity ◼

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Apart from standard therapies (CBT, EMDR, Neurofeedback), counseling, meditation, medication…

Annie Hopper’s DNRS program: limbic retraining: 15-60 min’s/day: www.retrainingthebrain.com: see testimonials CFS/FM/MCS/EMF sensitivity/POTS/Lyme-MSIDS share a common denominator: limbic system impairment For MCS, Mold, Food sensitivities, chronic pain, POTS, CFS, FM, Sensitivity to light, sound, smell, EMF Sensitivity, depression, anxiety, Lyme… People who did it improved fatigue, can eat diff foods, recovered from POTS, Lyme symptoms got better, w/ better mood/happiness.

Annie Hopper: DNRS Program, Hopper ISEAI, 2019

IX. Resistant POTS/dysautonomia ◼

Get to the source(s) of the problem: Lyme, coinfections, toxins (mold), MCAS, CDR, ? EDS (Ehler Danlos)

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Treat symptomatically: salt (tablets, 3 gm ++), Licorice +, 2 am, > 2-3 liters of fluid/day Florinef (fludrocortisone) 0.1 mg am. Raise dose as needed Midodrine: start 5 mg TID, ↑ 10 mg TID if BP not controlled or w/ resistant symptoms (dizziness changing position, presyncope, syncope, fatigue, palpit’s, anxiety, brain fog) Add Northera (droxidopa) 100 mg TID, ↑ by 100 mg TID Q 2 days, max dose 600 mg TID. Check supine BP w/meds TED support stockings? Cardio PT/rehab?

Annie Hopper DNRS, Vagal retraining, Address CDR

X. Mitochondrial Dysfunction: Cell Danger Response (CDR) ◼

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Cell Danger Response (CDR, Robert Naviaux): Persistent CDR creates blocks in healing. The path from chronic illness to healing has a beginning, middle and end.

Mitochondria have 3 developmental forms that undergo programmed interconversion when a cell is injured/stressed Beginning, M1: proinflammatory form for defense Middle, M0: uncommitted form for growth and biomass replacement End: M2: anti-inflammatory form for general conditions The Metabolic Features and Regulation of the Healing Cycle. Naviaux RK. Mitochondrion, September 2018.

X. Mitochondrial Dysfunction: Cell Danger Response (CDR) ◼ ◼ ◼

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The CDR coordinates mitochondrial (f) after injury Healing cycle is a genetically programmed 3 step process Metabolism controls progression through the healing cycle by using metabolites as ‘signaling molecules’ (metabokines): extracellular ATP is important at all stages When the CDR is chronically activated, the coordination between the two limbs of the vagus is disrupted. This results in disinhibiting the sympathetic nervous system and the HPA axis which dominate during illness.”

Metabolic features of the cell danger response. Naviaux RK. Mitochondrion, 2014 (ePub 2013).

“Vagal influences over mast cells” Stead, R, et al. Anatomical Neuroscience: Basic and Clinical, 125 (2006) 53-61;

XI. Genetic Evaluation: Why Won’t the Patient Get Better?

ISEAI talk, Bob Miller, May 2019: www.yourgeneticresource.com

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Bob Miller: Nutrigenetic Research Institute (200k SNP’s) Genetic weakness & epigenetic factors can impact detox ability and increase inflammation This inflammation leads to an imbalance of mTOR (growth) and Autophagy (cleaning) This may lead to excess mast cell activation and heme dysregulation, consequently, using up antioxidants and NADPH to neutralize the free radicals→ NADPH Steal NADPH can be used by NOX to make inflammation, and less NADPH is available for reducing (recycling) antioxidants.

Why Check Genetic Pathways and NADPH? ◼

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NAD (including NAD+ and NADH) and NADP (including NADP+ and NADPH) mediate: Energy metabolism + Mitochondrial functions Antioxidation/generation of ROS Gene expression Immunological functions Aging + Cell death Can look at SNP’s for potential NADPH Steal: Nutrigenetic Research Institute does a functional genetic analysis w/ cloud based software to interpret SNP’s, + customized formulas www.nutrigeneticresearch.com

Putting It Together: Crucial Steps in Healing the Difficult to Treat Patient ◼ ◼ ◼

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Evaluate and treat MCS and detoxification problems Evaluate and treat GI abnormalities Evaluate and treat chronic persistent infections and toxins, which may be driving MCAD and vagal nerve dysfunction w/POTS/dysautonomia. Use limbic + vagal retraining, esp. when PTSD/chronic illness is present (reset the system) Evaluate and treat immune dysfunction (under/overactive) Evaluate and treat sleep disorder(s) Evaluate and treat genetic abnormalities and mitochondrial dysfunction w/abnormal CDR

Thank you….