A phase I study of the safety, tolerability, and pharmacokinetics of contezolid acefosamil after intravenous and oral administration in healthy Chinese subjects.

Contezolid acefosamil (also known as MRX-4), a prodrug of contezolid, is under development for treatment of multidrug-resistant Gram-positive bacterial infections. A phase I single ascending dose (SAD) and multiple-dose placebo-controlled study was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of contezolid acefosamil in healthy Chinese subjects following intravenous (IV) and oral administration. Adverse events (AEs) and PK parameters were assessed appropriately. All subjects (n = 70) completed the trial. Overall, 67 cases of treatment-emergent adverse events (TEAEs) were observed in 49.1% (27 of 55) of the subjects receiving contezolid acefosamil. All TEAEs were mild in severity. No serious AEs or deaths were reported. After IV SAD (500-2,000 mg), the corresponding C max of the active drug contezolid increased from 1.95 ± 0.57 to 15.61 ± 4.88 mg/L, AUC0-inf from 40.25 ± 10.12 to 129.41 ± 38.30 h·mg/L, median T max from 2.00 to 2.75 h, and mean t 1/2 from 13.33 to 16.74 h. Plasma contezolid reached steady state on day 6 after multiple IV doses, with an accumulation ratio of 2.20-2.96. Oral SAD of 500 and 1,500 mg resulted in contezolid C max of 8.66 ± 2.60 and 37.10 ± 8.66 mg/L, AUC0-inf of 30.44 ± 7.33 and 162.36 ± 47.08 h·mg/L, and median T max of 2.50 and 2.98 h. Contezolid reached steady state on day 5 after multiple oral doses of 1,500 mg without significant accumulation. Contezolid C max and AUC0-inf increased with the dose of contezolid acefosamil. The good safety and PK profiles in this SAD and multiple-dose study can support further clinical development of contezolid acefosamil.

A phase IIb, open-label, randomized controlled dose ranging multi-centre trial to evaluate the safety, tolerability, pharmacokinetics and exposure-response relationship of different doses of delpazolid in combination with bedaquiline delamanid moxifloxacin in adult subjects with newly diagnosed, uncomplicated, smear-positive, drug-sensitive pulmonary tuberculosis.

BACKGROUND: Linezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure-response and exposure-toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin. METHODS: Seventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response. Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course. DISCUSSION: DECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinones. The primary efficacy endpoint is the change in bacterial load, an endpoint conventionally used in shorter dose-finding trials. Long-term follow-up after shortened treatment is possible through a safety rule excluding slow-and non-responders from potentially poorly performing dosages. TRIAL REGISTRATION: DECODE was registered in ClinicalTrials.gov before recruitment start on 22 October 2021 (NCT04550832).

Real-world evaluation of linezolid-associated serotonin toxicity with and without concurrent serotonergic agents.

BACKGROUND: The risk of linezolid-associated serotonin toxicity remains unclear. This study sought to evaluate the incidence of serotonin toxicity among hospitalized patients who received linezolid with or without concurrent serotonergic agents (SAs). Secondary outcomes were to assess the dose, agent selection and number of SAs. METHODS: A single-centre, retrospective cohort study of hospitalized patients aged ≥18 years who received at least one dose of linezolid with or without SAs between 1 January 2014 and 30 June 2021 was performed. Patients were excluded if they were aged <18 years, had linezolid ordered but not administered, were pregnant or were incarcerated. Up to five concurrent SAs were assessed, and dose category was classed as low, moderate or high (dose <33%, 33-66% or >66% of maximum daily dose, respectively). Serotonin toxicity was identified by searching patients' electronic medical records. If identified, the Sternbach criteria and Hunter criteria were applied. RESULTS: Of 2022 patients screened, 1743 were included in this study. Mean age, weight and linezolid duration were 58.5 years, 90.7 kg and 3.8 days, respectively. Approximately 67% (1168/1743) of patients received linezolid with at least one SA, and several patients received multiple SAs. Most patients (53.8%; 616/1144) received moderate- and/or high-dose SAs. Only two patients (0.11%) were identified as possible cases of serotonin toxicity based on the electronic medical record search. However, the incidence of serotonin toxicity was 0.06% (1/1743) based on the Sternbach criteria and 0% (0/1743) based on the Hunter criteria. CONCLUSIONS: Serotonin toxicity among hospitalized patients who received linezolid with or without SAs was exceedingly rare, even among those who received multiple and high-dose SAs.

The Novel Oxazolidinone TBI-223 Is Effective in Three Preclinical Mouse Models of Methicillin-Resistant Staphylococcus aureus Infection.

Staphylococcus aureus is an important cause of various infections in humans, including bacteremia, skin and soft tissue infections, and infections associated with implanted medical devices. The emergence of hospital- and community-acquired methicillin-resistant Staphylococcus aureus (MRSA) underscores the urgent and unmet need to develop novel, safe, and effective antibiotics against these multidrug-resistant clinical isolates. Oxazolidinone antibiotics such as linezolid have excellent oral bioavailability and provide coverage against MRSA infections. However, their widespread and long-term use is often limited by adverse effects, especially myelosuppression. TBI-223 is a novel oxazolidinone with potentially reduced myelosuppression, compared to linezolid, but its efficacy against MRSA infections is unknown. Therefore, the preclinical efficacy of TBI-223 (80 and 160 mg/kg twice daily) was compared with that of linezolid (40 and 80 mg/kg twice daily) and sham treatment in mouse models of MRSA bacteremia, skin wound infection, and orthopedic-implant-associated infection. The dosage was selected based on mouse pharmacokinetic analysis of both linezolid and TBI-223, as well as measurement of the MICs. In all three models, TBI-223 and linezolid had comparable dose-dependent efficacies in reducing bacterial burden and disease severity, compared with sham-treated control mice. Taken together, these findings indicate that TBI-223 represents a novel oxazolidinone antibiotic that may provide an additional option against MRSA infections. Future studies in larger animal models and clinical trials are warranted to translate these findings to humans. IMPORTANCE Staphylococcus aureus is the predominant cause of bloodstream, skin, and bone infections in humans. Resistance to commonly used antibiotics is a growing concern, making it more difficult to treat staphylococcal infections. Use of the oxazolidinone antibiotic linezolid against resistant strains is hindered by high rates of adverse reactions during prolonged therapy. Here, a new oxazolidinone named TBI-223 was tested against S. aureus in three mouse models of infection, i.e., bloodstream infection, skin infection, and bone infection. We found that TBI-223 was as effective as linezolid in these three models. Previous data suggest that TBI-223 has a better safety profile than linezolid. Taken together, these findings indicate that this new agent may provide an additional option against MRSA infections. Future studies in larger animal models and clinical trials are warranted to translate these findings to humans.

Efficacy and safety of tedizolid for the treatment of ventilated gram-positive hospital-acquired or ventilator-associated bacterial pneumonia in Japanese patients: Results from a subgroup analysis of a phase 3, randomized, double-blind study comparing tedizolid and linezolid.

INTRODUCTION: The results from the phase 3 study that evaluated the efficacy and safety of tedizolid phosphate, an oxazolidinone drug, for the treatment of gram-positive ventilated hospital-acquired bacterial pneumonia (vHABP)/ventilator-associated bacterial pneumonia (VABP) compared with linezolid (VITAL study), have been previously reported. We conducted a subgroup analysis to report the data obtained from Japanese patients enrolled in this study. METHODS: Patients aged ≥18 years with vHABP/VABP likely to be caused by gram-positive cocci were randomized 1:1 to tedizolid phosphate 200 mg once daily for 7 days or linezolid 600 mg twice daily for 10 days. In both treatment groups, patients with concurrent gram-positive bacteremia were treated for 14 days. Primary efficacy endpoints were day 28 all-cause mortality (ACM) and investigator-assessed clinical response at test-of-cure (TOC) in the intention-to-treat population. Safety outcomes included assessment of treatment-emergent adverse events. RESULTS: Fifty-three Japanese patients were randomized at received study drug (tedizolid, n = 28; linezolid, n = 25). Demographics and characteristics were generally similar between treatment groups. Rates of day 28 ACM were 10.7% and 20.0% with tedizolid and linezolid, respectively (difference, 9.3%; 95% CI, -10.1 to 28.7). Rates of investigator-assessed clinical cure at TOC were 78.6% and 72.0% with tedizolid and linezolid, respectively (difference, 6.6%; 95% CI, -16.7 to 29.8). Tedizolid phosphate was generally well tolerated and no new safety concerns were observed in the Japanese subgroup. CONCLUSION: The results from this subgroup analysis suggest generally favorable efficacy and safety of tedizolid in adult Japanese patients with vHABP/VABP. (ClinicalTrials.gov identifier: NCT02019420).

Long-term use of tedizolid for pulmonary nocardiosis.

Nocardiosis usually occurs in immunocompromised patients and causes infections in various organs, including the lungs, skin, and organs of the central nervous system. Herein, we report the case of a patient with minimal change nephrotic syndrome who had been on immunosuppressive drugs and developed pulmonary nocardiosis due to Nocardia nova complex and Pneumocystis pneumonia. For pulmonary nocardiosis, trimethoprim-sulfamethoxazole, linezolid, and clarithromycin were initiated sequentially, but were subsequently discontinued due to side effects; the treatment was completed with tedizolid. Tedizolid was used safely for 200 out of 286 days of antibiotic treatment, and clinical improvement was observed. Tedizolid is a bacteriostatic oxazolidine antibiotic that inhibits bacterial protein synthesis, the same mechanism as its predecessor, linezolid. Tedizolid is thought to cause less frequent myelosuppression than linezolid, at least for short-term use. In the future, tedizolid may be a promising alternative to linezolid in cases of nocardiosis that usually require long-term treatment.

Prospects of contezolid (MRX-I) against multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis.

Tuberculosis has become a great global public health threat. Compared with drug-susceptible tuberculosis (TB), the treatment regimens for multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) involve more severe adverse events and poorer treatment outcomes. Linezolid (LZD) is the first oxazolidinones used for TB. Thanks to its potent activity against Mycobacterium tuberculosis, LZD has become one of the key agents in the regimens against MDR/XDR-TB. However, this drug may cause intolerability and other adverse events. Contezolid, another novel oxazolidinone, can also inhibit M. tuberculosis, still with fewer adverse effects compared with LZD. This paper is to prospect the potentials of contezolid in the treatment of MDR/XDR-TB, with focus on its efficacy and possible adverse effects.

A Phase III multicentre, randomized, double-blind trial to evaluate the efficacy and safety of oral contezolid versus linezolid in adults with complicated skin and soft tissue infections.

OBJECTIVES: Contezolid is a novel oxazolidinone antibacterial agent for managing infections caused by aerobic and anaerobic Gram-positive bacteria including methicillin-resistant strains. A Phase III, multicentre, randomized, double-blind, active-controlled trial evaluated the efficacy and safety of contezolid versus linezolid in adults with complicated skin and soft tissue infections (cSSTIs). METHODS: Adult patients with cSSTI were randomized in a ratio of 1:1 to receive contezolid 800 mg or linezolid 600 mg q12h for 7-14 days. Clinical cure rate and safety were assessed at the test of cure (TOC) visit in the full analysis set (FAS) and clinical evaluable (CE) population. Non-inferiority was defined as a lower limit of the 95% CI around the treatment difference of clinical cure rates greater than -10%. Chinadrugtrials.org.cn registration identifier: CTR20150855. RESULTS: Clinical cure rates at TOC indicated non-inferiority of contezolid 800 mg to linezolid 600 mg q12h for patients in the FAS with clinical evaluation, FAS, and CE populations: 92.8% (271/292) versus 93.4% (284/304) (difference -0.6%, 95% CI: -4.7% to 3.5%), 81.4% (271/333) versus 84.5% (284/336) (difference -3.1%, 95% CI: -8.8% to 2.6%) and 90.5% (267/295) versus 90.1% (282/313) (difference 0.4%, 95% CI: -4.3% to 5.1%). Contezolid and linezolid showed similar efficacy for the cSSTIs caused by methicillin-susceptible or methicillin-resistant Staphylococcus aureus. Contezolid demonstrated significant lower incidence of leucopenia (0.3% versus 3.4%) and thrombocytopenia (0% versus 2.3%) than linezolid. The frequency of treatment-emergent adverse events was comparable between the two groups. CONCLUSIONS: Contezolid 800 mg q12h is as effective as linezolid for treatment of cSSTIs in adults, but safer than linezolid in terms of haematological abnormalities.

Single Ascending-Dose Study To Evaluate the Safety, Tolerability, and Pharmacokinetics of Sutezolid in Healthy Adult Subjects.

The primary objective of the study was to evaluate the safety and tolerability of single oral doses of sutezolid tablets administered under fasting conditions in healthy adult subjects. The secondary objective was to determine the pharmacokinetics (PK) of sutezolid and two metabolites, PNU-101603 and PNU-101244. Overall, sutezolid was well tolerated when administered as a 300-mg, 600-mg, 1,200-mg, or 1,800-mg dose in healthy adult subjects under fasting conditions. Maximum concentration (Cmax) of sutezolid, PNU-101603, and PNU-101244 increased in a less-than-proportional manner with an increase in sutezolid dose between 300 mg and 1,800 mg. Total exposure (AUClast [area under the concentration-time curve from time zero to the time of the last quantifiable concentration] and AUCinf [area under the plasma concentration time curve from time zero extrapolated to infinity]) of sutezolid, PNU-101603, and PNU-101244 increased proportionally with an increase in sutezolid dose.

Long-term safety and efficacy of anacetrapib in patients with atherosclerotic vascular disease.

AIMS: REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period. METHODS AND RESULTS: A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy. After stopping the randomly allocated treatment, 26 129 survivors entered a post-trial follow-up period, blind to their original treatment allocation. The primary outcome was first post-randomization major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization) during the in-trial and post-trial treatment periods, with analysis by intention-to-treat. Allocation to anacetrapib conferred a 9% [95% confidence interval (CI) 3-15%; P = 0.004] proportional reduction in the incidence of major coronary events during the study treatment period (median 4.1 years). During extended follow-up (median 2.2 years), there was a further 20% (95% CI 10-29%; P < 0.001) reduction. Overall, there was a 12% (95% CI 7-17%, P < 0.001) proportional reduction in major coronary events during the overall follow-up period (median 6.3 years), corresponding to a 1.8% (95% CI 1.0-2.6%) absolute reduction. There were no significant effects on non-vascular mortality, site-specific cancer, or other serious adverse events. Morbidity follow-up was obtained for 25 784 (99%) participants. CONCLUSION: The beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no adverse effects emerged on non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN) 48678192; ClinicalTrials.gov No. NCT01252953; EudraCT No. 2010-023467-18.

Serious adverse events with tedizolid and linezolid: pharmacovigilance insights through the FDA adverse event reporting system.

BackgroundTo investigate the adverse event (AE) profile of tedizolid and linezolid in post-marketing surveillance.Research design and methodsWe queried the worldwide FDA Adverse Event Reporting System and selected all records where tedizolid and linezolid were reported as suspect by removing potential duplicates. Disproportionality analysis was performed investigating designated medical events (DMEs) and specific AEs of clinical interest reported with tedizolid. The reporting odds ratios (RORs) were calculated, deemed significant by a lower limit of the 95% confidence interval (LL95%CI)>1, using linezolid as comparator. Case-by-case assessment of AEs reported in at least three cases with tedizolid was performed.ResultsOverall, 271 and 11,259 reports mentioning respectively tedizolid and linezolid were recorded, of which respectively 59 and 4,473 patients with DMEs or selected AEs were found. No difference emerged for the selected AEs except for increased reporting of hepatic failure (N = 3; LL95%CI = 1.06) with tedizolid considering reports collected after 2014. Extensive off-label use in terms of therapeutic indications (83.6%) and treatment duration was reported with tedizolid.ConclusionsSimilar AE reporting between the two oxazolidinones was found. Considering limitations of pharmacovigilance, this hypothesis of comparable safety profile should be tested prospectively through dedicated real-world studies.

Pharmacokinetics, Safety and Tolerability of Anacetrapib, a Novel Cholesteryl Ester Transfer Protein (CETP) Inhibitor, After Single and Multiple Doses in Healthy Chinese Subjects.

INTRODUCTION: Anacetrapib is a novel, powerful cholesteryl ester transfer protein (CETP) inhibitor with bidirectional lipid regulation, which was developed for dyslipidemia. The aim of this study is to evaluate the single- and multiple-dose pharmacokinetics (PK), safety and tolerability of anacetrapib in healthy Chinese subjects and assess the PK difference between Chinese and other populations. METHODS: Forty subjects were enrolled in an open-label study consisting of three panels (50 mg single dose; 100 mg single dose followed by 100 mg once-daily multiple doses for 10 days; a 200 mg single dose). Safety and tolerability were evaluated by monitoring adverse events, laboratory safety tests, ECGs, vital signs and physical examination. PK were evaluated and compared with historical data in black and white subjects. RESULTS: Anacetrapib was absorbed after administration of a single oral dose, with a median Tmax of 3.0-5.0 h and elimination half-life of 105.3-122.3 h. The AUC and Cmax of anacetrapib increased in a slightly less than dose-proportional manner over a dose range of 50-200 mg. Once-daily administration of 100 mg of anacetrapib for 10 days resulted in a median Tmax of 5.0 h with an apparent half-life of 193.7 h on Day 10 of multiple dosing. Anacetrapib accumulation ratios (Day 10 of multiple dosing/Day 1) were 1.39 (AUC0-24 h), 1.11 (Cmax) and 2.57 (C24 h). CONCLUSION: The PK properties of anacetrapib in Chinese subjects are comparable to those observed in the black population and in white subjects. Single and once-daily administration of anacetrapib was generally well tolerated in healthy Chinese subjects observed in this study. TRIAL REGISTRATION: chinadrugtrials.org.cn identifier number CTR20130983.

Long term safety, tolerability, and efficacy of intracutaneous zolmitriptan (M207) in the acute treatment of migraine.

OBJECTIVE: To determine the long-term safety and tolerability profile of M207 in the acute treatment of migraine. BACKGROUND: M207 is an investigational microneedle-based system for intracutaneous delivery of zolmitriptan for the treatment of migraine attacks. Following on the positive results of a Phase 2/3 placebo-controlled efficacy study (ZOTRIP), this study was designed to evaluate the safety of this novel product during repeated use for the treatment of migraine attacks. METHODS: In this 6-12 month open-label, multicenter observational study, participants used an eDiary to record headache symptoms and adverse events at specified intervals up to 48 h following treatment of a qualifying attack with M207 3.8 mg (intracutaneous zolmitriptan). Participants underwent clinical evaluations at specified intervals up to 12 months. RESULTS: Among 335 participants who treated ≥1 migraine attack, 257 completed 6 months and 127 completed 1 year of treatment. The most common reason for withdrawal from the study was a low frequency of reported attacks post randomization. Overall, 5963 migraine attacks were treated. Most participants (96%) experienced at least 1 adverse event, the vast majority of which concerned the application site, and > 95% of which were mild. Fifteen participants (4%) withdrew due to adverse events; 4 withdrew due to 7 application site reactions, 6 of which were mild. Participants achieved pain freedom in 2477/5617 (44%) of attacks, most bothersome symptom freedom in 3315/5330 (62%) of attacks, and pain relief 2 h post-dose in 4552/5617 (81%) of attacks. Sustained pain freedom 2-24 h was seen in 1761/4698 (38%) of attacks, and 2-48 h in 1534/4429 (35%) of attacks. CONCLUSIONS: The majority of participants experienced cutaneous adverse reactions such as application site erythema, swelling, and bleeding, and most reactions were scored as mild. These results are consistent with what was observed in the single migraine attack treatment ZOTRIP trial indicating that M207 is well tolerated in the setting of longer-term repeated use. Efficacy findings were also similar to those in the ZOTRIP trial. TRIAL REGISTRATION: Clinicaltrials.gov on September 13, 2017 ( NCT03282227 ).

Neuropsychiatric toxicity and cycloserine concentrations during treatment for multidrug-resistant tuberculosis.

BACKGROUND: Cycloserine, or its structural analogue terizidone, has been associated with neuropsychiatric toxicity (psychosis, depression, and neuropathy). Prospective clinical data on the incidence of and risk factors for neuropsychiatric toxicity in TB patients treated with cycloserine are limited. METHODS: A prospective evaluation of neuropsychiatric toxicity was performed using validated screening tools in patients with multidrug-resistant tuberculosis treated with terizidone. Cox proportional hazard modelling was performed to explore the effects of clinical variables and measures of cycloserine pharmacokinetics in plasma. RESULTS: A total 144 participants were recruited: 86 were male and 58 were female; their median age was 35.7 years and 91 (63%) were HIV-infected. Fifty-five (38%) participants developed at least one neuropsychiatric event (30 cases per 100 person-months): 50 (35%) neuropathy, 14 (10%) depression, and 11 (8%) psychosis. Neuropathy was independently associated with cycloserine clearance ((adjusted hazard ratio 0.34 (aHR), P = 0.03)) and high-dose pyridoxine (200 mg vs 150 mg daily, aHR: 2.79, P = 0.01). CONCLUSIONS: A high incidence of early neuropsychiatric toxicity was observed in this cohort of patients treated with terizidone. Cycloserine clearance and higher doses of pyridoxine are associated with incident or worsening peripheral neuropathy.

Tedizolid: a service evaluation in a large UK teaching hospital.

Tedizolid is a new oxazolidinone antibiotic with little real-life data on use outside of skin and soft tissue infections. There is a paucity of safety evidence in courses greater than 6 days. Our centre uses tedizolid predominantly when linezolid-associated adverse events have occurred. This service evaluation describes our experience to date. We performed a retrospective service evaluation by reviewing case notes, prescription charts, and laboratory system results for each patient prescribed tedizolid at our hospital and recording patient demographics, clinical details, and outcomes. Sixty patients received tedizolid between May 2016 and November 2018. Most were treated for bone or joint infections and had stopped linezolid prior to tedizolid prescription. Mean length of tedizolid therapy was 27 days. Haematological adverse effects were infrequent. Most patients (72%) finished the course and their clinical condition improved during treatment (72%). Adverse events were common, but often not thought to be tedizolid related. Tedizolid appears to be safe in prolonged courses within this context. It may be suitable for longer-term antibiotic therapy within a complex oral and parenteral outpatient antibiotic therapy (COPAT) service. Patients who do not tolerate linezolid can be safely switched to tedizolid if appropriate.

Oxazolidinone-containing Hybrids with Antibacterial Activity against Methicillin-resistant Staphylococcus aureus (MRSA): A Mini-review.

The increasing danger of methicillin-resistant Staphylococcus aureus (MRSA) and the limited therapeutic options for invasive MRSA infections make an urgent demand for the development of novel anti-MRSA agents. Oxazolidinone derivatives could inhibit protein synthesis by acting on the ribosomal 50S subunit of the bacteria and prevent the formation of a functional 70S initiation complex, so oxazolidinones are a novel class of antimicrobial agents with potential activity against a wide range of clinically significant multidrug-resistant Gram-positive pathogens. However, oxazolidinones such as linezolid are associated with significant adverse events, and myelosuppression represents the main unfavorable side effects. Moreover, MRSA isolates that are resistant to oxazolidinones have already emerged. Hybridization of oxazolidinone with other antibacterial pharmacophores has the potential to interact with multiple targets or to counterbalance the known side effects associated with each pharmacophore. Thus, oxazolidinone-containing hybrids are useful scaffolds for the development of novel anti-MRSA agents. This review covers the recent advances of oxazolidinonecontaining hybrids with anti-MRSA activity developed in the last decade to set up the direction for the design and development of oxazolidinone-containing hybrids with high efficiency and low toxicity.

Discovery of a Conformationally Constrained Oxazolidinone with Improved Safety and Efficacy Profiles for the Treatment of Multidrug-Resistant Tuberculosis.

Tuberculosis (TB) remains a serious public health challenge, and the research and development of new anti-TB drugs is an essential component of the global strategy to eradicate TB. In this work, we discovered a conformationally constrained oxazolidinone 19c with improved anti-TB activity and safety profile through a focused lead optimization effort. Compound 19c displayed superior in vivo efficacy in a mouse TB infection model compared to linezolid and sutezolid. The druggability of compound 19c was demonstrated in a panel of assays including microsomal stability, cytotoxicity, cytochrome P450 enzyme inhibition, and pharmacokinetics in animals. Compound 19c demonstrated an excellent safety profile in a battery of safety assays, including mitochondrial protein synthesis, hERG K+, hCav1.2, and Nav1.5 channels, monoamine oxidase, and genotoxicity. In a 4 week repeated dose toxicology study in rats, 19c appeared to have less bone marrow suppression than linezolid, which has been a major liability of the oxazolidinone class.

The first case of teeth discoloration induced by linezolid in children in China Mainland.

Linezolid is an oxazolidinone antimicrobial agent often used to treat multidrug-resistant Gram-positive bacterial infections. The common adverse reactions of linezolid are diarrhea, nausea, headache and bone marrow suppression, and so on. Here, we report the first case of teeth discoloration induced by linezolid linked with extrinsic discoloration in China Mainland. This case report highlights a rare adverse reactions of a commonly used antibiotic.