Gilles Amador

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.

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.

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.

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

In Vivo Assessment of the Antimicrobial Activity of a Calcium-Deficient Apatite Vancomycin Drug Delivery System in a Methicillin-Resistant Staphylococcus aureus Rabbit Osteomyelitis Experimental Model

ABSTRACT The antimicrobial activities of calcium-deficient apatite loaded with different concentrations (25, 100, and 500 μg/mg) of vancomycin as a filling biomaterial were evaluated in a methicillin-resistant Staphylococcus aureus (MRSA) rabbit acute osteomyelitis model. Bacterial counts in bone, bone marrow, and joint fluid samples treated with forms of the apatite were compared to those in tissue samples receiving a constant intravenous vancomycin infusion after 4 days. This study demonstrates that using a calcium-deficient apatite loaded with vancomycin dramatically decreases the bacterial counts in bone and marrow.

In vitro characterization of calcium phosphate biomaterial loaded with linezolid for osseous bone defect implantation.

Osteomyelitis is a severe bone infection frequently caused by Staphylococcus aureus, which shows significant resistance to methicillin. One therapeutic treatment would be to insert a bone substitute loaded to an antibiotic, which would enable the bone to be filled while the illness is being treated. Linezolid is an oxazolidinone antibiotic with a large spectrum of action. It is effective against most Gram-positive bacteria and displays a specific mode of action. The aim of this work was to study the association of linezolid with a calcium phosphate-deficient apatite matrix. Granules containing 10% and 50% linezolid were prepared by wet granulation and characterized. Porosity analyses performed by mercury porosimetry and scanning electron microscopy revealed that grain porosity with 50% linezolid was higher than that of the grains containing 10% linezolid. NMR analyses showed no change in structure of linezolid when linked to calcium-deficient apatite. These results were confirmed by studying the antibacterial activity of linezolid, which remained proportional to the quantity of loaded linezolid, proving that the antibiotic released was active. The in vitro release time varied from 9 days for granules containing 10% linezolid to 26 days for granules containing 50% linezolid.

Antibiotics Against Endocarditis – Past, Present and Future (Experimental Data)

“Bacterial infections are becoming increasingly resistant to existing antibiotics, and as the number of patients who have succumbed to these infections rises, the number of new antibiotics being developed continues to plummet.” This extract from a letter addressed to President Barack Obama by the president of Infectious Diseases Society of America (IDSA) attests to the urgent need for new therapeutic options to fight multidrug-resistant (MDR) bacteria. Drug-resistant infections and related morbidity and mortality are on the rise in the United States and around the world. Despite the growing antibiotic resistance among Gram-positive and Gram-negative pathogens causing severe infections in hospital and community settings, the number of new antibacterial drugs approved for marketing in the United States continues to decrease. In addition to this worrying situation, only a few novel therapeutics for drug-resistant infections are in the drug development pipeline (Boucher et al., 2009; European Centre for Disease Prevention and Control, 2009). Reports of bacterial isolates resistant to almost all available antibiotics highlight the crucial need for new antibiotic therapies, especially for Gram-negative infections (Maltezou, 2009). Recently, IDSA and United States authorities have developed creative incentives to stimulate new antibacterial research and development (Infectious Diseases Society of America, 2010).