Will “Improbable Resistance” Become of Daily Concern?

In this issue, Pound and Reel, pharmacists at the New Hanover Regional Medical Center and Campbell University College of Pharmacy & Health Sciences, Buies Creek, NC, present a case report, the importance of which, in terms of potential public health risk, should not be ignored. They describe a case of resistance to daptomycin in a patient who was not exposed to the drug previously, which suggests that resistance to this antibiotic may have become endemic. While increasingly louder voices are heard about the coming of an era of nontreatable infections (with gonorrhea being perhaps the first one), the discovery and clinical development of really new antibiotics (ie, directed against so-far unexploited targets and/or acting through radically different mechanism[s] of action) remain quite difficult if not unsuccessful. There has been actually very few new chemical entities entering the clinical arena over the last 20 years, but daptomycin was one of them. Its unique mode of action (among the currently registered antibiotics) starts with specific interactions with phosphatidylglycerol, a negatively charged phospholipid found in far greater abundance in bacterial membranes compared with eukaryotic cells. This leads to membrane distortion and mislocalization of proteins involved in cell division and cell wall synthesis, which culminate in fast and extensive cell death. Because changing membrane lipid structure and composition without loss of viability is a much more difficult process than introducing amino acid changes in protein targets, daptomycin discoverers (at Eli Lilly) and developers (at Cubist) could honestly believe that resistance would be very slow, if not impossible, to develop. Unfortunately, this proved wrong as enterococci were quick to show resistance not only in the laboratory but also in the clinics after administration of daptomycin (see the original case observed by Lewis et al in 2004, ie, only 1 year after approval of daptomycin in the United States). Resistance acquired during treatment is now commonly seen with many other antibiotics. However, in the present case, the patient was not exposed to daptomycin before showing bacteremia with a daptomycin-nonsusceptible Enterococcus faecium (which was also resistant to ampicillin, tetracycline, and vancomycin and intermediate to linezolid). As the patient had multiple previous hospitalizations and severe underlying pathologies (including a persistent fungal infection), it is presumed that it was a nosocomial infection. Unfortunately, no further detail is available, and the strain was not characterized with respect to its origin, the underlying mechanism(s) of resistance, or even the actual value of daptomycin MIC. The observation of Pound and Reel is not isolated. Thus, in early 2012, Kelesidis et al from UCLA at Los Angeles reported 9 cases of emergence of enterococcal daptomycin nonsusceptibility among patients with no prior exposure to daptomycin, which they associated to clonal spread from a possible community reservoir. More recently (December 2012), Judge et al published a retrospective case-case control study that included 60 cases with daptomycin nonsusceptible vancomycin-resistant enterococci for which daptomycin exposure occurred rarely. Together with the now well-accepted methods to prevent spreading of resistance such as antibiotic stewardship and infection control program in the hospital, proactive research for identifying community reservoirs of daptomycin nonsusceptible enterococci and their origin is therefore probably essential. Lastly, the case report of Pound and Reel showed us that the only way to eradicate the infection was to use quinupristin/dalfopristin (known better by its trade name SYNERCID). This is also interesting because SYNERCID is a drug that was discovered and developed by a major pharmaceutical company (Rhone-Poulenc, now integrated into Sanofi) but did not do well in the market because of what was perceived as significant levels of adverse effects. It was therefore abandoned EDITORIAL COMMENT