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Published on: July 9, 2012
In vitro activity of ceftaroline (PPI-0903M, T-91825) against bacteria with defined resistance mechanisms and
Shazad Mushtaq1, Marina Warner, Yigong Ge
1Antibiotic Resistance Monitoring and Reference Laboratory, Health Protection Agency Centre for Infections, 61 Colindale Avenue, London NW9 5EQ, 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 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.
Insights
Ceftaroline demonstrates potent in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae. While some resistance was observed in Enterobacteriaceae, ceftaroline did not select for resistance in MRSA or S. pneumoniae.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Ceftaroline is a novel N-phosphono prodrug cephalosporin.
- Its in vitro antimicrobial activity and potential for resistance selection were investigated.
Purpose of the Study:
- To evaluate the in vitro activity of ceftaroline against various bacterial pathogens.
- To assess the potential for ceftaroline to select for antimicrobial resistance.
Main Methods:
- Minimum Inhibitory Concentrations (MICs) determined by CLSI agar dilution with varied inocula.
- Mutant selection evaluated through single- and multi-step procedures.
Main Results:
- Ceftaroline exhibited potent activity against MRSA (0.5-2 mg/L) and Streptococcus pneumoniae (MICs ≤ 0.09 mg/L).
- Activity against Enterobacteriaceae varied, with higher MICs for strains possessing beta-lactamases (TEM, ESBLs, AmpC).
- Resistance selection was observed in Enterobacteriaceae but not in Staphylococcus aureus, Haemophilus influenzae, or Streptococcus pneumoniae.
Conclusions:
- Ceftaroline possesses significant anti-MRSA and anti-pneumococcal activity.
- Exceptional lability to classical TEM and SHV beta-lactamases was noted, reversible with clavulanate.
- Resistance selection was limited to Enterobacteriaceae, not observed in Gram-positive pathogens.
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