Efficacy of linezolid plus rifampin in an experimental model of methicillin-susceptible Staphylococcus aureus endocarditis

The efficacy of linezolid, alone or in combination with rifampin, against methicillin-susceptible Staphylococcus aureus in rabbits with experimental endocarditis was investigated. Linezolid (50 or 75 mg/kg of body weight), rifampin, and linezolid (25, 50, or 75 mg/kg) plus rifampin produced statistically significant reductions in bacterial counts compared with those in untreated controls. Plasma or valvular vegetation levels of linezolid in the groups treated with the linezolid-rifampin combination were similar to those in the respective linezolid-only treatment groups. At therapeutic levels of linezolid, rifampin resistance was not observed. The results from this experimental model of endocarditis suggest that while rifampin did not provide synergy to the linezolid dosing, it did not antagonize the efficacy of linezolid.     

In vivo efficacy of continuous infusion versus intermittent dosing of linezolid compared to vancomycin in a methicillin-resistant Staphylococcus aureus rabbit endocarditis model

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 log(10) 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.     

Different aminoglycoside-resistant phenotypes in a rabbit Staphylococcus aureus endocarditis infection model

The impact of different types of enzymatic resistance on the in vivo antibacterial activity of aminoglycosides (amikacin, gentamicin, and netilmicin) was studied in the rabbit endocarditis model with four strains of Staphylococcus aureus. Animals were treated in a manner simulating the administration of a single daily human dose. Amikacin had no effect on the three kanamycin-resistant strains despite apparent susceptibility in the disk diffusion test. Gentamicin appears to be the preferable aminoglycoside for treatment of staphylococcal infections.     

Efficacy of Telavancin in a rabbit model of aortic valve endocarditis due to methicillin-resistant Staphylococcus aureus or vancomycin-intermediate Staphylococcus aureus

The activities of telavancin and vancomycin were compared in vitro and in the rabbit model of aortic valve endocarditis against a methicillin-resistant Staphylococcus aureus strain, COL, and a vancomycin-intermediate S. aureus (VISA) strain, HIP 5836. Telavancin was bactericidal in time-kill studies at a concentration of 5 microg/ml against both COL and HIP5836. Vancomycin was bacteriostatic at 5 microg/ml and bactericidal at 10 microg/ml against COL and was bacteriostatic at 10 microg/ml against VISA strain HIP 5836. Compared to untreated controls, a twice-daily regimen of 30 mg/kg of telavancin reduced mean aortic valve vegetation titers of the COL strain by 4.7 log(10) CFU/g after 4 days of therapy and sterilized 6/11 vegetations compared to 3.4 log(10) CFU/g with 3/10 vegetations sterilized for a regimen of twice-daily vancomycin, 30 mg/kg; these differences were not statistically significant. Telavancin was significantly more effective than vancomycin in the VISA model, producing a 5.5 log(10) CFU/g reduction versus no reduction in CFU with vancomycin. In experiments comparing 2-day regimens of telavancin at 30 mg/kg and 50 mg/kg twice daily, organisms were rapidly eliminated from vegetations, but the effect was not different between the two doses. These results suggest that telavancin may be an effective treatment for endocarditis and other serious staphylococcal infections accompanied by bacteremia, including infections caused by staphylococci not susceptible to vancomycin.     

Efficacy of linezolid against methicillin-resistant or vancomycin-insensitive Staphylococcus aureus in a model of hematogenous pulmonary infection

We investigated the activities of linezolid, vancomycin, and teicoplanin in a murine model of hematogenous pulmonary infection with Staphylococcus aureus. Our results demonstrate that linezolid clearly reduced bacterial numbers in the methicillin-resistant S. aureus hematogenous infection model and significantly improved the survival rate of immunocompromised mice infected with vancomycin-insensitive S. aureus compared with vancomycin and teicoplanin. The pharmacokinetic profiles also reflected the effectiveness of linezolid.     

Efficacy of SCH56592 in a rabbit model of invasive aspergillosis

SCH56592 (SCH) was evaluated in an immunosuppressed rabbit model of invasive aspergillosis. SCH was more effective than similar doses of itraconazole and as effective as amphotericin B in the clearance of Aspergillus spp. from tissues. Compared with controls, SCH regimens reduced mortality, improved survival, and significantly reduced tissue colony counts.     

Nafcillin-gentamicin synergism in experimental staphylococcal endocarditis.

The bactericidal rate of nafcillin and the combination of nafcillin and gentamicin against Staphylococcus aureus were compared in vitro and in experimental endocarditis. The combination proved synergistic against 8 strains of S. aureus in broth. In rabbits with S. aureus endocarditis, the organism was eradicated more rapidly from cardiac vegetations when animals were treated with the combination than with nafcillin alone. Gentamicin alone was ineffective. This combination is under study in the therapy of acute endocarditis caused by penicillinase-producing S. aureus.     

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

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.     

Efficacy of linezolid in experimental otitis media

Therapy for otitis media (OM) due to resistant Streptococcus pneumoniae (MIC of penicillin, >/=2.0 microgram/ml) is challenging. Linezolid, an oxazolidinone, represent a new class of antimicrobial agents with excellent in vitro activity against penicillin-resistant S. pneumoniae; however, in vitro activity against nontypeable Haemophilus influenzae (NTHI) is limited. We evaluated its efficacy against experimental acute OM due to a multidrug-resistant S. pneumoniae isolate and two isolates of NTHI. The chinchilla model was utilized to evaluate the efficacy of linezolid against experimental infection due to S. pneumoniae or NTHI. Serum and middle ear antibiotic concentrations were determined, and sterilization of experimental OM was evaluated. Chinchillas were inoculated directly with S. pneumoniae into the superior bulla. Twenty-four hours after inoculation, all animals had positive middle ear and nasopharyngeal cultures. Animals were given linezolid at 25 mg/kg/dose twice a day (b.i.d.) by orogastric feeding tube or amoxicillin at 40 mg/kg/dose b.i.d. intramuscularly for 5 days. By day 5, all animals in the linezolid group had sterile middle ear cultures and eradication of S. pneumoniae from the nasopharynx. In the amoxicillin group, all nine animals remained middle ear and nasopharynx positive (P < 0.01). In animals inoculated with NTHI, 25 and 37.5 mg/kg b.i.d. failed to sterilize middle ear infection or eradicate colonization. Mean levels in middle ear fluid measured during experimental infection were 12.8 microgram/ml at 2 to 6 h and 4. 1 mirogram/ml at 16 to 17 h after orogastric dosing at 25 mg/kg. Linezolid achieved a high concentration in the middle ear during experimental OM. Linezolid eradicated multidrug-resistant S. pneumoniae from the middle ear and nasopharynx. Experimental infection and nasopharyngeal colonization due to NTHI persisted despite achievement of concentrations in the middle ear that were above the MIC (for NTHI).     

Comparison of efficacies of oral levofloxacin and oral ciprofloxacin in a rabbit model of a staphylococcal abscess

Oral levofloxacin was compared to oral ciprofloxacin in a Staphylococcus aureus subcutaneous abscess model in rabbits. Rabbits were surgically prepared with subcutaneous wiffle balls (43 mm in diameter) and allowed to recover for 4 to 6 weeks. Rabbits were infected by direct injection into the capsule with S. aureus ATCC 29213 (5 x 10(5) CFU) and were allowed to remain infected for 8 days before the initiation of anti-infective treatment. Efficacy was determined by assessing the bacterial load within the capsule over a 10-day treatment period. In single-dose pharmacokinetic studies in infected rabbits, similar area under the concentration-time curve/MIC ratios were obtained in the plasma and abscess fluid for levofloxacin at 45 mg/kg of body weight and ciprofloxacin at 200 mg/kg of body weight. Similar efficacies were seen with levofloxacin at 45 mg/kg/day and ciprofloxacin 400 mg/kg/day by day 10. In this model, levofloxacin was significantly more efficacious than ciprofloxacin (P < 0.01).     

Efficacy of linezolid alone or in combination with vancomycin for treatment of experimental endocarditis due to methicillin-resistant Staphylococcus aureus

The levels of effectiveness of linezolid, vancomycin, and the combination of linezolid and vancomycin were compared in the rabbit model of endocarditis caused by a clinical methicillin-resistant Staphylococcus aureus (MRSA) isolate. Vancomycin alone was more effective than either linezolid alone or the combination of linezolid and vancomycin for the treatment of endocarditis due to MRSA.     

Vancomycin treatment failure associated with heterogeneous vancomycin-intermediate Staphylococcus aureus in a patient with endocarditis and in the rabbit model of endocarditis

Heterogeneous resistance to vancomycin is thought to precede emergence of intermediate susceptibility to vancomycin in Staphylococcus aureus, but the clinical significance of heterogeneous resistance is unknown. Paired S. aureus isolates from a patient with endocarditis who relapsed after vancomycin treatment were tested for heterogeneous resistance to vancomycin. The pretreatment and the relapse clinical isolates (strains SF1 and SF2, respectively) were genotyped by pulsed-field gel electrophoresis. Susceptibility to vancomycin was assessed by the broth dilution method, population analysis, and time-kill studies and in the rabbit model of endocarditis. Strains SF1 and SF2 had similar genotypes, and the vancomycin MICs for the strains were 相似文献   

Comparison of a rabbit model of bacterial endocarditis and an in vitro infection model with simulated endocardial vegetations

Animal models are commonly used to determine the efficacy of various antimicrobial agents for treatment of bacterial endocarditis. Previously we have utilized an in vitro infection model, which incorporates simulated endocardial vegetations (SEVs) to evaluate the pharmacodynamics of various antibiotics. In the present study, we compared four experimental rabbit endocarditis protocols to an in vitro infection model in an effort to determine if these models are comparable. We have evaluated the activity of clinafloxacin, trovafloxacin, sparfloxacin, and ciprofloxacin in rabbit models against Staphylococcus aureus and Enterococcus spp. In vitro models were performed simulating the antibiotic pharmacokinetics obtained in the in vivo studies. Models were dosed the same as rabbit models, and SEVs were evaluated at the same time the rabbit vegetations were examined. Clinafloxacin and trovafloxacin were evaluated against methicillin-susceptible (MSSA1199) and -resistant (MRSA494) strains of S. aureus. Ciprofloxacin was studied against MSSA1199 and MSSA487. Sparfloxacin and clinafloxacin were evaluated against Enterococcus faecium SF2149 and Enterococcus faecalis WH245, respectively. We found that reductions in SEV bacterial density obtained in the in vitro model were similar to those obtained in rabbit vegetations, indicating that the SEV model may be a valuable tool for assessing antibiotic potential in the treatment of bacterial endocarditis.     

Coagulase-negative staphylococcal endocarditis: a view from the community hospital

Review of our experience with infectious endocarditis at a single community hospital showed coagulase-negative staphylococci to be our leading cause of endocarditis. The pathogenesis of coagulase-negative staphylococcal endocarditis (CNSE) involved either hematogenous seeding of native or prosthetic valves, or direct implantation at surgery. Cases involving native valves demonstrated an acute onset and rapidly deteriorating course, while prosthetic valve endocarditis was more indolent; both types were associated with multiple complications. Although the number of our cases is small, mortality from native valve CNSE was higher than that of prosthetic valve endocarditis. Patients treated medically fared better than those receiving both medical and surgical treatment, though the medically treated group may not have been as ill as those having valve replacement. Vancomycin caused serious adverse effects in two of the five patients receiving it.     

Comparison of staphylococcal and nonstaphylococcal endocarditis in narcotic addicts

In a 54-month retrospective review, we compared the clinical features of 26 narcotic addicts with staphylococcal endocarditis (group 1) and ten other addicts with nonstaphylococcal endocarditis (group 2). The admission temperature and the respiratory rate of patients in group 1 were significantly higher (P less thn .05 and less than .02 respectively) than those of patients in group 2. Group 1 also differed from group 2 in the following variables: (1) bilateral multiple pulmonary infiltrates in 46% vs none in group 2; (2) greater incidence of symptoms referable to the central nervous system (50% vs none in group 2); and (3) gastrointestinal symptoms of vomiting, diarrhea, or constipation in 62% vs 10% in group 2. Serious cardiovascular, renal, and other complications were more frequent in staphylococcal endocarditis. Tricuspid regurgitation occurred with equal frequency in both groups and was of no value in differentiating staphylococcal from nonstaphylococcal endocarditis.     

Efficacy of amphotericin B lipid complex in a rabbit model of coccidioidal meningitis

OBJECTIVES: We compared the efficacy of treatments in a rabbit model of coccidioidal meningitis (CM). METHODS: Rabbits were infected intracisternally with Coccidioides immitis and treated with intravenous amphotericin B lipid complex (ABLC), deoxycholate amphotericin B (dAMB), oral fluconazole or diluent [sterile 5% dextrose in water (D5W)]. Survival and cfu in brain, spinal cord and CSF were determined and histology studied. Amphotericin B (AMB) concentrations in serum, CSF and tissue were determined by bioassay. RESULTS: Fluconazole-treated rabbits and controls lost weight and had decreased mobility. All treatments prolonged survival (P = 0.005) and reduced cfu in brain and spinal cord (P 相似文献