68 research outputs found
Evaluation of Ceftaroline Activity against Heteroresistant Vancomycin-Intermediate Staphylococcus aureus and Vancomycin-Intermediate Methicillin-Resistant S. aureus Strains in an In Vitro Pharmacokinetic/Pharmacodynamic Model: Exploring the “Seesaw Effect”
A “seesaw effect” in methicillin-resistant Staphylococcus aureus (MRSA) has been demonstrated, whereby susceptibility to β-lactam antimicrobials increases as glyco- and lipopeptide susceptibility decreases. We investigated this effect by evaluating the activity of the anti-MRSA cephalosporin ceftaroline against isogenic pairs of MRSA strains with various susceptibilities to vancomycin in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model. The activities of ceftaroline at 600 mg every 12 h (q12h) (targeted free maximum concentration of drug in serum [fCmax], 15.2 μg/ml; half-life [t1/2], 2.3 h) and vancomycin at 1 g q12h (targeted fCmax, 18 μg/ml; t1/2, 6 h) were evaluated against 3 pairs of isogenic clinical strains of MRSA that developed increased MICs to vancomycin in patients while on therapy using a two-compartment hollow-fiber PK/PD model with a starting inoculum of ∼107 CFU/ml over a 96-h period. Bacterial killing and development of resistance were evaluated. Expression of penicillin-binding proteins (PBPs) 2 and 4 was evaluated by reverse transcription (RT)-PCR. The achieved pharmacokinetic parameters were 98 to 119% of the targeted values. Ceftaroline and vancomycin were bactericidal against 5/6 and 1/6 strains, respectively, at 96 h. Ceftaroline was more active against the mutant strains than the parent strains, with this difference being statistically significant for 2/3 strain pairs at 96 h. The level of PBP2 expression was 4.4× higher in the vancomycin-intermediate S. aureus (VISA) strain in 1/3 pairs. The levels of PBP2 and PBP4 expression were otherwise similar between the parent and mutant strains. These data support the seesaw hypothesis that ceftaroline, like traditional β-lactams, is more active against strains that are less susceptible to vancomycin even when the ceftaroline MICs are identical. Further research to explore these unique findings is warranted.This work was funded by an investigator-initiated grant from Forest Laboratories. M.J.R. is funded in part by NIH R21A1092055-01.
We thank Abbott Laboratories for the use of the fluorescence polarization immunoassay analyzer for determination of vancomycin concentrations.
We also thank Alexander Tomasz (The Rockefeller University, New York, NY) for providing strains JH-1 and JH-9. M.J.R. has received grant support, consulted for, or provided lectures for Astellas, Cubist, Forest, Pfizer, Novartis, and Rib-X. B.J.W., M.E.S., and G.W.K. have no potential conflicts of interest to declare
A novel inhibitor of multidrug efflux pumps in Staphylococcus aureus
GG918, a synthetic inhibitor of P-glycoprotein-mediated mammalian tumour multidrug resistance, was found to be equipotent to reserpine in enhancing the in vitro activity of norfloxacin and ciprofloxacin against strains of Staphylococcus aureus expressing distinct efflux-related multidrug resistance pumps. Four- to eight-fold reductions in MICs of these fluoroquinolones were observed for SA-1199B, a strain that overexpresses NorA (the major S. aureus multidrug transporter), and SA-K2068, which possesses a multidrug efflux-related pump distinct from NorA. Neither inhibitor potentiated the activity of newer fluoroquinolones such as levofloxacin or moxifloxacin by more than two-fold, and this effect was observed only in SA-1199B and SA-K2068. GG918 and reserpine exposure resulted in two- to four-fold reductions in norfloxacin and ciprofloxacin MICs in a fluoroquinolone-susceptible control strain and in strains expressing the MsrA and TetK proteins, which mediate efflux-related resistance to macrolides and tetracyclines, respectively, suggesting inhibition of as yet uncharacterized pumps for which norfloxacin and ciprofloxacin are substrates. In the MsrA- and TetK-expressing strains no more than a two-fold augmentation of erythromycin or tetracycline activity was observed with either inhibitor, suggesting minimal, if any, inhibitory activity against these efflux proteins. Using GG918 as a lead compound, a structure–activity evaluation may reveal a more potent and broader spectrum inhibitor of S. aureus antibiotic efflux pumps
Antibacterial and resistance modifying activity of Rosmarinus officinalis
As part of a project to characterise plant-derived natural products that modulate bacterial multidrug resistance (MDR), bioassay-guided fractionation of a chloroform extract of the aerial parts of Rosmarinus officinalis led to the characterisation of the known abietane diterpenes carnosic acid (1), carnosol (2) and 12-methoxy-trans-carnosic acid. Additionally, a new diterpene, the cis A/B ring junction isomer of 12-methoxy-trans-carnosic acid, 12-methoxy-cis-carnosic acid (5), was isolated. The major components were assessed for their antibacterial activities against strains of Staphylococcus aureus possessing efflux mechanisms of resistance. Minimum inhibitory concentrations ranged from 16 to 64 μg/ml. Incorporation of 1 and 2 into the growth medium at 10 μg/ml caused a 32- and 16-fold potentiation of the activity of erythromycin against an erythromycin effluxing strain, respectively. Compound 1 was evaluated against a strain of S. aureus possessing the NorA multidrug efflux pump and was shown to inhibit ethidium bromide efflux with an IC50 of 50 μM, but this activity is likely to be related to the inhibition of a pump(s) other than NorA. The antibacterial and efflux inhibitory activities of these natural products make them interesting potential targets for synthesis
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