Until the mid-1990s, methicillin (meticillin)-resistant Staphylococcus aureus
(MRSA) incidence was confined to the hospital setting (hospital-acquired MRSA [HA-MRSA]). However, in many medical centers throughout the United States, community-acquired strains of MRSA (CA-MRSA) have increased in frequency of isolation and have spread at an alarming rate, now reaching >60% incidence, primarily in skin and skin structure infections (8
). This has led to an important change in the choice of antibiotics in the management of community-acquired infections. Initially, CA-MRSA isolates were more susceptible than HA-MRSA to classes of antimicrobial agents such as tetracyclines, trimethoprim-sulfamethoxazole, clindamycin, or quinolones (12
). This difference in susceptibility profile is now diminishing as CA-MRSA strains tend to present a profile closer to that of HA-MRSA isolates, as reported for tetracycline and trimethoprim-sulfamethoxazole (15
). Furthermore, it has been shown that clinical and epidemiological characteristics are not reliable for distinguishing between methicillin-susceptible S. aureus
(MSSA) and MRSA skin infections (11
). As a result, there is a need for new intravenous (i.v.) and oral (p.o.) agents active against gram-positive bacterial infections that can be used for both inpatient and outpatient therapy.
For treating multidrug-resistant gram-positive bacteria, only linezolid currently offers the versatility of both i.v. and p.o. administration, enabling an i.v.-to-p.o. step-down approach. Linezolid displays high bioavailability, an acceptable safety profile, and excellent rates of clinical efficacy. However, linezolid is administered twice daily, and although the effect is reversible after discontinuation, mild myelosuppression is commonly observed after 10 to 14 days of therapy, requiring regular blood cell monitoring. In addition, enterococcal and staphylococcal strains resistant to linezolid have surfaced (6
), including some staphylococcal isolates containing transposon-associated or plasmid-borne resistance (5
). As a result, there is a need for a new agent with the potential to (i) be administered in a once-daily regimen; (ii) provide a broader safety margin, particularly with a lower myelosuppression potential at the therapeutic dose; and (iii) treat infections caused by organisms that have developed resistance to linezolid.
TR-701 (formerly DA-70218 and DA-7218) is a prodrug of the active oxazolidinone antibiotic TR-700 (formerly DA-7157 and 70157) that has completed phase 2 clinical development for complicated skin and skin structure infections. Data from phase 1 studies showed that TR-701 is rapidly absorbed and converted to TR-700, with a mean half-life ranging from 8 to 11 h, approximately twofold longer than that of linezolid and consistent with once-a-day dosing (1
). Examination of hematologic parameters over 21 days demonstrated that the 200-mg once-a-day projected therapeutic human dose of TR-701 did not demonstrate any hematological effects and was comparable to placebo (13
The microbiologically inactive prodrug TR-701 can be administered i.v. or p.o. and is readily converted to the microbiologically active form TR-700 by phosphatases. In previous studies, the activity of TR-700 was examined against a collection of Korean clinical isolates (2002 to 2004) (2
). TR-700 was four- to eightfold more potent than linezolid against both S. aureus
and coagulase-negative staphylococci, including methicillin-resistant strains. Similarly, TR-700 was two- to fourfold more potent than linezolid against both vancomycin-susceptible and -resistant enterococci. In a recent study evaluating the activity of TR-700 against linezolid-resistant isolates, TR-700 demonstrated 8- to 16-fold-greater potency than linezolid against all linezolid-resistant strains tested, including MRSA, strains of MRSA carrying the mobile cfr
methyltransferase gene, and vancomycin-resistant enterococci (14
). The purpose of our study was to assess the activity of TR-700 against recent clinical isolates of predominantly gram-positive bacteria isolated from non-Korean sites.
(This study was presented in part at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2007.)