ABSTRACT
Ulcerative colitis (UC) is a subtype of inflammatory bowel disease. Previous studies have suggested a link between senescence process and the body's inflammatory reaction, indicating that senescence may exacerbate UC, yet the relation between UC and senescence remains unclear. Tedizolid Phosphate (TED), a novel oxazolidinone antimicrobial, is indicated in acute bacterial skin infections, its impact on senescence is not known. Our research revealed that the UC inducer dextran sulfate sodium (DSS) triggers senescence in both colon epithelial NCM460 cells and colon tissues, and TED that screened from a compound library demonstrated a strong anti-senescence effect on DSS treated NCM460 cells. As an anti-senescence medication identified in this research, TED efficiently alleviated UC and colonic senescence in mice caused by DSS. By proteomic analysis and experimental validation, we found that DSS significantly inhibits the AMPK signaling pathway, while TED counteracts senescence by restoring AMPK activity. This research verified that the development of UC is accompanied with colon tissue senescence, and TED, an anti-senescence medication, can effectively treat UC caused by DSS and alleviate colon senescence. Our work suggests anti-senescence strategy is an effective approach for UC treatment.
Subject(s)
AMP-Activated Protein Kinases , Cellular Senescence , Colitis, Ulcerative , Colon , Dextran Sulfate , Signal Transduction , Animals , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/chemically induced , Colitis, Ulcerative/pathology , Signal Transduction/drug effects , Colon/drug effects , Colon/pathology , Cellular Senescence/drug effects , Humans , AMP-Activated Protein Kinases/metabolism , Mice , Mice, Inbred C57BL , Cell Line , Male , Oxazolidinones/pharmacology , Oxazolidinones/therapeutic use , Organophosphates/pharmacology , Organophosphates/therapeutic use , Disease Models, AnimalABSTRACT
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.
Subject(s)
Anti-Bacterial Agents , Gram-Positive Bacterial Infections , Oxazolidinones , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Oxazolidinones/pharmacology , Oxazolidinones/therapeutic use , Humans , Gram-Positive Bacterial Infections/drug therapy , Gram-Positive Bacterial Infections/microbiology , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Soft Tissue Infections/drug therapy , Soft Tissue Infections/microbiology , Animals , PyridonesABSTRACT
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.
Subject(s)
Anti-Bacterial Agents , Linezolid , Oxazolidinones , Tertiary Care Centers , Humans , Female , Adult , Middle Aged , Retrospective Studies , Oxazolidinones/therapeutic use , Linezolid/therapeutic use , Anti-Bacterial Agents/therapeutic use , Male , Mastitis/drug therapy , Mastitis/microbiology , Treatment Outcome , Soft Tissue Infections/drug therapy , Soft Tissue Infections/microbiology , Methicillin-Resistant Staphylococcus aureus/drug effects , TetrazolesSubject(s)
Antitubercular Agents , Diarylquinolines , Linezolid , Nitroimidazoles , Oxazoles , Refugees , Tuberculosis, Multidrug-Resistant , Humans , Linezolid/therapeutic use , Refugees/statistics & numerical data , Antitubercular Agents/therapeutic use , Diarylquinolines/therapeutic use , Germany , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/epidemiology , Somalia , Male , Ukraine/epidemiology , Female , Adult , Extensively Drug-Resistant Tuberculosis/drug therapy , Oxazolidinones/therapeutic use , Middle AgedABSTRACT
Delpazolid (LCB01-0371) is a novel oxazolidinone derivative with a good safety profile for treating gram-positive pathogenic infections such as Mycobacterium abscessus, a highly pathogenic drug-resistant Mycobacterium. In this study, we evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of delpazolid after 14 days of multiple oral administration, using data from adult patients with pulmonary tuberculosis. 800 mg once a day, 400 mg twice a day, 800 mg twice a day, and 1200 mg once a day delpazolid for 14 days were tested in 63 patients with pulmonary tuberculosis. For PK blood collection, inpatient and outpatient scheduling were separately implemented. Plasma concentrations of delpazolid were measured at visits 2, 4, 6, and 8 in outpatients, and four sparse blood samples were measured in inpatients. PD models were sequentially fitted using individual PK parameter estimates obtained from PK compartmental models. For PK modeling, 180 plasma concentrations of delpazolid from 56 patients were included. A two-compartment mixed first- and zero-order absorption model best described the time course of plasma concentration. For the PD model, 448 bacterial titer data from 60 patients were used. The time course of bacterial titers (log10 CFU/mL) was described by a model that consists of the growth and killing rate of bacteria with the sigmoid Emax model. The PK-PD simulation suggested that the bacterial titers are the lowest on the 800 mg bid regimen among the four, consistent with observed data, as all regimens substantially decrease. In the dose-response relationship, the effectiveness of delpazolid was suggested.
Subject(s)
Models, Biological , Oxazolidinones , Tuberculosis, Pulmonary , Humans , Male , Female , Oxazolidinones/pharmacokinetics , Oxazolidinones/administration & dosage , Oxazolidinones/therapeutic use , Adult , Middle Aged , Tuberculosis, Pulmonary/drug therapy , Aged , Antitubercular Agents/pharmacokinetics , Antitubercular Agents/therapeutic use , Antitubercular Agents/administration & dosage , Young Adult , Dose-Response Relationship, Drug , Administration, OralSubject(s)
Anti-Bacterial Agents , Clindamycin , Glycopeptides , Oxazolidinones , Shock, Septic , Soft Tissue Infections , Humans , Soft Tissue Infections/drug therapy , Shock, Septic/drug therapy , Glycopeptides/therapeutic use , Clindamycin/therapeutic use , Oxazolidinones/therapeutic use , Oxazolidinones/adverse effects , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/adverse effects , Drug Therapy, Combination , Clinical Trials as TopicABSTRACT
PURPOSE: Staphylococcus epidermidis is the most common causative microorganism of ventriculoperitoneal shunt infections. This study aimed to compare linezolid and vancomycin treatments and to examine the effect of these antibiotics alone and combined with hyperbaric oxygen therapy on the amount of bacterial colonies in the experimental S. epidermidis shunt infection model. METHODS: A shunt catheter was placed in the cisterna magna of 49 adult male Wistar albino rats. The rats were randomly divided into seven groups, as follows: sterile control, infected control, vancomycin, linezolid, hyperbaric oxygen, vancomycin + hyperbaric oxygen, linezolid + hyperbaric oxygen. In all groups except the sterile control group, 0.2 ml 107 CFU/mL S. epidermidis was inoculated to the cisterna magna. Parenteral vancomycin was administered 40 mg/kg/day to the vancomycin groups, and 50 mg/kg/day of enteral linezolid to the linezolid groups. Hyperbaric oxygen groups were given 100% oxygen at a pressure of 2.4 ATA for 50 min a day. One day after the last treatment, colony quantities in the shunt catheters and CSF were analyzed. RESULTS: The number of CSF colonies in the linezolid group was significantly lower than in the vancomycin group (p < 0.05). The number of CSF colonies in the linezolid + HBO group was significantly lower than in the vancomycin + HBO group (p < 0.05). CONCLUSIONS: Linezolid treatment was found to be more effective than vancomycin in ventriculoperitoneal shunt infection caused by S. epidermidis. There was no statistical difference among other treatment groups. Hyperbaric oxygen therapy is shown to contribute to the sterilization of cultures.
Subject(s)
Anti-Bacterial Agents , Disease Models, Animal , Hyperbaric Oxygenation , Linezolid , Rats, Wistar , Staphylococcal Infections , Staphylococcus epidermidis , Vancomycin , Ventriculoperitoneal Shunt , Animals , Linezolid/therapeutic use , Rats , Male , Ventriculoperitoneal Shunt/adverse effects , Hyperbaric Oxygenation/methods , Staphylococcal Infections/drug therapy , Staphylococcus epidermidis/drug effects , Anti-Bacterial Agents/therapeutic use , Acetamides/therapeutic use , Oxazolidinones/therapeutic useABSTRACT
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.
Subject(s)
Mycobacterium tuberculosis , Nitroimidazoles , Oxazolidinones , Tuberculosis, Multidrug-Resistant , Tuberculosis , Animals , Mice , Diarylquinolines/pharmacology , Diarylquinolines/therapeutic use , Antitubercular Agents/therapeutic use , Antitubercular Agents/pharmacology , Linezolid/pharmacology , Linezolid/therapeutic use , Tuberculosis/drug therapy , Nitroimidazoles/pharmacology , Oxazolidinones/pharmacology , Oxazolidinones/therapeutic use , Tuberculosis, Multidrug-Resistant/drug therapyABSTRACT
Oxazolidinones, such as tedizolid and linezolid, are bacteriostatic antibiotics that inhibit protein synthesis. Based on the findings from animal studies and their mechanism of action, these antibiotics are considered for managing toxic shock caused by clindamycin-resistant Group A Streptococcus (GAS; Streptococcus pyogenes). However, clinical reports on their usage in such cases are limited. Herein, we report a case of a 67-year-old woman with chronic myeloid leukemia who presented with fever, facial swelling, and myalgia. She was diagnosed with cellulitis and empirically treated with meropenem. Blood culture later revealed GAS, and she was diagnosed with streptococcal toxic shock syndrome. The antibiotic regimen was adjusted based on sensitivity results, with clindamycin initially replaced by linezolid and later switched to tedizolid owing to concerns about potential bone marrow suppression. Her condition improved, and she was discharged 15 days after admission. Therefore, tedizolid may be a safer option for managing toxic shock syndrome in patients with comorbidities that include thrombocytopenia.
Subject(s)
Anti-Bacterial Agents , Clindamycin , Shock, Septic , Streptococcal Infections , Streptococcus pyogenes , Humans , Female , Aged , Shock, Septic/drug therapy , Shock, Septic/microbiology , Anti-Bacterial Agents/therapeutic use , Streptococcus pyogenes/drug effects , Streptococcus pyogenes/isolation & purification , Streptococcal Infections/drug therapy , Streptococcal Infections/microbiology , Streptococcal Infections/complications , Clindamycin/therapeutic use , Drug Resistance, Bacterial , Treatment Outcome , Oxazolidinones/therapeutic use , Oxazolidinones/adverse effects , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications , Cellulitis/drug therapy , Cellulitis/microbiology , Microbial Sensitivity Tests , TetrazolesABSTRACT
Contezolid is a new oxazolidinone with in vitro and in vivo activity against Mycobacterium tuberculosis comparable to that of linezolid. Pre-clinical and clinical safety studies suggest it may be less toxic than linezolid, making contezolid a potential candidate to replace linezolid in the treatment of drug-resistant tuberculosis. We evaluated the dose-ranging activity of contezolid, alone and in combination with bedaquiline and pretomanid, and compared it with linezolid at similar doses, in an established BALB/c mouse model of tuberculosis. Contezolid had an MIC of 1 µg/mL, similar to linezolid, and exhibited similar bactericidal activity in mice. Contezolid-resistant mutants selected in vitro had 32- to 64-fold increases in contezolid MIC and harbored mutations in the mce3R gene. These mutants did not display cross-resistance to linezolid. Our results indicate that contezolid has the potential to replace linezolid in regimens containing bedaquiline and pretomanid and likely other regimens.
Subject(s)
Mycobacterium tuberculosis , Oxazolidinones , Tuberculosis, Multidrug-Resistant , Tuberculosis , Animals , Mice , Linezolid/pharmacology , Linezolid/therapeutic use , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Disease Models, Animal , Oxazolidinones/pharmacology , Oxazolidinones/therapeutic use , Diarylquinolines/pharmacology , Diarylquinolines/therapeutic use , Tuberculosis/drug therapy , Mycobacterium tuberculosis/genetics , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/microbiologyABSTRACT
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.
Subject(s)
Lung Diseases , Mycobacterium avium-intracellulare Infection , Oxazolidinones , Humans , Mice , Animals , Mycobacterium avium Complex , Mycobacterium avium-intracellulare Infection/drug therapy , Mycobacterium avium-intracellulare Infection/microbiology , Oxazolidinones/pharmacology , Oxazolidinones/therapeutic use , Anti-Bacterial Agents/pharmacology , Antitubercular Agents/pharmacology , Clarithromycin/therapeutic use , Macrolides/pharmacology , Lung Diseases/drug therapyABSTRACT
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.
Subject(s)
Arthritis, Infectious , Drug-Related Side Effects and Adverse Reactions , Oxazolidinones , Humans , Linezolid/adverse effects , Retrospective Studies , Oxazolidinones/therapeutic use , Acetamides/therapeutic use , Drug-Related Side Effects and Adverse Reactions/epidemiology , Arthritis, Infectious/drug therapyABSTRACT
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.
Subject(s)
Anti-Infective Agents , Oxazolidinones , Oxazolidinones/pharmacology , Oxazolidinones/therapeutic use , Anti-Infective Agents/pharmacology , Anti-Infective Agents/therapeutic use , Anti-Bacterial Agents/pharmacologyABSTRACT
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.
Subject(s)
Methicillin-Resistant Staphylococcus aureus , Oxazolidinones , Psychiatric Nursing , Skin Diseases, Infectious , Staphylococcal Infections , Humans , Vancomycin/therapeutic use , Vancomycin/pharmacology , Staphylococcus aureus , Anti-Bacterial Agents/adverse effects , Linezolid/pharmacology , Oxazolidinones/therapeutic use , Retrospective Studies , Acetamides/pharmacology , Staphylococcal Infections/drug therapy , Treatment Outcome , Skin Diseases, Infectious/chemically induced , Skin Diseases, Infectious/drug therapyABSTRACT
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 (AUCedema0â9) decreased in a TZD dose-dependent manner. In addition, the correlation between AUCedema0â9 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 AUCedema0â9 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.
Subject(s)
Methicillin-Resistant Staphylococcus aureus , Oxazolidinones , Rats , Mice , Animals , Anti-Bacterial Agents/therapeutic use , Carrageenan/pharmacology , Oxazolidinones/therapeutic use , Oxazolidinones/pharmacokinetics , Edema/chemically induced , Edema/drug therapy , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic useABSTRACT
New oxazolidinones are in clinical development for the treatment of tuberculosis and nontuberculous mycobacterial (NTM) infections, as a replacement for linezolid and tedizolid, which cause mitochondrial toxicity after prolonged treatment. Here, we carried out side-by-side measurements of mitochondrial protein synthesis inhibition and activity against clinically relevant mycobacterial pathogens of approved and novel oxazolidinones. We found a large range of selectivity indices suggesting TBI-223 and sutezolid as promising candidates against tuberculosis and NTM lung disease caused by Mycobacterium kansasii.
Subject(s)
Mycobacterium Infections, Nontuberculous , Oxazolidinones , Tuberculosis , Humans , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Oxazolidinones/pharmacology , Oxazolidinones/therapeutic use , Linezolid/pharmacology , Linezolid/therapeutic use , Mycobacterium Infections, Nontuberculous/drug therapy , Mycobacterium Infections, Nontuberculous/microbiology , Tuberculosis/drug therapy , Nontuberculous MycobacteriaABSTRACT
A regimen comprised of bedaquiline (BDQ, or B), pretomanid, and linezolid (BPaL) is the first oral 6-month regimen approved by the U.S. Food and Drug Administration and recommended by the World Health Organization for the treatment of extensively drug-resistant tuberculosis. We used a well-established BALB/c mouse model of tuberculosis to evaluate the treatment-shortening potential of replacing bedaquiline with either of two new, more potent diarylquinolines, TBAJ-587 and TBAJ-876, in early clinical trials. We also evaluated the effect of replacing linezolid with a new oxazolidinone, TBI-223, exhibiting a larger safety margin with respect to mitochondrial toxicity in preclinical studies. Replacing bedaquiline with TBAJ-587 at the same 25-mg/kg dose significantly reduced the proportion of mice relapsing after 2 months of treatment, while replacing linezolid with TBI-223 at the same 100-mg/kg dose did not significantly change the proportion of mice relapsing. Replacing linezolid or TBI-223 with sutezolid in combination with TBAJ-587 and pretomanid significantly reduced the proportion of mice relapsing. In combination with pretomanid and TBI-223, TBAJ-876 at 6.25 mg/kg was equipotent to TBAJ-587 at 25 mg/kg. We conclude that replacement of bedaquiline with these more efficacious and potentially safer diarylquinolines and replacement of linezolid with potentially safer and at least as efficacious oxazolidinones in the clinically successful BPaL regimen may lead to superior regimens capable of treating both drug-susceptible and drug-resistant TB more effectively and safely.
Subject(s)
Nitroimidazoles , Oxazolidinones , Tuberculosis, Multidrug-Resistant , Tuberculosis , Animals , Mice , Diarylquinolines/pharmacology , Diarylquinolines/therapeutic use , Antitubercular Agents/therapeutic use , Linezolid/therapeutic use , Tuberculosis/drug therapy , Nitroimidazoles/pharmacology , Nitroimidazoles/therapeutic use , Oxazolidinones/therapeutic use , Tuberculosis, Multidrug-Resistant/drug therapyABSTRACT
Linezolid (LZD) was the first oxazolidinone approved for treating drug-resistant tuberculosis. A newly approved regimen combining LZD with bedaquiline (BDQ) and pretomanid (PMD) (BPaL regimen) is the first 6-month oral regimen that is effective against multidrug- and extensively drug-resistant tuberculosis. However, LZD toxicity, primarily due to mitochondrial protein synthesis inhibition, may undermine the efficacy of LZD regimens, and oxazolidinones with higher efficacy and lower toxicity during prolonged administration are needed. OTB-658 is an oxazolidinone anti-TB candidate derived from LZD that could replace LZD in TB treatment. We previously found that OTB-658 had better anti-TB activity and safety than LZD in vitro and in vivo. In the present work, two murine TB models were used to evaluate replacing LZD with OTB-658 in LZD-containing regimens. In the C3HeB/FeJ murine model, replacing 100 mg/kg LZD with 50 mg/kg OTB-658 in the BDQ + PMD backbone significantly reduced lung and spleen CFU counts (P < 0.05), and there were few relapses at 8 weeks of treatment. Replacing 100 mg/kg LZD with 50 or 100 mg/kg OTB-658 in the pyrifazimine (previously called TBI-166) + BDQ backbone did not change the anti-TB efficacy and relapse rate. In BALB/c mice, replacing 100 mg/kg LZD with 100 mg/kg OTB-658 in the TBI-166 + BDQ backbone resulted in no culture-positive lungs at 4 and 8 weeks of treatment, and there were no significant differences in relapses rate between the groups. In conclusion, OTB-658 is a promising clinical candidate that could replace LZD in the BPaL or TBI-166 + BDQ + LZD regimens and should be studied further in clinical trials.
Subject(s)
Extensively Drug-Resistant Tuberculosis , Mycobacterium tuberculosis , Oxazolidinones , Tuberculosis, Multidrug-Resistant , Animals , Mice , Linezolid/therapeutic use , Linezolid/pharmacology , Antitubercular Agents/therapeutic use , Antitubercular Agents/pharmacology , Disease Models, Animal , Diarylquinolines/therapeutic use , Diarylquinolines/pharmacology , Oxazolidinones/therapeutic use , Tuberculosis, Multidrug-Resistant/drug therapy , Extensively Drug-Resistant Tuberculosis/drug therapyABSTRACT
BACKGROUND: Linezolid (Oxazolidinones) is commonly used against a variety of Gram-positive infections, especially methicillin-resistant Staphylococcus aureus (MRSA). The emerging resistance to linezolid curtail the treatment of infections caused by MRSA and other Gram-positive bacteria. Presence of cfr gene plays a crucial role in Linezolid resistance. OBJECTIVE: Present study was aimed to detect cfr gene among clinical MRSA isolates. MATERIALS AND METHODS: The suspected Staphylococcus aureus isolates were processed through Kirby Bauer disc diffusion methods for the confirmation of MRSA strains. Phenotypic Linezolid resistance was determined through broth micro-dilution method. The plasmid and DNA of Linezolid resistant isolates were subjected to molecular characterization for the presence of cfr gene. RESULTS: Among 100 Staphylococcus aureus isolates, 85 of them were confirmed as MRSA isolates. Categorically, 65% MRSA isolates were sensitive to linezolid with MIC lower than 8 µg/ml, whereas, 35% of them were resistant to linezolid having MIC greater than 8 µg/ml. MIC level of 128 µg/ml was observed among 3.5% of the resistant isolates. Similarly, MIC level of 64 µg/ml, 32 µg/ml, 16 µg/ml and 8 µg/ml were noted for 3.5%, 4.7%, 8.2% and 15.3% isolates respectively. Linezolid resistance cfr gene was detected only in 9.4% of the resistant isolates. CONCLUSION: Multi drug resistance among MRSA isolates is keenly attributed to the presence of cfr gene as evident in the present study, and horizontal dissemination of cfr gene among MRSA strains is accredited to cfr-carrying transposons and plasmids.
Subject(s)
Methicillin-Resistant Staphylococcus aureus , Oxazolidinones , Staphylococcal Infections , Humans , Linezolid/pharmacology , Linezolid/therapeutic use , Methicillin-Resistant Staphylococcus aureus/genetics , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Oxazolidinones/pharmacology , Oxazolidinones/therapeutic use , Staphylococcus aureus/genetics , Staphylococcal Infections/drug therapy , Microbial Sensitivity TestsABSTRACT
Contezolid (MRX-I, Youxitai) is an oral oxazolidinone drug being developed by MicuRx Pharmaceutical Co., Ltd., Shanghai, China. It was approved by China's National Medical Products Administration (NMPA) in June 2021, attaining its first approval for the treatment of complicated skin and soft tissue infections (cSSTIs). It is also under clinical development for acute bacterial skin and skin structure infections (ABSSSIs) in the U.S. after receiving qualified infectious disease product (QIDP) classification and fast track status by U.S. Food and Drug Administration (FDA) in September 2018. Contezolid is effective against a broad range of Gram-positive bacteria including activity against methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae and vancomycin-resistant Enterococci (VRE). It provides a major benefit over the most popular drug of its class, linezolid (Zyvox), by offering an improved safety profile and minimal effects concerning myelosuppression and monoamine oxidase (MAO) inhibition, two independent adverse events limiting linezolid use in the clinic. The recommended dosage regimen of contezolid is 800 mg every 12 hours for 7-14 days with regular food intake and it can be extended if required. At the mentioned dose under fed conditions, satisfactory efficacy against MRSA with a 90%; or higher cumulative fraction of response and probability of target attainment was achieved. Additionally, contezolid also exhibits activity against Mycobacterium tuberculosis and Mycobacterium abscessus.