John Bartlett's Game Changers in Infectious Disease: 2011

John G. Bartlett, MD


October 26, 2011

In This Article

Game Changers in the Field of Infectious Disease

The papers selected for this review contain important observations that are "game changers," defined as scientific observations that are likely to have substantial impact on the field of infectious diseases. In many instances, the paper selected is one of several that contribute to the issue but, in the author's opinion, is particularly important for its contribution to the totality of the issue.

New Mechanisms of Antibiotic Resistance

Kumarasamy and colleagues[1] reported their experience with gram-negative bacilli that are resistant to all carbapenems as a result of the newly recognized New Delhi Metallo-betalactamase 1 (NDM-1). These investigators described 37 strains identified in patients from England and 70 strains in patients from India and Pakistan. The isolates (Enterobacteriaceae with the bla NDM-1 gene) showed sensitivity limited to tigecycline (67% of strains) and colistin (100% of strains). The review also included an analysis of the air travel of these organisms as these patients flew from India or Pakistan to the United Kingdom.

The gene that confers this resistance pattern is plasmid mediated, harbored in the gut, and potentially transferrable to multiple coliforms, primarily Escherichia coli and Klebsiella. Factors contributing to this unusually challenging resistance pattern were obviously diverse, but the use of nonprescription antibiotics in India and Pakistan may have been important. In the study authors' view, this resistance pattern signaled the diminished and possible loss of value of beta-lactams, fluoroquinolones, and aminoglycosides.

Why Is This a Game Changer?

Resistance is the "elephant in the room" in the field of infectious diseases. Everyone in hospital practice is well aware of the issue, but now the future appears to be particularly ominous. We have always had the problem of resistance, as a result of antibiotic use and Mendelian laws, but in the past we have been bailed out by the production of new antibiotics. Pharmaceutical companies are no longer interested in antibiotic development and production for a variety of reasons, mostly economic.[2] As one pharmaceutical executive told me: "You take an antibiotic for 1-2 weeks but you take a statin for a lifetime. What would you make?"

The issue is far more complex, but to illustrate its magnitude, from 1983-1987, 16 new antibiotics were approved by the US Food and Drug Administration (FDA), but from 2008-2011, just 2 new systematic antibiotics were approved and neither addressed the issue of resistance. In fact, in 1990, 19 companies developed antibiotics, and now that number has declined to 4.[3]

The problem of antibiotic resistance is global. Kumarasamy and colleagues traced the NDM-1 to India, with the inference that abuse of over-the-counter antibiotics in that country was harmful to the rest of the world. As anticipated, with international travel, this plasmid with NDM-1 is now found in the United States.

The antibiotic resistance issue has not gone unnoticed and is currently receiving substantial attention from all corners. President Obama has asked the Trans-Atlantic Antibiotic Resistance Task Force to address the problem, indicating recognition of its international reach. Two bills introduced in Congress (the GAIN bill in the House and the STARR Act in the Senate) include proposals for financial incentives for the pharmaceutical industry to produce new antibiotics. Nevertheless, no antibiotics currently in phase 3 development are likely to resolve the problem of gram-negative bacilli resistance, so it will continue to evolve with no anticipated deterrence until 2016 at the earliest, considering the snail speed of the regulatory process.

What Does This Mean to the Practitioner?

Prepare to use a lot of colistin and anticipate more regulation. Colistin may be the only solution for many of these resistant bacteria, but the drug has been used with trepidation for nearly 50 years. Relatively little is known about colistin except that it is nephrotoxic[4] and colistin-resistant Klebsiella has already been reported.[5] Practitioners should prepare for more regulation because infection control and antibiotic stewardship are the primary weapons still available to slow the inevitable evolution of resistance. The emphasis will be on antibiotic restraint (for conditions such as otitis, sinusitis, bronchitis, etc.), pathogen-directed therapy, and short-course treatment.