I appreciate the concern by Neogi and colleagues(1) for the potential development of rifampin resistance among agents of tuberculosis in scenarios where systemic antituberculous medications are suboptimally used. However, this potential concern does not necessarily imply that rifampin resistance is likley to occur among mycobacterial or bacterial organisms, including staphylococci, in patients who receive devices coated with the optimal combination of rifampin and minocycline. In fact, several clinical studies have shown no evidence for development of rifampin resistance among bacterial organisms, including staphylococci, in patients who receive rifampin-minocycline coated vascular catheters (2-4).

The following two factors, among others, help explain why the liklihood of developing rifampin resistance among mycobacterial or bacterial organisms is very low in patients who receive rifampin-minocycline coated orthopedic devices. First, unlike with systemic therapy, these orthopedic devices coated with very small amounts of rifampin and minocycline do not result in systemic levels of either coating agent and, therefore, there is not much concern that rifampin molecules will predispose to evolution of resistance at distant bodily sites, including pulmonary tissues where mycobacteria may exist. Secondly, since rifampin and minocycline possess different mechanisms of antimicrobial activity (rifampin inhibits DNA-dependent RNA polymersae, whereas minocycline inhibits protein synthesis), it is very unlikley that organisms will develop concomitant resistance to rifampin and minocycline.

Since orthopedic devices coated with the combination of rifampin and minocycline retards the presence of bacteria within the layer of biofilm that acts as a reservoir for resistant organisms, this coating approach may, in fact, have a positive impact on infection control.

References:

1. Darouiche RO, Mansouri MD, Zakarevicz D, AlSharif A, Landon GC. In Vivo Efficacy of Antimicrobial-Coated Devices. J Bone Joint Surg Am. 2007;89:792-797.

2. Raad I, Darouiche R, Dupuis J, et al. Central venous catheters coated with minocycline and rifampin for the prevention of catheter- related colonization and bloodstream infections: a randomized, double- blind trial. Ann Intern Med. 1997;127:267-274.

3. Darouiche RO, Raad II, Heard SO, et al. A comparison of two antimicrobial-impregnated central venous catheters. N Engl J Med. 1999;340:1-8.

4. Chatzinikolaou I, Hanna H, Graviss L, et al. Clinical experience with minocycline and rifampin-impregnated central venous catheters in bone marrow transplantation recipients: efficacy and low risk of developing staphylococcal resistance. Infect Control Hosp Epidemiol. 2003;24:961- 965.

To The Editor:

We read with great interest the article “In Vivo Efficacy of Antimicrobial-Coated Devices”(1) and acknowledge the excellent experimental work.

With approximately 9 million people developing active tuberculosis (TB) every year and 1.7 million deaths resulting from TB infection annually, TB is far from under control and is a major public health problem in Asia and Africa(2). The increasing spread of multi-drug resistant TB (MDR-TB) and the recalcitrant nature of persistent infections pose additional challenges to treatment with currently available anti-TB drugs(2). The majority of people in a developing country like India are routinely exposed to mycobacterium tuberculosis (MTB) and the prevalence of MTB infection in all age groups in India is around 40%(3).

The antibiotic levels on the implant used in study are low(1);the coated human implant, if made, would increase rifampin levels proportionally. Our concern is that the suboptimal use of antituberculous medications creates a selective milieu in the host’s tissues where the initially low numbers of drug-resistant mutants are able to replicate, eventually replacing the initially drug-susceptible MTB population(4). Though this study(1) has used a companion drug to prevent development of resistance to staphylococcus aureus, there is no companion drug against MTB, thus increasing the chance of selecting resistant mutants. A study(5) has also shown emergence of rifampin resistance to MRSA in tuberculosis wards and, hence, the question arises why this can't it happen the reverse way round.

Rifampin-minocycline is a useful drug in the management of implant related infection,but a word of caution must be expressed regarding its use especially in developing countries. The possibilities of adding on to the burden of MDR – TB in such a scenario would seriously set back the public health programme of TB control which is a greater public health concern and where rifampin is a very important drug.

The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

References:

1. Darouiche RO, Mansouri MD, Zakarevicz D, AlSharif A, Landon GC. In Vivo Efficacy of Antimicrobial-Coated Devices. J Bone Joint Surg Am. 2007;89:792-797.

2. Medicines for tuberculosis. WHO Drug Information. Vol 20, No. 4, 2006. Available at http://www.who.int/druginformation/vol20num4_2006/DI20-4.pdf. Accessed on 8th Feb 2008.

3. Chakraborty AK. Epidemiology of tuberculosis: Current status in India. Indian J Med Res. 2004;120:248-276.

4. David HL. Probability of distribution of drug-resistant mutants in unselected populations of Mycobacterium tuberculosis. Appl Micro. 1970;20:810–814.

5. Sekiguchi J, Fujino T, Araake M, Toyota E, Kudo K, Saruta K, Yoshikura H, Kuratsuji T, Kirikae T. Emergence of rifampicin resistance in methicillin-resistant Staphylococcus aureus in tuberculosis wards. J Infect Chemother. 2006;12:47-50.