Pharmacy & Therapeutics - November 2008 - (Page 632)

DRUG FORECAST MICROBIOLOGY Ceftobiprole has demonstrated activity against clinically important gram-positive bacteria, including penicillin-resistant S. pneumoniae (PRSP), methicillin-resistant S. aureus (MRSA), and E. faecalis with MIC90 values of 0.25, 2, and 2 mcg/mL, respectively (Table 1).6–10 Ceftobiprole has also demonstrated potent in vitro activity against several clinical isolates of community-associated methicillin-resistant S. aureus (CA-MRSA), vancomycin-intermediate S. aureus (VISA), and vancomycin-resistant S. aureus (VRSA), with a minimum inhibitory concentration (MIC) of 2 mcg/mL.14,15 The clinical utility of ceftobiprole for infections caused by VISA and VRSA, however, has not been determined. In vitro resistance to ceftobiprole has been found in specific strains of S. aureus, with high-volume broth cultures containing subinhibitory concentrations of ceftobiprole.16 Banerjee et al. determined that one possible mechanism of ceftobiprole resistance was associated with multiple mecA mutations in several isolates expressing the mecA gene and another potential role for chromosomal genes mediating resistance in particular strains lacking mecA. Ceftobiprole is active against clinically impor tant gram-negative path ogens, including Citrobacter spp., Escherichia coli, Enterobacter spp., Klebsiella spp., Serratia marcescens, and Pseudomonas aeruginosa.6–10 Although ceftobiprole has demonstrated activity against isolates expressing AmpC beta-lactamases, it has not consistently shown activity against isolates expressing extended spectrum beta-lactamases (ESBLs). Investigators have not been able to demonstrate reliable in vitro activity of this agent against isolates of Enterococcus faecium, Stenotrophomonas maltophilia, Burkholderia cepacia, Acinetobacter spp., or clinically significant anaerobic bacteria like Bacteroides spp. (MIC90 values above 8 mcg/ mL). Breakpoints for susceptibility of ceftobiprole have not been established. PHARMACOKINETICS AND PHARMACODYNAMICS The pharmacokinetic properties of ceftobiprole have been evaluated in healthy volunteers, in patients with varying degrees of renal dysfunction, and in patients enrolled in clinical trials for the treatment of cSSSIs.11,17–20 The volume of distribution at steady state (Vss) is approximately 18 to 20 liters. Like other beta- lactams, this drug is comparable to the extracellular fluid compartment in adults. After a two-hour infusion of 500 mg, the peak plasma concentration (Cmax) and the area-under-the-curve (AUC) concentration in healthy volunteers were 29.2 mcg/mL and 90 mcg • hour/mL, respectively. Accumulation of ceftobiprole was not apparent after five days of administration of 500 mg every eight hours infused over two hours, Cmax 33 mcg/mL and an Table 1 In Vitro Activity of Ceftobiprole against Clinically Significant Pathogens Bacterial Isolate Gram-positive pathogens • Methicillin-susceptible Staphylococcus aureus (MSSA) • Methicillin-resistant S. aureus (MRSA) • Methicillin-susceptible coagulase-negative Staphylococcus spp. • Methicillin-resistant coagulase-negative Staphylococcus spp. • Penicillin-susceptible Streptococcus pneumoniae (PSSP) • Penicillin-intermediate S. pneumoniae (PISP) • Penicillin-resistant S. pneumoniae (PRSP) • Beta-hemolytic Streptococcus spp. • Enterococcus faecalis • Enterococcus faecium Gram-negative pathogens • Citrobacter freundii • Enterobacter spp. • Enterobacter cloacae • Escherichia coli • Escherichia coli (ESBL-positive) • Klebsiella pneumoniae • Klebsiella pneumoniae (ESBL-positive) • Proteus mirabilis • Indole-positive Proteus spp.* • Serratia marcescens • Haemophilus influenzae • Moraxella catarrhalis • Acinetobacter spp. • Pseudomonas aeruginosa • Stenotrophomonas maltophilia MIC50 0.25 1 0.12 1 ≤0.06 ≤0.06 0.25 ≤0.06 0.5 >8 ≤0.06 ≤0.06 ≤0.06 ≤0.06 >8 ≤0.06 >8 ≤0.06 ≤0.06 ≤0.06 ≤0.06 ≤0.06 >8 2 >8 MIC90 0.5 2 0.25 2 ≤0.06 0.12 0.25 ≤0.06 2 >8 2 >8 0.12 0.12 >8 >8 >8 0.12 >8 1 ≤0.06 0.12 >8 >8 >8 Range 0.25–2 0.12–2 ≤0.015–1 ≤0.015–4 ≤0.015–0.03 ≤0.015–0.5 ≤0.015–1 ≤0.015–0.06 0.12– >8 0.25– >8 ≤ 0.015– >8 ≤0.015– >8 ≤ 0.03– >8 ≤ 0.015–2 0.03– >8 ≤ 0.015– >8 ≤ 0.015– >8 ≤ 0.015–0.03 ≤ 0.015– >8 0.03– >8 0.12–0.25 ≤ 0.015–1 ≤ 0.015– >8 0.12– >8 >8 * Includes Proteus vulgaris, Providencia spp., and Morganella spp. ESBL = extended-spectrum beta-lactamase; MIC = minimum inhibitory concentration. Data from Walkty A,6 Jones ME, 7 Fritsche TR,8 Jones RN,9 and Pillar CM.10 632 P&T® • November 2008 • Vol. 33 No. 11

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Pharmacy & Therapeutics - November 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Heparin-Induced Thrombocytopenia Medication Utilization Patterns and Hypertension-Related Expenditures among Patients Who Were Switched From Fixed-Dose to Free-Combination Antihypertensive Therapy European Society for Medical Oncology and Association for the Study of Bone and Mineral Research Pharmaceutical Approval Update

Pharmacy & Therapeutics - November 2008

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