Pulmonary Disposition of Tedizolid following Administration of Once-Daily Oral 200-Milligram Tedizolid Phosphate in Healthy Adult Volunteers

Housman, Seth T.; Pope, J. Samuel; Russomanno, John H.; Salerno, Edward; Shore, Eric; Kuti, Joseph L.; Nicolau, David P.

doi:10.1128/aac.05354-11

Cited by 97 publications

(92 citation statements)

References 29 publications

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“…These exposures were comparable to that achieved in humans (109.30 mg · h/liter) following the administration of a 200-mg once-daily (QD) clinical dose. However, due to the differences in the tedizolid penetration ratios in mice and humans, the mean plasma fAUC 0 -24 achieved in mice with these doses were higher than that achieved in humans following a clinical dose (13). The ELF exposures of tedizolid in human and mouse models are summarized in Table 1.…”

Section: Resultsmentioning

confidence: 99%

“…The discrepancy in the findings between our study and Drusano et al could be attributed, at least in part, to the difference in the infection model utilized. Tedizolid shows substantial accumulation in the lung epithelium, as evidenced by its high ELF penetration ratio both in humans and in mice (13,14), which could account for its enhanced activity against lung infections through the direct effect of the drug even if the host immune defenses were suppressed.…”

Section: Discussionmentioning

confidence: 99%

“…In 2014, tedizolid was approved for the treatment of acute bacterial skin and skin structure infections caused by susceptible Gram-positive bacteria, such as Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible strains), various Streptococcus species, and Enterococcus faecalis (12). In light of its substantial pulmonary distribution in the epithelial lining fluid (ELF) observed in healthy adults (13), tedizolid is currently being studied in phase 3 for the treatment of life-threatening hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. Knowledge of the pharmacodynamics of tedizolid for the treatment of lung infections caused by this relevant Grampositive organism will help to support these efforts.…”

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confidence: 99%

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

Abdelraouf

Nicolau

2017

Antimicrob Agents Chemother

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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

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Abdelraouf

Nicolau

2017

Antimicrob Agents Chemother

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“…Another key difference between the current and previous studies is the infection site. One intuitive theory to explain the discrepancy is the differential penetration of the oxazolidinones into the lung infection site (12,16,24,26,55 (26). This PK difference at the infection site is a plausible explanation for the lower PD targets for oxazolidinones in pulmonary models compared to soft tissue models.…”

Section: Discussionmentioning

confidence: 99%

Comparative Pharmacodynamics of the New Oxazolidinone Tedizolid Phosphate and Linezolid in a Neutropenic Murine Staphylococcus aureus Pneumonia Model

Lepak

Marchillo

Pichereau

et al. 2012

Antimicrob Agents Chemother

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Staphylococcus aureus has become a leading cause of community-and hospital-acquired pneumonia. Furthermore, infection with community-and health care-acquired strains of methicillinresistant S. aureus (MRSA) is increasingly common and limits antimicrobial options (13,25,29,31). Tedizolid phosphate (TR-701) is a novel oxazolidinone prodrug. The active moiety, tedizolid (TR-700), exhibits potent activity against Gram-positive bacteria, including MRSA (48). The goals of our studies were to identify the pharmacodynamic (PD) target (AUC/MIC ratio) for TR-700 against methicillin-susceptible S. aureus (MSSA) and MRSA strains in a neutropenic murine pneumonia model and compare the PD targets of TR-700 to that of the only FDA-approved oxazolidinone antibiotic, linezolid. MATERIALS AND METHODSBacteria, media, and antibiotics. Eleven isolates of S. aureus were utilized for these experiments. The strains included four MSSA strains (ATCC 6538P, ATCC 25923, ATCC 29213, and ATCC Smith), one hospital-acquired MRSA strain (ATCC 33591), and six community-acquired MRSA strains (MW2, R2527, 04-045, 04-154, 05-051, and UW 307109). Organisms were grown, subcultured, and quantified in Mueller-Hinton broth (Difco Laboratories, Detroit, MI) and Mueller-Hinton agar (Difco Laboratories, Detroit, MI). Linezolid was obtained from the University of Wisconsin pharmacy. Tedizolid (TR-700) and tedizolid phosphate (TR-701) were supplied by the manufacturer (Trius Therapeutics, San Diego, CA). Prior to in vivo treatment studies, TR-701 was dissolved in sterile water at the appropriate drug concentrations. TR-700 was dissolved in sterile dimethyl sulfoxide (DMSO) and diluted with medium to the appropriate concentration for in vitro susceptibility testing.In vitro susceptibility studies. The MICs of linezolid and TR-700 were determined three times in duplicate using Clinical and Laboratory Standards Institute (CLSI) microdilution methods M07-A8 (15). The duplicates were identical, and the final results were reported as the median value of the three MIC tests (see Table 1).Murine infection model. All animal studies were approved by the Animal Research Committees of the University of Wisconsin and William S. Middleton Memorial VA Hospital. Six-week-old, specific-pathogenfree, female ICR/Swiss mice weighing between 24 and 27 g (Harlan Sprague-Dawley, Indianapolis, IN) were used for all studies. Three mice were utilized for each treatment and control group. Mice were rendered neutropenic (absolute neutrophil count of Ͻ100/mm 3 ) by injecting cyclophosphamide (Mead Johnson Pharmaceuticals, Evansville, IN) intraperitoneally 4 days (150 mg/kg of body weight) and 1 day (100 mg/kg) prior to experimental infection. Previous studies have shown that this regimen produces persistent neutropenia in this animal model for 5 days (3). Broth cultures of freshly plated bacteria were grown to logarithmic phase. The inoculum for each organism was diluted to a 0.3 absorbance at 580 nm. Viable plate count confirmation of the inoculum ranged from 10 6 to 10 7 CFU/ml. Anima...

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“…12,[20][21][22] Measurement of unbound concentrations in the ELF is likely to best describe antibiotic activity, particularly for highly protein bound antibiotics. In a prospective PK study of 13 critically ill patients with ventilator-associated pneumonia (VAP) treated with teicoplanin ( > 85% protein binding), the median unbound teicoplanin concentrations in blood and ELF were similar, 21 which suggested that the unbound fraction of drug penetrated well into the lung tissue.…”

Section: Protein Bindingmentioning

confidence: 99%

Defining Antibiotic Dosing in Lung Infections

Jamal

Abdul‐Aziz

Lipman

et al. 2013

Clinical Pulmonary Medicine

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Defining optimal antibiotic dosing for treatment of lung infections is challenging because of the interrelationship between patient characteristics (eg, pathophysiological changes of lung during an infection, albumin level, renal function), antibiotic characteristics (eg, physicochemical properties, protein binding), and bacterial pathogen susceptibility. Measurement of antibiotic concentration in the lung compartments, such as epithelial lining fluid (ELF), is important to describe the drug exposure at site of infection. This article reviews published data on antibiotic penetration described by the ELF to plasma (ELF:plasma) ratios and the probability of pharmacokinetic/ pharmacodynamics (PK/PD) attainment at the target site with current dosing regimens to outline dosing strategies that could optimize the PK/PD indices. Antibiotic physicochemical properties could be used to predict the extent of penetration into the lung tissues. Lipophilic antibiotics penetrate well into the lung compartments; however, standard dosing regimens generally seem to be insufficient to achieve optimal PK/PD indices in the ELF, particularly during severe infections. Aggressive dosing regimens are required for antibiotics that poorly or moderately penetrate the lung tissues, whereas nebulization could be the alternative method to enhance antibiotic concentration at the target site. Special populations such as the critically ill, patients on renal replacement therapy, and those with renal impairment need dosing to be individualized, as these populations have high PK variability. Dosing based on free drug concentrations should be considered preferred, as these concentrations frequently reflect the antibiotic concentration at the target site. Therefore, the use of therapeutic drug monitoring should be considered necessary, whenever possible, to guide dosing in lung infection.

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Pulmonary Disposition of Tedizolid following Administration of Once-Daily Oral 200-Milligram Tedizolid Phosphate in Healthy Adult Volunteers

Cited by 97 publications

References 29 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

Comparative Pharmacodynamics of the New Oxazolidinone Tedizolid Phosphate and Linezolid in a Neutropenic Murine Staphylococcus aureus Pneumonia Model

Defining Antibiotic Dosing in Lung Infections

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