Unveiling the multitargeted potential of deprodone and control comparison with linezolid against hydrolase and transferase enzymes of methicillin-resistant Staphylococcus aureus.

Staphylococcus aureus (S. aureus), commonly found on the skin and nose, causes minor skin conditions to life-threatening diseases, including boils or impetigo, pneumonia, and bloodstream infections. MRSA (Methicillin-Resistant S. aureus) is a strain resistant to many antibiotics and poses a significant challenge in clinical settings. Nowadays, the alternative drug Linezolid is used, and it is not clear when MRSA starts resistance to it, necessitating the need for more alternative drugs with the least chance of developing resistance. This study aims to identify a multitargeted drug candidate with better efficacy than Linezolid. We have taken three hydrolase and transferase proteins from S. aureus, performed the multitargeted docking studies with human-approved drugs, and compared them with the control drug Linezolid. The docking and MM\GBSA scores ranging from -6.79 to -5.78 Kcal/mol and - 37.47 to 30.16 Kcal/mol, respectively, that revealed Deprodone (used for inflammatory skin disorders, bowel disease, and fatty acid metabolism disorders) can be a far better and multitargeted drug candidate than Linezolid. We extended our studies to include extensive pharmacokinetics and molecular interaction fingerprints for interaction pattern studies. Also, the DFT computations optimised the drug, and we extended our studies for MD Simulation in water for 100 ns, which showed the complexes among the identified drug with proteins are entirely stable with acceptable deviation, fluctuations and many intermolecular interactions that make them stable. We also performed the MM\GBSA studies on MD simulation's all 1000 frames to understand the complex energy level. All the results reveal promising interactions between Deprodone and the targeted enzymes, suggesting its potential as a multitargeted therapeutic agent-however, experimental studies need to validate Deprodone against MRSA.

Development and validation of a risk prediction model for linezolid-induced anemia in elderly patients: a retrospective cohort study.

Background: Linezolid-induced anemia (LI-AN) is a severe adverse reaction, but risk factors of the LI-AN for elderly patients have not been established. Objectives: The objective of this study was to develop a nomogram capable of predicting LI-AN in elderly patients. Design: This is a retrospective study to develop and validate a nomogram for anemia prediction in elderly patients treated with linezolid. Methods: We retrospectively screened elderly patients treated with linezolid at Inner Mongolia People's Hospital from January 2020 to December 2023 and validated our findings using the MIMIC-IV 2.2 database. Anemia was defined as hemoglobin reduction to 75% of baseline value. Univariate and multivariable logistic regression models were used to identify predictors and construct the nomogram, which was evaluated using receiver operating characteristic (ROC) curve analysis, calibration plot, and decision curve analysis. Results: A total of 231 patients were enrolled in this study. The training set comprised 151 individuals, and anemia occurred in 28 cases (18.54%). In the external validation set of 80 individuals, 26 (32.5%) were diagnosed with anemia. The predictors included duration of linezolid therapy, patient estimated glomerular filtration rate value, and sequential organ failure assessment score ⩾2. The ROC curve for the training set was 0.830 (95% CI: 0.750-0.910), while a similar ROC curve of 0.743 (95% CI: 0.621-0.865) was obtained for the validation set. The calibration curve demonstrated good correlation between predicted and observed results, indicating that this study effectively predicts risk factors associated with LI-AN in elderly patients. Conclusion: The developed prediction model can provide valuable guidance for clinicians to prevent anemia and facilitate rational linezolid use in elderly patients.

Study analyzing the clinical data of elderly patients using linezolid to better understand what factors may contribute to anemia in patients Why was the study done? This study aimed to develop a tool that predicts the risk of anemia in elderly patients treated with linezolid, a medication that can cause severe side effects like low hemoglobin levels. Identifying factors that contribute to this adverse reaction can help doctors prevent it and ensure safer use of linezolid. What did the researchers do? The researchers studied the medical records of elderly patients treated with linezolid at Inner Mongolia People's Hospital over a 4-year period. To better understand which factors are related to the occurrence of anemia, so we can find ways to predict the occurrence of problems. What did the researchers find? Factors that increase the risk of anemia after using linezolid include the duration of use of linezolid, kidney function, and SOFA score, that is, the longer the use of linezolid, the worse the kidney function, the higher the SOFA score, and the more likely the patient is to develop anemia. What do the findings mean? The researchers successfully created a tool, called a prediction model, which can help doctors predict the likelihood of anemia in elderly patients taking linezolid. This can guide clinicians in monitoring and managing patients more effectively, potentially reducing the occurrence of anemia and ensuring safer use of linezolid in elderly populations.

Anti-infective therapies for Pythium insidiosum keratitis.

INTRODUCTION: Pythium insidiosum keratitis (PIK) is a rapidly progressing ocular disease predominantly found in tropical and subtropical regions. Characterized by severe corneal damage and high morbidity, this infection poses significant challenges in diagnosis and management, necessitating effective anti-infective therapies. AREAS COVERED: This report delves into the pathophysiology, clinical and microbiological diagnosis, and detailed insights into the anti-infective therapy for PIK, outlining current diagnostic challenges that complicate treatment. We review existing anti-infective therapies, including their efficacy and limitations, and discuss the role of surgical interventions in managing advanced cases. The report also highlights ongoing research into novel treatment approaches and the critical need for developing targeted therapies. EXPERT OPINION: Despite advances in understanding PIK, treatment remains complex due to pathogen resistance and diagnostic hurdles. Future research should focus on innovative anti-infective strategies, improved diagnostic techniques, and global surveillance to enhance therapeutic outcomes. Collaboration between ophthalmologists, microbiologists, and pharmacologists is essential to advance treatment protocols and improve patient prognosis.

Risk factors for linezolid - induced haematological toxicity in patients: a retrospective study.

INTRODUCTION: This single-center, observational cohort study aimed to investigate the risk factors associated with linezolid-induced hematological toxicity by analyzing the linezolid trough concentration (Cmin) obtained from patients undergoing treatment between January 2020 and December 2021. METHODOLOGY: A total of 111 eligible individuals were included in the study, of which 47 were diagnosed with linezolid-induced thrombocytopenia and 18 were diagnosed with linezolid-induced hemoglobin decrease. RESULTS: Binary logistic regression analysis revealed that creatinine clearance level (Ccr) < 50 mL/min/1.73 m2 (OR, 5.463; 95% CI, 1.249-23.888, p = 0.024) and Cmin > 7 mg/L (OR, 62.660; 95% CI, 14.293-274.708, p = 0.001) were risk factors associated with linezolid-induced thrombocytopenia. Area under the ROC curve for Cmin was 0.955, with a maximum Youden index of 0.837. The corresponding critical value was 6.94 mg/L (sensitivity 91.5%; specificity 92.2%). Ccr < 50 mL/min/1.73 m2 (OR, 7.282; 95% CI, 1.765-30.048, p = 0.006) and Cmin > 7mg/L (OR, 6.364; 95% CI, 1.937-20.910, p = 0.020) were found to be associated with linezolid-induced hemoglobin reduction. The area under the ROC curve for Cmin was 0.755, Youden index was 0.477 at the maximum, and the corresponding critical value was 7.53 mg/L (sensitivity 77.8%; specificity 69.9%). CONCLUSIONS: Renal insufficiency is a related risk factor for linezolid-induced hematological toxicity. Patients receiving linezolid treatment should be closely monitored with blood routine and plasma concentration, particularly in patients with moderate or severe renal insufficiency. The plasma trough concentration of linezolid could be a suitable predictor for linezolid-induced thrombocytopenia and anemia.

Genomic analysis of multi-drug resistant coagulase-negative staphylococci from healthy humans and animals revealed unusual mechanisms of resistance and CRISPR-Cas system.

BACKGROUND: Coagulase-negative staphylococci (CoNS) are evolving as major reservoirs and vectors of unusual and critical antimicrobial resistance (AMR) mechanisms. MATERIALS AND METHODS: In this study, the genomic characterization of 26 multidrug-resistant (MDR)-CoNS (S. borealis, S. saprophyticus, S. sciuri, S. hominis, S. epidermidis, S. pasteuri, S. hyicus, S. simulans, S. haemolyticus, and S. arlettae) previously obtained from the nasal cavity of healthy nestling storks, humans who had no contact with animals, pigs, and pig farmers, as well as dogs and dog owners from Spain was performed. High-quality draft genomes obtained by Illumina sequencing technology were used to determine their resistome, virulome, mobile genetic elements, and CRISPR-Cas types. The relatedness of three CoNS species with publicly available genomes was assessed by core-genome single nucleotide polymorphisms (SNPs). RESULTS: AMR genes to all classes of antibiotics in staphylococci were detected including unusual ones (mecC, ermT, and cfr), of which their corresponding genetic organizations were analyzed. About 96.1% of the MDR-CoNS strains harbored diverse adherence or immune evasion genes. Remarkably, one enterotoxin-C and -L-carrying S. epidermidis-ST595 strain from a nestling stork was detected. Moreover, various plasmid bound-biocide resistance genes (qacACGJ) were identified in 34.6% of the MDR-CoNS. Two genes that encode for cadmium and zinc resistance (cadD, czrC) were found, of which czrC predominated (42.3%). Complete CRISPR-Cas system was detected in 19.2% of the CoNS strains, of which cas-1, -2, and -9 predominated, especially in 75% of the S. borealis strains. The phylogenetic analysis identified clusters of related S. epidermidis lineages with those of other countries (SNP < 100). Also, highly related S. borealis isolates (SNP < 10) from pigs was confirmed for the first time in Spain. CONCLUSION: These findings showed that various ecological niches harbor CoNS that presented MDR phenotypes mediated by multiple AMR genes carried by mobile genetic elements with relatively low frequency of intact CRISPR-Cas systems. Furthermore, the transmission of some CoNS species in humans and animals is strongly suggested.

Investigation of a linezolid-resistant Staphylococcus epidermidis outbreak in a French hospital: phenotypic, genotypic, and clinical characterization.

Purpose: We aimed to retrospectively investigate an outbreak of linezolid-resistant Staphylococcus epidermidis (LRSE), at Tours University Hospital between 2017 and 2021. Methods: Twenty of the 34 LRSE isolates were included in the study. Antimicrobial susceptibility testing was performed using the disk diffusion method and MICs of last-resort antibiotics were determined using broth microdilution or Etest®. Seventeen of the 20 resistant strains were sent to the French National Reference Centre for Staphylococci to determine the mechanism of resistance to linezolid. The clonal relationship between LRSE strains was assessed by PFGE and the sequence type determined by MLST. We retrospectively evaluated a new typing tool, IR-Biotyper®, and compared its results to PFGE to evaluate its relevance for S. epidermidis typing. Medical records were reviewed, and antibiotic consumption was determined. Search for a cross transmission was performed. Results: All LRSE strains showed high levels of resistance to linezolid (MICs ≥ 256 mg/L) and were multi-drug resistant. Linezolid resistance was associated with the 23S rRNA G2576T mutation and none of the 17 strains analyzed carried the cfr gene. Ninety-five percent of the 20 LRSE studied strains were genetically related and belonged to sequence-type ST2. The dendrogram obtained from IR-Biotyper® showed 87% congruence with the PFGE analysis. Prior to isolation of the LRSE strain, 70% of patients received linezolid. No patients stayed successively in the same room. Conclusion: Linezolid exposure may promote the survival and spread of LRSE strains. At Tours University Hospital, acquisition of the resistant clone may also have been triggered by hand-to-hand transmission by healthcare workers. In addition, IR-Biotyper® is a promising typing tool for the study of clonal outbreaks due to its low cost and short turnaround time, although further studies are needed to assess the optimal analytical parameters for routine use.

Evaluation of the rational prescription of linezolid, the prevalence of thrombocytopenia and major drug interactions in patients with cardiovascular diseases: are there any cautions?

The present study evaluated the rational prescription of linezolid, the prevalence of thrombocytopenia, and major drug interactions in patients with cardiovascular diseases. We conducted a retrospective cross-sectional study on linezolid-treated patients at Shahid Chamran Heart Hospital in Isfahan from March 21, 2021, to March 20, 2022. Our research involved 132 patients who received linezolid. We reported 43.18% of linezolid prescriptions as irrational. Linezolid-induced thrombocytopenia is more common than previous studies, with a prevalence of 47.9%. We found a significant relationship between thrombocytopenia and the concomitant use of aspirin. The duration of treatment was identified as predicting factor for linezolid-induced thrombocytopenia. Moreover, the prevalence of interactions in the X and D categories was determined. Serotonergic and catecholamine medications were associated with 56.1% and 47.7% medication interactions, respectively. Our study found a high prevalence of linezolid-induced thrombocytopenia among patients with cardiovascular diseases. Based on this study, physicians should focus more closely on prescribing linezolid to patients with cardiovascular diseases. In addition to following rational antibiotic use, this susceptible group is also at an elevated risk of side effects (thrombocytopenia) and medication interactions.

Comparison of incidence of hyponatremia between linezolid and vancomycin in neonates and infants.

A previous study reported that the incidence of hyponatremia after linezolid (LZD) use was higher than that with vancomycin (VCM ) use in adults. However, hyponatremia due to LZD in neonates and infants was not investigated. This study aimed to compare the incidence of hyponatremia between LZD and VCM use in neonates and infants. The retrospective study was conducted at the Aichi Medical University Hospital. All patients who were cared for in NICU or GCU and received ≥ 3 days of LZD or VCM were included in this study. Hyponatremia was defined as serum sodium level ≤ 134 mEq/L and ≥ 5% decrease from baseline after administration of LZD or VCM. A total of 76 patients (LZD, N=36; VCM, N=37) were included. There was no significant difference in the incidence of hyponatremia between the two groups (19.4% vs 16.2%, p = 0.72). The proportion of patients with a minimum value of serum sodium ≤ 134 mEq/L during treatment was 47.3% in the LZD group and 35.1% in the VCM group (p = 0.29), and the decrease in serum sodium level from baseline to the minimum value was 80.5% and 78.4%, respectively (p = 0.85). In conclusion, there was no significant difference in the incidence of hyponatremia between the LZD and VCM groups. Therefore, it is not necessary to avoid LZD use in neonates and infants because of the risk of hyponatremia.

Incidence of serotonin syndrome in patients receiving tedizolid and concomitant serotonergic agents.

This study investigated the real-world incidence rate of serotonin syndrome in patients receiving tedizolid and concomitant serotonergic agents. A retrospective cohort of 479 adult patients was assessed between January 2015 and July 2023. Overall, a rare rate of 0.4% (2/479) of possible serotonin syndrome with tedizolid was identified. Given that concomitant serotonergic agents were commonly used, further study is warranted to determine causality.

Efflux pumps and membrane permeability contribute to intrinsic antibiotic resistance in Mycobacterium abscessus.

Mycobacterium abscessus is a pulmonary pathogen that exhibits intrinsic resistance to antibiotics, but the factors driving this resistance are incompletely understood. Insufficient intracellular drug accumulation could explain broad-spectrum resistance, but whether antibiotics fail to accumulate in M. abscessus and the mechanisms required for drug exclusion remain poorly understood. We measured antibiotic accumulation in M. abscessus using mass spectrometry and found a wide range of drug accumulation across clinically relevant antibiotics. Of these compounds, linezolid accumulates the least, suggesting that inadequate uptake impacts its efficacy. We utilized transposon mutagenesis screening to identify genes that cause linezolid resistance and found multiple transporters that promote membrane permeability or efflux, including an uncharacterized, M. abscessus-specific protein that effluxes linezolid and several chemically related antibiotics. This demonstrates that membrane permeability and drug efflux are critical mechanisms of antibiotic resistance in M. abscessus and suggests that targeting membrane transporters could potentiate the efficacy of certain antibiotics.

Toxin inhibition: Examining tetracyclines, clindamycin, and linezolid.

PURPOSE: The purpose of this review is to discuss the role of toxin inhibition in select infections and to provide recommendations for appropriate antimicrobial selection when toxin inhibition is indicated. SUMMARY: For select organisms, specifically Clostridioides difficile, Staphylococcus aureus, and Streptococcus pyogenes, toxin production plays an integral role in overall disease pathogenesis and progression. Some expert recommendations include utilization of an antimicrobial with toxin inhibition properties as primary or adjunctive therapy for certain infections due to these organisms, but evolving data have made the choice of antitoxin agent less clear. Clindamycin has been the long-standing standard of care agent for toxin inhibition in necrotizing S. aureus and S. pyogenes infections, but linezolid shows promise as an alternative either in the setting of drug shortages or simply when clindamycin is not optimal, while tetracyclines require further study for this indication. The role for adjunctive toxin inhibition in C. difficile infection (CDI) is less defined, as current first-line therapies already have antitoxin properties. CONCLUSION: Toxin inhibition plays a key role in successful management of patients with infections due to toxin-producing organisms. Adjunctive therapy with a tetracycline could be considered in severe, fulminant CDI, but the associated benefit is variable. The benefit of antitoxin treatment for necrotizing S. aureus and S. pyogenes has been more consistently documented. Recent studies support linezolid as an alternative to clindamycin as an adjunctive S. aureus treatment or as monotherapy when appropriate.

Erysipelothrix rhusiopathiae bacteremia treated with linezolid.

Erysipelothrix rhusiopathiae is a common zoonotic pathogen that rarely causes diseases in humans. It has three main disease manifestations: a localized cutaneous, a disseminated cutaneous, and a systemic form of infection, typically characterized as bacteremia with or without endocarditis. Human infections are often associated with occupational exposure to animals, animal products, or their excreta. We present a case of a 60-year-old woman found to have E. rhusiopathiae bacteremia associated with a leg laceration sustained after she fell into a sewer drain. Germane animal exposures were not identified; thus, the source of bacterium was attributed to sewage or sewage-contaminated water. She was initially treated with intravenous penicillin with clinical improvement. However, given the patient's social factors, prolonged oral antimicrobial therapy was considered. E. rhusiopathiae is routinely susceptible to penicillin, cephalosporins, and fluoroquinolones but resistant to vancomycin. The data on alternatives to beta-lactam therapy are limited. We report a case of E. rhusiopathiae bacteremia successfully treated with oral linezolid.

Unraveling novel mutation patterns and morphological variations in two dalbavancin-resistant MRSA strains in Austria using whole genome sequencing and transmission electron microscopy.

BACKGROUND: The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) strains resistant to non-beta-lactam antimicrobials poses a significant challenge in treating severe MRSA bloodstream infections. This study explores resistance development and mechanisms in MRSA isolates, especially after the first dalbavancin-resistant MRSA strain in our hospital in 2016. METHODS: This study investigated 55 MRSA bloodstream isolates (02/2015-02/2021) from the University Hospital of the Medical University of Vienna, Austria. The MICs of dalbavancin, linezolid, and daptomycin were assessed. Two isolates (16-33 and 19-362) resistant to dalbavancin were analyzed via whole-genome sequencing, with morphology evaluated using transmission electron microscopy (TEM). RESULTS: S.aureus BSI strain 19-362 had two novel missense mutations (p.I515M and p.A606D) in the pbp2 gene. Isolate 16-33 had a 534 bp deletion in the DHH domain of GdpP and a SNV in pbp2 (p.G146R). Both strains had mutations in the rpoB gene, but at different positions. TEM revealed significantly thicker cell walls in 16-33 (p < 0.05) compared to 19-362 and dalbavancin-susceptible strains. None of the MRSA isolates showed resistance to linezolid or daptomycin. CONCLUSION: In light of increasing vancomycin resistance reports, continuous surveillance is essential to comprehend the molecular mechanisms of resistance in alternative MRSA treatment options. In this work, two novel missense mutations (p.I515M and p.A606D) in the pbp2 gene were newly identified as possible causes of dalbavancin resistance.

Molecular Epidemiology and Horizontal Transfer Mechanism of optrA-Carrying Linezolid-Resistant Enterococcus faecalis.

The aim of this work was to provide a theoretical and scientific basis for the treatment, prevention, and control of clinical drug-resistant bacterial infections by studying the molecular epidemiology and horizontal transfer mechanism of optrA-carrying linezolid-resistant Enterococcus faecalis strains (LREfs) that were clinically isolated in a tertiary hospital in Kunming, China. Non-repetitive LREfs retained in a tertiary A hospital in Kunming, China. The strains were identified by Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The transferability and horizontal transfer mechanism of optrA gene were analyzed using polymerase chain reaction (PCR), whole-genome sequencing (WGS), and conjugation experiments. A total of 39 LREfs strains were collected, and all of them were multi-drug resistant. There were 30 LREfs strains (76.9%) carrying the optrA gene, The cfr, poxtA genes and mutations in the 23S rRNA gene were not detected. The conjugation experiments showed that only three of 10 randomly selected optrA-carrying LREfs were successfully conjugated with JH2-2. Further analysis of one successfully conjugated strain revealed that the optrA gene, located in the donor bacterium, formed the IS1216E-erm(A)-optrA-fexA-IS1216E transferable fragment under the mediation of the mobile genetic element (MGE) IS1216E, which was then transferred to the recipient bacterium via horizontal plasmid transfer. Carrying the optrA gene is the primary resistance mechanism of LREfs strains. The optrA gene could carry the erm(A) and fexA genes to co-transfer among E. faecalis. MGEs such as insertion sequence IS1216E play an important role in the horizontal transfer of the optrA gene.

Linezolid-resistant Enterococcus faecium clinical isolates from Pakistan: a genomic analysis.

BACKGROUND: Linezolid-resistant Enterococcus faecium (LRE) is a global priority pathogen. Thirteen LRE were reported from clinical specimens between November 2021 and April 2023 at two laboratories in Karachi, Pakistan. We aimed to investigate the strain types and genes associated with linezolid resistance among these isolates. Whole genome sequencing (WGS) was performed and analyzed by multilocus sequence typing (MLST). The presence of linezolid resistance genes was identified using ResFinder v4.1.11 and the LRE-finder tool. RESULTS: Twelve isolates belonged to clonal complex 17 (CC17); ST80 (n = 10), ST612 (n = 1) and ST1380 (n = 1). Six isolates showed the presence of optrA gene and G2576T mutations in the 23S rRNA gene, while six showed poxtA and cfr(D) genes. One isolate showed the combination of optrA, cfr(D) and poxtA genes. CONCLUSION: Our findings show the circulation of CC17 sequence types with a known outbreak potential and we identified molecular mechanisms of resistance that were not previously reported from Pakistan.

Successful treatment of Enterococcus gallinarum infection in a neonate with vancomycin: a case report.

BACKGROUND: Enterococcus gallinarum (EG) is typically found in the gastrointestinal tracts of birds and mammals. Although its strains are rarely isolated from clinical specimens, EG can lead to septicemia in immunocompromised individuals. EG infections are uncommon in household settings, but their incidence has been rising due to increased antibiotic usage and invasive treatments, particularly in Neonatal Intensive Care Units (NICUs). EG inherently exhibits resistance to vancomycin but is highly sensitive to linezolid. Despite showing in vitro resistance, vancomycin has shown clinical efficacy in treating EG meningitis. CASE PRESENTATION: A neonate born at 30 + 2 weeks gestation was admitted to the Neonatal Intensive Care Unit (NICU) after EG was detected in blood and cerebrospinal fluid cultures. Susceptibility testing indicated that the bacterial strain was resistant to vancomycin and sensitive to linezolid. Initially, vancomycin was selected for treatment. However, due to persistent EG cultures in the blood and cerebrospinal fluid, the treatment was adjusted to linezolid. This led to a rapid decrease in platelet (PLT) count, suspected to be an adverse reaction. Concurrently, the patient experienced recurrent fever and elevated inflammatory marker levels, prompting the discontinuation of linezolid and a return to vancomycin. Subsequent administration of vancomycin stabilized the patient's condition, as evidenced by improved C-reactive protein (CRP), procalcitonin (PCT), and cerebrospinal fluid parameters, ultimately leading to discharge after an eight-week treatment period. CONCLUSION: This retrospective analysis highlights the efficacy of vancomycin in treating EG infections, suggesting that specific genetic phenotypes may influence treatment sensitivity. Monitoring vancomycin blood levels is crucial for determining treatment effectiveness.

Pharmacology of emerging drugs for the treatment of multi-drug resistant tuberculosis.

Mycobacterium tuberculosis (TB) remains the leading cause of infection-related mortality worldwide. Drug resistance, need for multiple antimycobacterial agents, prolonged treatment courses, and medication-related side effects are complicating factors to TB cure. The introduction of treatment regimens containing the novel agents bedaquiline, pretomanid, and linezolid, with or without moxifloxacin (BPaL-M or BPaL, respectively) have substantially reduced TB-related morbidity and mortality and are associated with favorable rates of treatment completion and cure. This review summarizes key information on the pharmacology and treatment principles for moxifloxacin, bedaquiline, delamanid, pretomanid, linezolid, and tedizolid in the treatment of multi-drug resistant TB, with recommendations provided to address and attenuate common adverse effects during treatment.

Effectiveness and Safety of Varying Doses of Linezolid With Bedaquiline and Pretomanid in Treatment of Drug-Resistant Pulmonary Tuberculosis: Open-Label, Randomized Clinical Trial.

BACKGROUND: Treatment of drug-resistant tuberculosis with bedaquiline-pretomanid-linezolid regimen has demonstrated good treatment efficacy. Given linezolid's toxicity profile, prudence suggests reconsidering its dose and duration. We determined the effectiveness and safety of structured dose reduction of linezolid with bedaquiline and pretomanid in adults with pre-extensively drug-resistant (pre-XDR) or treatment-intolerant/nonresponsive multidrug-resistant (MDRTI/NR) pulmonary tuberculosis. METHOD: Adults with pre-XDR or MDRTI/NR pulmonary tuberculosis were enrolled in a multicenter, parallel-group, randomized clinical trial in India. Patients were randomized to 26 weeks of bedaquiline, pretomanid, and daily linezolid, at 600 mg for 26 weeks (arm 1); 600 mg for 9 weeks followed by 300 mg for 17 weeks (arm 2); or 600 mg for 13 weeks followed by 300 mg for 13 weeks (arm 3). Study end points included sustained cure, bacteriological failure, toxicity, and death. RESULTS: Of 403 patients enrolled, 255 (63%) were <30 years old, 273 (68%) had prior tuberculosis episodes, and 238 (59%) were malnourished. At the end of treatment, after excluding those with negative baseline cultures, cure was seen in 120 (93%), 117 (94%), and 115 (93%) in arms 1, 2, and 3 respectively. Myelosuppression seen in 85 patients each in arms 1 and 2 and 77 patients in arm 3, not significantly different. Peripheral neuropathy was noticed in 66 patients (30, 17, and 19 in arms 1, 2, and 3) at 10-26 weeks (P = .02). The linezolid dose was reduced because of toxicity in 13, 2, and 4 patients in arms 1, 2, and 3, respectively. CONCLUSIONS: In adults with pre-XDR or MDRTI/NR pulmonary tuberculosis, structured linezolid dose reduction to 300 mg/d is as effective as the standard 600-mg dose but with fewer cases of peripheral neuropathy when given with bedaquiline and pretomanid. CLINICAL TRIALS REGISTRATION: Clinical Trial Registry of India (CTRI/2021/03/032189).

Contezolid for the Treatment of Drug-Resistant Tuberculosis in China: A Clinical Case Series.

Background: Linezolid (LZD) is a cornerstone medication in the treatment of drug-resistant tuberculosis (DR-TB). However, it frequently triggers adverse effects such as bone marrow suppression, optic neuropathy, and peripheral neuropathy, all of which can impact treatment outcomes and prognosis. Contezolid (CZD), a novel oxazolidinone antibiotic, exhibits comparable antimicrobial efficacy against Mycobacterium tuberculosis as LZD, but with potentially enhanced safety profiles. Case Presentation: This report presents five cases (Cases 1-5) of LZD intolerance, wherein CZD served as an effective alternative treatment. In Cases 1-3, LZD administration resulted in bone marrow suppression, primarily manifested as anemia. Transitioning to CZD therapy led to a rise and stabilization of hemoglobin (HGB) levels in Cases 1-2, and a return to baseline values in Case 3. In Case 4, CZD treatment alleviated symptoms of LZD-induced peripheral neuritis, although complete resolution was not achieved, hinting at potential irreversibility of this type of peripheral neuropathy. In Case 5, direct CZD anti-TB therapy was initiated for recurrent leukopenia and neutropenia, resulting in no further severe myelosuppression and successful recovery. Conclusion: These case studies suggest that CZD could represent an effective and safe option for anti-TB therapy, especially for patients intolerant to LZD.

Pharmacokinetics and Safety of Linezolid Tablets of 2 Different Manufacturers in Healthy Chinese Subjects in Fasting and Fed States.

This study aimed to evaluate the pharmacokinetics (PKs) and safety of a generic drug, linezolid, compared to those of a reference drug in healthy Chinese subjects under both fasting and fed conditions. This was a randomized, open-label, 2-period, 2-sequence crossover study. The subjects received a single dose of the test or reference drug, linezolid (600 mg), in each period. The PK parameters were calculated using a non-compartmental method and compared between the 2 drugs. Bioequivalence was analyzed using geometric mean ratios (GMRs) of the 2 formulations and their corresponding 90% confidence intervals (CIs). The safety of the 2 formulations was assessed under both fasting and fed conditions. Forty-eight subjects completed the study, 24 each in the fasting and feeding groups. The average plasma concentration-time patterns of linezolid were similar for both medications under both conditions. The GMR and 90% CIs of the maximum plasma concentration and the area under the plasma concentration-time curve of linezolid were ranged from 0.80 to 1.25. Both drugs were well tolerated with a similar incidence of adverse drug reactions. In conclusion, the PK and safety profiles of the 2 formulations were comparable. Food intake did not influence the PK profiles of linezolid. These results suggest that the test drug can be used as an alternative to reference drugs.