Quantifying human health risks from virginiamycin used in chickens

The streptogramin antimicrobial combination Quinupristin-Dalfopristin (QD) has been used in the United States since late 1999 to treat patients with vancomycin-resistant Enterococcus faecium (VREF) infections. Another streptogramin, virginiamycin (VM), is used as a growth promoter and therapeutic agent in farm animals in the United States and other countries. Many chickens test positive for QD-resistant E. faecium, raising concern that VM use in chickens might compromise QD effectiveness against VREF infections by promoting development of QD-resistant strains that can be transferred to human patients. Despite the potential importance of this threat to human health, quantifying the risk via traditional farm-to-fork modeling has proved extremely difficult. Enough key data (mainly on microbial loads at each stage) are lacking so that such modeling amounts to little more than choosing a set of assumptions to determine the answer. Yet, regulators cannot keep waiting for more data. Patients prescribed OD are typically severely ill, immunocompromised people for whom other treatment options have not readily been available. Thus, there is a pressing need for sound risk assessment methods to inform risk management decisions for VM/QD using currently available data. This article takes a new approach to the QD-VM risk modeling challenge. Recognizing that the usual farm-to-fork ("forward chaining") approach commonly used in antimicrobial risk assessment for food animals is unlikely to produce reliable results soon enough to be useful, we instead draw on ideas from traditional fault tree analysis ("backward chaining") to reverse the farm-to-fork process and start with readily available human data on VREF case loads and QD resistance rates. Combining these data with recent genogroup frequency data for humans, chickens, and other sources (Willems et al., 2000, 2001) allows us to quantify potential human health risks from VM in chickens in both the United States and Australia, two countries where regulatory action for VM is being considered. We present a risk simulation model, thoroughly grounded in data, that incorporates recent nosocomial transmission and genetic typing data. The model is used to estimate human QD treatment failures over the next five years with and without continued VM use in chickens. The quantitative estimates and probability distributions were implemented in a Monte Carlo simulation model for a five-year horizon beginning in the first quarter of 2002. In Australia, a Q1-2002 ban of virginiamycin would likely reduce average attributable treatment failures by 0.35 x 10(-3) cases, expected mortalities by 5.8 x 10(-5) deaths, and life years lost by 1.3 x 10(-3) for the entire population over five years. In the United States, where the number of cases of VRE is much higher, a 1Q-2002 ban on VM is predicted to reduce average attributable treatment failures by 1.8 cases in the entire population over five years; expected mortalities by 0.29 cases; and life years lost by 6.3 over a five-year period. The model shows that the theoretical statistical human health benefits of a VM ban range from zero to less than one statistical life saved in both Australia and the United States over the next five years and are rapidly decreasing. Sensitivity analyses indicate that this conclusion is robust to key data gaps and uncertainties, e.g., about the extent of resistance transfer from chickens to people.