ReviewCeftaroline: a comprehensive update
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].
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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].
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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.
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