Commentary — February 2017
Tex Med. 2017;113(2):17-18.
By Oladapo A. Abodunde, MD; Paul Southern, MD; and James P. Luby, MD
Defining the optimal approach to microbial drug resistance may be the Holy Grail. The global impact of drug resistance on morbidity, mortality, and related health care costs have all been well elucidated. Within the framework of the extensively studied mechanisms of target modification, enzymatic neutralization, entry channel modulation, and efflux mechanisms, human pathogenic bacteria, viruses, and fungi continue to evolve novel resistance mutations to available antimicrobials. Important examples are the recently described MCR-1 gene in Escherichia coli and NDM-1 gene in Enterobacteriaceae. Multiple drug-resistant (MDR) and extensively drug-resistant pathogens are now among the most significant threats to human health, according to a study published in Clinical Infectious Diseases in 2010.
Accepted approaches to the epidemic of multidrug-resistant pathogens include direct (pharmacologic) and indirect (stewardship, etc.) methods. For instance, a study published in Clinical Infectious Diseases in 2011 suggested empirical combination therapy, pharmacokinetic/pharmacodynamic optimization, limiting duration of antimicrobial exposure, and active surveillance as core strategies for combating MDR infections in critically ill patients.
Use of alternative or second-line antibiotics, combination therapy, and development of new pharmacotherapeutic agents are the most important pharmacologic options available. With the need for alternative agents, several studies point to a resurgence in the use of older and often more toxic antimicrobials, including but not limited to the aminoglycosides and polymyxins. Synergistic antimicrobial (antibiotic-antibiotic or antibiotic-adjuvant) prescribing, on the other hand, is predicated on targeting multiple steps in a single pathway, inhibiting multiple pathways, or using multiple agents to neutralize a single target, according to a 2013 study published in Trends in Biotechnology. Several novel alternatives to conventional microbial inhibition are currently experimental and may not be ready for clinical use for several years, perhaps decades, as noted in a 2013 study published by F1000Prime Reports.
Currently used methods are generally effective but have limitations. Empirical therapy, especially in severe infections, is more challenging, leading many practitioners to resort to broad-spectrum antibiotics initially, promoting further drug resistance.
Newer diagnostics, including molecular techniques, matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF), and others are promising for rapid identification and resistance testing and will likely mitigate the widespread polypharmacy for empirical therapy besides aiding focused therapy, optimizing drug dosing and duration of treatment. Instituting second-line agents after failed treatments is often associated with prolonged antibiotic exposure, thereby increasing risk of toxicity and development of opportunistic infections, especially Clostridium difficile, according to a study published in Clinical Infectious Diseases in 2011.
The pace of new drug development is — at best — slow, and most of the newer agents belong to the existing classes of antimicrobials. Current studies indicate modest benefits of the recently approved drugs over older ones, and increasing resistance to these agents is likely over the next few years. To accelerate research, development, and approval of new pharmacological agents, several policies aimed at addressing this issue have been implemented, including the Orphan Drug Act of 1983 and several Food and Drug Administration initiatives. Specific to antibiotic development is the Generating Antibiotic Incentives Now, or GAIN, Act of 2012.
Most infectious disease practitioners have little or no influence on the process of developing new drugs or diagnostics, but the one thing we all can and should excel at is antimicrobial stewardship. We may be most effective in dealing with the entire gamut of drug resistance by developing and implementing stewardship policies at all levels.
Creating a successful infection prevention and antimicrobial stewardship policy requires expertise at many levels, including infectious disease physicians, pharmacists, microbiologists, epidemiologists, infection preventionists, and data managers. Considering our current stewardship practices have not adequately addressed the core challenge of drug resistance, there is opportunity for innovation in this field.
Oladapo A. Abodunde, MD, is a 2016 graduate of the Infectious Diseases Fellowship Program at The University of Texas Southwestern Medical School.
Paul Southern, MD, is an infectious diseases clinician and professor at UT-Southwestern. He is program director of the Infectious Diseases Fellowship Program.
James P. Luby, MD, is an infectious diseases clinician and professor at UT-Southwestern. His research interests include clinical virology and the epidemiology of infectious diseases.
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