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

Abstract

Ceftaroline, 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 of Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, Moraxella catarrhalis, Klebsiella pneumoniae, Staphylococcus aureus, and Enterococcus faecalis with elevated MICs. S. pneumoniae and S. pyogenes isolates in the present study were highly susceptible to ceftaroline (MIC range, 0.004 to 0.25 g/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 for H. influenzae and M. catarrhalis were 0.06 to 2 g/ml for four strains and 8 g/ml for a ␤-lactamase-positive, efflux-positive H. influenzae with a mutation in L22. One H. influenzae clone with an increased ceftaroline MIC (quinolone-resistant, ␤-lactamase-positive) was recovered after 20 days. The ceftaroline MIC for this isolate increased 16-fold, from 0.06 to 1 g/ml. MICs for S. aureus ranged from 0.25 to 1 g/ml. No S. aureus isolates tested with ceftaroline had clones with increased MIC (>4-fold) after 50 passages. Two E. faecalis isolates tested had ceftaroline MICs increased from 1 to 8 g/ml after 38 days and from 4 to 32 g/ml after 41 days, respectively. The parental ceftaroline MIC for the one K. pneumoniae extended-spectrum ␤-lactamase-negative isolate tested was 0.5 g/ml and did not change after 50 daily passages.

Resistencia a antibióticos de última línea en cocos Gram positivos: la era posterior a la vancomicina

“…Aunque sigue siendo activa, la ceftarolina en E. faecalis presenta CIM más altas, con una CIM 50 de 2 µg/ml y una CIM 90 de 4 µg/ml (133,135). Algunos estudios in vitro de selección de cepas resistentes, incluidas cepas de SARM-AC, S. aureus con heterorresistencia a la vancomicina, S. aureus sensible a la meticilina y S. pneumoniae resistente a la penicilina, no detectaron altos niveles de resistencia, lo que sugiere que la probabilidad de la emergencia de resistencia in vivo frente a esta nueva cefalosporina es baja (132,137,138).…”

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

“…However, its activity is adversely affected by increased efflux in A. baumannii and P. aeruginosa (955). Moreover, several new cephalosporin-␤-lactamase-inhibitor combinational products in clinical trials (e.g., ceftazidime-avibactam, ceftaroline-avibactam, and ceftolozane-tazobactam) (944) are still likely to be the substrates of RND pumps, as are other ␤-lactams and ␤-lactamase inhibitors (13,390,439,545), because avibactam cannot reverse efflux-mediated ceftazidime resistance (956), and both ceftaroline and ceftolozane (a new antipseudomonal cephalosporin) are still affected by efflux pump-and/or porin-related resistance mechanisms (although ceftolozane, containing multiple charged groups, appears less impacted by Mex pumps than many other ␤-lactams and did not select in vitro for pump overproducers in P. aeruginosa, unlike other agents) (417,(957)(958)(959). These observations could also illustrate their reduced or lack of synergistic activity against multidrug-resistant A. baumannii and P. aeruginosa (960)(961)(962).…”

No Decrease in Susceptibility to NVC-422 in Multiple-Passage Studies with Methicillin-Resistant Staphylococcus aureus, S. aureus, Pseudomonas aeruginosa, and Escherichia coli

“…ultiple-passage studies determine the effect of selective pressure of antibiotics on microorganisms (15), resulting in cumulative acquisition of mutations at the genetic level (3,5,6,13). The development of resistance is a result of the frequency of mutation, the number and type of mutations required to express resistance, the potency and concentration of the treating drug, and other factors (9,10,14).…”

“…Representative organisms Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and methicillin-resistant S. aureus (MRSA) were selected (1,3,12,17). Ciprofloxacin was selected as a broad-spectrum comparator.…”