A Randomized, Evaluator-Blind, Phase 2 Study Comparing the Safety and Efficacy of Omadacycline to Those of Linezolid for Treatment of Complicated Skin and Skin Structure Infections

ABSTRACTA randomized, investigator-blind, multicenter phase 2 trial involving patients with complicated skin and skin structure infections (cSSSI) compared the safety and efficacy of omadacycline, a broad-spectrum agent with activity against methicillin-resistantStaphylococcus aureus(MRSA), to those of linezolid (with or without aztreonam). Patients were randomized 1:1 to omadacycline (100 mg intravenously [i.v.] once a day [QD] with an option to transition to 200 mg orally QD) or linezolid (600 mg i.v. twice daily [BID] with an option to transition to 600 mg orally BID) at 11 U.S. sites. Patients suspected or documented to have infections caused by Gram-negative bacteria were given aztreonam (2 g i.v. every 12 h [q12h]) if randomized to linezolid or matching placebo infusions if randomized to omadacycline. Adverse events were reported in 46 (41.4%) omadacycline-treated and 55 (50.9%) linezolid-treated patients. Adverse events related to treatment were assessed by investigators in 24 (21.6%) omadacycline-treated and 33 (30.6%) linezolid-treated patients. The gastrointestinal tract was most commonly involved, with adverse events reported in 21 (18.9%) patients exposed to omadacycline and 20 (18.5%) exposed to linezolid. Rates of successful clinical response in the intent-to-treat (ITT) and clinical evaluable (CE) populations favored omadacycline (ITT, 88.3% versus 75.9%; 95% confidence interval [CI], 1.9 to 22.9; CE, 98.0% versus 93.2%; 95% CI, −1.7 to 11.3). For microbiologically evaluable (ME) patients withS. aureusinfections, the clinical success rates were 97.2% (70/72) in omadacycline-treated and 92.7% (51/55) in linezolid-treated patients. This phase 2 experience supports conclusions that omadacycline is well tolerated in cSSSI patients and that this aminomethylcycline has potential to be an effective treatment for serious skin infections.

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In VitroActivity and Microbiological Efficacy of Tedizolid (TR-700) against Gram-Positive Clinical Isolates from a Phase 2 Study of Oral Tedizolid Phosphate (TR-701) in Patients with Complicated Skin and Skin Structure Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00458-12 ◽

2012 ◽

Vol 56 (9) ◽

pp. 4608-4613 ◽

Cited By ~ 59

Author(s):

Philippe Prokocimer ◽

Paul Bien ◽

Carisa DeAnda ◽

Chris M. Pillar ◽

Ken Bartizal

Keyword(s):

Clinical Efficacy ◽

Phase 2 ◽

Coagulase Negative Staphylococci ◽

Gram Positive ◽

Double Blind ◽

Content Type ◽

Skin Structure ◽

Phase 2 Trial ◽

Complicated Skin

ABSTRACTTedizolid (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-resistantStaphylococcus 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 thein vitroactivity 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% wereS. aureus, and of these, 76% were MRSA. The MIC50and MIC90of tedizolid against both methicillin-susceptibleS. aureus(MSSA) and MRSA were 0.25 μg/ml, compared with a MIC50of 1 μg/ml and MIC90of 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 potentin vitroactivity 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.

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Safety, Tolerability, and Efficacy of GSK1322322 in the Treatment of Acute Bacterial Skin and Skin Structure Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03360-14 ◽

2014 ◽

Vol 58 (11) ◽

pp. 6518-6527 ◽

Cited By ~ 22

Author(s):

Ralph Corey ◽

Odin J. Naderer ◽

William D. O'Riordan ◽

Etienne Dumont ◽

Lori S. Jones ◽

...

Keyword(s):

Adverse Events ◽

Group Treatment ◽

Clinical Success ◽

Treated Group ◽

Success Rates ◽

Lesion Area ◽

Dose Selection ◽

Skin Structure ◽

Link Type ◽

Intent To Treat

ABSTRACTGSK1322322 represents a new class of antibiotics that targets an essential bacterial enzyme required for protein maturation, peptide deformylase. This multicenter, randomized, phase IIa study compared the safety, tolerability, and efficacy of GSK1322322 at 1,500 mg twice daily (b.i.d.) with that of linezolid at 600 mg b.i.d. in patients suspected of having Gram-positive acute bacterial skin and skin structure infections (ABSSSIs). The primary endpoint was assessment of the safety of GSK1322322, and a key secondary endpoint was the number of subjects with a ≥20% decrease in lesion area from the baseline at 48 and 72 h after treatment initiation. GSK1322322 administration was associated with mild-to-moderate drug-related adverse events, most commonly, nausea, vomiting, diarrhea, and headache. Adverse events (86% versus 74%) and withdrawals (28% versus 11%) were more frequent in the GSK1322322-treated group. Treatment with GSK1322322 and linezolid was associated with ≥20% decreases from the baseline in the lesion area in 73% (36/49) and 92% (24/26) of the patients, respectively, at the 48-h assessment and in 96% (44/46) and 100% (25/25) of the patients, respectively, at the 72-h assessment. Reductions in exudate/pus, pain, and skin infection scores were comparable between the GSK1322322 and linezolid treatments. The clinical success rates within the intent-to-treat population and the per-protocol population that completed this study were 67 and 91%, respectively, in the GSK1322322-treated group and 89 and 100%, respectively, in the linezolid-treated group. These results will be used to guide dose selection in future studies with GSK1322322 to optimize its tolerability and efficacy in patients with ABSSSIs. (This study has been registered atClinicalTrials.govunder registration no. NCT01209078 and athttp://www.gsk-clinicalstudyregister.com[PDF113414].)

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Telavancin versus Standard Therapy for Treatment of Complicated Skin and Skin Structure Infections Caused by Gram-Positive Bacteria: FAST 2 Study

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.50.3.862-867.2006 ◽

2006 ◽

Vol 50 (3) ◽

pp. 862-867 ◽

Cited By ~ 121

Author(s):

Martin E. Stryjewski ◽

Vivian H. Chu ◽

William D. O'Riordan ◽

Brian L. Warren ◽

Lala M. Dunbar ◽

...

Keyword(s):

Standard Therapy ◽

Clinical Success ◽

Therapy Group ◽

Success Rates ◽

Standard Therapy Group ◽

Gram Positive ◽

Double Blind ◽

Skin Structure ◽

Complicated Skin ◽

Cure Rates

ABSTRACT Telavancin is a bactericidal lipoglycopeptide with a multifunctional mechanism of action. We conducted a randomized, double blind, active-control phase II trial. Patients ≥18 years of age with complicated skin and skin structure infections caused by suspected or confirmed gram-positive organisms were randomized to receive either telavancin at 10 mg/kg intravenously every 24 h (q24h) or standard therapy (antistaphylococcal penicillin at 2 g q6h or vancomycin at 1 g q12h). A total of 195 patients were randomized and received at least one dose of study medication. Clinical success rates were similar in all analysis populations at test of cure. In microbiologically evaluable patients with Staphylococcus aureus at baseline (n = 91), 96% of the telavancin group and 90% of the standard-therapy group were cured. Among patients with methicillin-resistant S. aureus (MRSA) at baseline (n = 45), clinical cure rates were also 96% for telavancin and 90% for standard therapy. Microbiologic eradication in patients with S. aureus infection was better with telavancin compared to standard therapy (92% versus 78%, P = 0.07) and significantly better in patients with MRSA (92% versus 68%; P = 0.04). Therapy was discontinued for an adverse event (AE) in 6% and 3% of the patients receiving telavancin and standard therapy, respectively. Except for two cases of rash in the telavancin group, these AEs were similar in type and severity in the two groups. The overall incidences and severities of AEs and laboratory abnormalities were similar between the two groups. These data support the ongoing studies assessing the efficacy and safety of telavancin in the treatment of serious gram-positive infections, particularly involving MRSA.

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A nonrandomized phase 2 trial of oral thymic peptides in hospitalized patients with Covid-19

10.1101/2021.12.05.21267318 ◽

2021 ◽

Author(s):

Héctor M. Ramos-Zaldívar ◽

Karla G. Reyes-Perdomo ◽

Nelson A. Espinoza-Moreno ◽

Ernesto Tomás Dox-Cruz ◽

Thania Camila Aguirre Urbina ◽

...

Keyword(s):

Side Effects ◽

Adverse Events ◽

Standard Care ◽

Registry Data ◽

Control Group ◽

Phase 2 ◽

Safety And Efficacy ◽

Link Type ◽

Phase 2 Trial ◽

Thymic Peptides

AbstractBackgroundCoronavirus disease 2019 (Covid-19) active cases continue to demand the development of safe and effective treatments. This is the first clinical trial to evaluate the safety and efficacy of oral thymic peptides.MethodsWe conducted a nonrandomized phase 2 trial with a historic control group to evaluate the safety and efficacy of a daily 250-mg oral dose of thymic peptides in the treatment of hospitalized Covid-19 patients. Comparison based on standard care from registry data was performed after propensity score matching. The primary outcomes were survival, time to recovery and the number of participants with treatment-related adverse events or side effects by day 20.ResultsA total of 44 patients were analyzed in this study, 22 in the thymic peptides group and 22 in the standard care group. There were no deaths in the intervention group, compared to 24% mortality in standard care by day 20 (log-rank P=0.02). The Kaplan-Meier analysis showed a significantly shorter time to recovery by day 20 in the thymic peptides group as compared with standard care (median, 6 days vs. 12 days; hazard ratio for recovery, 2.75 [95% confidence interval, 1.34 to 5.62]; log-rank P=0.002). No side effects or adverse events were reported.ConclusionIn patients hospitalized with Covid-19, the use of thymic peptides reported no side effects, adverse events, or deaths by day 20. When compared with registry data, a significantly shorter time to recovery and mortality reduction was measured. The Catholic University of Honduras Medical Research Group (GIMUNICAH) is working on a more extensive phase 3 trial.Trial registrationClinicalTrials.govNCT04771013. February 25, 2021.

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Use of in vitro susceptibility and pathogen prevalence data to model the expected clinical success rates of tigecycline and other commonly used antimicrobials for empirical treatment of complicated skin and skin-structure infections

International Journal of Antimicrobial Agents ◽

10.1016/j.ijantimicag.2007.07.020 ◽

2007 ◽

Vol 30 (6) ◽

pp. 514-520 ◽

Cited By ~ 10

Author(s):

Helio S. Sader ◽

Rajiv Mallick ◽

Andreas Kuznik ◽

Thomas R. Fritsche ◽

Ronald N. Jones

Keyword(s):

Clinical Success ◽

Empirical Treatment ◽

Success Rates ◽

In Vitro Susceptibility ◽

Prevalence Data ◽

Skin Structure ◽

Complicated Skin ◽

Pathogen Prevalence

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TD-1792 versus Vancomycin for Treatment of Complicated Skin and Skin Structure Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00712-12 ◽

2012 ◽

Vol 56 (11) ◽

pp. 5476-5483 ◽

Cited By ~ 22

Author(s):

Martin E. Stryjewski ◽

Peter D. Potgieter ◽

Yu-Ping Li ◽

Steven L. Barriere ◽

Allan Churukian ◽

...

Keyword(s):

Clinical Success ◽

Study Medication ◽

Gram Positive ◽

Double Blind ◽

Content Type ◽

Skin Structure ◽

Complicated Skin ◽

The Difference ◽

Vancomycin Group ◽

Cure Rates

ABSTRACTTD-1792 is a first-in-class glycopeptide-cephalosporin heterodimer that exhibits bactericidal activity against Gram-positive pathogens. We conducted a randomized, double-blind, active-control, phase II trial in patients with complicated skin and skin structure infections caused by suspected or confirmed Gram-positive organisms. Patients 18 to 65 years old were randomized to receive 7 to 14 days of either TD-1792 (2 mg/kg of body weight intravenously [i.v.] every 24 h [q24h]) or vancomycin (1 g i.v. q12h, with dosage regimens adjusted per site-specific procedures). A total of 197 patients were randomized and received at least one dose of study medication. Rates of clinical success at the test-of-cure evaluation were similar in all analysis populations. Among 170 clinically evaluable patients, cure rates were 91.7% and 90.7% in the TD-1792 and vancomycin groups, respectively (95% confidence interval [CI] of −7.9 to 9.7 for the difference). In microbiologically evaluable patients with methicillin-resistantStaphylococcus aureusat baseline (n= 75), cure rates were 94.7% in the TD-1792 group and 91.9% in the vancomycin group. Microbiological eradication of Gram-positive pathogens (n= 126) was achieved in 93.7% and 92.1% of patients in the TD-1792 and vancomycin groups, respectively. Seven patients were discontinued from study medication due to an adverse event (AE): 2 and 5 in the TD-1792 and vancomycin groups, respectively. AEs were of similar types and severities between the two groups, other than pruritus, which was more common in patients who received vancomycin. No patients in the TD-1792 group experienced a serious AE. This study supports further clinical development of TD-1792 in patients with Gram-positive infection.

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Phase II Clinical Study of BC-3781, a Pleuromutilin Antibiotic, in Treatment of Patients with Acute Bacterial Skin and Skin Structure Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02106-12 ◽

2013 ◽

Vol 57 (5) ◽

pp. 2087-2094 ◽

Cited By ~ 63

Author(s):

W. T. Prince ◽

Z. Ivezic-Schoenfeld ◽

C. Lell ◽

K. J. Tack ◽

R. Novak ◽

...

Keyword(s):

Clinical Success ◽

Clinical Success Rate ◽

Response To Treatment ◽

Clinical Response Rate ◽

Success Rates ◽

Gram Positive ◽

Content Type ◽

Skin Structure ◽

Treatment Groups ◽

Vancomycin Group

ABSTRACTThis study investigated the potential of the novel systemic pleuromutilin antibiotic BC-3781 to treat patients with an acute bacterial skin and skin structure infection (ABSSSI) caused by a Gram-positive pathogen. Patients were randomized to intravenous BC-3781 100 mg, BC-3781 150 mg, or vancomycin 1 g every 12 h. Response to treatment was assessed daily and at test of cure (TOC). The primary endpoint was the clinical success rate at TOC in the modified intent-to-treat (MITT) and clinically evaluable (CE) analysis populations. Baseline characteristics, including the frequency of methicillin-resistantStaphylococcus aureus(MRSA), were comparable between the different treatment groups. Of 210 patients randomized, 186 (88.6%) patients completed the study. Clinical success at TOC in the CE population occurred in 54 (90.0%) patients in the BC-3781 100-mg group, 48 (88.9%) in the BC-3781 150-mg group, and 47 (92.2%) in the vancomycin group. At day 3, the clinical response rate was similar across the three treatment groups. Six patients discontinued study medication following an adverse event. The incidence rate for drug-related adverse events was lower for patients receiving BC-3781 (34.3% and 39.4% in the 100-mg and 150-mg groups, respectively) than those receiving vancomycin (53.0%). When BC-3781 was used to treat ABSSSIs caused by a Gram-positive pathogen, including MRSA, clinical success rates were comparable to those of the comparator, vancomycin. BC-3781 was generally well tolerated. These results provide the first proof of concept for the systemic use of a pleuromutilin antibiotic for the treatment of ABSSSIs.

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