Ribosome-Targeting Antibiotics Impair T Cell Effector Function and Ameliorate Autoimmunity by Blocking Mitochondrial Protein Synthesis.

While antibiotics are intended to specifically target bacteria, most are known to affect host cell physiology. In addition, some antibiotic classes are reported as immunosuppressive for reasons that remain unclear. Here, we show that Linezolid, a ribosomal-targeting antibiotic (RAbo), effectively blocked the course of a T cell-mediated autoimmune disease. Linezolid and other RAbos were strong inhibitors of T helper-17 cell effector function in vitro, showing that this effect was independent of their antibiotic activity. Perturbing mitochondrial translation in differentiating T cells, either with RAbos or through the inhibition of mitochondrial elongation factor G1 (mEF-G1) progressively compromised the integrity of the electron transport chain. Ultimately, this led to deficient oxidative phosphorylation, diminishing nicotinamide adenine dinucleotide concentrations and impairing cytokine production in differentiating T cells. In accordance, mice lacking mEF-G1 in T cells were protected from experimental autoimmune encephalomyelitis, demonstrating that this pathway is crucial in maintaining T cell function and pathogenicity.

Therapeutics for Vancomycin-Resistant Enterococcal Bloodstream Infections.

Vancomycin-resistant enterococci (VRE) are common causes of bloodstream infections (BSIs) with high morbidity and mortality rates. They are pathogens of global concern with a limited treatment pipeline. Significant challenges exist in the management of VRE BSI, including drug dosing, the emergence of resistance, and the optimal treatment for persistent bacteremia and infective endocarditis. Therapeutic drug monitoring (TDM) for antimicrobial therapy is evolving for VRE-active agents; however, there are significant gaps in the literature for predicting antimicrobial efficacy for VRE BSIs. To date, TDM has the greatest evidence for predicting drug toxicity for the three main VRE-active antimicrobial agents daptomycin, linezolid, and teicoplanin. This article presents an overview of the treatment options for VRE BSIs, the role of antimicrobial dose optimization through TDM in supporting clinical infection management, and challenges and perspectives for the future.

Linezolid Population Pharmacokinetic Model in Plasma and Cerebrospinal Fluid Among Patients With Tuberculosis Meningitis.

BACKGROUND: Linezolid is evaluated in novel treatment regimens for tuberculous meningitis (TBM). Linezolid pharmacokinetics have not been characterized in this population, particularly in cerebrospinal fluid (CSF), as well as, following its co-administration with high-dose rifampicin. We aimed to characterize linezolid plasma and CSF pharmacokinetics in adults with TBM. METHODS: In the LASER-TBM pharmacokinetic substudy, the intervention groups received high-dose rifampicin (35 mg/kg) plus 1200 mg/day of linezolid for 28 days, which was then reduced to 600 mg/day. Plasma sampling was done on day 3 (intensive) and day 28 (sparse). A lumbar CSF sample was obtained on both visits. RESULTS: Thirty participants contributed 247 plasma and 28 CSF observations. Their median age and weight were 40 years (range, 27-56) and 58 kg (range, 30-96). Plasma pharmacokinetics was described by a 1-compartment model with first-order absorption and saturable elimination. Maximal clearance was 7.25 L/h, and the Michaelis-Menten constant was 27.2 mg/L. Rifampicin cotreatment duration did not affect linezolid pharmacokinetics. CSF-plasma partitioning correlated with CSF total protein up to 1.2 g/L, where the partition coefficient reached a maximal value of 37%. The plasma-CSF equilibration half-life was ∼3.5 hours. CONCLUSIONS: Linezolid was readily detected in CSF despite high-dose rifampicin coadministration. These findings support continued clinical evaluation of linezolid plus high-dose rifampicin for the treatment of TBM in adults. Clinical Trials Registration. ClinicalTrials.gov (NCT03927313).

The Safety and Tolerability of Linezolid in Novel Short-Course Regimens Containing Bedaquiline, Pretomanid, and Linezolid to Treat Rifampicin-Resistant Tuberculosis: An Individual Patient Data Meta-analysis.

BACKGROUND: Effectiveness, safety, tolerability, and adherence are critical considerations in shifting to shorter tuberculosis (TB) regimens. Novel 6-month oral regimens that include bedaquiline (B), pretomanid (Pa), and linezolid (L), with or without a fourth drug, have been shown to be as or more effective than the established longer regimens for the treatment of multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB). We aimed to evaluate the safety and tolerability of linezolid in BPaL-containing regimens for the treatment of MDR/RR-TB among recently completed clinical trials. METHODS: A review and meta-analysis was undertaken including published and unpublished data from clinical trials, conducted between 2010 and 2021, that evaluated regimens containing BPaL for the treatment of MDR/RR-TB. Individual patient data were obtained. For each BPaL-containing regimen, we evaluated the frequency and severity of treatment-related adverse events. The risk difference of adverse events for each regimen was calculated, in comparison to patients assigned to receiving the lowest cumulative exposure of linezolid. RESULTS: Data from 3 clinical trials investigating 8 unique BPaL-containing regimens were included, comprising a total of 591 participants. Adverse events were more frequent in groups randomized to a higher cumulative linezolid dose. Among patients who were randomized to a daily dose of 1200 mg linezolid, 68 of 195 (35%) experienced a grade 3-4 adverse event versus 89 of 396 (22%) patients receiving BPaL-containing regimens containing 600 mg linezolid. CONCLUSIONS: Regimens containing BPaL were relatively well tolerated when they included a daily linezolid dose of 600 mg. These novel regimens promise to improve the tolerability of treatment for MDR/RR-TB.

Safety and effectiveness of three novel all-oral shortened regimens for rifampicin- or multidrug-resistant tuberculosis in Kazakhstan.

BACKGROUND: In 2019, WHO called for operational research on all-oral shortened regimens for multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). We report safety and effectiveness of three nine-month all-oral regimens containing bedaquiline (Bdq), linezolid (Lzd), and levofloxacin (Lfx) and reinforced with cycloserine (Cs) and clofazimine (Cfz), delamanid (Dlm) and pyrazinamide (Z), or Dlm and Cfz. METHODS: We conducted a prospective cohort study of patients initiating treatment for pulmonary MDR/RR-TB under operational research conditions at public health facilities in Kazakhstan. Participants were screened monthly for adverse events. Participants with baseline resistance were excluded from the study and treated with a longer regimen. We analyzed clinically relevant adverse events of special interest in all participants and sputum culture conversion and end-of-treatment outcomes among individuals who were not excluded. RESULTS: Of 510 participants, 41% were women, median age was 37 years (interquartile range: 28-49), 18% had a body mass index <18·5 kg/m2, and 51% had cavitary disease. Three hundred and ninety-nine (78%) initiated Bdq-Lzd-Lfx-Cs-Cfz, 83 (16%) started Bdq-Lzd-Lfx-Dlm-Z, and 28 (5%) initiated Bdq-Lzd-Lfx-Dlm-Cfz. Fifty-eight individuals (11%) were excluded from the study, most commonly due to identification of baseline drug resistance (n = 52; 90%). Among the remaining 452 participants, treatment success frequencies were 92% (95% confidence interval [CI]: 89 to 95), 89% (95%CI: 80 to 94), and 100% (95%CI: 86 to 100) for regimens with Cs/Cfz, Dlm/Z, and Dlm/Cfz respectively. Clinically-relevant adverse events of special interest were uncommon. CONCLUSION: All regimens demonstrated excellent safety and effectiveness, expanding the potential treatment options for patients, providers, and programs.

Treatment of Multidrug-resistant or Rifampicin-resistant Tuberculosis With an All-oral 9-month Regimen Containing Linezolid or Ethionamide in South Africa: A Retrospective Cohort Study.

BACKGROUND: In 2019, the South African tuberculosis program replaced ethionamide with linezolid as part of an all-oral 9-month regimen. We evaluated treatment outcomes for patients assigned to regimens including linezolid in 2019 and ethionamide in 2017. METHODS: This retrospective cohort study included patients treated for multidrug-resistant/rifampicin-resistant tuberculosis throughout South Africa between 1 January and 31 December 2017 and 1 January to 31 December 2019. The cohort treated with a 9-month regimen containing ethionamide for four months, was compared with a cohort treated with a 9-month regimen containing linezolid for 2 months. The regimens were otherwise identical. Inverse probability weighting of propensity scores was used to adjust for potential confounding. A log-binomial regression model was used to estimate adjusted relative risk (aRR) comparing 24-month outcomes between cohorts including treatment success, death, loss to follow up, and treatment failure. Adverse event data were available for the linezolid cohort. FINDINGS: In total, 817 patients were included in the cohort receiving ethionamide and 4244 in the cohort receiving linezolid. No evidence for a difference was observed between linezolid and ethionamide regimens for treatment success (aRR = 0.96, 95% confidence interval [CI] .91-1.01), death (aRR = 1.01, 95% CI .87-1.17) or treatment failure (aRR = 0.87, 95% CI .44-1.75). Loss to follow-up was more common in the linezolid group, although estimates were imprecise (aRR = 1.22, 95% CI .99-1.50). CONCLUSIONS: No significant differences in treatment success and survival were observed with substitution of linezolid for ethionamide as a part of an all-oral 9-month regimen. Linezolid is an acceptable alternative to ethionamide in this shorter regimen for treatment of multidrug-resistant/rifampicin-resistant tuberculosis.

Use of multiple pharmacodynamic measures to deconstruct the Nix-TB regimen in a short-course murine model of tuberculosis.

A major challenge for tuberculosis (TB) drug development is to prioritize promising combination regimens from a large and growing number of possibilities. This includes demonstrating individual drug contributions to the activity of higher-order combinations. A BALB/c mouse TB infection model was used to evaluate the contributions of each drug and pairwise combination in the clinically relevant Nix-TB regimen [bedaquiline-pretomanid-linezolid (BPaL)] during the first 3 weeks of treatment at human equivalent doses. The rRNA synthesis (RS) ratio, an exploratory pharmacodynamic (PD) marker of ongoing Mycobacterium tuberculosis rRNA synthesis, together with solid culture CFU counts and liquid culture time to positivity (TTP) were used as PD markers of treatment response in lung tissue; and their time-course profiles were mathematically modeled using rate equations with pharmacologically interpretable parameters. Antimicrobial interactions were quantified using Bliss independence and Isserlis formulas. Subadditive (or antagonistic) and additive effects on bacillary load, assessed by CFU and TTP, were found for bedaquiline-pretomanid and linezolid-containing pairs, respectively. In contrast, subadditive and additive effects on rRNA synthesis were found for pretomanid-linezolid and bedaquiline-containing pairs, respectively. Additionally, accurate predictions of the response to BPaL for all three PD markers were made using only the single-drug and pairwise effects together with an assumption of negligible three-way drug interactions. The results represent an experimental and PD modeling approach aimed at reducing combinatorial complexity and improving the cost-effectiveness of in vivo systems for preclinical TB regimen development.

Assessing potential drug-drug interactions between clofazimine and other frequently used agents to treat drug-resistant tuberculosis.

Clofazimine is included in drug regimens to treat rifampicin/drug-resistant tuberculosis (DR-TB), but there is little information about its interaction with other drugs in DR-TB regimens. We evaluated the pharmacokinetic interaction between clofazimine and isoniazid, linezolid, levofloxacin, and cycloserine, dosed as terizidone. Newly diagnosed adults with DR-TB at Klerksdorp/Tshepong Hospital, South Africa, were started on the then-standard treatment with clofazimine temporarily excluded for the initial 2 weeks. Pharmacokinetic sampling was done immediately before and 3 weeks after starting clofazimine, and drug concentrations were determined using validated liquid chromatography-tandem mass spectrometry assays. The data were interpreted with population pharmacokinetics in NONMEM v7.5.1 to explore the impact of clofazimine co-administration and other relevant covariates on the pharmacokinetics of isoniazid, linezolid, levofloxacin, and cycloserine. Clofazimine, isoniazid, linezolid, levofloxacin, and cycloserine data were available for 16, 27, 21, 21, and 6 participants, respectively. The median age and weight for the full cohort were 39 years and 52 kg, respectively. Clofazimine exposures were in the expected range, and its addition to the regimen did not significantly affect the pharmacokinetics of the other drugs except levofloxacin, for which it caused a 15% reduction in clearance. A posteriori power size calculations predicted that our sample sizes had 97%, 90%, and 87% power at P < 0.05 to detect a 30% change in clearance of isoniazid, linezolid, and cycloserine, respectively. Although clofazimine increased the area under the curve of levofloxacin by 19%, this is unlikely to be of great clinical significance, and the lack of interaction with other drugs tested is reassuring.

Bactericidal and sterilizing activity of novel regimens combining bedaquiline or TBAJ-587 with GSK2556286 and TBA-7371 in a mouse model of tuberculosis.

The combination of bedaquiline, pretomanid, and linezolid (BPaL) has become a preferred regimen for treating multidrug- and extensively drug-resistant tuberculosis (TB). However, treatment-limiting toxicities of linezolid and reports of emerging bedaquiline and pretomanid resistance necessitate efforts to develop new short-course oral regimens. We recently found that the addition of GSK2556286 increases the bactericidal and sterilizing activity of BPa-containing regimens in a well-established BALB/c mouse model of tuberculosis. Here, we used this model to evaluate the potential of new regimens combining bedaquiline or the more potent diarylquinoline TBAJ-587 with GSK2556286 and the DprE1 inhibitor TBA-7371, all of which are currently in early-phase clinical trials. We found the combination of bedaquiline, GSK2556286, and TBA-7371 to be more active than the first-line regimen and nearly as effective as BPaL in terms of bactericidal and sterilizing activity. In addition, we found that GSK2556286 and TBA-7371 were as effective as pretomanid and the novel oxazolidinone TBI-223 when either drug pair was combined with TBAJ-587 and that the addition of GSK2556286 increased the bactericidal activity of the TBAJ-587, pretomanid, and TBI-223 combination. We conclude that GSK2556286 and TBA-7371 have the potential to replace pretomanid, an oxazolidinone, or both components, in combination with bedaquiline or TBAJ-587.

Genomic characteristics of cfr and fexA carrying Staphylococcus aureus isolated from pig carcasses in Korea.

The emergence of transferable linezolid resistance genes poses significant challenges to public health, as it does not only confer linezolid resistance but also reduces susceptibility to florfenicol, which is widely used in the veterinary field. This study evaluated the genetic characteristics of linezolid-resistant Staphylococcus aureus strains isolated from pig carcasses and further clarified potential resistance and virulence mechanisms in a newly identified sequence type. Of more than 2500 strains isolated in a prior study, 15 isolated from pig carcasses exhibited linezolid resistance (minimum inhibitory concentration ≥ 8 mg/L). The strains were characterized in detail by genomic analysis. Linezolid-resistant S. aureus strains exhibited a high degree of genetic lineage diversity, with one strain (LNZ_R_SAU_64) belonging to ST8004, which has not been reported previously. The 15 strains carried a total of 21 antibiotic resistance genes, and five carried mecA associated with methicillin resistance. All strains harbored cfr and fexA, which mediate resistance to linezolid, phenicol, and other antibiotics. Moreover, the strains carried enterotoxin gene clusters, including the hemolysin, leukotoxin, and protease genes, which are associated with humans or livestock. Some genes were predicted to be carried in plasmids or flanked by ISSau9 and the transposon Tn554, thus being transmittable between staphylococci. Strains carrying the plasmid replicon repUS5 displayed high sequence similarity (99%) to the previously reported strain pSA737 in human clinical samples in the United States. The results illustrate the need for continuous monitoring of the prevalence and transmission of linezolid-resistant S. aureus isolated from animals and their products.

Risk factors and outcome associated with the acquisition of MDR linezolid-resistant Enterococcus faecium: a report from tertiary care centre.

OBJECTIVE: The aim of the study was to determine the resistance profile of linezolid-resistant Enterococcus faecium (LREfm) and to investigate risk factors and outcomes associated with LREfm infections. MATERIAL AND METHODS: A prospective case-control study was undertaken (2019 to 2022) and included 202 patients with LREfm infections (cases) and 200 controls with LSEfm infections. Clinical data was prospectively collected and analysed for risk factors and outcomes. Antimicrobial susceptibility was performed, and resistance profile was studied using WHOnet. RESULTS: Risk factors associated with LREfm infection were site of infection UTI (OR 5.87, 95% CI 2.59-13.29, p ≤ 0.001), prior use of carbapenem (OR 2.85 95% CI 1.62-5.02, p ≤ 0.001) and linezolid (OR 10.13, 95% CI 4.13-24.82, p ≤ 0.001), use of central line (OR 5.54, 95% CI 2.35-13.09, p ≤ 0.001), urinary catheter (OR 0.29, 95% CI 0.12-0.70, p ≤ 0.001) and ventilation (OR 14.87, 95% CI 7.86-28.11, p ≤ 0.007). The hospital stay 8-14 days (< 0.001) prior to infection and the mortality rate (p = 0.003) were also significantly high among patients with LREfm infections. Linezolid and vancomycin resistance coexisted; further, MDR, XDR and PDR phenotypes were significantly higher among LREfm. CONCLUSION: This study provided insight into epidemiology of MDR LREfm in a setting where linezolid use is high. The main drivers of infections with LREfm are multiple, including use of carbapenems and linezolid. Invasive procedures and increased hospital stay facilitate spread through breach in infection control practises. As therapeutic options are limited, ongoing surveillance of LREfm and VRE is critical to guide appropriate use of linezolid and infection control policies.

Synergistic properties of linezolid against Enterococcus spp. isolates: a systematic review from in vitro studies.

PURPOSE: Vancomycin-resistant enterococci (VRE) are a leading cause of hospital-acquired infections with limited therapeutic options. Combination of at least two antimicrobials is a possible strategy to obtain rapid and sustained bactericidal effects and overcome the emergence of resistance. We revised the literature on linezolid synergistic properties from in vitro studies to assess its activity in combination with molecules belonging to other antibiotic classes against Enterococcus spp. METHODS: We performed a systematic review of the literature from three peer-reviewed databases including papers evaluating linezolid synergistic properties in vitro against Enterococcus spp. isolates. RESULTS: We included 206 Enterococcus spp. isolates (92 E. faecalis, 90 E. faecium, 2 E. gallinarum, 3 E. casseliflavus, 19 Enterococcus spp.) from 24 studies. When an isolate was tested with different combinations, each combination was considered independently for further analysis. The most frequent interaction was indifferent effect (247/343, 72% of total interactions). The highest synergism rates were observed when linezolid was tested in combination with rifampin (10/49, 20.4% of interactions) and fosfomycin (16/84, 19.0%, of interactions). Antagonistic effect accounted for 7/343 (2.0%) of total interactions. CONCLUSION: Our study reported overall limited synergistic in vitro properties of linezolid with other antibiotics when tested against Enterococcus spp. The clinical choice of linezolid in combination with other antibiotics should be guided by reasoned empiric therapy in the suspicion of a polymicrobial infection or targeted therapy on microbiological results, rather than on an intended synergistic effect of the linezolid-based combination.

Risk exploration and prediction model construction for linezolid-resistant Enterococcus faecalis based on big data in a province in southern China.

BACKGROUND: Enterococcus faecalis is a common cause of healthcare-associated infections. Its resistance to linezolid, the antibiotic of last resort for vancomycin-resistant enterococci, has become a growing threat in healthcare settings. METHODS: We analyzed the data of E. faecalis isolates from 26 medical institutions between 2018 and 2020 and performed univariate and multivariate logistic regression analyses to determine the independent predictors for linezolid-resistant E. faecalis (LREFs). Then, we used the artificial neural network (ANN) and logistic regression (LR) to build a prediction model for linezolid resistance and performed a performance evaluation and comparison. RESULTS: Of 12,089 E. faecalis strains, 755 (6.25%) were resistant to linezolid. Among vancomycin-resistant E. faecalis, the linezolid-resistant rate was 24.44%, higher than that of vancomycin-susceptible E. faecalis (p < 0.0001). Univariate and multivariate regression analyses showed that gender, age, specimen type, length of stay before culture, season, region, GDP (gross domestic product), number of beds, and hospital level were predictors of linezolid resistance. Both the ANN and LR models constructed in the study performed well in predicting linezolid resistance in E. faecalis, with AUCs of 0.754 and 0.741 in the validation set, respectively. However, synthetic minority oversampling technique (SMOTE) did not improve the prediction ability of the models. CONCLUSION: E. faecalis linezolid-resistant rates varied by specimen site, geographic region, GDP level, facility level, and the number of beds. At the same time, community-acquired E. faecalis with linezolid resistance should be monitored closely. We can use the prediction model to guide clinical medication and take timely prevention and control measures.

Advances in contezolid: novel oxazolidinone antibacterial in Gram-positive treatment.

PURPOSE: The principal objective of this project was to review and thoroughly examine the chemical characteristics, pharmacological activity, and quantification methods associated with contezolid. METHODS: The article was based on published and ongoing preclinical and clinical studies on the application of contezolid. These studies included experiments on the physicochemical properties of contezolid, in vitro antimicrobial research, in vivo antimicrobial research, and clinical trials in various phases. There were no date restrictions on these studies. RESULTS: In June 2021, contezolid was approved for treating complicated skin and soft tissue infections. The structural modification of contezolid has resulted in better efficacy compared to linezolid. It inhibits bacterial growth by preventing the production of the functional 70S initiation complex required to translate bacterial proteins. The current evidence has indicated a substantial decline in myelosuppression and monoamine oxidase inhibition without impairing its antibacterial properties. Contezolid was found to have a more significant safety profile and to be metabolised by flavin monooxygenase 5, reducing the risk of harmful effects due to drug-drug interactions. Adjusting doses is unnecessary for patients with mild to moderate renal or hepatic insufficiency. CONCLUSION: As an oral oxazolidinone antimicrobial agent, contezolid is effective against multi-drug resistant Gram-positive bacteria. The introduction of contezolid provided a new clinical option.

Use of oxazolidinones (linezolid or tedizolid) for the treatment of breast infections. A case series from a tertiary referral hospital.

OBJECTIVES: Mastitis is mainly caused by Gram-positive bacteria and usually involves treatment with beta-lactam antibiotics and clindamycin. Oxazolidinones show good results in the treatment of skin and soft tissue infections (SSTIs) due to its pharmacokinetic characteristics. We aimed to describe clinical characteristics and outcomes of patients who received oxazolidinones for the treatment of SSTIs of the mammary tissue. METHODS: Retrospective single-centre study of patients with a diagnosis of breast infection who received treatment with oxazolidinones as initial or salvage therapy between September 2016 and November 2022. Patients were identified through the pharmacy database. The primary outcome was clinical cure. RESULTS: Twenty-nine patients received oxazolidinones: 27 received linezolid and 2 tedizolid. Median age was 41 years (IQR 31.0-56.5) and 28 patients were female. Ten patients (35%) had a history of breast cancer, while three (10%) had an immunosuppressive condition. Microbiological isolation was obtained in 24 individuals (83%). Predominant isolations were methicillin-resistant Staphylococcus aureus (8, 28%) and methicillin-susceptible S. aureus (7, 24%). Twenty-four patients (83%) received oxazolidinones as a salvage therapy, with a median duration of 14 days (IQR 10-17). Clinical cure was achieved in 24 patients (83%), while 4 relapsed after a median of 15 days (IQR 4-34). One was lost to follow-up. Three patients (10%) were taking selective serotonin reuptake inhibitors, and one of them concurrently received linezolid for 4 days with no adverse events recorded. Cytopenia during treatment was observed in 2/12 individuals. Oxazolidinones allowed hospital discharge in 11/13 hospitalized patients. CONCLUSIONS: Oxazolidinones could be considered as an alternative for treating breast infections.

Differential distribution of linezolid in diseased and nondiseased bones in patients with spinal tuberculosis.

BACKGROUND: Linezolid exhibits antibacterial activity against sensitive and drug-resistant strains of Mycobacterium tuberculosis. Knowledge on the distribution of linezolid in different types of bones in patients with spinal tuberculosis (TB) is lacking, which limits the pharmacokinetic and pharmacodynamic studies of linezolid. This study aimed to evaluate the distribution of linezolid in diseased and nondiseased bones in patients with spinal TB. METHODS: Spinal TB patients treated with linezolid-containing regimens and whose diseased and nondiseased bones were collected during surgery were enrolled retrospectively from January 2017 to February 2022. Blood, nondiseased bones, and diseased bones were collected simultaneously during the operation. Linezolid concentrations in the plasma, nondiseased bones, and diseased bones were subjected to high-performance liquid chromatography-tandem mass spectrometry. RESULTS: Seven eligible spinal TB patients, including one rifampicin-resistant case, were enrolled. Following a 600 mg oral administration of linezolid before surgery, the median concentrations of linezolid in plasma, nondiseased bone, and diseased bone of the seven patients were 8.23, 1.01, and 2.13 mg/L, respectively. The mean ratios of linezolid concentration in nondiseased bones/plasma, diseased bones/plasma and diseased bones/nondiseased bones reached 0.26, 0.49, and 2.27, respectively. The diseased bones/plasma presented a higher mean ratio of linezolid concentration than nondiseased bones/plasma, and the difference was statistically significant (t = 2.55, p = 0.025). Pearson's correlation analysis showed the positively correlation of linezolid concentrations in diseased and nondiseased bones (r = 0.810, p = 0.027). CONCLUSIONS: Linezolid exhibits a higher concentration distribution in diseased bones than in nondiseased bones.

Efficacy and safety of omadacycline for treating complicated skin and soft tissue infections: a meta-analysis of randomized controlled trials.

OBJECTIVE: In the present study, we aimed to compare the clinical efficacy and safety of omadacycline (OMC) with its comparators for the treatment of complicated skin and soft tissue infections (cSSTIs) in adult patients. METHODS: Randomized controlled trials (RCTs) evaluating OMC for cSSTIs were searched in databases of PubMed, Embase, Cochrane, Web of Science, and Clinical Trial, up to July 2022. The primary outcomes were clinical efficacy and microbiological response, with secondary outcome was safety. RESULTS: Four RCTs consisting of 1,757 patients were included, with linezolid (LZD) as a comparator drug. For clinical efficacy, OMC was not inferior to LZD in the modified intent-to-treat (MITT) (OR: 1.24, 95% Cl: [0.93, 1.66], P = 0.15) and clinically evaluable (CE) populations (OR: 1.92, 95% Cl: [0.94, 3.92], P = 0.07). For microbiological response, OMC was numerically higher than LZD in the microbiologically evaluable (ME) (OR: 1.74, 95% Cl: [0.81, 3.74], P = 0.16) and microbiological MITT (micro-MITT) populations (OR: 1.27, 95% Cl: [0.92, 1.76], P = 0.14). No significant difference was found in subpopulations of monomicrobial or polymicrobial mixed infection populations. The mortality and adverse event rates were similar between OMC and LZD. CONCLUSIONS: OMC was as good as LZD in terms of clinical efficacy and microbiological response, and has similar safety issues in treating cSSTIs. OMC might be a promising option for treating cSSTIs in adult patients.

Characterization of linezolid- and methicillin-resistant coagulase-negative staphylococci in a tertiary hospital in China.

BACKGROUND: Recently, linezolid-resistant staphylococci have become an emerging problem worldwide. Understanding the mechanisms of resistance, molecular epidemiology and transmission of linezolid-resistant CoNS in hospitals is very important. METHODS: The antimicrobial susceptibilities of all isolates were determined by the microdilution method. The resistance mechanisms and molecular characteristics of the strains were determined using whole-genome sequencing and PCR. RESULTS: All the strains were resistant to oxacillin and carried the mecA gene; 13 patients (36.1%) had prior linezolid exposure. Most S. epidermidis and S. hominis isolates were ST22 and ST1, respectively. MLST typing and evolutionary analysis indicated most linezolid-resistant CoNS strains were genetically related. In this study, we revealed that distinct CoNS strains have different mechanisms of linezolid resistance. Among ST22-type S. epidermidis, acquisition of the T2504A and C2534T mutations in the V domain of the 23 S rRNA gene, as well as mutations in the ribosomal proteins L3 (L101V, G152D, and D159Y) and L4 (N158S), were linked to the development of linezolid resistance. In S. cohnii isolates, cfr, S158Y and D159Y mutations in the ribosomal protein L3 were detected. Additionally, emergence of the G2576T mutation and the cfr gene were major causes of linezolid resistance in S. hominis isolates. The cfr gene, G2576T and C2104T mutations, M156T change in L3 protein, and I188S change in L4 protein were found in S. capitis isolates. CONCLUSION: The emergence of linezolid-resistant CoNS in the environment is concerning because it involves clonal dissemination and frequently coexists with various drug resistance mechanisms.

The effects of drug-drug interaction on linezolid pharmacokinetics: A systematic review.

OBJECTIVES: Linezolid is a commonly used antibiotic in the clinical treatment of gram-positive bacterial infections. The impacts of drug interactions on the pharmacokinetics of linezolid are often overlooked. This manuscript aims to review the medications that affect the pharmacokinetics of linezolid. METHODS: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we queried the PubMed, Embase, and Cochrane Library for publications from database establishment to November 3, 2023, using the search terms: "Linezolid" and "interaction," or "interact," or "drug-drug interaction," or "co-treatment," or "cotreatment," or "combined," or "combination." RESULTS: A total of 24 articles were included. Among the reported medication interactions, rifampicin, levothyroxine, venlafaxine, and phenobarbital could reduce the concentration of linezolid; clarithromycin, digoxin, cyclosporine, proton pump inhibitors, and amiodarone could increase the concentration of linezolid, while aztreonam, phenylpropanolamine, dextromethorphan, antioxidant vitamins, and magnesium-containing antacids had no significant effects on linezolid pharmacokinetics. The ratio of mean (ROM) of linezolid AUC in co-treatment with rifampicin to monotherapy was 0.67 (95%CI 0.58-0.77) and 0.63 (95%CI 0.43-0.91), respectively, in 2 studies, and co-treatment with 500 mg clarithromycin to monotherapy was 1.81 (95%CI 1.49-2.13). CONCLUSIONS: This systematic review found that numerous drugs have an impact on the pharmacokinetics of linezolid, and the purported main mechanism may be that linezolid is the substrate of P-glycoprotein. In clinical practice, it is prudent to pay attention to the changes in linezolid pharmacokinetics caused by interactions. Conducting therapeutic drug monitoring (TDM) is beneficial to improve efficacy and reduce adverse reactions of linezolid.

Estimation of linezolid exposure in patients with hepatic impairment using machine learning based on a population pharmacokinetic model.

PURPOSE: To investigate the pharmacokinetic changes of linezolid in patients with hepatic impairment and to explore a method to predict linezolid exposure. METHODS: Patients with hepatic impairment who received linezolid were recruited. A population pharmacokinetic model (PPK) was then built using NONMEM software. And based on the final model, virtual patients with rich concentration values was constructed through Monte Carlo simulations (MCS), which were used to build machine learning (ML) models to predict linezolid exposure levels. Finally, we investigated the risk factors for thrombocytopenia in patients included. RESULTS: A PPK model with population typical values of 3.83 L/h and 34.1 L for clearance and volume of distribution was established, and the severe hepatic impairment was identified as a significant covariate of clearance. Then, we built a series of ML models to predict the area under 0 -24 h concentration-time curve (AUC0-24) of linezolid based on virtual patients from MCS. The results showed that the Xgboost models showed the best predictive performance and were superior to the methods for estimating linezolid AUC0-24 based on though concentration or daily dose. Finally, we found that baseline platelet count, linezolid AUC0-24, and combination with fluoroquinolones were independent risk factors for thrombocytopenia, and based on this, we proposed a method for calculating the toxicity threshold of linezolid. CONCLUSION: In this study, we successfully constructed a PPK model for patients with hepatic impairment and used ML algorithm to estimate linezolid AUC0-24 based on limited data. Finally, we provided a method to determine the toxicity threshold of linezolid.