Multistep Resistance Development Studies of Ceftaroline in Gram-Positive and -Negative Bacteria

Abstract

ABSTRACTCeftaroline, the active component of the prodrug ceftaroline fosamil, is a novel broad-spectrum cephalosporin with bactericidal activity against Gram-positive and -negative isolates. This study evaluated the potential for ceftaroline and comparator antibiotics to select for clones ofStreptococcus pneumoniae,Streptococcus pyogenes,Haemophilus influenzae,Moraxella catarrhalis,Klebsiella pneumoniae,Staphylococcus aureus, andEnterococcus faecaliswith elevated MICs.S. pneumoniaeandS. pyogenesisolates in the present study were highly susceptible to ceftaroline (MIC range, 0.004 to 0.25 μg/ml). No streptococcal strains yielded ceftaroline clones with increased MICs (defined as an increase in MIC of >4-fold) after 50 daily passages. Ceftaroline MICs forH. influenzaeandM. catarrhaliswere 0.06 to 2 μg/ml for four strains and 8 μg/ml for a β-lactamase-positive, efflux-positiveH. influenzaewith a mutation in L22. OneH. influenzaeclone with an increased ceftaroline MIC (quinolone-resistant, β-lactamase-positive) was recovered after 20 days. The ceftaroline MIC for this isolate increased 16-fold, from 0.06 to 1 μg/ml. MICs forS. aureusranged from 0.25 to 1 μg/ml. NoS. aureusisolates tested with ceftaroline had clones with increased MIC (>4-fold) after 50 passages. TwoE. faecalisisolates tested had ceftaroline MICs increased from 1 to 8 μg/ml after 38 days and from 4 to 32 μg/ml after 41 days, respectively. The parental ceftaroline MIC for the oneK. pneumoniaeextended-spectrum β-lactamase-negative isolate tested was 0.5 μg/ml and did not change after 50 daily passages.