A comeback for antibiotic cycling?

Christiane Goulart and Miriam Barlow and colleagues have published an important study in this month’s PLOS One entitled “Designing Antibiotic Cycling Strategies by Determining and Understanding Local Adaptive Landscapes.

Because of the growing problem of antibiotic resistance, antibiotic cycling has been proposed as a strategy to preserve antibiotic susceptibility of disease-causing microbes. Unfortunately, these efforts have largely been disappointing. In 2004 Carl Bergstrom argued that antibiotic cycling was likely to be ineffective in the hospital setting, based on a computational approach informed by natural selection. At that time, Bergstrom left open the possibility that a cycling regime could work, but he warned that the theoretical underpinnings of such an approach had not been demonstrated.

Goulart, Barlow and colleagues have satisfied that precondition with their compelling recent study. (more…)

Parallel Evolution Guides Identification of Pathogenic Pathogen Mutations

The new tools for determining nucleotide sequences for whole genomes can sometimes present a problem of data analysis: How can mutations that influence important phenotypes be distinguished from mutations that may be of minimal or no impact on fitness, so-called passenger mutations that arise and persist primarily by chance and can greatly outnumber adaptive genetic variants?  Merely finding nucleotide substitutions or larger genomic differences in comparing independent isolates of a microbial pathogen does not automatically reveal which genetic variants are responsible for the medically-relevant differences in pathogen attributes.

Lieberman et al. (2011) have approached this problem by determining the whole genome sequences for 112 isolates of an opportunistic bacterial pathogen, Burkholderia dolosa, obtained from 14 cystic fibrosis (CF) patients, including the initial patient infected, who were all part of an epidemic of small scale in the Boston area.  A total of 39 individuals were infected in the course of the outbreak, and the patient samples were taken over a period of 16 years.  Bacterial samples were obtained primarily from the airways and from blood.  For these genome sequences, the average read depth was 37x, and the genomes were aligned based on a B. dolosa reference genome. (more…)

Evolutionary Erosion of Anti-Microbial Magic

In the early years of the last century, Paul Ehrlich coined the term “magic bullet” to indicate a therapeutic agent that targeted an infectious agent or tumor with exquisite specificity (Schwartz, 2004).  He was inspired by his work with antibodies to imagine a future age of impressively discriminating and extremely effective drugs.  Perhaps the class of therapeutic agents with the longest and most impressive record of illustrating this concept has been antibiotics.  However, as a recent example (Kumarasamy et al., 2010) from the vast and continuously growing literature on antibiotic resistance illustrates, the ever-expanding list of evolving mechanisms through which bacteria counteract the actions of these therapeutic agents has put their continuing effectiveness in jeopardy. (more…)

A Medical Application of Phylogenetic Analysis

A couple of months ago, my institution hosted a one-day symposium on phylogenetics. One of the speakers was John Avise, a member of the National Academy of Sciences and the individual generally credited with originating the field of phylogeography. His talk and those of two other speakers were focused on subjects most typically regarded as part of biology, not medicine. However, the fourth lecturer on the program applied some of the same methods and patterns of thought to the interactions between HIV and its human hosts, thereby illustrating the potential relevance of phylogenetic analysis to matters of clinical significance. A recent paper in Science (Harris et al., 2010) provides another such example.

Methicillin-resistant Staphylococcus aureus (MRSA) is a pathogen of major significance in many countries. According to Maryn McKenna (2010), author of a recent book on this pathogen, there are almost 19,000 deaths and almost 370,000 hospitalizations annually attributable to MRSA infections in the United States. The yearly total costs for these infections are estimated to be in the billions of dollars. (more…)