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

• Published in: Journal of antimicrobial chemotherapy 2007-08, Vol.60 (2), p.300-311
• Main Authors: Mushtaq, Shazad, Warner, Marina, Ge, Yigong, Kaniga, Koné, Livermore, David M.
• Format: Article
• Language: English
• Subjects: Acinetobacter; Acinetobacter - drug effects; Anti-Bacterial Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacteria; Bacteria - drug effects; Bacteria - genetics; Bacterial Proteins - genetics; Bacteroides - drug effects; beta-Lactamases - genetics; Biological and medical sciences; Ceftaroline; Cephalosporins - pharmacology; Chemotherapy; Citrobacter; Clavulanic Acid - pharmacology; Conjugation, Genetic; Drug Combinations; Drug resistance; Drug Resistance, Bacterial - genetics; Enterobacter; Enterobacteriaceae; Enterobacteriaceae - drug effects; Enterobacteriaceae Infections - microbiology; Enterococcus - drug effects; Enterococcus faecalis; ESBLs; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - genetics; Genotype & phenotype; Gram-Negative Bacteria - drug effects; Haemophilus influenzae; Humans; inoculum effects; Klebsiella; Medical sciences; Methicillin Resistance; Microbial Sensitivity Tests; Moraxella catarrhalis; Morganella morganii; Mutation; Pharmacology; Pharmacology. Drug treatments; Phenotype; Respiratory Tract Diseases - microbiology; Serratia; Staphylococcus - drug effects; Staphylococcus aureus; Streptococcus pneumoniae; β-lactamases
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkm150

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 β-lactamases, and were much higher for those with extended-spectrum β-lactamases (ESBLs), hyperproduced AmpC or K1 enzymes. MICs for strains with classical TEM/SHV β-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 β-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 β-lactam. Haemophilus influenzae and Moraxella catarrhalis were very susceptible, although with marginally raised MICs for β-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 β-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.