Pharmacy & Therapeutics - November 2008 - (Page 640)

DRUG FORECAST Table 2 Pooled Incidence of Treatment-Related Adverse Events For Complex Skin and Skin Structure Infections Ceftobiprole (n = 932) No. (%) 113 (12) 61 (7) 62 (7) 33 (4) 30 (3) 68 (7) 14 (4) 26 (5) 48 (9) 49 (5) 507 (54) 63 (7) 39 (4) Comparator Drug* (n = 661) No. (%) 49 (7) 27 (4) 32 (5) 25 (4) 2 (1) 39 (6) 8 (2) 13 (5) 26 (9) 62 (9) 352 (53) 47 (7) 32 (5) tion, 5% dextrose in water, and lactated Ringer’s solution. The researchers then mixed the solutions in equal amounts with 70 medications using simulated Y-site administration. Of the 70 drugs tested in combination with ceftobiprole, 32 (45.7%) were considered incompatible for Y-site administration regardless of the diluent used or the order of administration. For seven of the medications (10%), compatibility was dependent on the type of solution used to dilute ceftobiprole. Some of the clinically important medications found to be incompatible with ceftobiprole include aminoglycosides, amiodarone (Cordarone), calcium gluconate, diltiazem (Cardizem), dopamine, dobutamine, fluoroquinolones, human regular insulin, hydromorphone, labetalol (Normodyne, Trandate), magnesium sulfate, midazolam (Versed), morphine sulfate, and potassium phosphate. The timing of administration and availability of IV lines are expected to be a concern for patients receiving ceftobiprole with incompatible medications. Adverse Event Nausea Vomiting Diarrhea Constipation Dysgeusia† Headache Dizziness† Insomnia‡ Infusion-site reaction† Hypersensitivity§ Overall adverse drug events • One or more adverse drug events • One or more serious adverse drug events • Discontinued therapy because of adverse drug events * Comparator regimen: vancomycin (STRAUSS 1); vancomycin plus ceftazidime (STRAUSS 2). † Data reported for STRAUSS 1 only. ‡ Data reported for STRAUSS 2 only. § Data for STRAUSS 1 is a combination of rash and pruritus. The overall incidence of hypersensitivity was not reported in this trial. Data from Noel GJ. Clin Microbiol Infect 2007;13(Suppl 2):25–29;23 Noel GJ, Straus RS, Amsler K, et al. Antimicrob Agents Chemother 2008;52:37–44;24 and Noel GJ, Bush K, Bagchi P, et al. Clin Infect Dis 2008;46:647–655.26 CONCLUSION Ceftobiprole is an advanced-generation cephalosporin with a broad spectrum of activity against gram-negative pathogens, including P. aeruginosa and Enterobacteriaceae (ESBL-negative) with the added advantage of enhanced gram-positive activity against MRSA, PRSP, and ampicillin-susceptible E. faecalis. Activity against other clinically important pathogens (such as ESBL-producing Enterobacteriaceae, Acinetobacter spp., S. maltophilia, and Bacteroides spp.) remains limited; most of the isolates tested have an MIC above 8 mcg/mL. Ceftobiprole’s pharmacokinetic and pharmacodynamic profile is similar to that of other cephalosporins, including cefepime (Maxipime, Elan) and ceftazidime (Fortaz). Like other beta-lactams, the pharmacodynamic parameter most correlated with efficacy is the percentage of time in which the free serum concentration is above the MIC. The activity of ceftobiprole against clinically important gram-negative pathogens is comparable to that of ceftazidime. Ceftobiprole has proven efficacy in two phase 3 clinical trials for the treatment of cSSSIs, including diabetic foot infections, caused by gram-positive or gram-negative bacteria. Additional studies of cefto- DOSAGE AND ADMINISTRATION Based on the pharmacokinetic, pharmacodynamic, and clinical data published, ceftobiprole dosing is likely to be based on the indication and the intended bacterial coverage. For cSSSIs caused by culture-proven or presumed grampositive infections, the dose of ceftobiprole is expected to be 500 mg every 12 hours infused over one hour.23,24 For cSSSIs (including diabetic foot infections) caused by culture-proven or presumed gram-negative or mixed infections or for patients with CAP or HAP, the predicted dosing for ceftobiprole is expected to be 500 mg every eight hours infused over two hours.26–30 Ceftobiprole is eliminated primarily via the kidneys; thus, the dosage would probably need to be adjusted in patients with renal insufficiency. Preliminary data suggest that for patients with mild renal impairment (CrCl of 50 to 80 mL/minute), no dosage adjustment is needed.11,19,20 In patients with moderate renal impair- ment (CrCl of 30 to 50 mL/minute), the predicted dosing of ceftobiprole would probably be 500 mg every 12 hours. In patients with severe impairment (CrCl of below 30 mL/minute), the predicted dosing of ceftobiprole would be 250 mg every 12 hours. Of note, patients were excluded from STRAUSS 1 and STRAUSS 2 if they had severe renal dysfunction or oliguria (a urine output below 20 mL/hour that was unresponsive to fluid challenge).24,26 Pharmacokinetic data for ceftobiprole in patients receiving hemodialysis, peritoneal dialysis, or continuous renal replacement therapy have not been published; however, it is unlikely that a dosage adjustment would be necessary for patients with hepatic dysfunction. The physical compatibility of ceftobiprole with commonly administered IV medications has been reported.31 Chan et al. diluted ceftobiprole to a test concentration of 2 mg/mL using three separate solutions: 0.9% sodium chloride injec- 640 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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