Ceftobiprole: Antimicrobial Activity, Susceptibility, Administration and Dosage, Clinical Uses etc.

Ceftobiprole, formerly BAL9141 or Ro 63-9141, is a novel pyrrolidinone-3-ylidene-methyl cephalosporin with clinically demonstrable activity against methicillin-resistant Staphylococcus aureus (MRSA).

Ceftobiprole medocaril (BAL5788, JNJ 30982081, JNJ30982081, RO 65-5788, RO 655788) is a water-soluble prodrug of ceftobiprole. This antibiotic is the first beta-lactam antibiotic to have in vitro activity against MRSA and vancomycin-resistant S. aureus (VRSA). The structure of ceftobiprole and ceftobiprole medocaril is shown in Figure 34.1 (Bush et al., 2007).

ANTIMICROBIAL ACTIVITY

a. Routine susceptibility

Ceftobiprole has broad-spectrum activity against many Gram-positive pathogens including MRSA, VRSA, penicillin-resistant Streptococcus pneumoniae and some Gram-negative organisms (Bush et al., 2007; Murthy and Schmitt-Hoffmann, 2008). Ceftobiprole shows bactericidal action typical of a beta-lactam antibiotic (Deshpande et al., 2004).
In vitro antimicrobial activities of ceftobiprole against common pathogens are shown in Table 34.1.

Gram-positive organisms

Ceftobiprole exhibits potent bactericidal activity in vitro against most clinically relevant staphylococci and streptococci, including MRSA and penicillin-resistant S. pneumoniae (Table 34.1). The majority of clinically important Gram-positive bacteria will have minimum inhibitory concentration (MIC) values for ceftobiprole r2 mg/ml (Noel, 2007).

Ceftobiprole is unaffected by the common staphylococcal PC1 penicillinase (Hebeisen et al., 2001; Queenan et al., 2007). In a variety of studies, ceftobiprole was active against all staphylococci tested, irrespective of their susceptibility to other antimicrobial agents. On the basis of cumulative data from previous studies, MICs for methicillinsusceptible S. aureus (MSSA) strains (n = 248) were in the range of 0.25–2 mg/ml, and the MIC90 was 0.5 mg/ml (Jones, 2007). In these studies, MIC values of 925 MRSA isolates ranged from 0.06 to 2 mg/ ml, with an MIC90 of 2 mg/ml (Jones, 2007).

 Ceftobiprole MICs are not correlated with oxacillin and cefoxitin MICs (Denis et al., 2006). Ceftobiprole is active against S. pneumoniae, including multidrug resistant strains. Although its MIC values increase in parallel with those of penicillin and other cephalosporins, it is the most potent cephalosporin against penicillin-resistant pneumococci (Kosowska et al., 2005; Pillar et al., 2008); definitions used here are those of the Clinical and Laboratory Standards Institute (CLSI) for oral penicillin V, namely susceptible r0.06 mg/ml, intermediate 0.12–1 mg/ml, and resistant Z2 mg/ml (CLSI, 2008).

Gram-negative organisms

Ceftobiprole demonstrates antibacterial activity against Enterobacteriaceae that resembles that of cefepime more closely than that of ceftazidime (Jones, 2007). As with cefepime, ceftobiprole activity was decreased among isolates of Gram-negative bacilli producing extended-spectrum beta-lactamase (ESBLs) and other class A, B, and D cephalosporinases (Hebeisen et al., 2001; Rouse et al., 2006; Queenan et al., 2007; Pillar et al., 2008).

Anaerobes

Ceftobiprole has good in vitro activity against many anaerobic Grampositive organisms, but only a few anaerobic Gram-negative organisms (Goldstein et al., 2006) (Table 34.3). All tested Proprionibacterium acnes strains are susceptible, as are most peptostreptococci and clostridia. However, some strains of anaerobic Gram-positive organisms, including Peptostreptococcus anaerobius and Clostridium spp., show relatively higher MICs at 4–8 mg/ml (Goldstein et al., 2006; Ednie et al., 2007). Ceftobiprole has poor activity against C. difficile, with MIC values of 1–8 mg/ml (MIC90 values of 8 mg/ml) (Ednie et al., 2007).

b. Emerging resistance and cross-resistance

Gram-positive organisms

Phase III clinical trials and surveillance data have not identified ceftobiprole resistance in MRSA. The emergence of ceftobiprole resistance via chromosomal mutation has been evaluated in the laboratory. One multipassage resistance selection study in staphylococci demonstrated that ceftobiprole has a low potential to select for resistance (Bogdanovich et al., 2005). The highest MIC achieved for ceftobiprole after 50 passages in 1 of 10 strains was 8 mg/ml, which represented a 4-fold increase in the initial MIC. Single-passage selections showed very low frequencies of resistance to ceftobiprole irrespective of genotype or phenotype; the maximum ceftobiprole MIC of recovered clones was 8 mg/ml (Bogdanovich et al., 2005).

Gram-negative organisms

For H. influenzae or M. catarrhalis, only modest increases in MICs were found after 50 serial passages in the presence of subinhibitory concentrations of ceftobiprole, and single-passage selection showed that the selection frequency of H. influenzae or M. catarrhalis clones with elevated ceftobiprole MICs is quite low (Bogdanovich et al., 2006).

Ceftobiprole is stable in the presence of certain beta-lactamasemediated resistance mechanisms. Ceftobiprole is unaffected by the class A TEM-1 beta-lactamase and the class C AmpC beta-lactamase (Hebeisen et al., 2001; Queenan et al., 2007). Ceftobiprole is demonstrated to have a low propensity to induce AmpC betalactamases, or to select for stably derepressed mutants in strains producing the enzymes (Heep et al., 2005; Queenan and Bush, 2005; Queenan et al., 2007).

MECHANISM OF DRUG ACTION

As with all beta-lactam antibiotics, ceftobiprole inhibits bacterial wall synthesis, eventually leading to cell lysis, by binding to penicillinbinding proteins (PBPs). Ceftobiprole has demonstrated a strong affinity for the normal complement of PBPs (PBP 2, PBP 2x, PBP 1a) present in most species of bacteria, including staphylococci, pneumococci, and other Gram-positive and Gram-negative pathogens (Hebeisen et al., 2001; Bogdanovich et al., 2005).

MODE OF DRUG ADMINISTRATION AND DOSAGE

a. Adults

Ceftobiprole is administered twice- or thrice-daily by the intravenous (i.v.) route.

In view of the results of Monte Carlo simulation using the data from a small number (n = 12) of healthy volunteers, Mouton et al. (2004) predicted that doses of 500 and 750 mg i.v. twice daily would achieve a 100% target attainment rate at an fTWMIC of 40% for staphylococci with MICs r2 and r4 mg/ml, respectively (Mouton et al., 2004). b. Newborn infants and children There is no information on ceftobiprole use in pediatric populations.

c. Altered dosages

There are no data on dose adjustment for patients with impaired hepatic function, premature neonates, or the elderly. Since the pharmacodynamics of ceftobiprole is similar in males and females, no dosing adjustments are required based on gender (Murthy and Schmitt-Hoffmann, 2008).

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

Ceftobiprole has been developed as a water-soluble prodrug, ceftobiprole medocaril, because of the low water solubility of ceftobiprole at physiologic pH (0.1 mg/ml) (Hebeisen et al., 2001). Ceftobiprole medocaril has pharmacokinetic equivalence to ceftobiprole and has good solubility (W200 mg/ml) (Anon., 2006). Ceftobiprole medocaril 666.6 mg corresponds to ceftobiprole 500 mg, and is provided as a sterile lyophilized powder for infusion (Murthy and Schmitt-Hoffmann, 2008). There is no oral formulation of ceftobiprole.

b. Drug distribution

Serum levels in relation to dosage

A 750-mg dose of ceftobiprole administered as an intravenous infusion over 30 min in single- and multiple-dose studies resulted in a mean peak plasma concentration (Cmax) of 60–61 mg/ml, a mean area under the curve (AUC) value of 135–165 mg h/ml, and a mean half-life of 3–4 h (Schmitt-Hoffmann et al., 2004a; Schmitt-Hoffmann et al., 2004b). After a single 500-mg dose, a mean Cmax value of 36 mg/ml was reached at the end of the 30-min infusion, and the mean AUC value was 77 mg h/ml (Schmitt-Hoffmann et al., 2004b). After multiple 30-min i.v. infusions of the 500-mg dose, mean Cmax and AUC values were 41 mg/ml and 101 mg h/ml, respectively, at day 1 and 44 mg/ml and 108 mg h/ml, respectively, at day 8 (Schmitt-Hoffmann et al., 2004a).

Distribution of the drug in the body

Results from single- and multiple-dose pharmacokinetic studies demonstrate that the mean volume of distribution for ceftobiprole (16–20 l) approximates the extracellular volume in humans, suggesting extensive extracellular distribution, as with other beta-lactam antibiotics (Schmitt-Hoffmann et al., 2004a; Schmitt-Hoffmann et al., 2004b). Pharmacokinetic parameters in healthy adults are shown in Table 34.4.

c. Clinically important pharmacokinetic and pharmacodynamic features

Currently, no breakpoints for ceftobiprole have been defined by the Food and Drug Administration (FDA), CLSI, or the European Committee on Antimicrobial Susceptibility Testing (EUCAST). In published articles comparing susceptibility rates of various cephalosporins, r4 mg/ml was used for ceftobiprole when testing enterococci, Enterobacteriaceae, non-enteric Gram-negative bacilli, and staphylococci, whereas ceftobiprole breakpoints for Haemophilus spp. and streptococci were defined as r2 and r1 mg/ml, respectively (these are the levels currently utilized for cefepime, cefotaxime, and ceftriaxone) (Jones et al., 2002).

d. Excretion

Ceftobiprole is primarily excreted unchanged in the urine (Murthy and Schmitt-Hoffmann, 2008). The predominant mechanism responsible for elimination is glomerular filtration, with approximately 89% of the dose being excreted as the prodrug, active ceftobiprole, and open-ring metabolite (Murthy and Schmitt-Hoffmann, 2008).

Ceftobiprole undergoes minimal hepatic metabolism, and the primary metabolite is the beta-lactam ring-opened hydrolysis product (open-ring metabolite). Systemic exposure of the open-ring metabolite accounts for 4% of ceftobiprole exposure following single-dose administration; approximately 5% of the dose is excreted in the urine as the metabolite (Murthy and Schmitt-Hoffmann, 2008).

e. Drug interactions

No significant drug–drug interactions have yet been reported (Noel et al., 2008a; Noel et al., 2008b). Ceftobiprole does not appear to be eliminated via active tubular secretion, so probenecid does not interact with ceftobiprole (Murthy and Schmitt-Hoffmann, 2008).

Ceftobiprole does not significantly induce or inhibit relevant cytochrome P450 enzymes and is neither a substrate nor an inhibitor of P-glycoprotein (Murthy and Schmitt-Hoffmann, 2008).

TOXICITY

Preliminary data suggest that nausea and vomiting are the main sideeffect associated with ceftobiprole, although a caramel-buttery taste disturbance has been reported in some patients during drug infusion.
Collective data from two separate phase I studies of ceftobiprole medocaril in healthy male volunteers have shown that this prodrug is generally safe and well tolerated, and no serious adverse events were reported. In one study, 40 volunteers were randomized to receive placebo (n = 2 per dose) or ceftobiprole medocaril (n = 6 per dose) as a 200-ml i.v. infusion over 30 min. 

Laboratory abnormalities

No differences in changes in mean laboratory testing values between the baseline and the end of therapy, or in the incidence of abnormal values during therapy, were found for hematologic measurements, biochemical measurements, or urinalysis when results were compared between patients treated with ceftobiprole or vancomycin in a recent phase III trial (Noel et al., 2008b).

CLINICAL USES OF THE DRUG

a. Complicated skin and skin structure infections

Ceftobiprole is currently under review by regulatory authorities in the USA, Europe, and Canada for the treatment of cSSSIs.

One phase II trial focused on cSSSIs due to Gram-positive bacteria (n = 40). In this noncomparative trial, ceftobiprole 750 mg every 12h was given via a 30-min infusion for 7–14 days. Clinical cures were reported for all 35 clinically evaluable patients, including four patients with MRSA. Microbiologic eradication was reported for 91% (21/23) of microbiologically evaluable patients (Bush et al., 2007).

b. Nosocomial pneumonia

Ceftobiprole was compared with combination therapy of ceftazidime plus linezolid in a recent trial of patients with hospital-acquired pneumonia (Basilea, 2007).

c. Community-acquired pneumonia

Ceftobiprole is currently in phase III trials for community-acquired pneumonia, but the results of these studies are not yet available.

d. Infective endocarditis

No human data are yet available on the use of ceftobiprole for treatment of endocarditis. In a rabbit model of endocarditis due to MRSA and VISA, ceftobiprole was as effective as vancomycin against MRSA and superior to vancomycin against vancomycin-intermediate S. aureus (Chambers, 2005).

e. Infections of prostheses

No human data are yet available on the use of ceftobiprole for the therapy of staphylococcal infections associated with foreign implants such as orthopedic prostheses. In an animal study of chronic MRSA infection of a tissue cage, the in vivo activity of ceftobiprole against the infection was equivalent to that of vancomycin and did not lead to the emergence of resistant subpopulations (Vaudaux et al., 2005).

References

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