This article was originally posted on Dr. Richard Horowitz’s Medical Detective Substack. It is Part 4 of a 5-part series. You can find more helpful content by subscribing here. 

By Dr. Richard Horowitz

Double Dose Dapsone Combination Therapy (DDDCT)

In Bartonella Parts 1, 2, and 3, you learned the basics of Bartonella testing, symptoms, and treatment options, with a detailed discussion of laboratory work needed before starting the protocol, and how/why the medication and support supplements are being used to increase the tolerability and safety of DDDCT and HDDCT.

Please review this information with your doctor before proceeding with the antibiotic protocol listed below. The full protocol can be found in:

Horowitz, R.I.; Fallon, J.; Freeman, P.R. Comparison of the Efficacy of Longer versus Shorter Pulsed High Dose Dapsone Combination Therapy in the Treatment of Chronic Lyme Disease/Post Treatment Lyme Disease Syndrome with Bartonellosis and Associated Coinfections. Microorganisms 2023, 11, 2301. https://doi.org/10.3390/microorganisms11092301

Here’s the detailed and simplified version of the protocol.

The first week protocol

Gradually add the medication one by one to ensure GI tolerance. For example, on a Monday, start with Plaquenil (hydroxychloroquine) 200 mg once per day after meals, with Nystatin 500,000 U tablets, 2 twice per day, cimetidine 400 mg twice per day, and minocycline 50 mg twice per day.

Lower dose minocycline or doxycycline (50 mg twice per day) can be started if you have a history of GI intolerance to tetracyclines or risk of sun exposure. If there is no issue with GI tolerance, add rifampin 300 mg twice a day on Wednesday, several days later.

Since rifampin can affect medication levels in the body, especially hormones (thyroid, adrenals), a drug interaction check should be done in advance to understand whether other medication you are on will need to be adjusted. For example, if you have low thyroid function, you may increase thyroid medication slightly on rifampin, and then check levels several weeks later to ensure they are in good range.

Then, assuming all the medication has been tolerated Monday through Wednesday, add pyrazinamide (PZA) on Thursday for those with evidence of active Bartonella.

Dosing is based on body weight

The dosing is based on body weight (40-55 kg: 1000 mg once per day x 2 months; 56-75 kg, 1500 mg once per day x 2 months; 76-90 kg: 2000 mg once a day). Pyrazinamide is a Mycobacterium/persister drug used to shorten the course of therapy of tuberculosis; adding it, along with a tetracycline, rifampin, and dapsone, has a stronger effect on flushing Bartonella out of its hiding place.

Rarely, pyrazinamide will cause a rash (in roughly 5% of patients), and if that occurs, it should be stopped immediately. The rash will resolve quickly within 1-2 days off the medication.  If there is any doubt about sensitivity to medication, speak to your health care provider about using an H1 and H2 blocker prior to using PZA, like cetirizine (Zyrtec) 10 mg once a day with famotidine (Pepcid) 10-20 mg once a day.

So before starting the official 8-week DDDCT protocol, after breakfast and dinner and with a full stomach, take minocycline or doxycycline twice a day, 2 Nystatin twice a day, Plaquenil once a day, cimetidine twice a day, rifampin twice a day, and pyrazinamide once a day, apart from all the support supplements discussed in Bartonella, Part 3. These include probiotics twice per day, biofilm agents twice per day, and inflammatory/detox support twice per day.

The first week protocol is designed in a way to ensure there is no diarrhea, by slowing increasing medication, and also so you know if you react to any specific medication (i.e., Herxheimer reactions) before adding dapsone and folic acid supplements.

The 8-week DDDCT protocol

The 8-week protocol starts when all antibiotics are on board and tolerated (which adds an extra week to the protocol). Take probiotics as soon as you get up in the morning and last thing at bedtime. Always take antibiotics after breakfast and dinner together at the same time.

Be sure to not take your minerals (like Min RX 2 twice a day [Xymogen] and magnesium malate [NutramediX] 2- 4 twice a day) within 1-2 hours of antibiotics; take them at lunchtime and bedtime instead. Minerals can impair the absorption of tetracyclines, which is why they are taken apart.

Week 1

Add Dapsone 25 mg per Day and Folic Acid Support

*Dapsone 25mg once per day will be added to the prior regimen along with folic acid support to help reduce dapsone induced anemia

*Leucovorin (folinic acid) 25 mg, two twice per day

*Xaquil XR (L-methyl folate, Xymogen) two twice per day.

*Take these antibiotics:

*Minocycline 50 mg 1 twice per day with meals (or mino/doxy 50-100 mg twice a day)

*Rifampin 300mg 1 twice per day

*Plaquenil (hydroxychloroquine) 200mg once per day

*Nystatin 500,000 units 2 twice per day

*Cimetidine 400 mg twice per day

*Pyrazinamide (PZA) 500 mg, 2-4 tablets once per day (dose is dependent on body weight, as above).

*Take the support supplements listed in Bartonella Part 3.

Week 2

Increase Dapsone to 50 mg per Day

*Continue the same Week 1 regimen.

*Increase dapsone to 25 mg twice per day (50mg daily). That is the only change, as dapsone is gradually increased over the next 4 weeks for tolerability. If there are any severe Herxheimer reactions, use the Herxheimer protocol in Substack Bartonella Part 3.

Week 3

Increase Dapsone to 75 mg per Day

*Continue the same Week 1 regimen.

*Increase dapsone 25 mg to 2 in the morning and 1 in the evening (75 mg daily).

Week 4

Increase Dapsone to 100 mg per Day, Begin Methylene Blue and High Dose Antioxidants

*Take Week 1 antibiotics.

*Take these supplements at these increased doses to reverse methemoglobin levels:

*1000 to 2000 mg of glutathione twice per day

*Vitamin C 1-2 g twice per day

*Vitamin E 300 IUs twice per day

*NADH 5 mg 1-2 times per day

*Dapsone 100mg 1 per day (or 25 mg, two twice per day)

*Start methylene blue 50 mg twice per day

Weeks 5-8

Double Dose Dapsone Combination Therapy for the Next 4 Weeks

Week 5

*Take Week 1 antibiotics and supplements at these increased doses to reverse methemoglobin levels

*Dapsone 100mg, 1 twice per day (total dapsone, 200 mg per day)

*Add azithromycin (Zithromax) 250 mg twice per day with a full stomach. Clarithromycin (Biaxin) can alternatively be used instead of Zithromax if insurance coverage requires a different medication.

*Check a QT interval on the EKG prior to using Zithromax, or clarithromycin as Plaquenil, Zithromax and/or use of Zofran (ondasentron) for nausea may increase the QT. A repeat EKG is advisable when using Zithromax to ensure stability.

*Increase Methylene Blue to 100 mg, 1 twice per day.

*Increase Leucovorin 25 mg tablets to 4, twice per day (100 mg twice per day).

*Increase Xaquil XR (L-methyl folate) to 4 twice per day (60 mg twice a day). Higher doses of folic acid support will help to reduce dapsone induced anemia while using higher doses of dapsone.

*Increase glutathione from 1000 mg twice per day, to 2000 mg twice per day, if methemoglobin levels rise above 5%.

Week 6

*Continue Week 5 regimen.

*Increase methylene blue to 150 mg twice per day.

Week 7

*Continue Week 5 regimen.

*Increase methylene blue to 200 mg twice per day.

Week 8

*Continue Week 5 regimen.

*Increase methylene blue to 250 mg twice per day.

Week 9

High Dose Dapsone Combination Therapy (HDDCT) for the Next Week

*Continue Week 8 regimen, except increase Rifampin to 600 mg twice per day.

* Increase dapsone to two, 100 mg tablets twice per day, for a total dose of 400 mg of dapsone.

*Increase methylene blue to 300 mg twice per day.

*This will be a 6-day pulse for Bartonella as long as the blood counts and methemoglobin levels are in acceptable range. In some cases, a 4-day HDDCT pulse may be needed if borderline blood counts are present, or if there is no clear evidence of active Bartonella. Blood tests with a CBC, CMP, and methemoglobin level are done on day 3 or 4 of the this last week of antibiotic therapy.

Month 3, After Week 9 and Finishing HDDCT

*Stop all antibiotics. Stop Plaquenil, cimetidine, minocycline or doxycycline, Rifampin, Zithromax (or clarithromycin), and PZA.

*Stop dapsone.

*Go for repeat laboratory work (CBC, CMP, methemoglobin level) once you are 2-3 weeks off all antibiotics.

*Stay on:

*Nystatin 2 twice per day (to eliminate any yeast overgrowth)

*Leucovorin 4 twice per day

*L-methylfolate (Xaquil), 4 twice per day,

*All probiotics, biofilm support, and nutritional support with NAC, ALA, glutathione (GSH), Curcuplex, Oncoplex, etc.

*Taper methylene blue. Decrease the dose to 200 mg twice per day for 2 days; 100 mg twice a day for 2 days; 50 mg twice a day for 1- 2 days, and then stop it. Do not keep taking high dose MB after dapsone is finished (use the above protocol), as this could lead to increased hemolysis with lower red cell counts and symptoms/signs of serotonin syndrome.

If you have blue hands/lips and any symptoms suggestive of elevated methemoglobin at the end of the protocol once you have tapered MB, the decision to remain on lower dose MB and/or other high dose antioxidants must be based on blood levels of methemoglobin, not pulse oximetry (which doesn’t work on MB) or symptoms. This is important.

*Continue folic acid support with Leucovorin and Xaquil at the above doses until the CBC returns, when you go for labs about 3 weeks off the protocol. At that point, any anemia should be improving nicely, and doses can be decreased. If not, Leucovorin and Xaquil should continue at 3 twice per day for 1-2 more weeks, going into Month 4 (one month off antibiotics); usually Leucovorin and Xaquil are taken at a dose of 2 twice per day until the anemia has sufficiently resolved.

*Women should take extra B12 support (Methyl protect, Xymogen, one per day) and extra iron if there heavy menses during the protocol.

When the protocol is finished

Month 3

Mitochondrial support has been shown to be helpful for many patients after the protocol has completed. Do this for one month during Month 3 post-antibiotic therapy along with Nystatin, Leucovorin, Xaquil, probiotics, biofilm support, and other support supplements:

*ATP 360, 3 capsules once a day (Researched Nutritionals)

*ENADA (NADH) 1-2 per day

*Carnitex (Xymogen) 2 twice per day (not for those with alpha gal allergy)

*CoQ Power 400 mg twice per day (Researched Nutritionals) with CardioRibose (Researched Nutritionals), one scoop twice per day

*Mitoprime (Xymogen) one per day

*MitoNR (Designs for Health) one per day.

This protocol has had excellent success in chronically ill patients who suffered with chronic Lyme disease and Bartonella. You can watch the 90-minute dapsone documentary I filmed on 18 patients who were chronically ill who have now recovered their health with DDDCT and HDDCT:

https://players.brightcove.net/6314452011001/PAMDt93Yi_default/index.html?videoId=6353288590112

In Part 5, you’ll read about how to use the 2-week antibiotic pulses using HDDCT for chronic Bartonella. I’ll also review how to manage potential side effects in more detail. Stay tuned!

Dr. Richard Horowitz has treated 13,000 Lyme and tick-borne disease patients over the last 40 years and is the best-selling author of  How Can I Get Better? and Why Can’t I Get Better? You can subscribe to read more of his work on Substack or join his Lyme-based newsletter for regular insights, tips, and advice.