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Superbugs Keep Coming, but New Antibiotics Do Not
By Stan Deresinski, MD, FACP, FIDSA, Clinical Professor of Medicine, Stanford, Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor for Infectious Disease Alert.
The headlines once again warn of a new superbug threatening mankind. Having apparently grown weary of MRSA and Clostridium difficile, the media has apparently moved on to NDM-1. In an example of synecdoche, NDM-1, or New Delhi carbapenemase-1, is taken in these reports to refer to organisms that produce this metallocarbapenemase, which are most prevalent in south Asia but have now appeared in many parts of the world, including the United States, having been brought initially to these regions by colonized or infected travelers. While the first cases all had had contact with medical care in south Asia, some recent cases have had no such contact.
In addition to being resistant to β-lactam antibiotics, including carbapenems, NDM-1-producing organisms carry genes encoding additional resistant mechanisms, including a 16sRNA methylase that renders them resistant to all available aminoglycosides, though to date, they remain susceptible to colistin and tigecycline.
NDM-1 has reached the popular press as a result of a new publication reporting the finding that organisms carrying this resistance mechanism have been identified not only in environmental water, but also in tap water in New Delhi.1 Furthermore, it has been identified for the first time in 11 additional species in which it had not previously been detected, including Shigella boydii and Vibrio cholerae.
The overall problem of antibiotic resistance is extensive in many parts of the world, including areas within the United States and Europe, as well as regions of Africa, Latin America, and Asia. The problem in Asia was extensively highlighted at the 8th International Symposium on Antimicrobial Agents and Resistance held in Seoul, Korea, in early April 2011. A Chinese national surveillance program (CHINET) found that 56% of Escherichia coli and 41% of Klebsiella pneumonia were ESBL-producers, mostly of CTX-M, while approximately 60% of E. coli are resistant to ciprofloxacin. In addition, approximately 50% of Acinetobacter baumanii are resistant to carbapenems, although less than 25% of Pseudomonas aeruginosa are. The proportion of A. baumanii resistant to all antibiotics tested except tigecycline and colistin (which are not available in China) increased from 2.8% in 2007 to 17% in 2009. In India, 90% of A. baumanii are resistant to carbapenems. In addition, 23% of K. pneumoniaeisolated from patients with intra-abdominal infections in the Asia/Pacific region in 2009 were ESBL+ and, in the SMART study, 45%-50% of E. coli from intra-abdominal infections were resistant to levofloxacin and ciprofloxacin.
These data provide a vision into what may be facing us all a global post-antibiotic era. As a consequence of a perceived lack of sufficient financial incentive, large pharmaceutical companies currently show little or no interest in developing novel antibiotics active against these multidrug resistant (MDR) Gram-negative rod (GNR) pathogens. Antibiotics, of course, are administered for relatively short periods of time, in contrast to antihypertensives, for example, and, relative to cancer chemotherapeutic agents, are generally low cost. Furthermore, if a dramatic breakthrough in the development of a novel antibiotic for treatment of MDR GNR infections were to occur, as responsible stewards, we would discourage its use in order to "save it." Factors such as this appear to make solution of the problem of lack of new advances in antibiotic therapy almost impossible.
We can, however, extend the usefulness of antibiotics by responsible stewardship. The continued introduction of rapid point of care diagnostic testing, as well as susceptibility testing, will help in this endeavor, as will the use of biomarkers to assist in decisions regarding the timely discontinuation of antibiotic therapy.
However, antimicrobial stewardship programs in the United States are largely centered around acute care hospitals, while many more antibiotic doses are administered in chronic care facilities and the community at large. Furthermore, antibiotic resistance, as demonstrated by the data from Asia described above, is a global problem. Antibiotic resistance is a huge problem in the lesser developed world, where circumstances generally do not allow for sophisticated stewardship programs and where antibiotics are generally readily available to patients in the absence of a prescription.
Infectious Disease Society of America (IDSA) has stated that "Current data document the impending disaster due to the confluence of decreasing investment in antibacterial drug research and development concomitant with the documented rapid increase in the level of resistance to currently licensed drugs."2 The problem is huge, is extremely complicated, and requires urgent action. Think of the potential consequences to cancer chemotherapy and organ transplantation in a world in which infections due to organisms for which there is no effective therapy become increasingly common! In their "10 by '20" effort, the IDSA has called for the development to of 10 new antibiotics by 2020, calling for a global commitment. This commitment would require active participation by governments, the pharmaceutical and diagnostics industry, health care providers, policy and legal communities, universities, philanthropic organizations, and patient advocacy groups.2
The goal of the IDSA may prove to be "a bridge too far," but we will face a very different world of medicine from that which most of us currently occupy if a major effort is not made in antibiotic development. And we will all have to become brave in that new world.