Oral Linezolid Induced Early Onset Hepatic Encephalopathy- A Case Report of 65-year Old Diabetic Female.

INTRODUCTION: Linezolid is increasingly utilized to treat gram-positive bacteria that are resistant to other antibiotics like vancomycin-resistant Staphylococcus aureus, methicillinresistant Staphylococcus aureus as well as drug-resistant tuberculosis. It acts by inhibiting protein synthesis in bacteria. Although it is a relatively safe medicine, many reports of hepatotoxicity and neurotoxicity linked to long-term usage have been received but patients with pre-existing risk factors, such as diabetes and alcoholism, may have toxicity even after short-term use of linezolid. CASE PRESENTATION: Here we are presenting a case of a 65-year-old female with diabetes who developed hepatic encephalopathy after one week of treatment with linezolid prescribed for nonhealing diabetic ulcer after a culture sensitivity test. After the use of linezolid 600 mg BD for 8 days patient developed altered sensorium and breathlessness and had high bilirubin, SGOT, and SGPT. She was diagnosed with hepatic encephalopathy. Linezolid was withdrawn and after 10 days all laboratory parameters for liver function test were improved. CONCLUSION: Care should be taken when prescribing linezolid in such patients with pre-existing risk factors as they are prone to develop hepatotoxic and neurotoxic adverse effects even after short-term use of linezolid.

Intracellular and in vivo activities of oxazolidinone drugs against Mycobacterium avium complex infection.

The prevalence of Mycobacterium avium complex-pulmonary disease (MAC-PD) has become a growing concern worldwide, and current treatments involving macrolides (clarithromycin [CLR] or azithromycin), ethambutol, and rifampicin have limited success, highlighting the need for better therapeutic strategies. Recently, oxazolidinone drugs have been identified as novel anti-tuberculosis drugs effective against drug-resistant M. tuberculosis. However, the effects of these drugs against MAC are still controversial due to limited data. Here, we first evaluated the intracellular anti-MAC activities of two oxazolidinone drugs, linezolid (LZD) and delpazolid (DZD), against 10 macrolide-susceptible MAC strains and one macrolide-resistant M. avium strain in murine bone marrow-derived macrophages (BMDMs) and found that both drugs demonstrated similar potential. The synergistic efficacies with CLR were then determined in a chronic progressive MAC-PD murine model by initiating a 4-week treatment at 8 weeks post-infection. Upon assessment of bacterial burdens and inflamed lesions, oxazolidinone drugs exhibited no anti-MAC effect, and there was no significant difference in the synergistic effect of CLR between LZD and DZD. These findings suggest that oxazolidinone drugs inhibit intracellular bacterial growth, even against macrolide-resistant MAC, but their clinical application requires further consideration.

The N-Alkylation of Agelastatin A Modulates Its Chemical Reactivity.

Agelastatin A is a marine alkaloid with potent biological activity. To date, at least 17 different strategies have achieved its total synthesis, along with many analogues. The present study focuses on the acidity stability of some N-methyl derivatives of agelastatin A. The study made use of chemical reactions and spectroscopic acquisitions. The chemical structure of some derivatives can undergo a profound rearrangement. The results could shed light on the mechanism of action of agelastatin A and suggest the preparation of analogues with improved pharmacological efficacy.

Strategies for the Discovery of Oxazolidinone Antibacterial Agents: Development and Future Perspectives.

Oxazolidinones represent a significant class of synthetic bacterial protein synthesis inhibitors that are primarily effective against Gram-positive bacteria. The commercial success of linezolid, the first FDA-approved oxazolidinone antibiotic, has motivated researchers to develop more potent oxazolidinones by employing various drug development strategies to fight against antimicrobial resistance, some of which have shown promising results. Thus, this Perspective aims to discuss the strategies employed in constructing oxazolidinone-based antibacterial agents and summarize recent advances in discovering oxazolidinone antibiotics to provide valuable insights for potentially developing next-generation oxazolidinone antibacterial agents or other pharmaceuticals.

Rapid culture-based LNZ test for detection of linezolid susceptibility/resistance in staphylococci and enterococci.

A rapid, easy-to-handle, cost-effective and universal culture-based test was developed for the identification of linezolid resistance among the most clinically relevant enterococcal and staphylococcal species. Our technique was tested using linezolid-resistant (n = 50) and linezolid-susceptible (n = 67) Gram-positive isolates: 34 Enterococcus faecium, 20 Enterococcus faecalis, 20 Staphylococcus aureus, 38 Staphylococcus epidermidis, and 5 Staphylococcus capitis. The susceptibility/resistance phenotype of E. faecium, E. faecalis, S. aureus, and S. epidermidis to linezolid was detected within 4.5 hours, while an extended timeframe was actually required for S. capitis (6.5 hours). The Rapid LNZ test showed a full agreement with the standard broth microdilution method, independently of the molecular resistance mechanism and MIC values, with sensitivities and specificities of 100% for all species.

Efficacy and safety of intranasal agents for the acute treatment of migraine: a systematic review and network meta-analysis.

BACKGROUND: Intranasal agents may be ideal for the treatment of migraine patients. Many new acute intranasal-specific therapies have been developed, but few of them have been directly compared. The aim of this network meta-analysis (NMA) was to compare the efficacy and safety of various intranasal agents for the treatment of acute migraine in adult patients. METHODS: The Cochrane Register of Controlled Trials, Embase, and PubMed were searched from inception to 15 August 2023. Randomized controlled trials (RCTs) using intranasal agents (no restrictions on dose, formulation, dosing regimen or timing of the first dose) to treat adult patients with acute migraine were included. The primary efficacy endpoint was pain freedom at 2 h, and the primary safety endpoint was adverse events (AEs). The analysis process followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Nineteen studies (21 RCTs, 9738 participants) were included. Compared to the placebo, 5 mg of zolmitriptan using a conventional liquid nasal spray device was the most effective for pain freedom at 2 h [odds ratio (OR): 4.67, 95% confidence interval (CI): 3.43 to 6.43] and 24 h (OR: 5.49, 95% CI: 3.58 to 8.42) among all the interventions. Butorphanol nasal spray 1 mg was the most effective (OR: 8.62, 95% CI: 1.11 to 66.92) for pain freedom at 1 h, but with low-quality evidence. DFN-02 presented the highest freedom from nausea (OR: 4.95, 95% CI: 1.29 to 19.01) and phonophobia (OR: 5.36, 95% CI: 1.67 to 17.22) at 2 h, albeit with lower odds of achieving complete pain freedom. ROX-828 showed the highest improvement in freedom from photophobia at 2 h (OR: 4.03, 95% CI: 1.66 to 9.81). Dihydroergotamine nasal spray was significantly associated with the highest risk of AEs (OR: 9.65, 95% CI: 4.39 to 21.22) and was not recommended for routine use. Zavegepant nasal spray demonstrated the lowest risk of AEs (OR: 2.04, 95% CI: 1.37 to 3.03). The results of sensitivity analyses for the primary endpoints (pain freedom at 2 h and AEs) were generally consistent with those of the base case model. CONCLUSIONS: Compared with other new intranasal-specific therapies in treating migraine attacks, zolmitriptan nasal spray 5 mg was the most effective agent for pain freedom at 2 h. Zavegepant nasal spray 10 mg had the fewest adverse side effects.

Prolonged use of linezolid in bone and joint infections: a retrospective analysis of adverse effects.

OBJECTIVES: Antibiotic treatment for bone and joint infections generally lasts for 6 weeks or longer. Linezolid may be a good option for treating bone and joint infections, but there is an increased risk of potential serious adverse drug events (ADEs) when used for more than 28 days. The aim of this study was to obtain detailed information on the type and time to occurrence of the patient-reported ADEs, the dynamics of haematopoiesis over time, and the reasons for early discontinuation of linezolid when used for an intended maximum duration of 12 weeks. METHODS: This single-centre retrospective study was conducted at the Sint Maartenskliniek in The Netherlands. Patients were included if they were planned to use linezolid for more than 28 days. The main reason for discontinuation of linezolid, the ADE according to the Naranjo score, and the time to occurrence of ADEs were analysed. RESULTS: Among 78 patients, drug toxicity led to early discontinuation of linezolid in 11 (14%) patients before and nine (12%) after 28 days of therapy. The median treatment duration was 42 days. Gastrointestinal intolerance (42%) and malaise (32%) were the most common ADEs. In 75% of the cases the ADE occurred within 28 days of therapy. Sixty-seven patients were able to continue linezolid beyond 28 days, 87% of whom completed therapy as scheduled. Severe cytopenia, according to the Common Terminology Criteria for Adverse events (CTCA), was observed in four patients and was reversible after discontinuation of linezolid. One patient suffered optic neuropathy related to linezolid use. CONCLUSIONS: Linezolid could be considered an alternative option to the current standard of IV glycopeptides for the treatment of bone and joint infection for up to 12 weeks. If patients pass the first 28 days of therapy, the likelihood of successful completion of therapy is high with a low risk of serious ADEs.

Synthesis and Biological Activities of Oxazolidinone Pleuromutilin Derivatives as a Potent Anti-MRSA Agent.

A series of pleuromutilin derivatives containing an oxazolidinone skeleton were synthesized and evaluated in vitro and in vivo as antibacterial agents. Most of the synthesized derivatives exhibited potent antibacterial activities against three strains of Staphylococcus aureus (including MRSA ATCC 33591, MRSA ATCC 43300, and MSSA ATCC 29213) and two strains of Staphylococcus epidermidis (including MRSE ATCC 51625 and MSSE ATCC 12228). Compound 28 was the most active antibacterial agent in vitro (MIC = 0.008-0.125 µg·mL-1) and exhibited a significant bactericidal effect, low cytotoxicity, and weak inhibition (IC50 = 20.66 µmol·L-1) for CYP3A4, as well as exhibited less possibility to cause bacterial resistance. Furthermore, in vivo activities indicated that the compound was effective in reducing MRSA load in a murine thigh infection model. Moreover, it clearly facilitated the healing of MRSA skin infection and inhibited the secretion of the TNF-α, IL-6, and MCP-1 inflammatory factors in serum. These results suggest that oxazolidinone pleuromutilin is a promising therapeutic candidate for drug-resistant bacterial infections.

Hybridization of antimicrobial oxazolidinones with commercial drugs: A fight against the "superbugs".

Antimicrobial resistance caused by the emergence of antibiotic-resistant microbes, termed as "superbugs," poses a grave healthcare concern in the contemporary era. Though this phenomenon is natural, an incessant use of antibiotics due to their unregulated over-the-counter availability, and a lack of compliance with the legislation seem to be major contributing factors. This phenomenon has further complicated the treatment of common infectious diseases thereby leading to prolonged illness, disability, and even death. In addition, a sizeable impact on the healthcare cost is met due to a prolonged stay at the medical facilities to receive an intensive care. Overall, the gains of "Millennium Development Goals" and the accomplishment of Sustainable Development Goals are at risk due to the emerging antimicrobial resistance. Since an early identification and development of novel antibiotic classes that evade antimicrobial resistance appears improbable, the strategy of hybridization of the existing antibiotics with efficacious pharmacophores and drug molecules with a different mechanism of antimicrobial action can be a silver lining for the management of superbugs. In this regard, we aim to provide a perspective for the applicability of the hybridization of oxazolidinone class of antibiotics with other drugs for evading antimicrobial resistance.

Clinical efficacy of psychiatric nursing-based vancomycin in the treatment of Staphylococcus aureus infectious skin diseases.

To study the clinical effect of psychiatric nursing-based vancomycin in patients with staphylococcus aureus infectious skin disease. A retrospective analysis was performed on 100 patients with staphylococcus aureus infectious skin disease admitted to our hospital from March 2019 to July 2020. Al patients received psychiatric nursing and were divided into control group (mupiroxine) and experimental group (vancomycin) according to the treatment mode, with 50 patients in each group. The effective rate of treatment, adverse reactions, disappearance time of dermatological clinical symptoms and recurrence after one course of treatment were compared between the two groups. The effective rate of the experimental group was significantly higher than that of the control group (P<0.05).The incidence of adverse reactions and the disappearance time of clinical symptoms in the experimental group were significantly lower than those in the control group (P<0.05). After one course of treatment, the number of patients with recurrence in the experimental group was significantly lower than that in the control group (P<0.05). Vancomycin might be a boon for patients with staphylococcus aureus infectious skin diseases, with good effectiveness and safety profiles.

The anti-inflammatory effect of tedizolid on carrageenan-induced footpad edema rat model.

Tedizolid (TZD) is an oxazolidinone anti-methicillin-resistant Staphylococcus aureus (MRSA) drug. Linezolid (LZD), another oxazolidinone, has been shown to have an anti-inflammatory effect. TZD has been shown to exhibit an anti-inflammatory effect in a murine model of hematogenous pulmonary infection. In this study, we further investigated the anti-inflammatory effect of TZDs using a carrageenan-induced rat footpad edema model. TZD was administered at 0, 10, 20, and 40 mg/kg to the carrageenan-induced rat footpad edema model, and the edema rate was measured over time up to 9 h later. The area under the time curve of the edema rate profile (AUCedema0→9) decreased in a TZD dose-dependent manner. In addition, the correlation between AUCedema0→9 and the area under the time curve of free TZD plasma concentration (fAUCblood) obtained from the pharmacokinetic study of TZD in the carrageenan-induced rat footpad edema model was examined. fAUCblood and AUCedema0→9 showed a good negative correlation. These results indicate that TZD suppresses carrageenan-induced footpad edema and that TZD exerts its anti-inflammatory effects in a plasma concentration-dependent manner.

Biocatalytic Synthesis of Metaxalone and Its Analogues.

A biocatalytic approach for the synthesis of metaxalone and its analogues was developed based on the reaction of epoxides and cyanate catalyzed by halohydrin dehalogenase. Gram-scale synthesis of chiral and racemic metaxalone was achieved with 44% (98% ee) and 81% yields, respectively, by protein engineering of the halohydrin dehalogenase HHDHamb from Acidimicrobiia bacterium. Additionally, various metaxalone analogues were synthesized at 28-40% yields (90-99% ee) for chiral forms and 77-92% yields for racemic forms.

An Enterococcus faecium Isolated from Bovine Feces in Italy Shares optrA- and poxtA-Carrying Plasmids with Enterococci from Switzerland.

To investigate the occurrence of oxazolidinone resistance genes, 18 florfenicol-resistant enterococci were isolated from 66 fecal samples collected from several cattle farms in central Italy. The PCR screening indicated that only a bovine florfenicol-resistant isolate, Enterococcus faecium 249031-C, was positive for the presence of optrA and poxtA genes. The strain was tested for its susceptibility to florfenicol, chloramphenicol, linezolid, tedizolid, tetracycline, erythromycin, and vancomycin. Whole Genome Sequencing analysis showed that E. faecium 249031-C, belonging to the ST22 lineage, harbored two plasmids: the optrA-carrying p249031-S (179 kb) and the poxtA-carrying p1818-c (23 kb). p249031-S, containing a new optrA-carrying Tn7695 transposon, was closely related to the plasmid pF88_1 of E. faecium F88, whereas p1818-c had already been detected in a human E. faecium, both enterococci were from Switzerland. The linezolid resistance genes were cotransferred to the E. faecium 64/3 recipient. Circular forms from both optrA- and poxtA-carrying genetic contexts were obtained. The occurrence of oxazolidinone resistance genes in a bovine E. faecium isolate and their localization on conjugative and mobilizable plasmids pose a risk for public health.

Monitoring Salivary Concentrations of Tedizolid and Linezolid Using Rats.

BACKGROUND AND OBJECTIVE: Therapeutic drug monitoring (TDM) is an effective tool for the management of patients who are administered linezolid. The use of saliva for TDM has potential advantages over the use of plasma; however, only a few reports have compared drug concentrations in the saliva and plasma. Moreover, there are no reports on the salivary concentration of tedizolid, an oxazolidinone antibiotic similar to linezolid. In the present study, the concentrations of tedizolid and linezolid in rat submandibular saliva were compared with those measured in the plasma. METHODS: Tedizolid (10 mg/kg, n = 6) and linezolid (12 mg/kg, n = 5) were administered via the rat tail vein. Submandibular saliva and plasma samples were collected for up to 8 h after the initiation of drug administration, and assayed for the concentrations of tedizolid and linezolid. RESULTS: A strong correlation was found between the saliva and plasma concentrations of tedizolid (r = 0.964, p < 0.001) and linezolid (r = 0.936, p < 0.001). The value of tedizolid maximum concentration of drug (Cmax) was 0.99 ± 0.08 µg/mL in the saliva and 14.46 ± 1.71 µg/mL in the plasma. Meanwhile, the Cmax of linezolid was 8.01 ± 1.42 µg/mL in the saliva and 13.00 ± 1.90 µg/mL in the plasma. According to these results, the saliva/plasma concentration ratios of tedizolid and linezolid in rats were 0.0513 ± 0.0080 and 0.6341 ± 0.0339, respectively. CONCLUSIONS: Considering the correlation between saliva and plasma concentrations of tedizolid and linezolid, as well as the characteristics of saliva, the results of this study suggest that saliva is a useful matrix for TDM.

Concentration of contezolid in cerebrospinal fluid and serum in a patient with tuberculous meningoencephalitis: A case report.

Central nervous system (CNS) tuberculosis (TB) is a devastating and often life-threatening disease caused by Mycobacterium tuberculosis. Contezolid, a new oxazolidinone, has demonstrated potent antimycobacterial activity in both in-vivo and in-vitro studies, with lower toxicity than linezolid. However, pharmacokinetic data are still not available for contezolid in the CNS of patients with CNS TB. This article reports the steady-state concentrations of contezolid in serum and cerebrospinal fluid (CSF) of a patient receiving contezolid as part of multi-drug treatment for tuberculous meningoencephalitis. At weeks 7 and 11 (7 h post-dose) after initiation of contezolid therapy, the serum concentrations of contezolid were 9.64 mg/L and 9.36 mg/L, respectively. In CSF, the observed concentrations of contezolid were 0.54 mg/L and 1.15 mg/L, respectively. The CSF:serum concentration ratios were 0.056 and 0.123 at weeks 7 and 11, respectively. The observed concentrations in CSF were above the minimum inhibitory concentration of contezolid against M. tuberculosis, and were close to the estimated serum unbound fraction of contezolid (10%), suggesting that unbound contezolid has high CSF permeability.

Characterization of an optrA-harbouring unconventional circularizable structure located on a novel ICESa2603 family-like integrative and conjugative element ICESsuHN38 in Streptococcus suis.

OBJECTIVES: To identify the novel genetic elements involved in the horizontal transfer of the oxazolidinone/phenicol resistance gene optrA in Streptococcus suis. METHODS: Whole-genome DNA of the optrA-positive isolate S. suis HN38 was subjected to WGS via both Illumina HiSeq and Oxford Nanopore platforms. MICs of several antimicrobial agents (erythromycin, linezolid, chloramphenicol, florfenicol, rifampicin and tetracycline) were determined by broth microdilution. PCR assays were performed to identify the circular forms of the novel integrative and conjugative element (ICE) ICESsuHN38, but also the unconventional circularizable structure (UCS) excised from this ICE. The transferability of ICESsuHN38 was evaluated by conjugation assays. RESULTS: S. suis isolate HN38 harboured the oxazolidinone/phenicol resistance gene optrA. The optrA gene was flanked by two copies of erm(B) genes in the same orientation, located on a novel ICESa2603 family-like ICE, designated ICESsuHN38. PCR assays revealed that a novel UCS carrying the optrA and one copy of erm(B) could be excised from ICESsuHN38. Conjugation assays confirmed that ICESsuHN38 was able to successfully transfer into the recipient strain S. suis BAA. CONCLUSIONS: In this work, a novel optrA-carrying mobile genetic element, a UCS, was identified in S. suis. The optrA gene was flanked by copies of erm(B) and its location on the novel ICESsuHN38 will aid its horizontal dissemination.

Simple and Efficient Synthesis of 3-Aryl-2-oxazolidinone Scaffolds Enabling Increased Potency toward Biofilms.

Infectious diseases caused by bacterial pathogens are a leading cause of mortality worldwide. In particular, recalcitrant bacterial communities known as biofilms are implicated in persistent and difficult to treat infections. With a diminishing antibiotic pipeline, new treatments are urgently required to combat biofilm infections. An emerging strategy to develop new treatments is the hybridization of antibiotics. The benefit of this approach is the extension of the useful lifetime of existing antibiotics. The oxazolidinones, which include the last resort antibiotic linezolid, are an attractive target for improving antibiofilm efficacy as they present one of the most recently discovered classes of antibiotics. A key step in the synthesis of new 3-aryl-2-oxazolidinone derivatives is the challenging formation of the oxazolidinone ring. Herein we report a direct synthetic route to the piperazinyl functionalized 3-aryl-2-oxazolidinone 17. We also demonstrate an application of these piperazine molecules by functionalizing them with a nitroxide moiety as a strategy to extend the useful lifetime of oxazolidinones and improve their potency against Methicillin-resistant Staphylococcus aureus (MRSA) biofilms. The antimicrobial susceptibility of the linezolid-nitroxide conjugate 11 and its corresponding methoxyamine derivative 12 (a control for biofilm dispersal) was assessed against planktonic cells and biofilms of MRSA. In comparison to linezolid and our lead compound 10 (a piperazinyl oxazolidinone derivative), the linezolid-nitroxide conjugate 11 displayed a minimum inhibitory concentration that was 4-16-fold higher. The opposite effect was seen in biofilms where the linezolid-nitroxide hybrid 11 was >2-fold more effective (160 µg/mL versus >320 µg/mL) in eradicating MRSA biofilms. The methoxyamine derivative 12 performed on par with linezolid. The drug-likeness of the compounds was also assessed, and all compounds were predicted to have good oral bioavailability. Our piperazinyl oxazolidinone derivative 10 was confirmed to be lead-like and would be a good lead candidate for future functionalized oxazolidinones. The modification of antibiotics with a dispersal agent appears to be a promising approach for eradicating MRSA biofilms and overcoming the antibiotic resistance associated with the biofilm mode of growth.

Chiral Separation of Oxazolidinone Analogs by Capillary Electrophoresis Using Anionic Cyclodextrins as Chiral Selectors: Emphasis on Enantiomer Migration Order.

Comparative chiral separations of enantiomeric pairs of four oxazolidinone and two related thio-derivatives were performed by capillary electrophoresis, using cyclodextrins (CDs) as chiral selectors. Since the selected analytes are neutral, the enantiodiscrimination capabilities of nine anionic CD derivatives were determined, in 50 mM phosphate buffer pH = 6. Unanimously, the most successful chiral selector was the single isomeric heptakis-(6-sulfo)-ß-cyclodextrin (HS-ß-CD), which resulted in the highest enantioresolution values out of the CDs applied for five of the six enantiomeric pairs. The enantiomer migration order (EMO) was the same for two enantiomeric pairs, irrespective of the CD applied. However, several examples of EMO reversals were obtained in the other cases. Interestingly, changing from randomly substituted, multi-component mixtures of sulfated-ß-CD to the single isomeric chiral selector, enantiomer migration order reversal occurred for two enantiomeric pairs and similar observations were made when comparing heptakis-(2,3-di-O-methyl-6-O-sulfo)-ß-CD, (HDMS-ß-CD) with HS-ß-CD. In several cases, cavity-size-dependent, and substituent-dependent EMO reversals were also observed. Minute differences in the structure of the analytes were also responsible for several cases of EMO reversal. The present study offers a complex overview of the chiral separation of structurally related oxazolidinones, and thio-analogs, highlighting the importance of the adequate choice of chiral selector in this group of compounds, where enantiomeric purity is of utmost importance.

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).

Optimization and Antibacterial Evaluation of Novel 3-(5-Fluoropyridine-3-yl)-2-oxazolidinone Derivatives Containing a Pyrimidine Substituted Piperazine.

In this study, a series of novel 3-(5-fluoropyridine-3-yl)-2-oxazolidinone derivatives were designed and synthesized based on compounds previously reported, and their antibacterial activity was investigated. Then their antibacterial activity was investigated for the first time. Preliminary screening results showed that all these compounds exhibited antibacterial activity against gram-positive bacteria, including 7 drug-sensitive strains and 4 drug-resistant strains, among which compound 7j exhibited an 8-fold stronger inhibitory effect than linezolid, with a minimum inhibitory concentration (MIC) value of 0.25 µg/mL. Further molecular docking studies predicted the possible binding mode between active compound 7j and the target. Interestingly, these compounds could not only hamper the formation of biofilms, but also have better safety, as confirmed by cytotoxicity experiments. All these results indicate that these 3-(5-fluoropyridine-3-yl)-2-oxazolidinone derivatives have the potential to be developed into novel candidates for the treatment of gram-positive bacterial infections.