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

Ceftaroline, also referred to as PPI-0903M or T-91825, is one of the anti-methicillin-resistant Staphylococcus aureus (MRSA) cephalosporins currently under development. Ceftaroline is the bioactive metabolite of ceftaroline fosamil, formerly PPI-0903 or TAK-599, an N-phosphonoamino water-soluble cephalosporin prodrug (Iizawa et al., 2004). Similar to ceftobiprole, it shows potent activity against MRSA, while maintaining the broad Gram-negative activity and favorable safety profile of cephalosporins. The structure of ceftaroline and ceftaroline fosamil is illustrated in Figure 33.1 (Iizawa et al., 2004).

ANTIMICROBIAL ACTIVITY

a. Routine susceptibility

The in vitro antimicrobial activity of ceftaroline covers a wide range of Gram-positive and Gram-negative pathogens similar to that observed for other anti-MRSA cephalosporins, such as ceftobiprole.

Gram-positive cocci

Ceftaroline is highly active against most aerobic Gram-positive organisms (Table 33.1). Most importantly, ceftaroline has potent activity against Staphylococcus spp., including MRSA and oxacillinresistant coagulase-negative staphylococci. The minimum inhibitory concentration (MICs) of ceftaroline for MRSA are 0.5–2 mg/ml, compared with 0.12–0.25 mg/ml for methicillin-susceptible S. aureus; corresponding values for coagulase-negative staphylococci are 0.25–2 and 0.06–0.12 mg/ml, respectively (Mushtaq et al., 2007). The MIC90 of ceftaroline against clinical isolates of MRSA is 2 mg/ml (Iizawa et al., 2004; Sader et al., 2005). This activity of ceftaroline is comparable to those of vancomycin, teicoplanin, linezolid, and arbekacin (Iizawa et al., 2004; Sader et al., 2005).

Gram-positive bacilli

In a study including 11 Bacillus cereus strains, one B. circulans strain, and eight Bacillus spp. strains, MICs of ceftaroline ranged from 0.06 to 32.4 ug/ml, with MIC90 of 8 mg/ml (Sader et al., 2005). Ceftaroline has excellent activity against some Gram-positive organisms, such as Proprionibacterium spp., and Peptostreptococcus spp., and marginal activity against Clostridium difficile (MIC50 2 mg/ml and MIC90 4 mg/ml) (Sader et al., 2005). There are currently no studies of the susceptibility of other Gram-positive bacilli to ceftaroline.

Gram-negative cocci

Ceftaroline retains excellent activity against Neisseria meningitidis with MIC90 r0.016 mg/ml (Table 33.2) (Sader et al., 2005). The antibiotic is also highly active against Moraxella catarrhalis with MIC90 0.12–0.5 mg/ml (Iizawa et al., 2004; Sader et al., 2005). MICs for M. catarrhalis isolates are lower than or equal to those of the other cephalosporins tested (Mushtaq et al., 2007).

Gram-negative bacilli

Ceftaroline is highly active against Haemophilus influenzae with MIC90s 0.06 mg/ml or less (Iizawa et al., 2004; Sader et al., 2005). The MICs are marginally increased for H. influenzae strains with chromosomal ampicillin resistance, with a geometric mean 0.03 mg/ml compared with r0.015 mg/ml for fully susceptible isolates (Mushtaq et al., 2007). The antimicrobial spectrum of activity of ceftaroline against Gramnegative bacilli is similar to those of the third-generation cephalosporins. It is active against wild-type strains of the Enterobacteriaceae (Sader et al., 2005). The vast majority of Citrobacter freundii, E. coli, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, and Serratia marcescens are inhibited at r2 mg/ml of ceftaroline (Sader et al., 2005).

b. Emerging resistance and cross-resistance

Like other third-generation cephalosporins, extended-spectrum betalactamase (ESBL)-producing strains, regardless of species, show decreased susceptibilities to ceftaroline (MIC90 W32 mg/ml; see Table 33.2) (Sader et al., 2005). Ceftaroline is hydrolyzed by ESBLs and class C beta-lactamases and presumably also by class B metallo-betalactamases. This greater susceptibility to beta-lactamases results in overall activity of ceftaroline against Gram-negative pathogens that is more like that of ceftriaxone than that of cefepime or ceftobiprole (Sader et al., 2005). Resistance due to class A beta-lactamases was reversed by clavulanate (Mushtaq et al., 2007). Studies evaluating the combination of ceftaroline and a novel beta-lactamase inhibitor, NXL-104, are currently under way (Forest laboratories Inc., 2008).

MECHANISM OF DRUG ACTION

Like other beta-lactam agents, ceftaroline inhibits the bacterial cell wall synthesis by binding to penicillin-binding protein (PBPs). Like ceftobiprole, ceftaroline demonstrates high affinity for PBP-2a (or PBP-2u), a peptidoglycan transpeptidase that is responsible for betalactam resistance in MRSA. This accounts for its strong antibacterial activity against MRSA (Ishikawa et al., 2003). In contrast, its affinities for other PBPs, including PBP-1, -2, -3, and -4 of MRSA, were similar to those of ceftriaxone (Ishikawa, 2002).

MODE OF DRUG ADMINISTRATION AND DOSAGE

a. Adults Ceftaroline is administered intravenously

In a phase II study of patients with complicated skin and skin structure infections (cSSSI), ceftaroline 600 mg twice daily was administered intravenously in adults (Talbot et al., 2007). For S. pneumoniae respiratory tract infection, ceftaroline 600 mg twice daily should be adequate from a pharmacodynamic standpoint, when the ceftaroline MIC is r1 mg/ml (Van Bambeke et al., 2007).

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

Ceftaroline is not administered orally. After intravenous administration, the prodrug, ceftaroline fosamil, is rapidly transformed into ceftaroline in plasma (Ge et al., 2006c). Ceftaroline exhibits a low level of plasma protein binding in humans (o20%), as it does in rabbits (o20%) (Ge and Hubbel, 2006). According to the manufacturer’s unpublished data, the serum half-life of ceftaroline observed in healthy volunteers after a 1-h infusion of a 600-mg dose, is 1.57–2.63 h (Jacqueline et al., 2007). The half-life of ceftaroline 600 mg in human serum simulated from a rabbit endocarditis model is 2.4 h (Jacqueline et al., 2007).

b. Drug distribution

When a 600-mg dose (approximately 10 mg/kg) of ceftaroline is infused over 1 h to healthy volunteers, peak concentration (Cmax) is 18.96–21.02 mg/ml and area under the curve (AUC) is 56.08 mg/l h (Jacqueline et al., 2007). Simulated Cmax and AUC in human serum from animal studies are 21.9 7 3.0 mg/ml h and 71.2 mg/l h, respectively (Jacqueline et al., 2007). Human pharmacokinetics are summarized in Table 33.4.

c. Clinically important pharmacokinetic and pharmacodynamic features

No antimicrobial susceptibility breakpoint for ceftaroline has been established by the Clinical and Laboratory Standards Institute (CLSI) or the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for this drug (CLSI, 2008).

d. Excretion

Ceftaroline and its metabolites are mainly eliminated through renal excretion (Ge et al., 2006a). As seen with most beta-lactams, renal impairment has a mild to moderate effect on the pharmacokinetics of ceftaroline (Table 33.5). A decrease in renal function correlates with an increase in elimination half-life and a decrease in clearance, but has little effect on Cmax. In other words, there is an increase in AUC and t1/2, but not in Cmax, in subjects with renal impairment. It appears that there is no dose adjustment requirement for subjects with mild renal impairment; further pharmacokinetic modeling and simulation are needed to determine whether appropriate dose adjustment is necessary in subjects with moderately impaired renal function (Ge et al., 2006c).

e. Drug interactions

Ceftaroline shows little P450-dependent metabolism in vitro and is expected to have a low likelihood of P450-related drug–drug interactions (Ge and Hubbel, 2006).

TOXICITY

There is only one study reporting adverse effects in humans (Talbot et al., 2007). Ceftaroline exhibited a safety and tolerability profile consistent with that of other marketed cephalosporins (Talbot et al., 2007). Most adverse events from ceftaroline are mild and not related to treatment. Drug-related adverse event (AEs) that occurred in Z5% of subjects in either treatment group are shown in Table 33.6 (Talbot et al., 2007). Five serious adverse event (SAEs) were reported in five (5.1%) subjects for both treatment groups. Three SAEs (gangrene in the right toe, recurrent skin infection, and pulmonary edema) in the ceftaroline group were assessed to be unrelated to the drug. In the standard therapy group, interstitial nephritis (related) and re-infection (unrelated) were reported. All SAEs resolved and no death occurred during the study.

CLINICAL USES OF THE DRUG

Several animal studies have shown ceftaroline to be useful for the treatment of MRSA infections (Iizawa et al., 2004). In mice, the effect of ceftaroline against systemic infection caused by clinical isolates of MRSA was comparable or superior to that of vancomycin, linezolid, teicoplanin, and arbekacin (Iizawa et al., 2004). In addition, ceftaroline at a dose of 20 mg/kg significantly decreased bacterial counts in the lungs of mice in an experimental pneumonia model caused by MRSA (Iizawa et al., 2004).

a. Skin and skin structure infections

A phase II trial of ceftaroline was performed to evaluate the safety and efficacy of ceftaroline versus standard therapy in treating complicated skin and skin structure infections (Talbot et al., 2007). Adults with cSSSI were randomized to receive ceftaroline (600 mg every 12 h) or vancomycin (1 g every 12 h) with or without adjunctive aztreonam (1 g every 8 h) for 7–14 days.

References

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