The Increasing Threat of Multidrug-Resistant Gram-Negative Infections

Luke F. Chen, MBBS, MPH, CIC, FRACP; Matthew E. Falagas, MD, MSc, Dsc

Disclosures

November 23, 2010

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Luke F. Chen, MBBS, MPH, CIC, FRACP: Hello. My name is Luke Chen. I'm from the Division of Infectious Diseases and International Health at Duke University [Durham, North Carolina]. Today we are talking about the evolving epidemiology and increasing threat of gram-negative infections, particularly multidrug-resistant gram-negative infections. With me is Dr. Matthew Falagas, Director of the Alfa Institute of Biomedical Sciences in Athens, Greece, and Adjunct Associate Professor of Medicine at Tufts University School of Medicine in Boston, Massachusetts. Thank you for joining us, Dr. Falagas.

Matthew E. Falagas, MD, MSc, DSc: Thank you for the invitation, Dr. Chen.

Dr. Chen: We have been hearing and talking a lot about multidrug-resistant gram-negative pathogens. Is there any way that you can help us understand the difference between the terminologies, such as "multidrug-resistant gram-negative" and "pan-resistant gram-negative"?

Dr. Falagas: There is tremendous diversity in the definitions of gram-negative bacilli with respect to their resistance patterns. People frequently confuse the terms "multidrug-resistant" (MDR), "extensively drug-resistant" (XDR), and "pan-drug resistant" (PDR) gram-negative bacilli infections. An expert committee that was initiated by the European Centre for Disease Prevention and Control (ECDC), with experts from the US Centers for Disease Control and Prevention (CDC) and other professional and international organizations, held several meetings to resolve this issue. It is important for clinicians and researchers to understand the terminology and the definitions. In some countries, for example, pathogens are called "pan-drug resistant," which means resistant to all available antimicrobial agents, despite the fact that there are therapeutic options.

Dr. Chen: These differences are obviously important to understand. Could clinicians look at their laboratory reports to understand them?

Dr. Falagas: Absolutely. The laboratory report will provide the clinician with information on the antimicrobial susceptibility pattern. MDR is defined as a pathogen that is resistant to at least 3 antimicrobial [classes of] agents, to which it [could have been] susceptible. When a pathogen is XDR, there are 1 or 2 antimicrobial options, and PDR or pan-drug resistant, is as the term implies, resistance to all commercially available antimicrobial agents.

Dr. Chen: We are hearing about these different categories, but can you tell us whether any common nosocomial infections or community-acquired infections are caused by these multidrug-resistant gram-negative [pathogens]?

Dr. Falagas: Pseudomonas aeruginosa has, for years, been a common cause of nosocomial infection associated with considerable morbidity and mortality. However, we have seen during the last year in several settings the development of infections due to Acinetobacter. Acinetobacter was once considered just a contaminant, but now we know that there is a considerable mortality attributable to Acinetobacter itself. We have seen infections due to this pathogen in several nosocomial settings in many parts of the world, especially in Asian countries, in South European countries, and in South American countries. The problem is now coming to North America and, unfortunately, to Northern Europe.

Dr. Chen: You have highlighted how the epidemiology is really changing in different parts of the world, and relevant to the United States, we are seeing more and more of these pathogens.

Dr. Falagas: We are also seeing an increasing incidence of Klebsiella nosocomial infections in many parts of the world.

Dr. Chen: Multidrug resistance has huge implications in terms of treatment. Can you tell us what treatment options there are, if any?

Dr. Falagas: For P aeruginosa, we used to consider several antimicrobial classes; among them are the antipseudomonal penicillins and the antipseudomonal cephalosporins. One could consider monobactam, or the carbapenems, special quinolones with antipseudomonal action, aminoglycosides, and now polymyxin. For Acinetobacter [besides those mentioned above], considerations are sulbactam as well as tetracyclines and tigecycline (a glycylcycline molecule).

Dr. Chen: There are some treatment options left, but we are seeing increasingly resistant pathogens and sometimes the treatment options are severely limited. What are some of the treatments of last resort if we see a multidrug-resistant or extensively drug-resistant gram-negative pathogen?

Dr. Falagas: Overuse of antimicrobial agents and problems with infection control practices have led to the development of multidrug-resistant gram-negative bacterial infections. We used to use carbapenems as the main option in several countries for those severe infections; however, now there are several mechanisms of resistance, including carbapenemase production among Acinetobacter, Pseudomonas, and Klebsiella isolates. Subsequently, carbapenems are sometimes not active against those serious infections. That is why clinicians around the world have reconsidered the use of older antimicrobial agents, including polymyxins. In Greece, in particular, we had an epidemic of nosocomial infections due to Acinetobacter, Pseudomonas, and Klebsiella that were resistant to carbapenems, and we had to use polymyxins, specifically colistin (polymyxin E). In addition to polymyxins, we have used fosfomycin in intravenous form to treat Klebsiella, particularly infections that are resistant to carbapenems and all other classes of antimicrobial agents.

Dr. Chen: As you were saying, carbapenems were the go-to drugs, the gold standard for some of these drug-resistant pathogens, but [now] we are using them less and less because more of our pathogens are becoming resistant to them. With Klebsiella pneumoniae, for example, K pneumoniae carbapenemases are eliminating the use of carbapenems, so tigecycline and colistin have been increasingly used. You mentioned fosfomycin and colistin; those 2 drugs tend to have high rates of nephrotoxicity. Don't they?

Dr. Falagas: Actually, colistin was considered very nephrotoxic and even neurotoxic years ago. The [older] literature supported the probability of developing nephrotoxicity with intravenous polymyxin at 30% or so.[1] Recent studies, including our studies in Athens, Greece, but also studies that were performed in South America, in Asian countries, and in other South European countries, showed that the nephrotoxicity related to colistin intravenous use is about 10%-15% and in most cases is transient.[1,2,3] In other words, it goes away when you discontinue the medication. In regard to fosfomycin, the true issue is the emergence of antimicrobial resistance when you use fosfomycin in monotherapy. We have used fosfomycin in combination treatment with other antimicrobial agents in our attempt to make this really effective for our patients.

Dr. Chen: It sounds like you do have some reassuring news about the low frequency of nephrotoxicity with some of those agents. Thank you for summarizing the epidemiology and the pathogens that we are encountering more and more. We are hearing, though, that on the horizon there is a new metallo-beta-lactamase, the New Delhi metallo-beta-lactamase-1 or NDM-1. Can you tell us a little bit more about it? How should clinicians and researchers interpret this new mechanism of resistance?

Dr. Falagas: This is bad news because the development and dissemination of another mechanism of resistance against carbapenems definitely poses more therapeutic challenges for clinicians in many parts of the world. This NDM-1, which has been found in Enterobacteriaceae, is definitely a problem that leads to more resistance among those pathogens and leaves even fewer therapeutic options for hospital-acquired infections and community-acquired infections in some parts of the world, such as India and elsewhere.

Dr. Chen: It is news for us to be very careful and concerned about. Now, we are here at IDSA [Infectious Diseases Society of America] in Vancouver [British Columbia, Canada]. A lot of interesting data are being presented. I wonder whether you've had the chance to look at some of the abstracts and maybe tell us what interesting things we should look out for [at the meeting]?

Dr. Falagas: I think that there are interesting data presented here that show the increasing role of multidrug-resistant gram-negative bacilli infections not only for patients in the hospital setting, but also in the community.

There are also data supporting the increasing role of Acinetobacter in North American hospitals, and data show that the therapeutic options have become limited. Other data clarify further the effectiveness and safety of older antibiotics, including polymyxins.

Dr. Chen: All in all, multidrug-resistant gram-negative infections are not going away. In fact, they are getting more prevalent, and the nosocomial incidence is going up as well as [in] the community setting. We thank you for your wonderful and expert comments. This is Luke Chen with Dr. Matthew Falagas.

Dr. Falagas: Thank you for the invitation.

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