of cephalosporins that are active against methicillin-resistant staphylococci. MRSA are susceptible to ceftobiprole at an MIC50/MIC90 of 2/2 and MRCNS are similarly susceptible with a range of 0.125–4 µ g/mL (Bogdanovich et al 2005a). Ceftobiprole also demonstrates excellent time-kill kinetics and in S. aureus a good post-antibiotic effect (PAE) at MIC and sub-MIC concentrations (Pankuch and Applebaum 2006). In a study of isolates from diabetic foot infections, staphylococci were speciated and had excellent ceftibiprole MIC90 values (µ g/mL): methicillin-susceptible S. aureus (MSSA), 0.5; MRSA 1.0; S. epidermidis 1.0; S. haemolyticus 2.0, and S. ludgenensis 0.5. New glycopeptides Several derivatives of vancomycin have been developed and brought to clinical trials. Telavancin is a rapidly bactericidal lipoglycopeptide with excellent staphylococcal activity. In a study of telavancin versus standard therapy for treatment of skin and soft tissue infection, CNS caused 13 of 122 staphylococcal infections (Stryjewski et al 2006). The MIC90 for telavancin was 0.25 µ g/mL (0.06–0.25) among CNS iso- lates that had a MIC90 of 2.0 for oxacillin. Televancin also is one of the few newer agents to exhibit activity in bioﬁlms (Gander et al 2005). A 3-log decrease in 2 CNS isolates was demonstrated in a so-called Sorbarod bioﬁlm model. Dalbavancin is another lipoglycopeptide that inhibits cell-wall synthesis. In a British study of 92 isolates from 60 hospital laboratories, 100% of the isolates were inhibited by 1 µ g/mL of drug (Mushtaq et al 2004). The E-test MIC correla- tion was excellent with broth dilution but less correlation with agar dilution methodology (Fritsche et al 2006). In another study of dalbavancin compared to other agents including oritavancin, an experimental glycopeptide, dalbavancin had exceptional activity at the MIC90 level (0.06 µ g/mL) for both MSCNS and MRCNS (King et al 2004). In that study, ortivancin had an MIC90 of 2.0 µ g/mL and 4.0 µ g/mL for MSCNS and MRCNS. Interestingly, dalbavancin has a very long half-life (7.5 days) that, when marketed, will challenge prescribers who are used to much shorter dosing intervals. Other agents Other agents are on the Gram-positive therapy horizon, but very few have shown enough promise to come to clinical trials. One agent, API-1252, from a group called enoyl-acyl carrier protein reductases, has shown excellent antistaphy- lococcal activity. The MICs for S. epidermidis isolates from Canada to API-1252 were excellent, with MIC90 for methicillin-suscetible S. epidermidis (MSSE) and MRSE of Therapeutics and Clinical Risk Management 2007:3(6) Antibiotic resistance in coagulase-negative staphylococci 0.06 and 0.03 µ g/mL respectively, only slightly higher than the MIC90s for S. aureus (Karlowsky et al 2007). A second group worth mentioning are the acyldepsipeptides (ADEPs) which have a unique mechanism of action and are quite active against Gram-positive bacteria. ADEPs activate the protease function of ClpP proteins to cause a dysregulation of proteolysis (Brötz-Osterhelt et al 2005). The MIC50 for S. aureus of one ADEP, is as low as 0.05 µ g/mL, but data for CNS have yet to be published. The effect of staphylococcal bioﬁlm on antimicrobial susceptibility Bioﬁlms consists of a complex extracellular matrix that can have profound effects on the ability of antimicrobials to inhibit and kill bacteria and fungi. Bioﬁlms are extremely common in infections due to CNS, bacteria that have special sets of genes that regulate and determine cell-wall associ- ated adhesion and bioﬁlm production (Mack et al 2006). The regulation of bioﬁlm production for most staphylococci involves complex schemes (agr, sar, sigB) that result in sets of genes being turned on and off depending on the current cellular environment. Bioﬁlm regulation involves up and down regulation of genes that mediate information storage, cellular processes and signaling, metabolism and other func- tions (Yao et al 2006). It has been known several years that bioﬁlms interact with antimicrobials (Khardori et al 1991). Early work suggested that subtherapeutic levels of certain agents like fluoroquinolones and glycopeptides would not prevent attachment of bacteria but that β-lactam agents and vanco- mycin could inhibit aggregative activity (Rupp and Hamer 1998). The mechanism of bioﬁlm-associated antimicrobial resistance is likely multifactorial. Unlike other methods to test antimicrobial susceptibility, methods that address bioﬁlm susceptibility to antimicrobial agents have been needed to deﬁne fully the inﬂuence of bioﬁlm on susceptibility (Patel 2005). To that end, very recent work comparing planktonic bacteria to bioﬁlm-grown ones has shown large differences in susceptibility. Almost all single agents studied (linezolid, cefazolin, oxacillin, vancomycin, gentamicin, azithromycin, ciproﬂoxacin and fusidic acid) had a marked increase in the MBC versus the MIC using what is called a modiﬁcation of the Calgary Bioﬁlm Device (Saginur et al 2006). Rifampin alone had some predictable equivalence between the MIC and the MBC. For S. epidermidis isolates, certain combina- tions, almost always containing rifampin, were bactericidal against 90% of bioﬁlms (examples rifampin/vancomycin/ gentamicin; rifampicin/ciprofloxacin/fusidic acid), but 1149