Cédric Jacqueline

In Vivo Efficacy of Ceftaroline (PPI-0903), a New Broad-Spectrum Cephalosporin, Compared with Linezolid and Vancomycin against Methicillin-Resistant and Vancomycin-Intermediate Staphylococcus aureus in a Rabbit Endocarditis Model

ABSTRACT Using the rabbit endocarditis model, we compared the activity of a new broad-spectrum cephalosporin, ceftaroline, with those of linezolid and vancomycin against methicillin-resistant Staphylococcus aureus. After a 4-day treatment, ceftaroline exhibited superior bactericidal in vivo activity against resistant S. aureus strains and appeared to be the most effective drug against a heterogeneous glycopeptide-intermediate S. aureus strain.

In Vitro and In Vivo Synergistic Activities of Linezolid Combined with Subinhibitory Concentrations of Imipenem against Methicillin-Resistant Staphylococcus aureus

ABSTRACT Indifference or moderate antagonism of linezolid combined with other antibiotics in vitro and in vivo have mainly been reported in the literature. We have assessed the in vitro activities of linezolid, alone or in combination with imipenem, against methicillin-resistant Staphylococcus aureus (MRSA) strains using the dynamic checkerboard and time-kill curve methods. Linezolid and low concentrations of imipenem had a synergistic effect, leading us to evaluate the in vivo antibacterial activity of the combination using the rabbit endocarditis experimental model. Two MRSA strains were used for in vivo experiments: one was a heterogeneous glycopeptide-intermediate clinical S. aureus strain isolated from blood cultures, and the other was the S. aureus COL reference strain. Animals infected with one of two MRSA strains were randomly assigned to one of the following treatments: no treatment (controls), linezolid (simulating a dose in humans of 10 mg/kg of body weight every 12 h), a constant intravenous infusion of imipenem (which allowed the steady-state concentration of about 1/32 the MIC of imipenem for each strain to be reached in serum), or the combination of both treatments. Linezolid and imipenem as monotherapies exhibited no bactericidal activity against either strain. The combination of linezolid plus imipenem showed in vivo bactericidal activity that corresponded to a decrease of at least 4.5 log CFU/g of vegetation compared to the counts for the controls. In conclusion, the combination exhibited synergistic and bactericidal activities against two MRSA strains after 5 days of treatment. The combination of linezolid plus imipenem appears to be promising for the treatment of severe MRSA infections and merits further investigations to explore the mechanism underlying the synergy between the two drugs.

In Vivo Efficacy of Continuous Infusion versus Intermittent Dosing of Linezolid Compared to Vancomycin in a Methicillin-Resistant Staphylococcus aureus Rabbit Endocarditis Model

ABSTRACT Linezolid is the first drug issued from the oxazolidinones, a novel class of antimicrobial agents with potent activity against gram-positive pathogens. A rabbit endocarditis model was used to compare the in vivo activities of different linezolid regimens mimicking intermittent dosing of 10 mg/kg of body weight every 12 h for 5 days or continuous (constant-rate) infusion of a daily dose of 20 mg/kg (for 5 days) or 40 mg/kg (for 3 and 5 days) and the activities of intermittent dosing and continuous infusion of vancomycin (for 5 days). The in vivo activities of these regimens were tested against three strains of methicillin-resistant Staphylococcus aureus. A human-like pharmacokinetic simulation was used for linezolid in order to improve the extrapolation of the results to human therapy. All linezolid regimens significantly reduced the numbers of S. aureus cells in aortic valve vegetations compared to the numbers in the control groups. Linezolid intermittent dosing had an in vivo bacteriostatic effect. Switching from intermittent dosing to continuous infusion (at the same dose) led to in vivo bactericidal activity, with a decrease of at least 3 log10 CFU/g of vegetation compared to the counts for the controls. After 5 days of treatment, continuous infusion of linezolid (corresponding to a daily dose of 40 mg/kg in humans) seemed to be at least as effective as vancomycin against the three strains. No resistant variant was isolated from the vegetations during any of the treatments. These data suggest that continuous infusion of linezolid could be an appropriate alternative to the use of glycopeptides for the treatment of severe methicillin-resistant S. aureus infections.

Efficacy of the new cephalosporin ceftaroline in the treatment of experimental methicillin-resistant Staphylococcus aureus acute osteomyelitis

OBJECTIVES To evaluate the activity of a new cephalosporin, ceftaroline, in comparison with other antistaphylococcal drugs (linezolid and vancomycin) at projected human therapeutic doses against methicillin-resistant Staphylococcus aureus (MRSA) and glycopeptide-intermediate S. aureus (GISA) strains. METHODS Using a rabbit experimental model of acute osteomyelitis, efficacy was assessed following 4 days of treatment by colony counts of infected bone tissues (joint fluid, femoral bone marrow and bone). RESULTS Although vancomycin remains the standard treatment for MRSA osteomyelitis, it was ineffective against the MRSA strain and poorly active against GISA infections in this model. Ceftaroline and linezolid demonstrated significant activity in bone marrow and bone, and were significantly better than vancomycin treatment. However, ceftaroline was the only drug to exhibit significant activity against MRSA in infected joint fluid. CONCLUSIONS The present study supports ceftaroline as a promising therapeutic option for the treatment of severe MRSA infections, including osteomyelitis.

Efficacy of daptomycin combined with rifampicin for the treatment of experimental meticillin-resistant Staphylococcus aureus (MRSA) acute osteomyelitis

Daptomycin exhibits rapid bactericidal activity against Gram-positive organisms, including meticillin-resistant Staphylococcus aureus (MRSA). Daptomycin in combination with rifampicin needs to be assessed in bone infection. An MRSA acute osteomyelitis model was used. Daptomycin and vancomycin were compared, alone or in combination with rifampicin, over 4 days. Surviving bacteria were counted in bone, bone marrow and joint fluid. Vancomycin and daptomycin as single therapies were ineffective, but both combinations were significantly more effective than the corresponding monotherapy. Combination of daptomycin and rifampicin could prevent S. aureus from developing resistance. This combination could be a useful alternative to treat MRSA osteomyelitis at an early stage.

Impact of bacterial biofilm on the treatment of prosthetic joint infections

Microbial biofilm contributes to chronic infection and is involved in the pathogenesis of prosthetic joint infections. Biofilms are structurally complex and should be considered a dynamic system able to protect the bacteria from host defence mechanisms and from antibacterial agents. Despite the use of antibiotics recognized as effective against acute infections, prosthetic joint infections require long-term suppressive treatment acting on adherent bacteria. Conventional in vitro susceptibility testing methods are not suitable for biofilm-associated infections given that these tests do not take into account the physiological parameters of bacterial cells in vivo. Most anti-staphylococcal drugs are able to inhibit in vitro the adhesion of bacteria to a surface, considered to be the first step in biofilm formation. Recent studies suggest that the lack of activity of antibiotics against biofilm-embedded bacteria seems to be more related to the decreased effect of the drug on the pathogen than to the poor penetration of the drug into the biofilm. Eradication of biofilm-embedded bacteria is a very difficult task and combination therapy is required in the treatment of persistent infections involving biofilm. Although several combinations demonstrate potent efficacy, rifampicin is the most common partner drug of effective combinations against staphylococcal biofilms. Considering the complexity of biofilm-related infections, further studies are needed to assess the activity of new therapeutic agents in combination with antibiotics (quorum-sensing inhibitors, biofilm disruptors and specific anti-biofilm molecules).

pH-controlled delivery of gentamicin sulfate from orthopedic devices preventing nosocomial infections

Since the beginning of the 1970s, controlled release technology has witnessed great advancement, and motivated numerous researchers in materials science. These systems overcome the drawbacks of traditional drug dosage form, and offer more effective and favorable methods to optimize drug delivery in optimum dose to specific sites or to prolong delivery duration. This paper deals with the synthesis of pH-controlled drug delivery systems for bone implant, allowing the local release of gentamicin sulfate (GS), an antibiotic commonly used to prevent infections during orthopedic surgeries. We present a biomaterial synthesis allowing the controlled release of GS at the site of surgical implantation (over an adjustable period of time). In our design, spherical nanoparticles (NPs) functionalized by the chosen antibiotic (Gentamicin sulfate, GS), are chemically anchored to the biomaterial surface. A cleavage reaction of the chemical bond between NPs and GS, effected by the contact of material with a solution presenting an acidic pH (in the case of infection, there is a decrease of the physiological medium pH), induces controlled release of the bioactive molecule in its native form. In this paper, we discuss the synthesis of a bioactive titanium based biomaterial in general, and the grafting of the NPs onto the titanium surfaces in particular. We have paid particular attention to the characterization of the drug surface density and the release kinetic of the active molecule as a function of the pH. In vitro bacterial growth inhibition tests after GS delivery at acidic pH (with Staphylococcus aureus) have also been carried out in order to prove the efficiency of such biomaterials.

Comparison of ceftaroline fosamil, daptomycin and tigecycline in an experimental rabbit endocarditis model caused by methicillin-susceptible, methicillin-resistant and glycopeptide-intermediate Staphylococcus aureus

OBJECTIVES The aim of this study was to compare the in vivo activities of the new antistaphylococcal drugs ceftaroline fosamil, daptomycin and tigecycline at projected human therapeutic doses against methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA) and glycopeptide-intermediate S. aureus (GISA) strains in a rabbit model of endocarditis. METHODS The efficacy of therapeutic regimens in our model was evaluated following 4 days of treatment by determining colony counts of infected vegetations. Emergence of resistant variants during therapy was assessed. RESULTS Using this model of infective endocarditis, ceftaroline fosamil and daptomycin demonstrated high bactericidal in vivo activity (reduction of >5 log(10) cfu/g of vegetation) after a 4 day treatment against MSSA, MRSA and GISA strains. Both drugs were more efficacious than tigecycline, which showed moderate activity but failed to exhibit a bactericidal effect. Ceftaroline was superior to daptomycin in terms of sterilization of the vegetations. Emergence of resistant variants during daptomycin therapy was observed in two animals (one in the MSSA group and one in the MRSA group) but was not observed in ceftaroline- or tigecycline-treated animals. CONCLUSIONS The novel β-lactam agent ceftaroline fosamil was the most active bactericidal drug in this model and is a promising therapeutic option for the treatment of severe S. aureus infections, including those caused by MRSA and GISA strains.

In Vitro and In Vivo Assessment of Linezolid Combined with Ertapenem: a Highly Synergistic Combination against Methicillin-Resistant Staphylococcus aureus

ABSTRACT Linezolid in combination with ertapenem showed in vitro synergy against methicillin-resistant Staphylococcus aureus strains. We confirmed this interaction in vivo by using a rabbit endocarditis experimental model and simulation of the human pharmacokinetics in animals for both antibiotics. Linezolid plus ertapenem exhibited highly synergistic activity in vivo after 4 days of treatment.

In Vivo Activity of a Novel Anti-Methicillin-Resistant Staphylococcus aureus Cephalosporin, Ceftaroline, against Vancomycin-Susceptible and -Resistant Enterococcus faecalis Strains in a Rabbit Endocarditis Model: a Comparative Study with Linezolid and Vancomycin

ABSTRACT We assessed the in vitro and in vivo efficacy of the novel parenteral broad-spectrum cephalosporin ceftaroline against Enterococcusfaecalis in time-kill experiments and in a rabbit endocarditis model with simulated human dosing. Ceftaroline was more active than either vancomycin or linezolid against vancomycin-sensitive and -resistant isolates of E. faecalis.