Ceftobiprole: An Extended-Spectrum Anti–Methicillin-Resistant Staphylococcus aureus Cephalosporin

Shawn D Anderson, PharmD; John G Gums, PharmD, FCCP


The Annals of Pharmacotherapy. 2008;42(6):806-816. 

In This Article

Pharmacokinetics and Pharmacodynamics

Single- and multiple-dose pharmacokinetics of ceftobiprole have been evaluated in healthy volunteers.[33,34] These results, along with additional pharmacokinetic and pharmacodynamic data,[35,36] are summarized below and in Table 2 . Ceftobiprole medocaril is a water-soluble prodrug that is rapidly converted in seconds to active drug, diacetyl, and carbon dioxide by plasma esterases. An insignificant amount of ceftobiprole is then converted to an open-ring metabolite via hydrolysis. Ceftobiprole minimally inhibits hepatic enzymes (8–28%) at the highest concentrations tested (50–100 µmol/L), does not induce hepatic enzymes, and is not a substrate or inhibitor of P-glycoprotein.[35]

After single, 30-minute, ascending-dose intravenous infusions, peak plasma concentrations (C max ) were observed at the end of infusion.[33] C max and area under the concentration–time curve (AUC) exhibit linear dose response up to the maximum dose studied (1000mg). The apparent volume of distribution at steady-state (V ss ) is 18–20 L, which is approximately the volume of the extracellular fluid compartment in adults. Plasma protein binding averages 16% to mostly albumin and α 1 -acid glycoprotein. The majority of ceftobiprole is recovered in the urine as unchanged drug (83%) in addition to small amounts of prodrug (0.3%) and open-ring metabolite (0.8%).[35] The mean total renal clearance (Cl ren ) ranges from 68 to 85mL/min and unbound fraction in plasma is 62%. Therefore, Cl ren of the unbound fraction is 110–136mL/min, which equates to a normal glomerular filtration rate of 125mL/min in adults. Cl ren , V ss , and half-life (t 1/2 ) are all independent of dose (range 125–1000mg).

A multiple-dose study was performed in 16 healthy men taking ceftobiprole medocaril at doses of 500 and 750mg or placebo.[34] Subjects were given one 30-minute infusion of ceftobiprole or placebo diluted to 200 mL in 5% dextrose on days 1 and 8, and two 30-minute infusions or placebo 12 hours apart on days 2–7. Single- and multiple-dose pharmacokinetics were similar. Drug accumulation was assessed by comparing AUC on day 1 with AUC on day 8. Mean ± SD accumulation levels (AUC day8 /AUC day1 ) were minimal at 1.06 ± 0.18 for the 500-mg dose and 1.04 ± 0.09 for the 750-mg dose, suggesting no alteration in clearance during therapy. Again, linearity exists for C max and AUC, while V ss , plasma protein binding, Cl ren , and t 1/2 are independent of dose. Similar pharmacokinetic results were replicated at ceftobiprole doses of 1000mg every 8 hours as a 90-minute infusion 37 and 500mg every 8 hours as a 2-hour infusion.[38]

Ceftobiprole is similar to other β-lactam antibiotics in that the time above the MIC (T >MIC) correlates to clinical efficacy. A fraction of T >MIC (fT >MIC) of at least 40% is most commonly sought in gram-positive organisms, although maximal killing is achieved at 50%.[38] Thirty-minute infusions of ceftobiprole medocaril at 500–1000mg resulted in fT >MIC of 42–58% for a 12-hour dosing interval at an MIC of 4 µg/mL for MRSA.[33] In the multiple-dose study, 30-minute infusions led to fT >MIC of 40–58% for 500mg every 12 hours and 58–75% for 750mg every 12 hours.[34] Considering these data, 500mg every 12 hours infused over 30 minutes may be an option in methicillin-resistant staphylococcal infections with an MIC up to 4 µg/mL, but 750mg every 12 hours infused over 30 minutes is expected to achieve maximal killing.

Two studies utilized Monte Carlo simulation to predict target attainments rates (TARs), or the probability of achieving a specific pharmacodynamic value, and dosing regimens for Phase 3 clinical trials of ceftobiprole.[39,40] These results are summarized in Table 3 for the most applicable targets of fT >MIC of 40%, 50%, and 60%. TARs were predicted for dosing schedules of mostly 500mg, either every 8 or 12 hours, over 30-minute to 2-hour infusions. An optimal dosing regimen is close to 100% TAR. In summary, TARs greater than or equal to 90% at a maximal bactericidal target of fT >MIC of 50% at an MIC of 2 µg/mL are predicted to occur with all dosing regimens, with the exception of 500mg every 8 hours infused over 30 minutes with an estimated creatinine clearance (Cl cr ) of 120mL/min (TAR 88%) and 500mg every 12 hours infused over 1 hour with normal Cl cr of 80–120mL/min (TAR 84–74%) in the Lodise et al.[39] analysis. However, Mouton et al.[40] determined that a 30-minute infusion of 500mg every 12 hours provides 100% TAR. A possible explanation for this discrepancy is the number and characteristics of subjects from whom pharmacokinetic data were collected. The Lodise et al.[39] analysis may be considered more robust considering that more subjects were analyzed (150 vs 12) and subjects were diverse, including 22 intravenous drug users. This is important because intravenous drug users often have higher clearances, thus explaining lower TARs. From these Monte Carlo simulations, maximum bactericidal activity at all susceptible gram-positive isolates (MIC 4 µg/mL) is likely to occur at 500mg every 8 hours infused over 1–2 hours or at 30-minute infusions of 750mg every 12 hours. Since the majority of MRSA isolates have MICs less than or equal to 2 µg/mL and ceftobiprole retains bacteriostatic activity at lower targets, 500mg every 12 hours infused over 0.5–1 hour may still be clinically effective.

Gram-negative pathogens have higher targets than gram-positive pathogens and higher doses or more frequent dosing is often required. The fT >MIC for bacteriostatic effect is 40% and, for bactericidal effect, is 60%. Utilizing the aforementioned Monte Carlo simulations, 500mg every 8 hours (2-h infusion) is the dose with the highest TARs.[39,40] These analyses demonstrate that 500mg every 8 hours as a 2-hour infusion is expected to provide mostly bacteriostatic activity in susceptible gram-negative infections and bactericidal activity in susceptible gram-positive infections. This dosing scheme is expected to be used as empiric therapy and in polymicrobial infections such as diabetic foot infections and pneumonia.


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