tedizolid and Staphylococcal-Skin-Infections

An increase of skin and soft tissue infections involving Staphylococcus aureus has been reported in community and hospital settings. Methicillin resistance in S. aureus is associated with treatment failure and increased mortality. Recently, new antimicrobials with enhanced activity against methicillin-resistant Staph. aureus have been approved for the treatment of skin and soft tissue infections. Among these, novel oxazolidinones and lipoglycopeptides represent options with favorable pharmacokinetic characteristics and safety profiles.. Newly approved compounds include tedizolid, characterized by the availability of both oral and intravenous formulation and once daily administration and dalbavancin, a long-acting antimicrobial allowing for weekly administration. These new molecules present advantages, such as enhanced activity against multidrug-resistant Gram-positive bacteria and favorable safety profiles.. We have reviewed the pharmacokinetic characteristics and the implications for use in skin and soft tissue infections of tedizolid and dalbavancin. Advantages associated with the use of these compounds include the possibility for early patient discharge, reduced hospital length of stay, and outpatient treatment, with potential impact on morbidity, mortality, and overall health-care costs.

Topics: Administration, Intravenous; Administration, Oral; Anti-Infective Agents; Community-Acquired Infections; Cross Infection; Humans; Lipoglycopeptides; Oxazolidinones; Soft Tissue Infections; Staphylococcal Skin Infections; Teicoplanin; Tetrazoles

Tedizolid, a novel oxazolidinone with activity against a wide range of Gram-positive pathogens, was evaluated in two noninferiority phase 3 acute bacterial skin and skin structure infection trials. The data from individual trials showed its noninferior efficacy compared to that of linezolid and a favorable tolerability profile. To evaluate potential differences, the pooled data were analyzed. The patients received 200 mg of tedizolid once daily for 6 days or 600 mg of linezolid twice daily for 10 days. Efficacy was evaluated at 48 to 72 h (primary endpoint), on days 11 to 13 (end of therapy [EOT]), and 7 to 14 days after the EOT (posttherapy evaluation). Treatment-emergent adverse events and hematologic and clinical laboratory parameters were collected. The baseline characteristics were comparable between the treatment groups: 852/1,333 (64%) patients were from North America, and the majority of infections were caused by Staphylococcus aureus. Tedizolid was noninferior to linezolid (early clinical responses, 81.6% versus 79.4%, respectively). The early responses remained relatively consistent across various host/disease factors and severity measures. Nausea was the most frequently reported adverse event (tedizolid, 8.2%; linezolid, 12.2%; P=0.02), with onset occurring primarily during the first 6 days. Fewer tedizolid than linezolid patients had platelet counts of <150,000 cells/mm3 at the EOT (tedizolid, 4.9%; linezolid, 10.8%; P=0.0003) and during the postbaseline period through the last day of active drug visit (tedizolid, 6.4%; linezolid, 12.6%; P=0.0016). Efficacy was achieved with a 6-day once-daily course of therapy with the option of an intravenous/oral regimen, and fewer low platelet counts and gastrointestinal side effects were reported with tedizolid than with linezolid, all of which aligns well with antimicrobial stewardship principles. (These studies have been registered at ClinicalTrials.gov under registration no. NCT01170221 and NCT01421511.).

Topics: Acetamides; Anti-Bacterial Agents; Double-Blind Method; Female; Humans; Linezolid; Male; Oxazolidinones; Skin Diseases, Bacterial; Skin Diseases, Infectious; Staphylococcal Skin Infections; Tetrazoles

Tedizolid, the active moiety of tedizolid phosphate, is a recently approved oxazolidinone antibacterial with activity against a wide range of Gram-positive pathogens, including resistant strains such as methicillin-resistant Staphylococcus aureus. To date, 6 days of 200 mg tedizolid once daily has been shown to be noninferior to 10 days of 600 mg linezolid twice daily in two randomized, double-blind phase 3 trials (ESTABLISH-1 and ESTABLISH-2) for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs). The intent of this study was to characterize the platelet profiles of patients receiving tedizolid relative to linezolid over the course of treatment using pooled data from these two trials. The occurrences of clinically defined and statistical analysis plan-specified reduced platelet counts were assessed at the study days 7 to 9 visit, the study days 11 to 13 visit, and the posttherapy evaluation (PTE) visit. At the study days 7 to 9 visit, incidences of reduced platelet counts were low and largely similar between the groups. The only notable difference was a lower incidence of thrombocytopenia (platelet counts, <150,000 cells/mm(3)) among patients who received tedizolid (3.2%) relative to those who received linezolid (5.6%). At the study days 11 to 13 visit, patients who received tedizolid had lower incidences of platelet counts of <150,000 cells/mm(3) (-5.9%), <112,500 cells/mm(3) (-2.4%), and <100,000 cells/mm(3) (-1.9%) than patients in the linezolid group. Similar differences were noted at the PTE visit. Findings across the two phase 3 ABSSSI trials suggest that 6 days of 200 mg tedizolid daily confers a low potential for reduced platelet counts among patients with ABSSSIs. (The ESTABLISH-1 and ESTABLISH-2 trials have been registered at ClinicalTrials.gov under registration numbers NCT01170221 and NCT01421511, respectively.).

Topics: Acetamides; Anti-Bacterial Agents; Blood Platelets; Double-Blind Method; Drug Administration Schedule; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Oxazolidinones; Platelet Count; Staphylococcal Skin Infections; Tetrazoles

Tedizolid (TR-700, formerly torezolid) is the active moiety of the prodrug tedizolid phosphate (TR-701), a next-generation oxazolidinone, with high potency against Gram-positive species, including methicillin-resistant Staphylococcus aureus (MRSA). A recently completed randomized, double-blind phase 2 trial evaluated 200, 300, or 400 mg of oral tedizolid phosphate once daily for 5 to 7 days in patients with complicated skin and skin structure infections. This report examines the in vitro activity of tedizolid and Zyvox (linezolid) against Gram-positive pathogens isolated at baseline and describes the microbiological and clinical efficacy of tedizolid. Of 196 isolates tested, 81.6% were S. aureus, and of these, 76% were MRSA. The MIC(50) and MIC(90) of tedizolid against both methicillin-susceptible S. aureus (MSSA) and MRSA were 0.25 μg/ml, compared with a MIC(50) of 1 μg/ml and MIC(90) of 2 μg/ml for linezolid. For coagulase-negative staphylococci (n = 7), viridans group streptococci (n = 15), and beta-hemolytic streptococci (n = 3), the MICs ranged from 0.03 to 0.25 μg/ml for tedizolid and from 0.12 to 1 μg/ml for linezolid. The microbiological eradication rates at the test-of-cure visit (7 to 14 days posttreatment) in the microbiologically evaluable population (n = 133) were similar in all treatment groups, with overall eradication rates of 97.7% for all pathogens, 97.9% for MRSA, and 95.7% for MSSA. The clinical cure rates for MRSA and MSSA infections were 96.9% and 95.7%, respectively, across all dose groups. This study confirms the potent in vitro activity of tedizolid against pathogenic Gram-positive cocci, including MRSA, and its 4-fold-greater potency in comparison with linezolid. All dosages of tedizolid phosphate showed excellent microbiological and clinical efficacy against MRSA and MSSA.

Topics: Acetamides; Adolescent; Adult; Aged; Anti-Bacterial Agents; Culture Media; Double-Blind Method; Drug Administration Schedule; Female; Humans; Linezolid; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Organophosphates; Oxazoles; Oxazolidinones; Skin; Staphylococcal Skin Infections; Staphylococcus; Tetrazoles

Skin and soft tissue infections (SSTI) are among the most commonly occurring infections and evidence suggests that these are increasing world-wide. The aetiology is diverse, but Staphylococcus aureus predominate and these are often resistant to antimicrobials that were previously effective. Tedizolid is a new oxazolidinone-class antibacterial indicated for the treatment of adults with SSTI caused by Gram-positive pathogens, including S. aureus. The aim of this study was to evaluate the in vitro efficacy of tedizolid in comparison to other clinically used antibacterials against antibiotic sensitive- and resistant-staphylococci, grown in planktonic cultures and as biofilms reflecting the growth of the microorganism during episodes of SSTI. Against a panel of 66 clinical staphylococci, sensitivity testing revealed that a lower concentration of tedizolid was required to inhibit the growth of staphylococci compared to linezolid, vancomycin and daptomycin; with the tedizolid MIC

Topics: Anti-Bacterial Agents; Biofilms; Drug Resistance, Multiple, Bacterial; Humans; Linezolid; Microbial Sensitivity Tests; Oxazolidinones; Soft Tissue Infections; Staphylococcal Skin Infections; Staphylococcus; Tetrazoles

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) causes severe skin and soft tissue infections in hospitals and, more recently, in the community. Tedizolid is a new second-generation oxazolidinone derivative having greater in vitro potency than linezolid against this type of microorganism.\ Objectives: To evaluate the antimicrobial activity of tedizolid and other comparator antibiotics in MRSA isolates causing skin and soft tissue infections in Colombian hospitals.\ Materials and methods: We conducted a prospective, multi-center descriptive study in seven tertiary-level hospitals in Colombia along a 12-month period. MRSA isolates were collected from adult patients with skin and soft tissue infections. Tedizolid, linezolid, vancomycin, daptomycin, trimethoprim-sulfamethoxazole, and clindamycin minimum inhibitory concentration (MIC) was determined by ETEST® (bioMérieux).\ Results: MRSA isolates were obtained from 102 patients with an average age of 46.8 years of whom 56 (54.9%) were men. Infection was community-acquired in 77 cases (75.4%). Abscess-related samples predominated (69 patients: 67.6%). All isolates were susceptible to tedizolid, linezolid, daptomycin, trimethoprim-sulfamethoxazole, and vancomycin. Tedizolid had greater in vitro activity than linezolid. Tedizolid MIC intervals ranged from 0.125 μg/mL to 0.5 μg/mL while those of linezolid ranged from 1μg/mL to 2μg/mL.\ Conclusions: MRSA strains circulating in Colombia are highly susceptible to tedizolid and can be considered a therapeutic alternative for hospitals and/or community-acquired skin and soft tissue infections.. Introducción. Staphylococcus aureus resistente a meticilina (SARM) causa infecciones graves de la piel y los tejidos blandos en los hospitales y, en los últimos años, en la comunidad. El tedizolid es una nueva oxazolidinona cuya potencia in vitro ha demostrado ser mayor que la del linezolid frente a este microorganismo.Objetivo. Conocer la actividad antimicrobiana del tedizolid y de algunos antibióticos de comparación en aislamientos de SARM causante de infecciones de piel y tejidos blandos en hospitales de Colombia.Materiales y métodos. Se hizo un estudio multicéntrico prospectivo y descriptivo a lo largo de doce meses en siete hospitales de tercer nivel de Colombia. Se recolectaron aislamientos de SARM de pacientes adultos con infección de piel y tejidos blandos. Se determinó la concentración inhibitoria mínima (CIM) mediante la técnica de ETEST® (bioMérieux) del tedizolid, el linezolid, la vancomicina, la daptomicina, el trimetoprim-sulfametoxazol y la clindamicina.Resultados. Se obtuvieron aislamientos de SARM de 102 pacientes, de los cuales 56 (54,9 %) eran hombres; el promedio de edad fue de 46,8 años. La infección tuvo origen en la comunidad en 77 casos (75,4 %). El tipo de muestra que predominó fue el absceso (69 pacientes: 67,6 %). Todos los aislamientos fueron sensibles a tedizolid, linezolid, daptomicina, trimetoprim-sulfametoxazol y vancomicina. La actividad in vitro del tedizolid fue mayor que la del linezolid. Los intervalos de la CIM del tedizolid oscilaron entre 0,125 μg/ml y 0,5 μg/ml en tanto que los del linezolid fluctuaron entre 1 μg/m y 2 μg/ml.Conclusiones. Las cepas circulantes de SARM en Colombia presentaron una gran sensibilidad al tedizolid, por lo cual sería una alternativa terapéutica para las infecciones de piel y tejidos blandos en nuestro medio.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colombia; Female; Hospitals; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Oxazolidinones; Prospective Studies; Soft Tissue Infections; Staphylococcal Skin Infections; Tetrazoles; Young Adult

Tedizolid (formally torezolid) is an expanded-spectrum oxazolidinone with enhanced in vitro potency against Gram-positive pathogens, including methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). The efficacies of human simulated exposures of tedizolid and linezolid against S. aureus in an immunocompetent mouse thigh model over 3 days were compared. Four strains of MRSA and one of MSSA with tedizolid and linezolid MICs ranging from 0.25 to 0.5 and from 2 to 4 μg/ml, respectively, were utilized. Tedizolid or linezolid was administered in a regimen simulating a human steady-state 24-h area under the free concentration-time curve of 200 mg every 24 h (Q24) or 600 mg Q12, respectively. Thighs were harvested after 4, 8, 12, 24, 36, 48, and 72 h, and efficacy was determined by the change in bacterial density. The mean bacterial density in control mice increased over the 3-day period. After 24 h of treatment, a reduction in bacterial density of ≥1 log CFU was observed for both the tedizolid and linezolid treatments. Antibacterial activity was enhanced for both agents with a reduction of ≥2.6 log CFU after 72 h of treatment. Any statistically significant differences (P ≤ 0.05) in efficacy between the agents were transient and did not persist throughout the 72-h treatment period. The tedizolid and linezolid regimens demonstrated similar in vivo efficacies against the S. aureus isolates tested. Both agents were bacteriostatic at 24 h and bactericidal on the third day of treatment. These data support the clinical utility of tedizolid for skin and skin structure infections caused by S. aureus, as well as the bactericidal activity of the oxazolidinones after 3 days of treatment.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Bacterial Load; Female; Linezolid; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Oxazolidinones; Staphylococcal Skin Infections; Tetrazoles; Thigh