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Charles Stratton, MD

Introduction - Charles Stratton, M.D.

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I am a new member of the RRDi. I am an infectious diseases specialist as well as a clinical microbiologist. I direct the Clinical Microbiology Laboratory at Vanderbilt University Medical Center. My research interests include Chlamydophila pneumoniae and its role in causing secondary infections in chronic inflammatory diseases.

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Hi,

Welcome to the RRDi M.A.C.! :hi:

This thread actually has an interesting discussion about Cpn.

Here's a part of it:

I ran across a study which seems to create a strong link between rosacea and infection with the gram-negative bacteria, Chlamydia pneumoniae. Since then, I've done quite a bit more research on this link and I've put together some of this research in a pdf that I have forwarded along to be attached to this thread.

Would you please take a look at it, and give me your opinions?

(The pdf file can be found here)

I thought it was a very interesting thread, and I'd be interested to know your thoughts on a connection between Cpn and rosacea.

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Dr. Stratton asked me to post his reply to Steve's question:

From: Dr. Charles Stratton

Subject: Re: help with the forum - Macintosh

Date: March 1, 2007 5:31:32 AM HST

To: director@irosacea.org

In regards to this, I did answer a specific question regarding the use of NAC (see below) that follows this comment/question.

The use of NAC in the therapy of chronic C. pneumoniae infections is explained below. Alone, I do not think it would eradicate this pathogen. We recommend it be used in combination with other antibiotics. Take care.

ELIMINATION OF EXTRACELLULAR ELEMENTARY BODIES.

Elementary bodies are the only infectious forms of Chlamydia. During the unique life cycle of Chlamydia, extracellular elementary bodies are produced, and it is these elementary bodies that infect new host cells. Extracellular elementary bodies in healthy humans are more common than appreciated. For example, during the winter respiratory tract infection season, 33% of healthy blood donors had positive cultures for C. pneumoniae from buffy coat samples of their blood (1). Clearly these infectious elementary bodies in the systemic circulation or in any other extracellular fluids should be eliminated before they are able to infect a new host cell. Fortunately, there are unique physiochemical agents that are specifically able to eliminate these extracellular chlamydial elementary bodies. Unless these extracellular elementary bodies are eliminated in the host, antichlamydial therapy for chronic chlamydial infections must be prolonged until all of these extracellular elementary bodies have infected host cells and thus can be eliminated during their metabolically active stages. This clearly is undesirable as it prolongs the therapy of chronic chlamydial infections as well as increases the chance for resistance.

Infectious chlamydial elementary bodies can be made less infectious by the use of thiol-containing compounds. Specific thiol-containing compounds that may be effective include meso-2,3-dimercaptosuccinic acid (meso-DMSA), an oral chelating agent currently used to treat lead poisoning (2). Meso-DMSA is a weak acid with four ionizable hydrogens. Moreover, meso-DMSA has two highly charged carboxyl groups, which prevent its passage through human cell membranes. Meso-DMSA thus remains in the extracellular fluid where it readily can encounter extracellular chlamydial elementary bodies. The two thiol (sulfhydryl) groups on the succimer molecule are able to dissolve the disulfide bonds in outer membranes of extracellular chlamydial elementary bodies. For Chlamydiae, the dissolution of the outer membrane thereby initiates the transition of the elementary body form to the reticulate body form. Because this occurs in the extracellular milieu where there is no available energy source for the chlamydiae, the nascent reticulate body perishes.

Another thiol-containing compound that inhibits the infectivity of chlamydial elementary bodies is penicillamine (3). Penicillamine, D L-ß, ß-dimethlcysteine, is a sulfhydryl amino acid that was first isolated from the urine of patients with chronic liver disease who were receiving parenteral penicillin. Its use against chlamydial elementary bodies, however, may be somewhat curtailed by a variety of undesirable side effects (4), which do not appear to be problems with meso-DMSA.

In addition, there is an alternative method of providing a controlled release of penicillamine under physiologic conditions that provides greater safety. This simply is the use of oral penicillins as these undergo, in part, acid hydrolysis to penicillamine in the human host. Thus, oral penicillins such as amoxicillin can be used as a low-cost alternative to meso-DMSA and/or penicillamine. The in-vivo production of penicillamine from the degradation of penicillins undoubtedly accounts, in part, for the well-known in-vitro ability of penicillins to prevent the development of infectious chlamydial elementary bodies in cell cultures (5-8).

Finally, N-acetyl cysteine is another thiol-containing compound that has been safely used in humans for many years (9, 10) and also breaks down the disulfide bonds in the elementary body.

1. Cirino F, Webley WC, Croteau NL, Andrzejewski C Jr, Stuart ES. Detection of Chlamydia in the peripheral blood cells of normal donors using in vitro culture, immunofluorescent microscopy and flow cytometry techniques. BMC Infectious Diseases 2006; 6:23

2. Aposhian HV, Aposhian MM. Meso-2,3-dimercaptosuccinic acid: chemical, pharmacological and toxicological properties of an orally effective metal chelating agent. Annual Review of Pharmacology and toxicology 1990; 30: 279 - 306.

3. Perrett D. The metabolosm and pharmacology of D-penicillamine in man. Journal of Rheumatology 1981; 8(Suppl 7): 51 - 55.

4. Scheinberg IH. Toxicity of penicillamine. Postgraduate Medical Journal 1974; 44(Suppl): 11 - 13.

5. Tamura A, Manire GP. Effect of penicillin on the multiplcation of meningopneumonitis organisms (Chlamydia psittici). Journal of Bacteriology 1968; 96: 875 - 880.

6. Kramer MJ, Gordon FB. Ultrastructural analysis of the effects of penicillin and chlortetracycline on the development of a genital tract Chlamydia. Infection and Immunity 1971; 3: 333 - 341.

7. Kuo C-C, Grayston JT. In vitro susceptibility testing of Chlamydia sp. TWAR. Antimicrobial Agents and Chemotherapy 1988; 32: 257 - 258.

8. Shiao LC, Wang S-P, Grayston JT. Sensitivity and resistance of TRIC agents to penicillin, tetracycline, and sulfa drugs. American Journal of Ophthalmology 1967; 63: 1558 - 1568.

9. Dekhuijzen PN. Antioxidant properties of N-acetylcycteine: their relevance in relation to chronic obstructive pulmonary disease. European Respiratory Journal 2004; 23:629-36.

10. Atmaca G. Antioxidant effects of sulfur-containing amino acids. Yonsei Medical Journal 2004; 45:776-88.

However, to “take a look at it, and give me your opinions” is way too broad a question and would require a great deal of effort and would result in pages of written material, which no one would read due to the length. Moreover, it would be speculative on my part as there is not a lot of data available. I would be happy to answer specific questions to the best of my ability, but feel the “give me your opinions” is not a valid question for this kind of forum.

Dr. Stratton

Hi,

Welcome to the RRDi M.A.C.! :hi:

This thread actually has an interesting discussion about Cpn.

Here's a part of it:

(The pdf file can be found here)

I thought it was a very interesting thread, and I'd be interested to know your thoughts on a connection between Cpn and rosacea.

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Dr. Stratton asked me to post his reply to Steve's question:

From: Dr. Charles Stratton

Subject: Re: help with the forum - Macintosh

Date: March 1, 2007 5:31:32 AM HST

To: director@irosacea.org

In regards to this, I did answer a specific question regarding the use of NAC (see below) that follows this comment/question.

The use of NAC in the therapy of chronic C. pneumoniae infections is explained below. Alone, I do not think it would eradicate this pathogen. We recommend it be used in combination with other antibiotics. Take care.

ELIMINATION OF EXTRACELLULAR ELEMENTARY BODIES.

Elementary bodies are the only infectious forms of Chlamydia. During the unique life cycle of Chlamydia, extracellular elementary bodies are produced, and it is these elementary bodies that infect new host cells. Extracellular elementary bodies in healthy humans are more common than appreciated. For example, during the winter respiratory tract infection season, 33% of healthy blood donors had positive cultures for C. pneumoniae from buffy coat samples of their blood (1). Clearly these infectious elementary bodies in the systemic circulation or in any other extracellular fluids should be eliminated before they are able to infect a new host cell. Fortunately, there are unique physiochemical agents that are specifically able to eliminate these extracellular chlamydial elementary bodies. Unless these extracellular elementary bodies are eliminated in the host, antichlamydial therapy for chronic chlamydial infections must be prolonged until all of these extracellular elementary bodies have infected host cells and thus can be eliminated during their metabolically active stages. This clearly is undesirable as it prolongs the therapy of chronic chlamydial infections as well as increases the chance for resistance.

Infectious chlamydial elementary bodies can be made less infectious by the use of thiol-containing compounds. Specific thiol-containing compounds that may be effective include meso-2,3-dimercaptosuccinic acid (meso-DMSA), an oral chelating agent currently used to treat lead poisoning (2). Meso-DMSA is a weak acid with four ionizable hydrogens. Moreover, meso-DMSA has two highly charged carboxyl groups, which prevent its passage through human cell membranes. Meso-DMSA thus remains in the extracellular fluid where it readily can encounter extracellular chlamydial elementary bodies. The two thiol (sulfhydryl) groups on the succimer molecule are able to dissolve the disulfide bonds in outer membranes of extracellular chlamydial elementary bodies. For Chlamydiae, the dissolution of the outer membrane thereby initiates the transition of the elementary body form to the reticulate body form. Because this occurs in the extracellular milieu where there is no available energy source for the chlamydiae, the nascent reticulate body perishes.

Another thiol-containing compound that inhibits the infectivity of chlamydial elementary bodies is penicillamine (3). Penicillamine, D L-ß, ß-dimethlcysteine, is a sulfhydryl amino acid that was first isolated from the urine of patients with chronic liver disease who were receiving parenteral penicillin. Its use against chlamydial elementary bodies, however, may be somewhat curtailed by a variety of undesirable side effects (4), which do not appear to be problems with meso-DMSA.

In addition, there is an alternative method of providing a controlled release of penicillamine under physiologic conditions that provides greater safety. This simply is the use of oral penicillins as these undergo, in part, acid hydrolysis to penicillamine in the human host. Thus, oral penicillins such as amoxicillin can be used as a low-cost alternative to meso-DMSA and/or penicillamine. The in-vivo production of penicillamine from the degradation of penicillins undoubtedly accounts, in part, for the well-known in-vitro ability of penicillins to prevent the development of infectious chlamydial elementary bodies in cell cultures (5-8).

Finally, N-acetyl cysteine is another thiol-containing compound that has been safely used in humans for many years (9, 10) and also breaks down the disulfide bonds in the elementary body.

1. Cirino F, Webley WC, Croteau NL, Andrzejewski C Jr, Stuart ES. Detection of Chlamydia in the peripheral blood cells of normal donors using in vitro culture, immunofluorescent microscopy and flow cytometry techniques. BMC Infectious Diseases 2006; 6:23

2. Aposhian HV, Aposhian MM. Meso-2,3-dimercaptosuccinic acid: chemical, pharmacological and toxicological properties of an orally effective metal chelating agent. Annual Review of Pharmacology and toxicology 1990; 30: 279 - 306.

3. Perrett D. The metabolosm and pharmacology of D-penicillamine in man. Journal of Rheumatology 1981; 8(Suppl 7): 51 - 55.

4. Scheinberg IH. Toxicity of penicillamine. Postgraduate Medical Journal 1974; 44(Suppl): 11 - 13.

5. Tamura A, Manire GP. Effect of penicillin on the multiplcation of meningopneumonitis organisms (Chlamydia psittici). Journal of Bacteriology 1968; 96: 875 - 880.

6. Kramer MJ, Gordon FB. Ultrastructural analysis of the effects of penicillin and chlortetracycline on the development of a genital tract Chlamydia. Infection and Immunity 1971; 3: 333 - 341.

7. Kuo C-C, Grayston JT. In vitro susceptibility testing of Chlamydia sp. TWAR. Antimicrobial Agents and Chemotherapy 1988; 32: 257 - 258.

8. Shiao LC, Wang S-P, Grayston JT. Sensitivity and resistance of TRIC agents to penicillin, tetracycline, and sulfa drugs. American Journal of Ophthalmology 1967; 63: 1558 - 1568.

9. Dekhuijzen PN. Antioxidant properties of N-acetylcycteine: their relevance in relation to chronic obstructive pulmonary disease. European Respiratory Journal 2004; 23:629-36.

10. Atmaca G. Antioxidant effects of sulfur-containing amino acids. Yonsei Medical Journal 2004; 45:776-88.

However, to “take a look at it, and give me your opinions” is way too broad a question and would require a great deal of effort and would result in pages of written material, which no one would read due to the length. Moreover, it would be speculative on my part as there is not a lot of data available. I would be happy to answer specific questions to the best of my ability, but feel the “give me your opinions” is not a valid question for this kind of forum.

Dr. Stratton

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The question I will address is the possible relationship between Chlamydia pneumoniae (Cpn) and rosacea. There are two possible relationships that I can see. I will address each on separately.

First Possible Relationship: Cpn might cause rosacea. We know that Cpn circulates in the blood stream in the form of infectious elementary bodies. Indeed, 25% of healthy blood donors are culture-positive for Cpn in their blood collected by the Red Cross, which can only occur if the infectious elementary body is circulating in the blood stream. Infectious elementary bodies circulating in the blood stream are going to end up in the capillary blood vessels of the skin, among other places. We also know that Cpn is able to infect endothelial cells. Therefore, it is possible that infectious elementary bodies in the skin capillary blood vessels could infect endothelial cells in these blood vessels. In some persons, genetic factors (such as subtle immunodeficiencies) might allow the Cpn infection in the blood vessels to become clinically apparent as a skin disorder that has received the name "rosacea".

Second Possible Relationship: Cpn infection of rosacea might make the disorder worse. We know that Cpn circulates in the blood stream in the form of infected white blood cells. White blood cells may be attracted to rosacea skin lesions due to the inflammatory nature of these lesions. If Cpn-infected white blood cells reached these rosacea lesions, the Cpn might then secondarily infect these lesions. The increased inflammatory reaction due to the secondary Cpn infection would then make the rosacea worse.

If the first hypothesis is correct, then appropriate treatment of Cpn (meaning many months/years of combination antibiotic therapy along with an agent like NAC that destroys elementary bodies) should clear up the rosacea. If the second hypothesis is correct, appropriate treatment should help, but not clear up rosacea.

There are two ways to address these two hypotheses. The first is to do research to determine if Cpn can be found in rosacea lesions. If Cpn is found in these lesions, additional research is needed to see if appropriate therpay will eradicate the Cpn from the lesions. A second way would be to do a double-blind, randomized, cross-over study with appropriate thearpy and see if this therapy clears up the rosacea.

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Hi Dr Stratton & all,

Thanks so much for your comments. I also believe strongly that additional research and/or studies are the best way to address the issue of any potential link between Cpn and rosacea.

BTW, I also believe Steve posted his question prior to your reply in the Rosacea and Chlamydia pneumoniae thread and also prior to my editing out the information about NAC. Sorry for the confusion. I've since moved the information about a potential link between Cpn and Rosacea to the RSRP wiki to avoid having old copies of the pdf floating around:

http://rosacea-research.org/wiki/index.php...ydia_pneumoniae

JimK, founder of the website cpnhelp.org asked me to put together a page as well for the cpnhelp website identifying the support for a potential link between Chlamydia pneumonaie and rosacea. He also made quite a few very helpful suggestions for doing so, and I believe this new page presents a much clearer case for a potential link:

http://www.cpnhelp.org/chlamydia_pneumoniae_an_0

The page was just added to cpnhelp today and we are soliciting input for changes to strengthen the case further. We'd of course appreciate any suggestions from you and other members of the RRDi MAC as well.

Thanks again...

Dan

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