Explore the vast range of titles available.

Linezolid is a key component globally in first-line therapy for drug-resistant tuberculosis but has considerable toxicity. New and safer alternative oxazolidinones are needed. Sutezolid is one such promising alternative. We aimed to evaluate preliminary efficacy and safety of sutezolid and to identify an optimal dose. PanACEA-SUDOCU-01 was a prospective, open-label, randomised, phase 2b dose-finding study in four tuberculosis trial sites in Tanzania and South Africa. Adults aged 18–65 years with newly diagnosed, drug-sensitive, smear-positive tuberculosis were enrolled and randomly assigned (1:1:1:1:1) by a probabilistic minimisation algorithm using a web-based interface, stratified by site, sex, and HIV status, to receive no sutezolid (U0), sutezolid 600 mg once daily (U600), sutezolid 1200 mg once daily (U1200), sutezolid 600 mg twice daily (U600BD), or sutezolid 800 mg twice daily (U800BD), all administered orally for 12 weeks followed by standard therapy for 6 months. All participants received oral bedaquiline (400 mg once daily for 14 days followed by 200 mg thrice weekly), oral delamanid (100 mg twice daily), and oral moxifloxacin (400 mg once daily). For the primary endpoint, measured in the modified intention-to-treat population, sputum samples were taken weekly to measure the change in bacterial load measured by time to positivity using the mycobacterial growth indicator tube system. Safety was assessed through weekly electrocardiography, safety blood tests, vision testing, and physical and neurological examinations. Intensive pharmacokinetic measurements were done on day 14 to determine exposure to sutezolid, bedaquiline, delamanid, and moxifloxacin. This trial is registered with ClinicalTrials.gov (NCT03959566). Between May 20, 2021, and Feb 17, 2022, 186 individuals were screened for eligibility, 75 of whom were enrolled and randomly assigned to U0 (n=16), U600 (n=15), U1200 (n=14), U600BD (n=15), or U800BD (n=15). 56 (75%) participants were male and 19 (25%) were female. The final pharmacokinetic–pharmacodynamic model showed a benefit of sutezolid, with an increase in time to positivity slope steepness of 16·7% (95% CI 0·7–35·0) at the maximum concentration typical for the 1200 mg dose, compared with no sutezolid exposure. A maximum effect of sutezolid exposure was not observed within the investigated dose range. Six (8%) participants (one in the U600 group, two in the U600BD group, one in the U800BD group, and two retrospectively identified in the U600 group) had an increase in a QT interval using Fridericia correction greater than 60 ms from baseline. Two (3%) participants in the U600BD group had grade 4 adverse events, one each of neutropenia and hepatotoxicity, but they were not deemed associated with the use of sutezolid by the investigators. No neuropathy was reported. Sutezolid, combined with bedaquiline, delamanid, and moxifloxacin, was shown to be efficacious and added activity to the background drug combination, although we cannot make a final dose recommendation yet. This study provides valuable information for the selection of sutezolid doses for future studies, and described no oxazolidinone class toxicities at the doses used. EDCTP2 programme funded by the EU; German Ministry for Education and Research; German Center for Infection Research; and Nederlandse Organisatie voor Wetenschappelijk Onderzoek.

Linezolid plays a crucial role in the first-line treatment of drug-resistant tuberculosis globally. Its prolonged use can lead to neurological and haematological toxicity, highlighting the need for safer oxazolidinones. Delpazolid, a novel oxazolidinone, might be safer. We aimed to evaluate the safety and efficacy of delpazolid and identify an optimal dose. PanACEA-DECODE-01 was a prospective, randomised, open-label, phase 2b, multicentre, dose-finding trial done in five tuberculosis trial sites in Tanzania and South Africa. Adults aged 18–65 years, who weighed 40–90 kg, and had newly diagnosed, smear positive pulmonary tuberculosis were randomly assigned (1:1:1:1:1) through centralised allocation, using a probabilistic minimisation algorithm to receive no delpazolid (D0), delpazolid 400 mg once daily (D400), delpazolid 800 mg once daily (D800), delpazolid 1200 mg once daily (D1200), or delpazolid 800 mg twice daily (D800BD), all administered orally for 16 weeks with follow-up to week 52. All participants received bedaquiline (400 mg orally once daily for the first 14 days, then 200 mg orally thrice weekly), delamanid (100 mg orally twice daily), and moxifloxacin (400 mg orally once daily). Randomisation was stratified based on bacterial load in sputum as measured by GeneXpert cycle threshold (<16 vs ≥16), site, and HIV status. The primary efficacy objective was to establish an exposure–response model with the primary endpoint, measured in the modified intention-to-treat population, of change in mycobacterial load measured by time to positivity using the liquid culture mycobacterial growth indicator tube system. A secondary outcome was the time on treatment to sustained conversion to negative sputum culture in liquid media. The primary safety outcome was the occurrence of oxazolidinone class toxicities defined as peripheral or optical neuropathy, incident leukopenia, anaemia or thrombocytopenia, or adverse events in line with tyramine pressor response, all of grade 2 or higher, possibly, probably or definitely related to delpazolid. This study was registered with ClinicalTrials.gov, NCT04550832. Between Oct 28, 2021, and Aug 31, 2022, 156 individuals were screened for eligibility, 76 of whom were enrolled and randomly assigned to D0 (n=15), D400 (n=15), D800 (n=15), D1200 (n=16), or D800BD (n=15). 60 (79%) of 76 participants were male and 16 (21%) were female. Population pharmacokinetic–pharmacodynamic modelling suggests maximal microbiological activity at a daily total exposure of delpazolid (area under the concentration curve from 0 h to 24 h [AUC0–24]) of 50 mg/L per h; close to the median exposure observed after a 1200 mg dose. This maximal effect was estimated at a 38% (95% CI 4–83; p=0·025) faster decline in bacterial load compared with no delpazolid. In the secondary time-to-event analysis, there was no significant difference in time to culture conversion between treatment arms or exposure tertile. When all delpazolid-containing groups were combined, the hazard ratio for the time to sustained culture conversion to negative, comparing all delpazolid-containing groups with the group without delpazolid was 1·53 (95% CI 0·84–2·76). Two drug-related serious adverse events (one gastritis and one anaemia) occurred in the D800BD group, with high individual AUC0–24. Apart from the anaemia and one event of brief, moderate neutropenia observed at only one visit in the D800 group not in line with the characteristics of oxazolidinone class toxicity, no oxazolidinone class toxicities occurred. The pharmacokinetic–pharmacodynamic modelling results suggest that delpazolid adds efficacy on top of bedaquiline, delamanid, and moxifloxacin; and that a dose of 1200 mg once daily would result in exposures with maximum efficacy. That dose was shown to be safe, raising hope that linezolid toxicities could be averted in long-term treatment. Delpazolid is a promising drug for future tuberculosis treatment regimens and could be widely usable if safety and efficacy are confirmed in larger trials. LigaChem Biosciences, EDCTP2 programme supported by the EU; German Ministry for Education and Research; German Center for Infection Research; Swiss State Secretariat for Education, Research and Innovation; and Nederlandse Organisatie voor Wetenschappelijk Onderzoek.

Background. Post hoc analyses of clinical trial data suggested that linezolid may be more effective than vancomycin for treatment of methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. This study prospectively assessed efficacy and safety of linezolid, compared with a dose-optimized vancomycin regimen, for treatment of MRSA nosocomial pneumonia. Methods. This was a prospective, double-blind, controlled, multicenter trial involving hospitalized adult patients with hospital-acquired or healthcare—associated MRSA pneumonia. Patients were randomized to receive intravenous linezolid (600 mg every 12 hours) or vancomycin (15 mg/kg every 12 hours) for 7-14 days. Vancomycin dose was adjusted on the basis of trough levels. The primary end point was clinical outcome at end of study (EOS) in evaluable per-protocol (PP) patients. Prespecified secondary end points included response in the modified intent-to-treat (mITT) population at end of treatment (EOT) and EOS and microbiologic response in the PP and mITT populations at EOT and EOS. Survival and safety were also evaluated. Results. Of 1184 patients treated, 448 (linezolid, n = 224; vancomycin, n = 224) were included in the mITT and 348 (linezolid, n = 172; vancomycin, n = 176) in the PP population. In the PP population, 95 (57.6%) of 165 linezolid-treated patients and 81 (46.6%) of 174 vancomycin-treated patients achieved clinical success at EOS (95% confidence interval for difference, 0.5%-21.6%; P = .042). All-cause 60-day mortality was similar (linezolid, 15.7%; vancomycin, 17.0%), as was incidence of adverse events. Nephrotoxicity occurred more frequently with vancomycin (18.2%; linezolid, 8.4%). Conclusions. For the treatment of MRSA nosocomial pneumonia, clinical response at EOS in the PP population was significantly higher with linezolid than with vancomycin, although 60-day mortality was similar.

Treatment of acute bacterial skin infection is becoming more complicated as antimicrobial resistance increases. In this trial of dalbavancin, a lipoglycopeptide with a long half-life, once-weekly dosing was shown to be noninferior to vancomycin–linezolid for treating infection. Acute bacterial skin and skin-structure infections are among the most common reasons for the hospitalization of adults in the United States today. 1 These infections are caused most often by Staphylococcus aureus and streptococci. 2 Methicillin-resistant S. aureus (MRSA) accounts for many of these infections and presents a particular treatment challenge because current therapies are limited by toxicity, resistance, or the lack of an oral formulation. 3 Associated medical costs are substantial. 4 Dalbavancin (Durata Therapeutics) is a lipoglycopeptide antibiotic agent with in vitro and in vivo activity against gram-positive pathogens, including a minimal inhibitory concentration (MIC) required to inhibit the growth of 90% . . .

This study assessed the tolerability and pharmacokinetic (PK) properties of a new-generation oxazolidinone, contezolid (MRX-I), and its major inactive metabolite, M2, after single oral administrations of 800, 1200, and 1600 mg in the fed state, and compared the efficacy of 3 dosing regimens in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection based on PK/pharmacodynamic (PD) analysis. A Phase I study at a single study center was conducted with 2 parts. In the first part, 20 healthy subjects received a single oral dose of 1200 or 1600 mg of contezolid or placebo in the fed state in a double-blind, placebo-controlled, dose-escalation tolerance study. In the second part of the study, 52 subjects received a single oral dose of 800 mg of contezolid in the fed state in a single-center, randomized, blinded, 4-period, crossover, thorough QT study. Noncompartmental analyses were used to evaluate the PK properties of contezolid and M2. Steady-state concentrations of contezolid following the 3 dosing regimens (800, 1200, and 1600 mg q12h) were simulated by employing a newly developed 2-compartmental PK model. The minimum inhibitory concentration (MIC) distributions of contezolid were analyzed in 178 Staphylococcus, Enterococcus, and Streptococcus clinical isolates. Monte Carlo simulations were conducted to predict the efficacy of the 3 dosing regimens to obtain probability of target attainment and cumulative fraction of response. Single-dose oral administrations of 800, 1200, and 1600 mg of contezolid were well tolerated in healthy subjects in the fed state, and nonlinear PK was observed. The mean plasma exposures to M2 exceeded 17.3% of contezolid exposure in the 3 groups. Both MIC50 and MIC90 (MICs that inhibit the growth of 50% and 90% of microorganisms, respectively) of contezolid against MRSA were 1 mg/L with clinical isolates from China. PK/PD analysis and Monte Carlo simulations predicted that 800 mg q12h of oral contezolid would be efficacious against MRSA infection, with a MIC of ≤4 mg/L (probability of target attainment, >90%; cumulative fraction of response, >90%). Contezolid is a well-tolerated treatment option for MRSA infection, including at supratherapeutic doses up to 1600 mg. The regimen of 800 mg q12h could achieve efficacy in treating bacterial infection with MRSA. To our knowledge, this is the first PK study to predict that a dosing regimen of 800 mg q12h of oral contezolid is sufficient for treating MRSA infection, with a MIC of ≤4 mg/L. A Phase III study of this suggested dosing regimen is being conducted. Chinadrugtrials.org.cn identifier: CTR20161074.

New antibiotics are needed to treat infections caused by drug-resistant bacteria. Tedizolid is a novel oxazolidinone antibacterial drug designed to provide enhanced activity against Gram-positive pathogens. We aimed to assess the efficacy and safety of intravenous to oral tedizolid for treatment of patients with acute bacterial skin and skin-structure infections. ESTABLISH-2 was a randomised, double-blind, phase 3, non-inferiority trial done between Sept 28, 2011, and Jan 10, 2013, at 58 centres in nine countries. Patients (aged ≥12 years) with acute bacterial skin and skin-structure infections (cellulitis or erysipelas, major cutaneous abscess, or wound infection) that had a minimum lesion area of 75 cm2 and were suspected or documented to be associated with a Gram-positive pathogen, were randomly assigned (1:1), via an interactive voice-response system with block randomisation, to receive intravenous once-daily tedizolid (200 mg for 6 days) or twice-daily linezolid (600 mg for 10 days), with optional oral step-down. Randomisation was stratified by geographic region and type of acute bacterial skin and skin-structure infection. The primary endpoint was early clinical response (≥20% reduction in lesion area at 48–72 h compared with baseline), with a non-inferiority margin of −10%. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01421511. 666 patients were randomly assigned to receive tedizolid (n=332) or linezolid (n=334). 283 (85%) patients in the tedizolid group and 276 (83%) in the linezolid group achieved early clinical response (difference 2·6%, 95% CI −3·0 to 8·2), meeting the prespecified non-inferiority margin. Gastrointestinal adverse events were less frequent with tedizolid than linezolid, taking place in 52 (16%) of 331 patients and 67 (20%) of 327 patients in the safety population. Treatment-emergent adverse events leading to discontinuation of study drug were reported by one (<1%) patient in the tedizolid group and four (1%) patients in the linezolid group. Intravenous to oral once-daily tedizolid 200 mg for 6 days was non-inferior to twice-daily linezolid 600 mg for 10 days for treatment of patients with acute bacterial skin and skin-structure infections. Tedizolid could become a useful option for the treatment of acute bacterial skin and skin-structure infections in the hospital and outpatient settings. Cubist Pharmaceuticals.

Cadazolid is a novel quinoxolidinone antibiotic developed for treating Clostridium difficile infection. We aimed to investigate the safety and efficacy of cadazolid compared with vancomycin in patients with C difficile infection. IMPACT 1 and IMPACT 2 were identically designed, multicentre, double-blind, placebo-controlled, non-inferiority, randomised phase 3 trials. IMPACT 1 was done in Australia, Brazil, Canada, France, Germany, Italy, the Netherlands, Peru, Poland, Romania, Spain, and the USA, and IMPACT 2 was done in Argentina, Belgium, Brazil, Canada, Chile, Croatia, Czech Republic, Greece, Hungary, Israel, Romania, Slovakia, South Korea, the UK, and the USA. Patients (aged 18 years or older) with mild-to-moderate or severe C difficile infection (diarrhoea with positive glutamate dehydrogenase and toxin A or B enzyme immunoassays) were randomly assigned (1:1) with a randomisation list stratified by centre and C difficile infection episode type (block size of four), and allocation was masked to investigators and participants. Patients received either oral cadazolid 250 mg twice daily with vancomycin-matching placebo capsule four times daily or oral vancomycin 125 mg four times a day with cadazolid-matching placebo suspension twice daily for 10 days, with 30 days of follow-up. The primary efficacy outcome was non-inferiority (margin −10%) of cadazolid versus vancomycin for clinical cure in the modified intention-to-treat and per-protocol populations. Clinical cure was defined as resolution of diarrhoea with no additional treatment for C difficile infection. These trials are registered with ClinicalTrials.gov, numbers NCT01987895 (IMPACT 1) and NCT01983683 (IMPACT 2). Between March 28, 2014, and March 24, 2017, for IMPACT 1, and Dec 13, 2013, and May 2, 2017, for IMPACT 2, 1263 participants were randomly assigned to receive cadazolid (306 in IMPACT 1 and 298 in IMPACT 2) or vancomycin (326 in IMPACT 1 and 311 in IMPACT 2). In the modified intention-to-treat population in IMPACT 1, 253 (84%) of 302 had clinical cure in the cadazolid group versus 271 (85%) of 318 in the vancomycin group. In IMPACT 2, 235 (81%) of 290 versus 258 (86%) of 301 had clinical cure. In the per-protocol population, 247 (88%) of 282 versus 264 (92%) of 288 had clinical cure in IMPACT 1 and 214 (87%) of 247 versus 237 (92%) of 259 in IMPACT 2. Non-inferiority for clinical cure to vancomycin was shown in IMPACT 1 but not in IMPACT 2 (IMPACT 1 treatment difference: −1·4 [95% CI −7·2 to 4·3] for modified intention to treat and −4·1 [–9·2 to 1·0] for per protocol; IMPACT 2: −4·7 [–10·7 to 1·3] for modified intention to treat and −4·9 [–10·4 to 0·6] for per protocol). The safety and tolerability profiles of the two antibiotics were similar. Cadazolid was safe and well tolerated but did not achieve its primary endpoint of non-inferiority to vancomycin for clinical cure in one of two phase 3 C difficile infection trials. Therefore, further commercial development of cadazolid for C difficile infection is unlikely. Actelion Pharmaceuticals.

Background. The oxazolidinone PNU-100480 is superior to linezolid against experimental murine tuberculosis. Two metabolites contribute to but do not fully account for its superiority. This study examined the safety, tolerability, pharmacokinetics, and mycobactericidal activity of single ascending doses of PNU-100480. Methods. Nineteen healthy volunteers received 2 escalating single oral doses (35–1500 µg) of PNU-100480 or placebo. Eight subjects received 4 daily doses of 300 mg of linezolid. Drug concentrations and bactericidal activity against Mycobacterium tuberculosis in whole-blood bactericidal culture were measured. Results. All doses were safe and well tolerated. PNU-100480 doses to 1000 mg were well absorbed and showed approximately proportional increases in exposures of parent and metabolites. The geometric mean maximal concentrations of PNU-100480, PNU-101603, and PNU-101244 (sulfoxide and sulfone metabolites) at 1000 mg were 839, 3558, and 54 ng/mL, respectively. The maximal whole-blood bactericidal activity (−0.37 ± .06 log/day) occurred at combined PNU levels ⩾2 times the minimum inhibitory concentration. The observed geometric mean maximal concentration for linezolid was 6425 ng/mL. Its maximal whole-blood bactericidal activity also occurred at ⩾2 times the minimum inhibitory concentration, but it was only −0.16 ± .05 log/day (P<.001). Neither drug showed enhanced activity at higher concentrations. Conclusions. Single doses of PNU-100480 to 1000 mg were well tolerated and exhibited antimycobacterial activity superior to 300 mg of linezolid at steady state. Additional studies are warranted to define its role in drugresistant tuberculosis. Clinical trial registration ClinicalTrials.gov identifiers NCT00871949 and NCT00990990.

Contezolid (MRX-I) is a novel oxazolidinone with potent in vitro activity against gram-positive pathogens. The aim of this study was to establish the dose-pharmacokinetic (PK) exposure-pharmacodynamic (PD)–response relationship and to quantitatively evaluate the variability of MRX-I after continuous oral administration of 600 mg BID and 800 mg BID for 14 days under fed conditions in patients with skin and skin structure infections. Another goal was to evaluate the 2 dosing regimens against methicillin-resistant Staphylococcus aureus infections based on PK/PD analysis. PK data from healthy volunteers and patients were pooled to develop a population PK model using a nonlinear mixed effect modeling method. Monte Carlo simulations were used to predict probability of target attainment (PTA) and cumulative fraction of response after single oral administration of 600 and 800 mg of MRX-I under fed conditions. The PK profile of oral administration of MRX-I was described by using a 2-compartment model with first-order elimination. Absorption of MRX-I may be affected by food intake. Type of volunteers could affect absorption constant rate and volume of distribution in the peripheral compartment, and weight could affect volume of distribution in the central department. No obvious effect on PK parameters was identified for other factors such as age, sex, creatinine clearance, concomitant medicine, and baseline diseases. Based on Monte Carlo simulation, MRX-I 600 or 800 mg BID up to 14 days on ordinary fed status could produce satisfactory efficacy against methicillin-resistant S aureus, with cumulative fraction of response >90% for fAUC0–24/MIC targeted at 2.3. At MIC ≤2.0 μg/mL for MRX-I 600 mg BID, or at MIC ≤4.0 μg/mL for MRX-I 800 mg BID, with continuous administration for 14 days at fed status, both regimens could obtain satisfactory clinical and antibacterial efficacy, with PTA >90%. Hence, the MRX-I regimen of 800 mg BID for 7–14 days can be recommended for confirmative clinical trials in patients with skin and skin structure infections. PK profiles of MRX-I were well captured by using a 2-compartment PK model, and disease status, food intake, and weight were found to significantly affect PK profiles. A dosing regimen of 800 mg BID for 7–14 days with ordinary food intake was recommended for pivotal study based on simulated fAUC0–24/MIC and PTA values. Results suggest that dose adjustments are not necessary for patient sex in confirmatory studies. Chinese Clinical Trial Registration identifier: CTR20140056.

LCB01-0371 is a novel broad-spectrum oxazolidinone antibacterial agent under investigation for the treatment of infection by gram-positive pathogens, including methicillin-resistant Staphylococcus aureus. This study evaluated the safety, tolerability, and pharmacokinetics of LCB01-0371 after a single intravenous (IV) infusion and determined its absolute oral bioavailability at a therapeutic dose of 800 mg. : This study was conducted in 2 parts. The first part was a single-blind, placebo-controlled, escalating single IV dose study (200, 400, 800, and 1200 mg) of LCB01-0371 via 2 different infusion regimens (250 mL over 60 min or 150 mL over 30 min) in 36 healthy male volunteers. The second part was an open-label, 2-way crossover design study in which 8 subjects were randomly assigned to 1 of 2 sequences of a single oral (800 mg) or IV (400 mg) administration of LCB01-0371. Safety assessments were conducted at regular intervals. Blood and urine were serially sampled, and drug concentrations were measured for up to 24 h to calculate pharmacokinetic parameters. LCB01-0371 after IV administration was generally safe and well tolerated up to 800 mg regardless of the infusion regimen. Adverse events were mild, excluding nausea at the highest dose, and resolved spontaneously. After a single IV administration, LCB01-0371 exhibited linear pharmacokinetic properties over the range of 200–800 mg. The elimination t1/2, volume of distribution, and clearance ranged from 1.48 to 1.68 h, 57.74–76.72 L, and 33.17–43.31 L/h, respectively, and they remained unchanged over the corresponding dose range. Cmax, AUC0–last, and AUC0–∞ increased in a dose-dependent manner. The dose-normalized total exposure after single PO and IV dosing were equivalent, with 90% CIs of the geometric least squares mean ratio of 86.6%–110% for AUC0–last and 86.6%–111% for AUC0–∞. The dose-normalized Cmax was not equivalent between oral and IV dosing, with a 90% CI of the geometric least squares mean ratio of 50.0%–105%. The absolute oral bioavailability of LCB01-0371 after a single 800-mg dose was 99.75%. After a single IV administration, LCB01-0371 was well tolerated in healthy volunteers at doses up to 800 mg, and it exhibited linear pharmacokinetic properties. The comparable total systemic exposure between IV and oral administration supports the ability to switch administration routes without a need for dose adjustment. ClinicalTrials.gov identifier: NCT02882789.