Activity of a New Oral Streptogramin, XRP2868, against Gram-Positive Cocci Harboring Various Mechanisms of Resistance to Streptogramins

Abstract

The antibacterial activity of XRP2868, a new oral streptogramin composed of a combination of RPR132552 (streptogramin A) and RPR202868 (streptogramin B), was evaluated against a collection of clinical grampositive isolates with characterized phenotypes and genotypes of streptogramin resistance. The effects of genes for resistance to streptogramin A or B on the activity of XRP2868 and its components were also tested by cloning these genes individually or in various combinations in gram-positive recipient strains susceptible to quinupristin-dalfopristin. The species tested included Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, and other species of streptococci. XRP2868 was generally fourfold more potent than quinupristin-dalfopristin against S. aureus, E. faecium, and streptococci and had activity against E. faecalis (MICs ‫؍‬ 0.25 to 1 g/ml). XRP2868 appeared to be affected by the same mechanisms of resistance as those to quinupristin-dalfopristin. Nevertheless, the strong activity of factor A of the oral streptogramin enabled the combination to be very potent against streptograminsusceptible staphylococci, streptococci, and E. faecium (MICs ‫؍‬ 0.03 to 0.25 g/ml) and to retain low MICs against the strains harboring a mechanism of resistance to factor A or factor B of the streptogramin. However, the combination of mechanisms of resistance to factors A and B caused an increase in the MICs of XRP2868, which reached 1 to 4 g/ml. As with the other streptogramins, there was a reduction in the bactericidal effect of XRPR2868 when the staphylococcal strains acquired a constitutively expressed erm gene.Multidrug resistance in gram-positive cocci has increased at an alarming rate in clinical settings worldwide, and overcoming bacterial resistance has become more important than ever. Several new drugs have been proposed as alternatives for the treatment of severe infections caused by multiply resistant gram-positive organisms, i.e., linezolid, daptomycin, tigecycline, and quinupristin-dalfopristin. Quinupristin-dalfopristin, an injectable streptogramin, was among the first to be developed internationally (3). Streptogramins have the advantage of bactericidal activity against pneumococci and staphylococci, provided that they are susceptible to clindamycin (11). However, quinupristin-dalfopristin can be administered only parenterally; and except for pristinamycin, which is available in France, oral streptogramins are not available (5). In addition, the administration of quinupristin-dalfopristin requires the presence of a deep-vein catheter because of venous toxicity (21). Therefore, the value of the international development of a new oral streptogramin that can be used as a replacement or as the treatment of first choice has become obvious.XPR2868 is a new investigational oral streptogramin that is composed of a mixture of 70% RPR132552 (streptogramin group A) and 30% RPR202868 (streptogramin group B) (18). The new compound was shown to inhibi...

Time-Kill Activity of the Streptogramin NXL 103 against Gram-Positive and -Negative Bacteria

“…Previous studies have shown that NXL 103 inhibits staphylococci, S. pneumoniae, nonpneumococcal streptococci, H. influenzae, and anaerobes at Յ1 g/ml. NXL 103 is approximately 4 times as potent as quinupristin-dalfopristin against S. aureus, Enterococcus faecium, streptococci, and H. influenzae (7,8,14,16). Our MIC results reflect those published previously by both us and others.…”

“…Rapid kill kinetics against all of the strains tested, with the exception of MRSA, adds to the attractive properties of NXL 103. Quinupristin-dalfopristin has been described as often being bacteriostatic against MRSA, possibly mediated by constitutive erm(B) production by most MRSA strains (7,8,14,16). This was reflected in the results obtained with NXL 103.…”

“…NXL 103 (XRP 2868) is an experimental broad-spectrum oral streptogramin comprising two components, RPR 202868 and RPR 132552 (7,8,14,16). The clinically available intravenously administered streptogramin quinupristin-dalfopristin has rapid bactericidal activity against susceptible organisms.…”

Synergy of Streptogramin Antibiotics Occurs Independently of Their Effects on Translation

“…Rapid hydrolysis of the diethylaminoethylsulfonyl group at a physiological pH converts dalfopristin to virginiamycin M (11). In vitro studies have shown that the streptogramin A flopristin in NXL 103 has higher antimicrobial activity than that of its counterpart in Synercid, dalfopristin, suggesting that the increased activity of NXL 103 is mainly due to flopristin (6,7). The streptogramin B component quinupristin of Synercid carries a quinuclidinylthiomethyl group compared to a methylmorpholine group in linopristin of NXL 103 (Fig.…”

“…To overcome venous irritation caused by Synercid, and in order to reduce health care costs, a new and orally available streptogramin combination, flopristin-linopristin (NXL 103), a 70:30 (wt/wt) mixture of flopristin to linopristin, has been developed for use in the outpatient setting. NXL 103 has been shown to be more effective than Synercid in treating a large number of Gram-positive bacteria and their clinical isolates (6)(7)(8)(9) and also has the potential to become an important drug in the treatment of community-acquired pneumonia and complex skin and soft tissue infections, including MRSA (10).…”