Comparative In Vitro and Bactericidal Activity of Oxazolidinone Antibiotics Against Multidrug-Resistant Enterococci

Bostic, Grace; Perri, Mary Beth; Thal, L A; Zervos, Marcus J.

doi:10.1016/s0732-8893(97)00210-1

Cited by 58 publications

(31 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Given that the increase in lung bacterial burden in the untreated control mice at 24 h was consistent between the two models, the apparent absence of evidence of inoculum effect with the oxazolidinediones (11,25,26), and that enhanced kill was observed in the immunocompetent animals despite the higher starting inoculum, we believe that our comparative assessments are valid. While these initial starting inocula may have an influence on the overall magnitude of kill, our observation of enhanced tedizolid efficacy in immunocompetent hosts is consistent with previous in vivo studies with the compound (15).…”

Section: Discussionmentioning

confidence: 77%

Comparative In Vivo Efficacies of Tedizolid in Neutropenic versus Immunocompetent Murine Streptococcus pneumoniae Lung Infection Models

Abdelraouf

Nicolau

2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Given that tedizolid exhibits substantial lung penetration, we hypothesize that it could achieve good efficacy against Streptococcus pneumoniae lung infections. We evaluated the pharmacodynamics of tedizolid for treatment of S. pneumoniae lung infections and compared the efficacies of tedizolid human-simulated epithelial lining fluid (ELF) exposures in immunocompetent and neutropenic murine lung infection models. ICR mice were rendered neutropenic via intraperitoneal cyclophosphamide injections and then inoculated intranasally with S. pneumoniae suspensions. Immunocompetent CBA/J mice were inoculated similarly. Single daily tedizolid doses were administered 4 h postinoculation (termed 0 h). Changes in log 10 CFU at 24 h compared with 0-h controls were estimated. Ratios of area under the free-drug concentration-time curve to MIC (fAUC 0 -24 /MIC) required to achieve various efficacy endpoints against each isolate were estimated using the Hill equation. Tedizolid doses in neutropenic and immunocompetent mice that mimic the human-simulated ELF exposure were examined. Stasis, 1-log reduction, and 2-log reduction were achieved at fAUC 0 -24 /MIC of 8.96, 24.62, and 48.34, respectively, in immunocompetent mice and 19.21, 48.29, and 103.95, respectively, in neutropenic mice. Tedizolid at 40 mg/kg of body weight/day and 55 mg/kg/day in immunocompetent and neutropenic mice, respectively, resulted in ELF AUC 0 -24 comparable to that achieved in humans following a 200-mg once-daily clinical dose. These human-simulated ELF exposures were adequate to attain Ͼ2-log reduction in bacterial burden at 24 h in 3 out of 4 isolates in both models and 1.58-and 0.74-log reductions with the fourth isolate in immunocompetent and neutropenic mice, respectively. Tedizolid showed potent in vivo efficacy against S. pneumoniae in both immunocompetent and neutropenic lung infection models, which support its consideration for S. pneumoniae lung infections.KEYWORDS oxazolidinedione, pharmacodynamics, pneumonia S treptococcus pneumoniae represents a challenging pathogen for clinicians, as this organism has been responsible for a wide range of potentially life-threatening infections in both the community and nosocomial settings, including communityacquired pneumonia, sepsis, and meningitis (1). Pneumococcal pneumonia is a serious public health problem resulting in approximately 600,000 hospital admissions or visits to health care providers among adults annually (2). In 30% of severe S. pneumoniae infections, the bacteria are found to be resistant to at least one class of antibiotics, such as ß-lactams and macrolides, which complicates treatment and can result in as many as 7,000 deaths annually (2-4). Resistant pneumococcal pneumonia cases result in additional visits to health care providers and account for approximately $96 million in extra medical costs (2). Vancomycin tolerance, a precursor phenotype to resistance, has

show abstract

Section: Discussionmentioning

confidence: 77%

Comparative In Vivo Efficacies of Tedizolid in Neutropenic versus Immunocompetent Murine Streptococcus pneumoniae Lung Infection Models

Abdelraouf

Nicolau

2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Eperzolid and linezolid are two investigational oxazolidinone agents which are in phase II and phase III clinical trials, respectively. They show excellent activity against multiantibiotic-resistant enterococci characterized by low MICs (28). Clinical efficacy and safety studies are needed to determine their ultimate utility.…”

Section: Treatmentmentioning

confidence: 99%

Vancomycin-Resistant Enterococci

Çetinkaya

Falk

Mayhall

2000

Clinical Microbiology Reviews

643

344

View full text Add to dashboard Cite

“…Because of the emergence of S. aureus strains with intermediate-level resistance to vancomycin (MIC, 8 mg/mL) and the increased frequency of serious VRE infections, vancomycin is becoming a less dependable therapeutic option. Although chloramphenicol and rifampin, doxycycline, novobiocin, high-dose ampicillin/sulbactam, gentamicin, and bacitracin have been used to treat VRE infections, the development of resistance during treatment and clinical failure are common [13][14][15][16].…”

mentioning

confidence: 99%

“…They inhibit protein synthesis by binding to the 50s ribosome subunit and preventing formation of the initiation complex. In vitro and in vivo studies have demonstrated that linezolid, an oxazolidinone analog, has significant bacteriostatic activity against multiresistant gram-positive pathogens such as coagulase-negative Staphylococcus species, S. aureus, VRE, and Streptococcus pneumoniae through inhibition of protein synthesis [14,23,24]. This strongly suggests that linezolid has promise for the clinical treatment of resistant gram-positive infections.…”

mentioning

confidence: 99%

Use of Linezolid, an Oxazolidinone, in the Treatment of Multidrug-Resistant Gram-Positive Bacterial Infections

Chien

Kucia

Salata

2000

Clinical Infectious Diseases

171

View full text Add to dashboard Cite

We report our experience with linezolid in an investigation of its use against resistant gram-positive bacterial infections. Fifteen patients who had renal failure (n=6), recent liver transplantation (n=5) or surgery (n=6), cancer (n=3), endocarditis (n=2), or human immunodeficiency virus infection (n=1), along with infections due to vancomycin-resistant enterococcus (VRE), and 2 patients with infections due to methicillin-resistant Staphylococcus species who had adverse reactions to vancomycin were treated with linezolid (600 mg every 12 h for 5-42 days (mean+/-SD, 20.5+/-3.5 days). Abscess drainage or prosthetic device removal was undertaken. Microbiological cure occurred in all 10 patients who completed therapy, and all 7 patients alive at follow-up were free of infection. No deaths were attributable to the index infection. Adverse events associated with linezolid use were mild leukopenia in 1 patient and nausea in another. It appears that administration of linezolid, in conjunction with surgical intervention or device removal, is an effective treatment option for serious resistant gram-positive bacterial infections.

show abstract

Comparative In Vitro and Bactericidal Activity of Oxazolidinone Antibiotics Against Multidrug-Resistant Enterococci

Cited by 58 publications

References 15 publications

Comparative In Vivo Efficacies of Tedizolid in Neutropenic versus Immunocompetent Murine Streptococcus pneumoniae Lung Infection Models

Comparative In Vivo Efficacies of Tedizolid in Neutropenic versus Immunocompetent Murine Streptococcus pneumoniae Lung Infection Models

Vancomycin-Resistant Enterococci

Use of Linezolid, an Oxazolidinone, in the Treatment of Multidrug-Resistant Gram-Positive Bacterial Infections

Contact Info

Product

Resources

About