Virginie Le Mabecque

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.

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.

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.

Efficacy of ceftolozane in a murine model of Pseudomonas aeruginosa acute pneumonia: in vivo antimicrobial activity and impact on host inflammatory response

OBJECTIVES To assess the activity of ceftolozane, a novel oxyimino-cephalosporin, in comparison with ceftazidime and piperacillin/tazobactam against a multidrug-resistant Pseudomonas aeruginosa strain using a murine model of pneumonia. METHODS Quantitative bacteriology, survival, histological examination, myeloperoxidase activity, proinflammatory cytokine levels in lungs and endothelial permeability were evaluated to determine the effects of ceftolozane and comparators on P. aeruginosa-induced pneumonia. RESULTS After 48 h of treatment, ceftolozane reduced the bacterial load by 3-4 log(10) cfu/g of lung. Systemic dissemination of the pulmonary infection and development of lung damage were inhibited in all β-lactam-treated animals. P. aeruginosa-induced pneumonia led to elevated concentrations of tumour necrosis factor-α, interleukin (IL)-1β and macrophage inflammatory protein (MIP)-2 in the lungs. While the levels of proinflammatory cytokines decreased following ceftazidime and piperacillin/tazobactam therapy, ceftolozane exhibited increased concentrations of IL-1β and MIP-2 after 24 h of infection, resulted in significantly increased levels of recruited neutrophils within the infected lung without increasing lung endothelial permeability. CONCLUSIONS These data strongly support ceftolozane as an effective option for the treatment of severe P. aeruginosa respiratory infections by improving the early pulmonary inflammatory response without impairing 48 h post-infection homeostasis.

Activity of Glycopeptides against Staphylococcus aureus Infection in a Rabbit Endocarditis Model: MICs Do Not Predict In Vivo Efficacy

ABSTRACT The in vivo efficacy of vancomycin and teicoplanin against five Staphylococcus aureus strains with different susceptibilities to them and methicillin was studied. Rabbits were allocated at random to groups for endocarditis induction with one of these five strains and then treated for 2 days with vancomycin or teicoplanin. Each treated group was compared with a control group infected with the same strain. Vancomycin and teicoplanin showed similar activities. Low MICs did not predict better in vivo results.

Evaluation of the in vivo efficacy of intramuscularly administered ceftaroline fosamil, a novel cephalosporin, against a methicillin-resistant Staphylococcus aureus strain in a rabbit endocarditis model

Sir, Ceftaroline fosamil is the prodrug form of a novel, parenteral, broad-spectrum cephalosporin, ceftaroline, exhibiting bactericidal activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA), as well as common Gram-negative pathogens. To date, Phase III trials using intravenous (iv) administration of ceftaroline fosamil (herein after referred to as ceftaroline) have been completed for complicated skin and skin structure infections and for community-associated pneumonia. Pathogens such as MRSA are becoming more virulent and are no longer confined to acute-care settings. Ceftaroline may be administered by both iv and intramuscular (im) routes, facilitating outpatient antibiotic therapy for MRSA. Recently, Ge et al. assessed the pharmacokinetic profile for iv and im ceftaroline treatment in different animal species, and demonstrated favourable pharmacokinetic profiles following im administration. Teicoplanin, a glycopeptide antibiotic, may be administered either intravenously or intramuscularly and was used as a positive control. The aim of the present study was to assess the in vivo activity of three different doses of ceftaroline against MRSA compared with teicoplanin after im administration in a rabbit model of endocarditis. In the present study, we used an MRSA strain (P9) isolated from blood cultures exhibiting heterogeneous high-level methicillin resistance (methicillin MIC1⁄4128 mg/L). MICs of ceftaroline, teicoplanin and vancomycin were 1, 0.5 and 1 mg/L, respectively. In vivo studies were performed with New Zealand white female rabbits weighing 2.5–3.0 kg. Animals were treated in accordance with institutional policies and the guidelines stipulated by the animal welfare committee. The Committee of Animal Ethics of the University of Nantes approved all animal experimentation in this study. Using a well-established rabbit endocarditis model, experimental endocarditis was induced with an inoculum of 10 cfu of the MRSA isolate. Treatment was started 24 h after inoculation and antibiotics (ceftaroline and teicoplanin) were administered twice daily using the im route for 4 days. Animals (10 per group) were randomly assigned to no treatment (controls), 40 mg/kg ceftaroline im twice daily, 20 mg/kg ceftaroline im twice daily, 5 mg/kg ceftaroline im twice daily or 20 mg/kg teicoplanin im twice daily. Animals were euthanized at the beginning of the treatment period (controls) or at the end of the im treatment (12 h after the last injection). Aortic valve vegetations were excised, weighed and homogenized in 0.5 mL of saline buffer and used for quantitative cultures on agar. Bacterial counts were determined after 24 h of incubation at 378C. The lower detection limit was 1 cfu per 50 mL of undiluted vegetation homogenate. Statistical analyses were performed with GraphPad Prism software (version 4.0; GraphPad Software, San Diego, CA, USA). Analysis of variance was used to compare the antibacterial effects (bacterial counts) between the different groups, followed by a Bonferroni’s test to compare groups two by two. A P value of ≤0.05 was considered significant. After im administration of 5, 20 and 40 mg/kg doses of ceftaroline, the Cmax increased approximately in proportion to the dose (5.18, 15.75 and 37.85 mg/L, respectively) and the plasma half-life increased from 0.74 to 1.14 h. The in vivo outcome after a 4 day treatment regimen and the rate of sterilization of the vegetations produced by the MRSA strain are shown in Table 1. A dose-dependent response was observed with sterilization rates for ceftaroline of 100%, 80% and 33% for the 40, 20 and 5 mg/kg ceftaroline doses, respectively. The difference between the 20 and 40 mg/kg doses was not statistically significant (P.0.05). In vivo bactericidal activity was consistent across all animals tested at the 40 mg/kg dose and for most animals (8/10) at the 20 mg/kg dose of ceftaroline. As a positive control, 20 mg/kg teicoplanin im demonstrated bactericidal activity, with a sterilization rate of 60%. Using murine thigh and lung infection models, Andes and Craig determined that the T.MIC was the pharmacokinetic– pharmacodynamic parameter that best correlated with efficacy of ceftaroline. In our study, the mean %T.MICs for a 1 mg/L target with 20 mg/kg ceftaroline given by im injection were 46% and 31% over 8 and 12 h, respectively. Using an infective endocarditis rabbit model, the %T.MICs attained with im administration were associated with bactericidal activity against MRSA after a 4 day treatment. The efficacy of im ceftaroline in the present study was similar to that

Efficacy of doripenem in the treatment of Pseudomonas aeruginosa experimental pneumonia versus imipenem and meropenem

OBJECTIVES The aim of this study was to compare doripenem with imipenem and meropenem in an experimental rabbit model of Pseudomonas aeruginosa pneumonia and then to compare different doripenem doses and methods of intravenous administration. METHODS Using a rabbit experimental model of pneumonia, efficacy was assessed following 2 days of treatment by colony counts of different tissues (lung, spleen and blood culture). RESULTS Mean pulmonary bacterial loads were 3.17 ± 0.53, 3.42 ± 0.61 and 2.75 ± 0.59 log(10) cfu/g for imipenem, doripenem (0.5 g three times daily) and meropenem, respectively, compared with 7.57 ± 0.99 cfu/g for control animals. At a higher dose (1 g three times daily), doripenem showed significantly better efficacy (2.70 ± 0.65 log(10) cfu/g) than the standard regimen of doripenem. Sterilization of spleen cultures was achieved with standard regimens of imipenem (1 g three times daily) and a higher dose of doripenem. CONCLUSIONS In this model of P. aeruginosa pneumonia, doripenem had an efficacy equivalent to that of meropenem and imipenem at a high dose of 1 g three times a day and lower efficacy at a standard dose (0.5 g three times daily) than the other two agents in terms of bacteria cultivated from spleens. Doripenem is a new drug that offers new therapeutic options, especially for difficult-to-treat infections such as pneumonia due to non-fermenting Gram-negative bacteria.