JAC Advance Access originally published online on June 4, 2007
Journal of Antimicrobial Chemotherapy 2007 60(2):300-311; doi:10.1093/jac/dkm150
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In vitro activity of ceftaroline (PPI-0903M, T-91825) against bacteria with defined resistance mechanisms and phenotypes
1 Antibiotic Resistance Monitoring and Reference Laboratory, Health Protection Agency Centre for Infections, 61 Colindale Avenue, London NW9 5EQ, UK 2 Peninsula Pharmaceuticals Inc., 1751 Harbor Bay Parkway, Alameda, CA 94502, USA
Received 23 March 2007; returned 16 April 2007; revised 19 April 2007; accepted 19 April 2007
* Corresponding author. Tel: +44-20-8327-7223; Fax: +44-20-8327-6264; E-mail: david.livermore{at}hpa.org.uk
Background: Ceftaroline (PPI-0903M, T-91825) is a novel cephalosporin, administered as an N-phosphono prodrug. We investigated its in vitro activity and resistance selection potential.
Methods: MICs were determined by CLSI agar dilution, but with varied inocula. Mutant selection was investigated in single- and multi-step procedures.
Results: MICs for methicillin-resistant Staphylococcus aureus (MRSA) were 0.5–2 mg/L, compared with 0.12–0.25 mg/L for methicillin-susceptible S. aureus; corresponding values for coagulase-negative staphylococci were 0.25–2 and 0.06–0.12 mg/L, respectively. Even with 2% NaCl added, all MRSA were susceptible at 2 mg/L. MICs for Enterococcus faecalis were from 0.25 to 8 mg/L; E. faecium was resistant. MICs for Escherichia coli, Klebsiella spp., Morganella morganii and Proteeae without acquired resistance were 0.06–0.5 mg/L versus 0.12–1 mg/L for Enterobacter, Serratia and Citrobacter spp. and 2–8 mg/L for Acinetobacter spp. MICs rose to 1–2 mg/L for many Enterobacteriaceae with classical TEM ß-lactamases, and were much higher for those with extended-spectrum ß-lactamases (ESBLs), hyperproduced AmpC or K1 enzymes. MICs for strains with classical TEM/SHV ß-lactamases rose if the inoculum was increased to 106 cfu/spot; this effect was even more marked for those with ESBLs. Resistance due to Class A ß-lactamases was reversed by clavulanate. Geometric mean MICs were 0.005, 0.05 and 0.09 mg/L for penicillin-susceptible, -intermediate and -resistant Streptococcus pneumoniae strains, respectively—lower than for any comparator ß-lactam. Haemophilus influenzae and Moraxella catarrhalis were very susceptible, although with marginally raised MICs for ß-lactamase-positive Moraxella strains and for haemophili with chromosomal ampicillin resistance. Ceftaroline selected AmpC-derepressed Enterobacter mutants similarly to cefotaxime in single-step experiments; in multi-step procedures it selected ESBL variants of blaTEM in E. coli. Resistance selection was not seen with S. aureus, H. influenzae or pneumococci.
Conclusions: Ceftaroline has impressive anti-MRSA and anti-pneumococcal activity. Slight lability to classical TEM and SHV ß-lactamases is exceptional for an oxyimino-cephalosporin, but was reversible with clavulanate, as was the greater resistance mediated by ESBLs. Resistance selection occurred with Enterobacteriaceae, not MRSA.
Keywords: inoculum effects , ESBLs , ß-lactamases
Present address. Cerexa Inc., 1751 Harbor Bay Parkway, Alameda, CA 94502, USA.
Present address. Peninsula Pharmaceuticals Inc., 1900 Charleston Road, Mountain View, CA 94043, USA.
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