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Antimalarial Drugs For Lyme Disease

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The Science Behind Cryptolepis

Doxycycline and Lyme Disease Treatment

According to a 2020 study published in Frontiers in Medicine, new data shows seven herbal medicines are highly active in test tubes against Borrelia burgdorferi , the bacteria that causes Lyme disease. Of the seven, only Cryptolepis sanguinolenta extract caused complete eradication of B. burgdorferi. The implications of this study are far reaching, as they show that Cryptolepis sanguinolenta has the potential to improve treatment of persistent Lyme disease.

According to the study, the seven herbal medicines that have the potential ability to kill B. burgdorferi in test tubes include Cryptolepis sanguinolenta, Cistus incanus, Juglans nigra , Polygonum cuspidatum , Artemisia annua , Uncaria tomentosa , and Scutellaria baicalensis .

In the study, only Cryptolepis sanguinolenta extract caused complete eradication of B. burgdorferi. Cryptolepis uses have traditionally included support for treatment of malaria and the tick-borne infection Babesia. The implications of this study are far reaching, as they show that Cryptolepis sanguinolenta has the potential to improve treatment of persistent Lyme disease and suggest the need for additional laboratory and clinical studies regarding the extracts active constituents and ability to effectively eradicate B. burgdorferi in vitro and in vivo.

The results revealed that Cryptolepis sanguinolenta extract showed strong activity against both growing B. burgdorferi and non-growing stationary phase B. burgdorferi.

Tier One Babesia Treatments In Lyme Disease

The following approaches work about 85 percent of the time based on my experience. Dosing is for adults. All of the tier one approaches are prescription medicines. Atovaquone-based treatments are more established and often have better insurance coverage. Quinoline-based treatments that include the newer tafenoquine and older primaquine are quite effective, but I reserve these for when atovaquone-based treatments are not working or for when a person has babesia relapse.

Treating Late Stage Lyme Disease

Most cases of Lyme disease involve a rash and flu-like symptoms that resolve within 1 month of antibiotic treatment. However, some people go on to develop late-stage Lyme disease, which includes Lyme arthritis and neurologic Lyme disease.

Untreated, slightly more than half of people infected with B. burgdorferi will develop Lyme arthritis. About 10% to 20 % of people develop neurologic Lyme disease. A very small percentage may develop acrodermatitis chronica atrophicans, a serious type of skin inflammation occurring more frequently in Europe. These conditions are treated for up to 28 days with antibiotic therapy.

If arthritis symptoms persist for several months, a second 2 to 4 week course of antibiotics may be recommended. Oral antibiotics are used for Lyme arthritis and acrodermatitis chronica atrophicans.

In rare cases, people with arthritis may need intravenous antibiotics. A 2 to 4 week course of intravenous ceftriaxone is used for treating severe cases of neurological Lyme disease. For milder cases, 2 to 4 weeks of oral doxycycline is an effective option.

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Drug Combinations Against Stationary Phase Borrelia

In March of 2015, some of the researchers from the above study expanded upon the results from the 2014 drug screen. They took the top 27 drug candidates and drug combinations and tested their activity against microcolony . They published their results in a research paper titled Drug Combinations against Borrelia burgdorferi persisters in vitro: eradication achieved by using daptomycin, cefoperazone, and doxycycline.

The researchers discovered the biofilm forms of Borrelia bacteria were more resistant to antibiotics that had good activity against round body persister forms suggesting antibiotics used alone had limited effect. Then they evaluated 81 drug combinations against microcolony and round body forms. Daptomycin alone could not eradicate microcolonies, but when combined with other drugs, daptomycin was effective against round body forms and microcolonies. The most effective drug combination against microcolonies was daptomycin + doxycycline + cefoperazone.

Evaluation Of Natural Products For Their Activity Against B Burgdorferi Stationary Phase Cultures

MONTH 1

B. burgdorferi B31 was cultured for 7 days in microaerophilic incubator as stationary phase cultures . To evaluate potential anti-persister activity of the natural products, their stocks and their control solvents were added to 100 L of the B. burgdorferi stationary phase culture in 96-well plates to obtain the desired concentrations. The botanical medicines and natural product extracts were tested with the concentration of 1, 0.5, and 0.25% antibiotics of daptomycin, doxycycline, and cefuroxime were used as controls at a final concentration of 5 g/ml. All the tests mentioned above were run in triplicate. The microtiter plates were sealed and incubated at 33°C without shaking for 7 days with 5% CO2.

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Background And Diagnosis Of Borrelial Lymphocytoma

Borrelial lymphocytoma is a rare cutaneous manifestation of Lyme disease in Europe, which presents as a solitary bluish-red swelling with a diameter of up to a few centimeters . The most common site of borrelial lymphocytoma is the ear lobe in children and the breast, on or near the nipple, in adults. Mild, localized discomfort often accompanies the skin lesion. Borrelial lymphocytoma is characterized histologically by a dense polyclonal and predominantly B lymphocytic infiltration of the cutis and subcutis, frequently with germinal center formation . Borrelial lymphocytoma may be the only sign of Lyme disease or merely one of several manifestations during the course of the illness. It often appears near the site of a prior tick bite and frequently arises in the vicinity of a previous or concurrent erythema migrans lesion, but compared with erythema migrans, it usually emerges later and lasts longer .

Additional Antibiotic Combinations Against Chronic Lyme

Following up on previous results identifying disulfiram as a top hit, researchers wanted to perform studies on disulfiram in combinations with other antibiotics and additional combinations to determine the most effective. In 2020, the paper Evaluation of Disulfiram Drug Combinations and Identification of Other More Effective Combinations against Stationary Phase Borrelia burgdorferi was published. Antibiotics used in combination were either traditionally used antibiotics for Lyme disease or antimicrobial compounds with strong activity against stationary phase Borrelia.

Disulfiram in two-drug combinations was not as effective as cefuroxime + clarithromycin or cefuroxime + nitroxoline. In three-drug combinations with disulfiram, disulfiram + cefuroxime + nitroxoline was most effective, followed by disulfiram + cefuroxime + nitazoxanide. Removing disulfiram from the three-drug combinations, cefuroxime + clarithromycin + furazolidone, cefuroxime + nitroxoline + furazolidone, and cefuroxime + nitazoxanide + clarithromycin was significantly more effective than the disulfiram combinations.

Unfortunately, nitroxoline and furazolidone are not available in the United States, but the combination of cefuroxime + nitazoxanide + clarithromycin is readily available. It is important to note that these studies were performed on cultures in a laboratory, and benefits may not directly translate in animal studies or humans.

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How Resistance To Antimalarial Drugs Arises

The emergence of drug-resistant organisms can be considered in two discrete phases: the initial de novo event that first produces the resistant mutant, and the subsequent selection process that leads to its preferential transmission and spread. Resistance arises from spontaneous mutations or gene duplications, which are independent of . Once formed, however, resistant mutants have a survival advantage in the presence of antimalarial drugs and, conversely, a survival disadvantage in the absence of at least certain antimalarial drugs. The resulting fitness cost may lead to a declining of resistance once drug pressure is removed .

Factors affecting the development of resistance include: the parasite mutation rate, the degree of resistance conferred by the genetic change, the fitness cost of the resistance mechanism, the proportion of all transmissible infection exposed to the drug, the drug concentration profile, the individual and community patterns of drug use, and the profile of the community .

The role of drug elimination in the development of parasite resistance has recently been reviewed, and modeled . Drugs with long elimination phases are, in essence, selective filters, allowing infection by resistant parasites to flourish while the residual drug levels suppress infection by sensitive parasites . Slowly eliminated drugs such as mefloquine provide such a filter for months after drug administration. The resulting selection pressure can be enormous.

Mic Values Of Round Body Active Antibiotics

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In our previous study, we found that the activity of antibiotics against non-growing persisters was not always correlated with their activity against growing B. burgdorferi . We therefore used log phase cultures to test the MICs of selected active hits artemisinin and ciprofloxacin that had excellent activity against the round bodies of B. burgdorferi using the SYBR Green I/PI assay and microscope counting. The MIC value of artemisinin was quite high at 50100 g/ml for growing B. burgdorferi, indicating that artemisinin is much less active against growing organisms, despite its high activity against the non-growing round bodies of B. burgdorferi persisters. In contrast, ciprofloxacin was quite active against the growing B. burgdorferi with a low MIC , which is in agreement with a previous study , indicating that it is active against both growing form and non-growing round body form of B. burgdorferi.

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Drug Screen And Antibiotic Susceptibility Testing

To qualitatively determine the effect of antibiotics in a high-throughput manner, 10 l of each compound from the pre-diluted plate or pre-diluted stock was added to 3 days amoxicillin induced round body form from a 5 day-old stationary phase B. burgdorferi culture in the 96-well plate. The final volume per well was adjusted to 100 l. Plates were sealed and placed in 33°C incubator for 7 days. SYBR Green I/PI viability assay was used to assess the live and dead cells after antibiotic exposure as described . Briefly, 10 l of SYBR Green I was mixed with 30 l propidium iodide into 1.0 ml of sterile dH2O. Then 10 l staining mixture was added to each well and mixed thoroughly. The plates were incubated at room temperature in the dark for 15 min followed by plate reading at excitation wavelength at 485 nm and the fluorescence intensity at 535 nm and 635 nm in microplate reader . With least-square fitting analysis, the regression equation and regression curve of the relationship between percentage of live and dead bacteria as shown in green/red fluorescence ratios was obtained. The regression equation was used to calculate the percentage of live cells in each well of the 96-well plate.

Causes Of Persistent Lyme Disease

The great debate between conventional medicine and physicians who routinely diagnose and treat Lyme disease is whether Lyme disease can become chronic. It has taken the COVID pandemic for the conventional medical community to appreciate that infections can persist and cause long-term symptoms. It can take many years and multiple doctors visits for someone suffering from a myriad of symptoms to get an accurate diagnosis of Lyme disease.

Evidence of why Lyme disease can persist includes immune system dysregulation, autoimmune reaction, oxidative damage from the infection, and persistent bacterial infection. One or more of these underlying causes may be occurring simultaneously.

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What Are The Possible Side Effects Of Anti

Most people who take anti-malarial medications experience no side effects. If side effects do occur, they are usually minor and last only for a short period of time.

Potential side effects of anti-malarial drugs include:

  • Skin rashes and pigment change. Atabrine, specifically, can cause yellow pigmentation of skin. Sometimes Plaquenil can also deposit in the tissues of the body and cause the skin to take on a greenish tone.
  • Retinal damage There is a small chance that retinal damage will occur while taking hydroxychloroquine or chloroquine . For this reason, you should see your ophthalmologist at least once per year so that she/he may check for retinal deposits. Retinal damage caused by hydroxychloroquine is generally reversible, but damage caused by chloroquine may not be. More information on this effect can be found above.
  • Less common side effects:
  • Nervousness, irritability, dizziness
  • Major neurological side effects: confusion, seizures These are quite rare, but if you experience them, alert your doctor immediately.
  • Exacerbation of psoriasis If you have psoriasis, Plaquenil may make your condition worse. Talk to your doctor if you have this condition.

Ruling Out Other Diseases

When Life Hands you Lyme...: Babesia:

Many other infections and medical conditions can produce fever, headache, muscle aches, and fatigue, including a very wide variety of common, generally benign viral illnesses. They can also produce some of the neurologic or cardiac features characteristic of early Lyme disease. The same tick that causes Lyme disease can also transmit other infections.

Co-Infections Transmitted by the Ixodes Tick

Babesiosis, Rocky Mountain Spotted Fever , and human granulocytic anaplasmosis are transmitted by the same tick that carries Lyme disease. People may be co-infected with one or more of these infections, all of which can cause flu-like symptoms. If these symptoms persist and there is no rash, it is less likely that Lyme disease is present.

Other Tick-Borne Infections

A number of other tick-borne diseases may resemble Lyme disease. The most important of these is southern tick-associated rash illness , which is caused by the bite of the Lone star tick, usually in southern and Southeastern parts of the United States. It causes a rash very similar to Lyme disease. The bacterium responsible for STARI remains unknown, but may be B. lonestari.

Allergic Reactions and Insect Bites

Other Diseases

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Background And Diagnosis Of Late Neurologic Lyme Disease

Late neurologic Lyme disease may present as encephalomyelitis, peripheral neuropathy, or encephalopathy . Because most patients with Lyme disease are now diagnosed and treated early in the course of infection, these more indolent forms of neurologic Lyme disease are quite rare. Encephalomyelitis is a unifocal or multifocal inflammatory CNS disease . Collectively, only 1 patient with encephalomyelitis has been diagnosed over the past 5 years by panel members , in spite of both community-based and referral clinical practices. This severe neurologic manifestation of Lyme disease has been diagnosed primarily in Europe.

In untreated patients, encephalomyelitis has been monophasic and slowly progressive, principally involving white matter. Two-tier seropositivity with serum samples and evidence of intrathecal antibody production to B. burgdorferi are expected . Intrathecal antibody production, however, may persist for years following successful treatment, so this parameter does not provide a useful marker of disease activity . CSF examination typically shows a lymphocytic pleocytosis, a moderately elevated protein level, and a normal glucose level . Sensitivity of PCR for detection of B. burgdorferi DNA in the CSF of such patients is extremely low. MRI of the affected part of the neuraxis can demonstrate areas of inflammation, typically with increased signal on T2 and FLAIR imaging and enhancement following contrast administration .

Treatment Of Lyme Disease

Early diagnosis and proper antibiotic treatment of Lyme disease is important and can help prevent late Lyme disease. The following treatment regimens reflect CDCs interpretation of the most current data for four important manifestations of Lyme disease. These regimens are consistent with guidanceexternal icon published by the by the Infectious Disease Society of America, American Academy of Neurology, and American College of Rheumatology.

Some patients report persistent symptoms of pain, fatigue, or difficulty thinking even after treatment for Lyme disease. The state of the science relating to persistent symptoms associated with Lyme disease is limited, emerging, and unsettled.

Additional researchexternal icon is needed to better understand how to treat, manage, and support people with persistent symptoms associated with Lyme disease. In light of these research gaps, recommendations for treatment of persistent symptoms in people previously treated for Lyme disease are not provided here.

If you are interested in information on chronic Lyme diseaseexternal icon, see NIHs website.

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Induction Of Round Body Form Of B Burgdorferi By Amoxicillin

Beta-lactam antibiotics are among the most commonly used drugs for the treatment of Lyme disease, but intriguingly in vitro induce spirochetal B. burgdorferi to form round bodies that are subsequently resistant to many antibiotics . In order to identify FDA-library drugs active against the round body form of B. burgdorferi, we first assessed conditions that yielded the highest induction of round body forms. The 6-day or older culture could not be induced to round body form completely with even 100 g/ml amoxicillin , whereas a 5-day B. burgdorferi culture treated with 50 g/ml amoxicillin for 72 h was the best condition for producing round bodies. Microscopic examination showed that in 5-day old culture after 3-day amoxicillin induction, up to 96% of the B. burgdorferi spirochetes could be induced into round bodies by amoxicillin . To confirm that the induced round body form was still viable, we performed a subculture test in fresh BSK-H medium. Microscopy analysis revealed that amoxicillin-induced round bodies of B. burgdorferi could revert to spirochetes in BSK-H medium after 5 days subculture , indicating that the round bodies induced by amoxicillin treatment remained viable upon subculture.

Evaluation Of Activity Of Natural Product Extracts Against Stationary Phase B Burgdorferi

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Table 2. Activity of natural products against growing and stationary phase B. burgdorferi.

Figure 1. Effect of natural product extracts on the viability of stationary phase B. burgdorferi. A 7-day old B. burgdorferi stationary phase culture was treated with the natural product extracts at 1, 0.5, and 0.2% for 7 days followed by staining with SYBR Green I/PI viability assay and fluorescence microscopy.

We also tested several other herbs and substances that are used by Lyme patients including Stevia rebaudiana, Andrographis paniculata, Grapefruit seed extract, Ashwagandha somnifera, Colloidal silver, Lauricidin, and antimicrobial peptide LL-37, but found they had little or no activity against stationary phase B. burgdorferi cells.

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Food And Drug Administration Package Insert For Doxycycline

There have been numerous trade-name and generic formulations of doxycycline hyclate marketed in the United States. The FDA website offers a webpage for each formulation each page lists the package insert updates, but downloadable package inserts are not available for all listed updates, and in older drugs this can mean that many years of updates are unavailable. This is also true of drugs that are currently on the market. For drugs that have been discontinued, often no downloadable package inserts are available. The oldest available package insert for doxycycline was dated 2005 . Package inserts are listed on the webpage with an action date, but the date provided in the downloaded package insert document may occasionally differ from the action date posted on the webpage . Occasionally a downloaded document contained no date . Because package inserts dated prior to 2005 were not available, it could not always be determined whether a formulation had ever been indicated for malaria prophylaxis or, if it was, when the indication was added. For example, the Doryx® capsule was approved in 1985, but the earliest package insert available for download is 2005 , 11 years after doxycycline was approved for malaria prophylaxis.

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