Quantifying Human Health Risks from Virginiamycin Use in Food Animals in China.

Virginiamycin (VM), a streptogramin antibiotic, has been used to promote healthy growth and treat illnesses in farm animals in the United States and other countries. The combination streptogramin Quinupristin-Dalfopristin (QD) was approved in the United States in 1999 for treating patients with vancomycin-resistant Enterococcus faecium (VREF) infections. Many chickens and swine test positive for QD-resistant E. faecium, raising concerns that using VM in food animals might select for streptogramin-resistant strains of E. faecium that could compromise QD effectiveness in treating human VREF infections. Such concerns have prompted bans and phase-outs of VM as growth promoters in the United States and Europe. This study quantitatively estimates potential human health risks from QD-resistant VREF infections due to VM use in food animals in China. Plausible conservative (risk-maximizing) quantitative risk estimates are derived for future uses, assuming 100% resistance to linezolid and daptomycin and 100% prescription rate of QD to high-level (VanA) VREF-infected patients. Up to one shortened life every few decades to every few thousand years might occur in China from VM use in animals, although the most likely risk is zero (e.g., if resistance is not transferred from bacteria in food animals to bacteria infecting human patients). Sensitivity and probabilistic uncertainty analyses suggest that this conclusion is robust to several data gaps and uncertainties. Potential future human health risks from VM use in animals in China appear to be small or zero, even if QD is eventually approved for use in human patients.

Synercid Aventis.

Rhône-Poulenc Rorer (RPR) developed Synercid (RP-59500), an injectable synergistic combination of quinupristin and dalfopristin as a treatment for a variety of infections caused by Gram-positive anaerobic bacteria. The treatment was approved in the UK in July 1999, for use in patients with nosocomial pneumonia, skin and soft tissue infections and clinically significant infections due to Enterococcus faecium when there is no other active antibacterial agent [337556,335257]. It was launched in the UK and the US in September 1999 [342899]. In December 1999, Synercid successfully completed the Mutual Recognition Procedure in the EU under Aventis Pharma for use in patients with these infections [351525]. In September 2000, Merrill Lynch predicted first-year sales in 1999 of Euro 15 million, rising to Euro 171 million in 2004 [384874]. In January 1999, BT Alex Brown predicted sales of US $88 million in 1999 rising to US $450 million in 2002 [318220]. In April 1999, ABN Amro predicted annual sales of DM 30 million in 1999, rising to DM 150 million in 2002 [328676].

Development and validation of a potentiometric biosensor assay for tylosin with demonstrated applicability for the detection of two other antimicrobial growth-promoter compounds in feedstuffs.

A potentiometric biosensor assay based on a commercially available polyclonal antibody was developed to detect tylosin residues in animal feed. The method can be used as a rapid (less than 45 min) laboratory-based procedure or as a portable field-test for the simultaneous measurement of up to 12 different samples. For both procedures the qualitative detection capability (CCß) for tylosin was determined as 0.2 mg kg(-1) in a range of animal feeds with a measurement repeatability at concentrations between 0.2 and 4 mg kg(-1) of ≤13% coefficient of variation (%CV). The field-test format was capable of detecting tylosin residues at operating (external air) temperatures ranging between +4 and 37°C, although some reduction in signal was observed at the lower temperatures. The laboratory-based tylosin assay was evaluated using 16 medicated and 22 non-medicated feeds and was found to give comparable data with a confirmatory method based upon liquid chromatography-tandem mass spectrometry (LC-MS/MS). The potential to develop a multi-probe format assay for the simultaneous detection of tylosin, spiramycin and virginiamycin was also demonstrated. Cross-validation in a second laboratory showed the assay to be transferable, reliable and robust.

Effect of quinupristin/dalfopristin on 3T3 and Eahy926 cells in vitro in comparison to other antimicrobial agents with the potential to induce infusion phlebitis.

Infusion phlebitis is a common clinical problem that is observed with some antimicrobial agents, when being administered intravenously. In this study, cultured murine fibroblasts and immortalised human endothelial cells were exposed to three antibiotics at clinically relevant concentrations to assess their toxic potential in two established cytotoxicity assays. BALB/c 3T3 fibroblasts and Eahy926 endothelial cells were exposed to quinupristin/dalfopristin (QD), erythromycin and levofloxacin at increasing concentrations. For assessment of cytotoxicity the cells were incubated with neutral red (NR) or stained with crystal violet (CV). Measurements were done by photometry. At the concentration range tested QD and erythromycin showed a concentration-dependent cytotoxic effect in both cell cultures. In 3T3 cells the half-maximal effect concentration (EC50) was 20 mg/l for QD and 340 mg/l for erythromycin in the NR uptake test and 12 and 200 mg/l, respectively, in the CV assay. In Eahy926 cells the EC50 was 50 mg/l for QD and 880 mg/l for erythromycin in the NR uptake test and 40 and 750 mg/l, respectively, in the CV assay. No EC50 could be established in both cell types for levofloxacin. Eahy926 cells were less sensitive to cytotoxic stimuli than 3T3 fibroblasts. Cytotoxic effects in both cell cultures occurred in the following order: QD > erythromycin >> levofloxacin. This ranking correlates well with the frequency of local adverse effects observed with the infusion of these antibiotics in patients. Thus, these in vitro assays may serve as an estimate for the prediction of local tolerability of antibiotics when administered parenterally.

Effect of virginiamycin on feed intake, daily gains, ruminal volatile fatty acids and blood parameters in veal calves.

The effect of a peptolide antibiotic virginiamycin on the growth, rumen and blood parameters was followed in 8 milk-fed calves, 4 weeks old initially. Calves were individually housed in metabolic cages. The experiment was ended at the age of 16 weeks. Virginiamycin was supplied at 80 mg per head per day. Calves receiving virginiamycin gained 5.1% more than control calves. Feed intake per 1 kg of body weight gain was higher in control calves. Virginiamycin significantly increased molar percentage of propionate and decreased molar acetate: propionate ratio in rumen fluid. Serum iron, hematocrit and hemoglobin were significantly increased in the treated group in the last period of the trial. Virginiamycin lowered serum protein and urea and tended to decrease activity of aminotransferases.