Review
Ceftaroline: a comprehensive update

https://doi.org/10.1016/j.ijantimicag.2011.01.017Get rights and content

Abstract

Ceftaroline is a novel broad-spectrum cephalosporin antibiotic currently under US Food and Drug Administration (FDA) review for a new drug application (NDA), filed by Cerexa, Inc. (a wholly owned subsidiary of Forest Laboratories), for the treatment of complicated skin and skin-structure infections (cSSSIs) and community-associated pneumonia (CAP). The antibiotic acts by binding to penicillin-binding proteins in bacteria, consistent with other β-lactams. The antimicrobial spectrum of ceftaroline ranges from aerobic and anaerobic Gram-positive bacteria, including drug-resistant isolates of staphylococci, i.e. heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA), to anaerobic Gram-negative pathogens such as Moraxella catarrhalis and Haemophilus influenzae (including β-lactamase-positive strains), as well as bacteria with multiple resistance phenotypes. Ceftaroline fosamil is the prodrug that is rapidly dephosphorylated by in vivo plasma phosphatases to the active drug ceftaroline, which follows a two-compartmental pharmacokinetic model and is eliminated primarily by renal excretion, with a plasma half-life of ca. 2.5 h. Ceftaroline is well tolerated, which is consistent with its good safety profile similar to other cephalosporins in clinical trials. Thus, it would be a promising drug to fight multidrug-resistant superbugs such as S. aureus and Streptococcus pneumoniae for the treatment of cSSSIs and CAP.

Introduction

Ceftaroline fosamil [1], [2], [3] (synonyms PPI-0903 and TAK-599) is a novel, parenteral, broad-spectrum, bactericidal, advanced-generation cephalosporin that shows potent activity against many bacteria owing to its high binding affinity to penicillin-binding proteins (PBPs), especially PBP2a in meticillin-resistant Staphylococcus aureus (MRSA) and PBP2x in penicillin-resistant Streptococcus pneumoniae (PRSP) [4], [5]. It has profound activity against the Gram-positive bacteria S. aureus, penicillin-intermediate S. pneumoniae (PISP) and PRSP, against respiratory Gram-negative pathogens such as Moraxella catarrhalis and Haemophilus influenzae (including β-lactamase-positive strains), as well as against bacteria with multiple resistance phenotypes [6], [7], [8], [9]. Phase III clinical trials of ceftaroline were concluded in 2009 and data emerging from these studies were submitted by Cerexa, Inc. to the US Food and Drug Administration (FDA) for approval of new drug application (NDA) 200327 on 30 December 2009. Results demonstrated that it was well tolerated in patients and has a consistent safety profile reflective of other cephalosporins [10].

Section snippets

Historical background

In 2003, Ishikawa et al. discovered ceftaroline fosamil, which was developed by Takeda Chemical Industries Ltd. (Osaka, Japan), and an investigational new drug application was submitted in December 2004. More recently, on 8 September 2010, Forest Laboratories received FDA advisory committee approval for the treatment of complicated skin and skin-structure infections (cSSSIs) and community-associated pneumonia (CAP) following completion of phase III clinical trials. The developmental pathway of

Physiochemical properties

According to International Nonproprietary Names for Pharmaceutical Substances (INN), ceftaroline fosamil is an anhydrous, acetate-free compound with the molecular formula C22H21N8O8PS4 and a molecular weight of 684.68 atomic mass units (amu) [16]. The melting point of the prodrug as reported in the literature [4] is 221–223 °C (decomposed). Solubility of the prodrug in water is better (>100 mg/mL) than that of ceftaroline (2.3 mg/mL) at pH 7.0, whilst maintaining good stability for a period of 8 h

Chemistry and structure–activity relationship

Ceftaroline is a β-lactam antibiotic that is chemically 3-[4-(1-methyl-4-pyridinio)-1,3-thiazol-2-yl]thio-7β-[2-(5-phosphonoamino-1,2,4-thiadiazol-3-yl)-2(Z)-ethoxyiminoacetamido]-3-cephem-4-carboxylate acetic acid solvate.

As observed with a variety of cephalosporins, variation in position 7 of the acyl amino side chain and substitution on the cephem ring contribute different activity profiles [18].

  • The side chain containing an alkoxyimino group at the C-7 acyl moiety provided in vitro anti-MRSA

Mechanism of action

Ceftaroline's action is similar to that of other β-lactams as it exerts its bactericidal effect by binding to membrane PBPs that are responsible for transpeptidase or transglycosidase reactions in cell wall biosynthesis [20], [21], [22], [23]. Their inhibition produces a lethal effect on the bacterial cell wall, leading to bacterial death.

There are four natural PBPs in S. aureus and ceftaroline binds to all of them, but with maximum affinity for PBP2a. This feature is utilised against MRSA,

Antimicrobial spectrum

In vitro studies indicate that ceftaroline has a similar antimicrobial spectrum to ceftobiprole, the only other member of this unnamed subclass of cephalosporins [27]. Its antimicrobial spectrum [28], [29], [30], [31], [32], [33], [34], [35], [36], [37] is presented in Table 1.

Resistance

By virtue of its bactericidal mode of action, ceftaroline has a low propensity for development of resistance. In fact, resistance to ceftaroline occurs at low frequency in vitro for all key pathogens. Intrinsic resistance requires resistance–nodulation–cell division (RND) pumps in Gram-negative bacteria for whom the predominant mode of resistance is hydrolysis of β-lactam rings by β-lactamase enzymes, whilst in Gram-positive bacteria it is through modification of PBPs either by gene acquisition

Absorption

Pharmacokinetic data for ceftaroline obtained from studies performed in healthy adult volunteers [45], [46], [47] following single and multiple varied doses are summarised in Table 2. Maximum plasma concentration (Cmax) and the area under the concentration–time curve (AUC) for the prodrug, ceftaroline and inactive ceftaroline metabolite increased approximately in proportion to dose and were independent of dosing duration. There is no accumulation of drug over the dose range for the population

Pharmacodynamics

Andes and Craig [51] suggested that the percent of the time that the serum concentration was above the MIC (%T > MIC) was the best pharmacokinetic/pharmacodynamic (PK/PD) parameter to predict the efficacy of ceftaroline. The magnitude of the PK/PD index for ceftaroline was initially evaluated in the murine neutropenic thigh infection model with several organisms. A bacteriostatic effect was achieved when free drug concentration exceeded the MIC for 30% of the dosing interval (30%T > MIC) for

Adverse effects and drug interactions

Clinical phase I, II and III trials showed mild adverse effects with a good safety profile for ceftaroline compared with other cephalosporins. The most common treatment-related adverse effects observed with ceftaroline were diarrhoea (4.2–6.5%), nausea (2.3–6.2%), headache (3.4–5.3%), insomnia (3.1–3.5%), crystalluria (9%) and elevated levels of blood creatine phosphokinase, alanine aminotransferase and aspartate aminotransferase [52], [53], [54]. Ceftaroline also causes a change in the colour

Dose

The proposed clinical dosing regimen of ceftaroline is 600 mg every 12 h (q12h) as a 1-h i.v. infusion for 5–7 days for the treatment of CAP and for 5–14 days for cSSSIs [52], [54]. No dose adjustment is needed in patients with mild renal impairment [creatinine clearance (CLCr) >50–80 mL/min), whilst a dosage reduction to 400 mg i.v. q12h is recommended in patients with moderate renal impairment (CLCr > 30–50 mL/min) [50]. At present, no specific guidelines are available for dosage adjustment in

Therapeutic efficacy

Ceftaroline showed good activity and superior bactericidal activity against hospital- and community-associated MRSA, including isolates positive for the Panton–Valentine leukocidin (pvl) gene, heterogeneous vancomycin-intermediate S. aureus (hVISA), vancomycin-intermediate S. aureus (VISA), vancomycin-resistant S. aureus (VRSA) and quinupristin/dalfopristin-non-susceptible, tetracycline-resistant, mupirocin-resistant, linezolid-resistant, daptomycin-non-susceptible and fluoroquinolone-resistant

Future development

Emergence of antibacterial resistance is ever-persisting and requires lead or novel analogues to combat it. ESBL-producing bacteria are of particular concern because of the emergence of multidrug-resistant isolates. As ceftaroline is labile to many β-lactamases, such as AmpC and extended-spectrum types, it is being trialled in combination with NXL104 [62], [63] [trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-2-carboxamidesodium salt]. This is a novel inhibitor of serine β-lactamase, in a

Acknowledgment

The authors would like to thank the management of the Rajendra Institute of Technology & Sciences (Sirsa, India) for providing the necessary support and encouragement for carrying out this review.

Funding: No funding sources.

Competing interests: None declared.

Ethical approval: Not required.

References (64)

  • S. Mushtaq et al.

    In vitro activity of ceftaroline (PPI-0903M, T-91825) against bacteria with defined resistance mechanisms and phenotypes

    J Antimicrob Chemother

    (2007)
  • H.S. Sader et al.

    Antimicrobial activity and spectrum of PPI-0903M (T-91825), a novel cephalosporin, tested against a worldwide collection of clinical strains

    Antimicrob Agents Chemother

    (2005)
  • R. Corey et al.

    CANVAS-1: randomized, double-blinded, phase 3 study (P903-06) of the efficacy and safety of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin structure infections (cSSSIs)

  • C. Vidaillac et al.

    In vitro activity of ceftaroline against methicillin-resistant Staphylococcus aureus and heterogeneous vancomycin-intermediate S. aureus in a hollow fiber model

    Antimicrob Agents Chemother

    (2009)
  • T. Ishikawa et al.

    Studies on anti-MRSA parenteral cephalosporins. I. Synthesis and antibacterial activity of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-hydroxyiminoacetamido]-3-(substituted imidazo[1,2-b]-pyridazinium-1-yl)methyl-3-cephem-4-carboxylates and related compounds

    J Antibiot (Tokyo)

    (2000)
  • T. Ishikawa et al.

    Studies on anti-MRSA parenteral cephalosporins. II. Synthesis and antibacterial activity of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-alkoxyiminoacetamido]-3-(substituted imidazo[1,2-b]pyridazinium-1-yl)methyl-3-cephem-4-carboxylates and related compounds

    J Antibiot (Tokyo)

    (2000)
  • T. Ishikawa et al.

    Studies on anti-MRSA parenteral cephalosporins. III. Synthesis and antibacterial activity of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-alkoxyiminoacetamido]-3-[(E)-2-(1-alkylimidazo[1,2-b]pyridazinium-6-yl)thiovinyl]-3-cephem-4-carboxylates and related compounds

    J Antibiot (Tokyo)

    (2001)
  • T. Ishikawa et al.

    Studies on anti-MRSA parenteral cephalosporins. IV. A novel water-soluble N-phosphono type prodrug for parenteral administration

    J Antibiot (Tokyo)

    (2001)
  • World Health Organization. International nonproprietary names for pharmaceutical substances (INN): list 59. WHO Drug...
  • Forest Laboratories, Inc. Soluble dosage forms containing cephem derivatives suitable for parenteral administration....
  • G. Patrick

    An introduction to medicinal chemistry

    (2005)
  • G.P. Page

    Emerging cephalosporins

    Expert Opin Emerg Drugs

    (2007)
  • E. Sauvage et al.

    The penicillin-binding proteins: structure and role in peptidoglycan biosynthesis

    FEMS Microbiol Rev

    (2008)
  • C. Goffin et al.

    Biochemistry and comparative genomics of SxxK superfamily acyltransferases offer a clue to the mycobacterial paradox: presence of penicillin-susceptible target proteins versus lack of efficiency of penicillin as therapeutic agent

    Microbiol Mol Biol Rev

    (2002)
  • I. Massova et al.

    Kinship and diversification of bacterial penicillin-binding proteins and β-lactamases

    Antimicrob Agents Chemother

    (1998)
  • A.L. Koch

    Bacterial wall as target for attack: past, present, and future research

    Clin Microbiol Rev

    (2003)
  • N.L. Ben Zakour et al.

    Pathogenomics of the staphylococci: insights into niche adaptation and the emergence of new virulent strains

    FEMS Microbiol Lett

    (2008)
  • H.P.M. Moisan et al.

    Binding of ceftaroline (CPT) to penicillin-binding proteins (PBPs) of Streptococcus pneumoniae (SPN) and methicillin-resistant Staphylococcus aureus (MRSA)

  • Clinical and Laboratory Standards Institute. http://www.clsi.org [accessed 8 February...
  • C. Jacqueline et al.

    Efficacy of the new cephalosporin ceftaroline in the treatment of experimental methicillin-resistant Staphylococcus aureus acute osteomyelitis

    J Antimicrob Chemother

    (2010)
  • Y. Ge et al.

    Comparative pharmacokinetics of ceftaroline in rats, rabbits, and monkeys following a single intravenous or intramuscular injection

    Antimicrob Agents Chemother

    (2010)
  • C. Jacqueline et al.

    In vivo activity of a novel anti-methicillin-resistant Staphylococcus aureus cephalosporin, ceftaroline, against vancomycin-susceptible and -resistant Enterococcus faecalis strains in a rabbit endocarditis model: a comparative study with linezolid and vancomycin

    Antimicrob Agents Chemother

    (2009)
  • Cited by (0)

    View full text