Subantimicrobial Doses of Tetracycline

University of Southern California, Los Angeles, CA

To the Editor:

The April issue of Arteriosclerosis, Thrombosis, and Vascular Biology contains an article by Brown et al regarding the use of "subantimicrobial doses of doxycycline" as an inhibitor of matrix metalloproteinases, using 40 mg of doxycycline (20 mg twice a day).1 This group has claimed in the past and intimated in this article that such doses are too low to affect bacteria and hence will not disturb the indigenous microbial flora or induce or select microbial resistance. Such claims are simply inaccurate.

Such 20-mg, twice daily doses of doxycycline daily produce blood levels of 0.79 micrograms/mL (±0.285 micrograms/mL), as clearly stated by the proponents of this dosing for the "management" of periodontal disease.2,3 Doxycycline is effective in the management of infectious diseases at serum dose levels 0.04 micrograms per ml4 and has been life-saving (infections caused by vancomycin-resistant enterococci and staphylococci) at blood levels of 0.06 to 0.25 micrograms/mL.3

Tetracyclines are paramount in the antimicrobial armamentarium as promoters of microbial resistance gene transfer and as inducers of resistance gene expression.3 Tetracycline resistance genes are also very commonly associated with the resistance genes for other antibiotics in integrons.3 To select for one resistance gene is likely to select for all. Only nanomolar amounts of tetracycline are required to derepress the efflux system that forms their major mechanism for resistance.5 Tetracycline stimulates colonic microbial resistance gene transfer in Escherichia coli which may only occur when the drug is present.3 Microbes use nanograms of antibiotics to control their ecology, and to intimate that micrograms of the same drug are "subtherapeutic" for all microorganisms is nonsensical.

It is time to acknowledge that the antimicrobial therapy of cardiovascular disease is highly problematic because it may result in the loss of the macrolides and tetracyclines against major human killers such as Streptococcus pneumoniae. Tetracyclines are now the drugs of choice against community-acquired pneumonia, Helicobacter pylori, and rickettsial diseases, and as prophylaxis for malaria. A clear risk–benefit determination is in order.

References

Brown DL, Desai KK, Vakili BA, Nouneh C, Lee HM, Golub LM. Clinical and biochemical results of the metalloproteinase inhibition with subantimicrobial doses of doxycycline to prevent coronary syndromes (MIDAS) pilot trial. Arterioscler Thromb Vasc Biol. 2004; 24: 733–738.

Thomas J, Walker C, Bradshaw M. Long-term use of subantimicrobial dose of doxycycline does not lead to changes in antimicrobial susceptibility. J Periodontol. 2000; 71: 1472–1483.

Pallasch TJ. Global antibiotic resistance and its impact on the dental community. J Calif Dent Assn. 2000; 28: 215–233.

Mandell GL, Bennett JE, Dolin R, Eds. Mandell, Douglas, and Bennet’s Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, Pa: Churchill Livingstone; 2000.

Chopra I, Roberts M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev. 2001; 65: 232–260.

David L. Brown

Department of Medicine, Beth Israel Medical Center, New York, NY, and Albert Einstein College of Medicine, Bronx, NY

Lorne M. Golub

Department of Oral Biology and Pathology, School of Dental Medicine, State University of New York, Stony Brook, NY

John G. Thomas

Departments of Pathology and Periodontics, West Virginia University Schools of Medicine and Dentistry, Morgantown, WV

In Response:

We appreciate the interest of Dr Pallasch in our recent publication. However we are surprised that a manuscript that makes no claim regarding the impact of low doses of doxycycline on indigenous microbial flora or microbial resistance has stimulated his current letter.

Although the in vitro studies on limited numbers of isolates cited by Dr Pallasch have shown a number of multiple resistance mechanisms, this finding has never been found to have clinical relevance in human populations. In fact, review of national data (400 000 isolates) by electronic surveillance has shown exactly the opposite.1 In tracking the sensitivity profiles to 23 different antibiotics in clinical specimens, patterns of tetracycline resistance have remained essentially unchanged after adjustment for CDC region, type of institution, consumption of tetracycline-containing food products, and the introduction of low-dose doxycycline for the treatment of periodontal disease (Periostat) in 1998. Furthermore, there was no evidence that tetracycline selected for cross-resistance. Nor did the development of tetracycline resistance promote the progression from cutaneous to blood-borne infection, indicating tetracycline resistance is neither a virulence factor2,3 nor a survival factor.4

Dr Pallasch seems unaware of the emerging science of Host Modulation Therapy (HMT) for chronic diseases in which biofilms are implicated in their pathogenesis.5 The recognition of the importance of biofilms in the pathogenesis of cystic fibrosis, otitis media, endocarditis, periodontitis, and indwelling catheter infections has led to a new era of research and treatment in which a combination of anti-infectives and immune modulators are complementary in disease management.6,7 Subinhibitory concentrations of tetracycline and macrolide antibiotics have both been used successfully as biologic modifiers without any evidence of the development of clinically significant microbial resistance.8

Finally, we agree with Dr Pallasch that construction of a risk-benefit ratio is always important when evaluating a potential new therapy. However, in this case it must be borne in mind that tetracyclines are rarely if ever used in the treatment of patients with life-threatening infections, and cardiovascular disease is the leading cause of death in industrialized nations. Thus, the risk-benefit ratio strongly favors further investigation of low-dose doxycycline to treat cardiovascular disease.

References

Thomas J, Povroznik L, Tupta-Vesilicky L, Frere K, Mayfield D. Tracking Resistance Profiles of Oral Pathogens Using the Surveillance Network (TSN) Database USA 2000. Annual Meeting of the American Association of Periodontology, Honolulu, HI, September 15–21, 2000. www.mrlworld.com

Thomas K, Masters R, Krafczyk T, Hobbs G. Resistant Phenotype and Perio-pathogen Signature. 2001 Annual Meeting, American Academy of Periodontology, Philadelphia, PA.

Thomas J, Yakubu D, Martin C, Crout R, Bretz W, Weyant R. Defining Appalachian Communities by Antibiotic Resistance Profiles. AADR, San Antonio, TX 2003.

Marsh PD. Are dental diseases examples of ecological catastrophes? Microbiology. 2003; 149: 279–284.

Costerton W, Veeh R, Shirtliff M, Pasmore M, Post C, Ehrlich G. The application of biofilm sciences to the study and control of chronic bacterial infections. J Clin Invest. 2003; 112: 1466–1477.

Rubin BK, Henke MO. Immunomodulatory activity and effectiveness of macrolides in chronic airway disease. Chest. 2004; 125: 70S–78S.

Jaffe A, Bush A. Anti-inflammatory effects of macrolides in lung disease. Pediatr Pulmonol. 2001; 31: 464–473.

Wozniak D, Keyser R. Effects of subinhibitory concentrations of macrolide antibiotics on Pseudomonas aeruginosa. Chest. 2004; 125: 62S–69S