In vitro activity of ceftaroline (PPI-0903M, T-91825) against bacteria with defined resistance mechanisms and phenotypes.
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 beta-lactamases, and were much higher for those with extended-spectrum beta-lactamases (ESBLs), hyperproduced AmpC or K1 enzymes. MICs for strains with classical TEM/SHV beta-lactamases rose if the inoculum was increased to 10(6) cfu/spot; this effect was even more marked for those with ESBLs. Resistance due to Class A beta-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 beta-lactam. Haemophilus influenzae and Moraxella catarrhalis were very susceptible, although with marginally raised MICs for beta-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 beta-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.
Mushtaq
Shazad
S
Antibiotic Resistance Monitoring and Reference Laboratory, Health Protection Agency Centre for Infections, 61 Colindale Avenue, London NW9 5EQ, UK.
Warner
Marina
M
Ge
Yigong
Y
Kaniga
Koné
K
Livermore
David M
DM
D000150:Acinetobacter / Q000187:drug effects; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics; D001439:Bacteroides / Q000187:drug effects; D002511:Cephalosporins / Q000494:pharmacology*; D019818:Clavulanic Acid / Q000494:pharmacology; D003227:Conjugation, Genetic; D004338:Drug Combinations; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004755:Enterobacteriaceae / Q000187:drug effects; D004756:Enterobacteriaceae Infections / Q000382:microbiology; D016983:Enterococcus / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006801:Humans; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010641:Phenotype; D012140:Respiratory Tract Diseases / Q000382:microbiology; D013210:Staphylococcus / Q000187:drug effects; D001618:beta-Lactamases / Q000235:genetics; D000097583:Ceftaroline
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002511:Cephalosporins; D019818:Clavulanic Acid; D004338:Drug Combinations; D001618:beta-Lactamases; D000097583:Ceftaroline; C048795:AmpC beta-lactamases