Pharmacy and Therapeutics - January 2008 - (Page 44) DRUG FORECAST Biedenbach et al., 200729 In a susceptibility study, Biedenbach and associates tested dalbavancin’s efficacy against staphylococci and beta-hemolytic streptococci isolates that had been collected from medical centers in the U.S. Altogether, 2,490 isolates were valid for analysis, including 1,009 MRSA strains, 762 MSSA strains, 182 MRCNS strains, 58 MSCNS strains, and 479 S. pyogenes strains. The specimens were collected from SSTIs (41%), bloodstream infections (28%), respiratory tract infections (21%) and unknown sources of infection (10%). The drug’s MICs against MSSA and MRSA were 0.125 mcg/mL and 0.19 mcg/mL, respectively. The potency of dalbavancin was eight to 16 times greater than that of vancomycin against Staphylococcus spp. All coagulase-negative strains were inhibited at concentrations ranging from 0.125 to 0.19 mcg/mL, compared with a vancomycin concentration of 2 mcg/mL. Dalbavancin was 16 times more potent than vancomycin against Streptococcus spp. (MIC, 0.0.47 mcg/mL). Lin et al., 200533 and Mushtaq et al., 200434 (MIC < 0.06 mcg/mL). In this study, dalbavancin was also activ e against other gram-positive bacteria, including Streptococcus bovis (MIC < 0.06 mcg/mL), Bacillus spp. (MIC < 0.25 mcg/mL), Corynebacterium spp. (MIC < 0.25 mcg/mL) and Listeria spp. (MIC < 0.12 mcg/mL). Goldstein EJ, et al., 200630 Goldstein and associates studied the efficacy of dalbavancin in eradicating anaerobic gram-positive isolates from patients with diabetic foot infections. Overall, dalbavancin was active against all 120 anaerobic isolates, including Clostridium per fringens and other clostridia, Peptoniphilus asaccharolyticus, Finegoldia magna, Anaerococcus prevotii, Peptostreptococcus anaerobius, Peptoniphilus harei, Peptostreptococcus vaginalis, Micromanas micros, and Anaerococcus tetradius with MICs of 0.125 mcg/ mL or less. Gram-Negative Organisms Jones et al., 200135 Another in vitro study confirmed that the potency of dalbavancin against susceptible and resistant S. aureus, CNS, and Viridans streptococci was up to 16 times superior to that of vancomycin.34 In a separate study, pneumococcal species were found to be highly susceptible to dalbavancin (MIC, 0.06 mcg/mL), compared with vancomycin (MIC, 0.5 mcg/ mL).33 Streit et al., 200414 Dalbavancin was intrinsically inactive against gram-negative bacteria. Like other glycopeptides, it possessed minimal activity against Haemophilus influenzae; Citrobacter, Acinetobacter, and Enterobacter spp.; Klebsiella pneumoniae; Escherichia coli; and Pseudomonas aeruginosa.35 EFFICACY IN VIVO Seltzer et al., 200336 The bactericidal activity of dalbavancin was assessed against 6,339 clinical isolates, including strains from the U.S. and Europe. Most of the isolates were resistant organisms (39%, MRSA; 10%, VRE; and 28%, penicillin-resistant pneumococci). More than 99% of the MICs for dalbavancin were below 1 mcg/mL. Dalbavancin was also potent against vancomycin-susceptible enterococci, including E. faecalis (MIC, 0.06 mcg/mL) and E. faecium (MIC, 0.12 mcg/mL). However, dalbavancin displayed decreased susceptibility against VRE (MIC, from less than 0.015 to more than 32 mcg/ mL). The drug was highly active against penicillin-resistant pneumococci In a multicenter, randomized, controlled, open-label, phase 2 clinical trial, dalbavancin was evaluated in patients with SSTIs caused by gram-positive organism s. Sixty-two subjects were assigned to one of the three regimens: • a single IV infusion of dalbavancin 1,100 mg (n = 20) • an initial infusion of dalbavancin 1,000 mg, followed by 500 mg a week later (n = 21) • a comparative standard-of-care antibiotic, including ceftriaxone (Rocephin, cefazolin, piperacillin/tazobactam (Zosyn, Wyeth), clindamycin, vancomycin, linezolid, and cephalexin (Keflex, Middle Brook/ Advancis/ Dista) (n = 21) If gram-negative or anaerobic organisms were suspected or identified, additional coverage with aztreonam (Azactam, Elan), ceftrazidime (For taz, GlaxoSmithKline), or metronidazole (Flagyl, Pfizer) was added. The primar y efficacy endpoint was a clinical response, including cure, improvement, or failure at the follow-up visits: day 24 for a single dose of dalbavancin, day 34 for the two doses of dalbavancin, and day 14 after the last dose of the comparator regimen. Gram-positive pathogens isolated at the baseline exam included S. aureus; MRSA; S. pyogenes; beta-hemolytic (nontypable) streptococci; group B, C, G streptococci; Viridans streptococci; and Peptostreptococcus spp. The MIC of dalbavancin against 25 baseline pathogens was 0.12 mcg/mL, including 0.12 mcg/mL for 24 isolates and 0.25 mcg/mL for one isolate. Overall success rates in the clinically evaluable group at the follow-up visit were 62% for patients receiving the single dose, 94% for those receiving the twodose regimen, and 76% for the comparator group. Clinical success in the intentto-treat population was 60% for the single dose, 91% for two doses, and 76% for the comparator regimen, respectively. At the follow-up visit, the rate of S. aureus eradication, including MSSA and MRSA, was higher with two doses of dalbavancin (90%) than with the single dose (50%) or the comparator (60%) regimen. Clinical success rates in eradicating MRSA were 80% for the two-dose dalbavancin regimen and 50% for the singledose and comparator groups. Jauregui et al., 200537 In a multicenter, phase 3, non-inferiority, randomized, double-blind trial, dalbavancin was compared with linezolid therapy for suspected or confirmed complicated SSTIs. The dalbavancin patients received an initial IV infusion of 1,000 mg, followed by a 500-mg infusion on the eighth day. Linezolid was given as 600 mg IV or orally every 12 hours for 14 days. Aztreonam or metronidazole was used empirically for gram-negative infections. Overall, 571 patients were assigned to the dalbavancin group, and 283 patients received linezolid. Most patients were men (61%), with a mean age of 47 years, and Caucasian (68%). Mainly, SSTIs were spontaneous in nature (50%), associated 44 P&T® • January 2008 • Vol. 33 No. 1
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