Linezolid

Prevention of the 70S Initiation Complex Formation

Interaction with the Peptidyltransferase Centre (PTC)

Bacteriostatic Activity against Staphylococci and Enterococci

This compound is generally considered to exhibit bacteriostatic activity against staphylococci and enterococci. patsnap.comoup.comdrugbank.com This means that while it inhibits the growth and reproduction of these bacteria by preventing protein synthesis, it does not typically kill them outright. wikipedia.orgpatsnap.com Time-kill assays have demonstrated this bacteriostatic effect against staphylococci and enterococci when using the conventional definition of bactericidal activity (a ≥3.0 log cfu/mL reduction in viable bacteria over 24 hours). oup.com Despite its in vitro bacteriostatic classification against these organisms, some authors suggest that this compound may "behave" as a bactericidal antibiotic in vivo due to its ability to inhibit the production of toxins by staphylococci and streptococci. wikipedia.org

Bactericidal Activity against Most Streptococcal Isolates

In contrast to its effect on staphylococci and enterococci, this compound demonstrates bactericidal activity against most isolates of streptococci. oup.comaafp.orgdrugbank.com This indicates that this compound is capable of killing streptococcal bacteria. Studies have shown that this compound's activity against streptococci is comparable to or even superior to that of vancomycin. asm.org

G2576T Point Mutation in 23S Ribosomal RNA

The most prevalent mechanism of this compound resistance involves a point mutation at position 2576 in the 23S rRNA gene, where guanine (G) is substituted by thymine (T) (using E. coli numbering). annlabmed.orgnih.govmicrobiologyjournal.orgd-nb.infooup.com This G2576T mutation is a well-established cause of this compound resistance in both staphylococci and enterococci. nih.govoup.comnih.gov Studies have shown a direct correlation between the number of 23S rRNA gene copies carrying the G2576T mutation and the level of this compound resistance; a higher number of mutated alleles leads to increased resistance. nih.govoup.comdovepress.comoup.com For instance, in S. aureus, which typically has five copies of the 23S rRNA gene, the accumulation of the G2576T mutation in multiple copies results in a stepwise increase in this compound minimum inhibitory concentrations (MICs). nih.govdovepress.comoup.com

Research findings highlight the significance of this mutation. A study on this compound-susceptible Enterococcus isolates (MIC = 4 mg/L) found that 40% contained either a putative resistance gene or the G2576T mutation, or a combination thereof. mdpi.com The ability to predict phenotypic resistance from genotype was highest for G2576T-mediated resistance compared to gene-mediated resistance. mdpi.com Another study on MRSA isolates detected decreased this compound susceptibility in strains with a G2576T mutation, noting that the resistance level increases with the number of 23S rRNA allele mutations and copies. dovepress.com

Other 23S rRNA Mutations (e.g., T2500A, G2447T, G2603T)

Besides G2576T, other mutations in the domain V of the 23S rRNA gene have been associated with this compound resistance. These include T2500A, G2447T (or G2447U), and G2603T. annlabmed.orgmicrobiologyjournal.orgd-nb.infonih.govjlabphy.organnlabmed.org While G2576T is the most common, the presence of other mutations indicates multiple potential sites within the 23S rRNA gene where alterations can confer resistance. oup.com

For example, the T2500A mutation has been identified in clinical S. aureus isolates and was mainly associated with this compound resistance in MRSA strains from patients previously treated with the antibiotic. oup.comannlabmed.org A study found that all this compound-resistant MRSA isolates confirmed by broth microdilution had a T2500A mutation in two copies of the gene. annlabmed.org The G2447T mutation has also been reported in S. aureus. microbiologyjournal.orgnih.gov The G2603T mutation has been observed in this compound-resistant Staphylococcus haemolyticus, representing a novel mutation reported in India. jlabphy.orgthieme-connect.com Other reported mutations in the domain V of 23S rRNA include C2534T, T2504A, G2215A, and G2631T, among others in clinical staphylococcal isolates. d-nb.infojlabphy.orgthieme-connect.com

Mutations in Ribosomal Proteins (uL3, uL4)

Mutations in genes encoding ribosomal proteins, particularly uL3 (encoded by rplC) and uL4 (encoded by rplD), have also been linked to this compound resistance. nih.govresearchgate.netdovepress.comasm.organnlabmed.orgmicrobiologyjournal.orgd-nb.infopnas.orgoup.com These proteins are located near the PTC, and mutations can affect the binding site of this compound. asm.organnlabmed.orgpnas.org

Mutations in uL3 and uL4 are considered a less frequent mechanism compared to 23S rRNA mutations or acquired resistance genes. annlabmed.org However, studies have reported their association with this compound resistance, sometimes in combination with 23S rRNA mutations. asm.organnlabmed.org For instance, some studies have reported multiple L3 mutations in S. aureus, often co-occurring with the G2576T 23S rRNA mutation and L4 insertions. asm.org Alterations in the conserved structural domains of ribosomal proteins L3 and L4 have been associated with reduced susceptibility to this compound in Enterococcus species, typically resulting in lower MICs (4–8 µg/mL) compared to those conferred by high-level resistance mechanisms. dovepress.comannlabmed.org Research suggests that mutations in uL3 can lead to structural rearrangements in the ribosome that impact the antibiotic binding site. pdbj.org

cfr Gene and its Variants (e.g., cfr(D))

The cfr gene encodes a 23S rRNA methyltransferase that modifies adenine at position 2503 (A2503) in the 23S rRNA. mdpi.comnih.govasm.orgasm.org This methylation alters the this compound binding site and confers resistance not only to oxazolidinones but also to several other classes of antibiotics targeting the PTC, including phenicols, lincosamides, pleuromutilins, and streptogramin A. This is known as the PhLOPSA phenotype. mdpi.comd-nb.infoasm.orgasm.orgasm.orgnih.gov

The cfr gene was initially identified in staphylococci of animal origin and has since been found in various Gram-positive and Gram-negative bacteria from both animal and human sources globally. mdpi.comonehealthejp.euasm.orgnih.gov Its presence on mobile genetic elements like plasmids contributes significantly to its dissemination. dovepress.comd-nb.infoasm.org Variants of the cfr gene, such as cfr(B), cfr(C), cfr(D), and cfr(E), have also been identified, and they similarly encode methyltransferases that confer resistance. researchgate.netasm.orgnih.gov The cfr(D) gene, for instance, has been found in Enterococcus faecium isolates, often located on plasmids, and can be co-transferred with other resistance genes like optrA. mdpi.comasm.orgnih.govredemc.netnih.gov Research has characterized the cfr(D) gene, showing it encodes a protein with amino acid identity to other Cfr variants and can confer the PhLOPSA phenotype when expressed in certain bacteria. redemc.netnih.gov

Data on the prevalence of cfr varies by region and bacterial species. In a study of this compound-susceptible Enterococcus isolates with MICs of 4 mg/L, the cfr gene was detected in a small percentage of E. faecium isolates. mdpi.com However, cfr-mediated resistance is a significant concern due to its transferable nature and the multidrug resistance phenotype it confers. europeanreview.orgd-nb.infoasm.orgasm.org

optrA Gene

The optrA gene encodes an ABC-F ribosomal protection protein that mediates resistance to oxazolidinones (this compound and tedizolid) and phenicols through a ribosomal protection mechanism. mdpi.comnih.govresearchgate.netdovepress.comannlabmed.orgasm.orgfrontiersin.org Unlike cfr, which confers resistance through methylation, OptrA is thought to interfere with this compound binding to the ribosome. mdpi.com

The optrA gene was first identified in Enterococcus faecalis and has since been detected in various Enterococcus species and other bacteria from both human and animal sources. mdpi.comonehealthejp.eueuropeanreview.organnlabmed.orgfrontiersin.org It can be located on both plasmids and chromosomes, with a higher prevalence on plasmids, contributing to its mobility. europeanreview.orgdovepress.com

Studies have shown that the optrA gene is a significant mechanism of this compound resistance, particularly in enterococci. dovepress.comijmcmed.org In a study of low-level this compound-resistant E. faecalis strains, all isolates harbored the optrA gene, either alone or in combination with ribosomal protein mutations. annlabmed.org Another study on this compound-resistant E. faecium in India found that the optrA gene was the most common mechanism of resistance (83.3%), followed by the G2576T mutation. ijmcmed.org The optrA gene has also been found to co-occur with other resistance genes like cfr(D) and poxtA on the same plasmid or within the same isolate, further complicating resistance patterns. mdpi.comasm.orgnih.govredemc.net

The presence of optrA in phenotypically this compound-susceptible isolates with MICs below the clinical breakpoint has been reported, suggesting that these isolates could rapidly develop resistance under this compound selective pressure. mdpi.comfrontiersin.org

Compound Names and PubChem CIDs

Interactive Data Table (Example based on search results)

Here is an example of how data on resistance mechanisms in a specific study could be presented in a table. Please note that creating a truly "interactive" table in this text-based format is not possible, but the structure below represents how such data could be organized.

Table 1: Distribution of Acquired Resistance Genes and G2576T Mutation in Enterococcus Isolates (MIC = 4 mg/L) mdpi.com

Note: Data is approximate based on interpretation of search result snippets. mdpi.com

Table 2: Prevalence of Resistance Mechanisms in this compound-Resistant Enterococcus Isolates

Note: Data is approximate based on interpretation of search result snippets.

poxtA Gene

The poxtA gene is an acquired resistance determinant that encodes an ATP-binding cassette (ABC)-F protein. nih.govantimicrobianos.com.armdpi.com This protein confers decreased susceptibility to oxazolidinones, phenicols, and tetracyclines through a mechanism of ribosomal protection. nih.govantimicrobianos.com.ar The poxtA gene has been detected in various Gram-positive bacteria, including Enterococcus faecalis and Enterococcus faecium, and is often located within mobile genetic elements like composite transposons, facilitating its dissemination. nih.govresearchgate.net Studies have reported poxtA as a prevalent oxazolidinone resistance mechanism in E. faecium. researchgate.net

Horizontal Gene Transfer Mechanisms

Horizontal gene transfer (HGT) plays a crucial role in the spread of this compound resistance, particularly through the acquisition of mobile genetic elements carrying resistance genes. mdpi.commicrobiologyjournal.orgnih.gov Key transferable this compound resistance genes include cfr, cfr(B), cfr(D), optrA, and poxtA. nih.govmdpi.com The cfr gene, encoding an rRNA methyltransferase, confers resistance to multiple drug classes, including oxazolidinones, and has been found on plasmids capable of horizontal transfer between staphylococci. nih.govmicrobiologyjournal.orgasm.org The optrA gene, encoding an ABC-F protein, is another significant transferable mechanism, frequently found on mobile genetic elements such as plasmids and insertion sequences, enabling its transfer among enterococci and potentially to other Gram-positive bacteria. nih.govantimicrobianos.com.arnih.govresearchgate.net The co-occurrence of multiple this compound resistance genes on the same mobile genetic element further enhances the risk of rapid dissemination through HGT. mdpi.com

RNA Methyltransferase Mutations (e.g., methylating G2445 of 23S rRNA)

While the acquired cfr gene encodes a methyltransferase that modifies A2503, other RNA methyltransferases can also be involved in this compound resistance. asm.orgnih.gov For instance, mutations inactivating the spr0333 methyltransferase, which targets G2445 in the 23S rRNA, have been shown to result in decreased susceptibility to this compound in Streptococcus pneumoniae. nih.govnih.govresearchgate.net This loss of methylation at G2445 is clearly involved in resistance, although it may require the presence of other mutations, such as those in the 23S rRNA. researchgate.net

Increased Expression of ABC Transporter Genes

Increased expression of ABC transporter genes has been reported as a non-ribosomal this compound resistance mechanism, particularly in Streptococcus pneumoniae. asm.orgnih.govresearchgate.net Mutations upstream of ABC transporter genes, such as spr1021 and spr1887 (or patA and patB), have been correlated with increased expression of these genes and neighboring genes in the same operon. nih.govresearchgate.netwipo.intasm.org Gene inactivation experiments have supported the role of these ABC transporters in conferring resistance to this compound and other antibiotics. nih.govwipo.int Overexpression of the patA and patB genes, for example, confers efflux-mediated resistance. asm.org

Mutations in fadD32 Gene in Mycobacteria

In mycobacteria, a mutation in the fadD32 gene represents a resistance determinant that is not directly related to the structure of the rRNA. nih.govresearchgate.netnih.gov The FadD32 protein is a fatty acyl-AMP ligase involved in the synthesis of mycolic acids, which are essential components of the mycobacterial cell wall. nih.govnih.gov A mutation, such as c.880t (His294Tyr), in the fadD32 gene in Mycobacteroides abscessus has been observed to confer this compound resistance, increasing the minimum inhibitory concentration (MIC). nih.govnih.govresearchgate.netmtsf.org This mutation may lead to alterations in the cell wall, potentially increasing its hydrophobicity and reducing the uptake of hydrophilic drugs like this compound. nih.govresearchgate.netmtsf.org

Mycobacterial Efflux Proteins

Mycobacterial efflux proteins have also been implicated in this compound resistance. nih.govresearchgate.netnih.gov Studies have shown that gene mutations leading to the over-expression of efflux pumps can remove intracellular this compound molecules. nih.govresearchgate.net In Mycobacterium abscessus, efflux pumps such as LmrS and MmpL9 have been shown to play a role in this compound resistance, with resistant strains exhibiting higher transcriptional levels of these genes. asm.org The addition of efflux pump inhibitors has been shown to decrease this compound MICs in some resistant mycobacterial strains, further supporting the role of efflux pumps in resistance. asm.orgmdpi.com A novel M. abscessus-specific MmpL protein, MAB_2303, has been characterized as a this compound efflux pump. biorxiv.orgplos.org

Enterococcus faecium (VRE) and Enterococcus faecalis

Enterococci, particularly Enterococcus faecium (including VRE) and Enterococcus faecalis, are important nosocomial pathogens where this compound resistance is a concern. dovepress.com this compound was approved for the management of VRE infections in the United States in 2000, with this compound-resistant Enterococcus being reported a year later. dovepress.com Surveillance programs like ZAAPS and the this compound Experience and Accurate Determination of Resistance program have reported the proportion of this compound resistance in Enterococcus as 0.22% (21/9,417) and 0.78% (67/8,604), respectively. dovepress.com

Streptococcus pneumoniae

This compound resistance in Streptococcus pneumoniae appears to be less common compared to staphylococci and enterococci, although surveillance is still important. A meta-analysis reported that the prevalence of this compound resistance among S. pneumoniae isolates fluctuated between 0% and 4.86% in studies conducted between 2014 and 2024. researchgate.netnih.gov Earlier surveillance data from 2004-2012 indicated 100% susceptibility of S. pneumoniae isolates to this compound in a large-scale global study. researchgate.net A study in Shanghai found no this compound-resistant S. pneumoniae isolates among those collected from children with pneumonia. frontiersin.org Similarly, a study in Turkey found no resistance to this compound among S. pneumoniae clinical isolates. diclemedj.org

Mycobacteria (e.g., Mycobacterium tuberculosis, NTM)

This compound has been included in treatment regimens for drug-resistant mycobacterial infections, including multidrug-resistant Mycobacterium tuberculosis (MDR-TB) and non-tuberculous mycobacteria (NTM). researchgate.netresearchgate.net this compound resistance has been documented in both MTB and NTM in various parts of the world. researchgate.net Studies on the in vitro susceptibility of NTM to this compound have been conducted. In a study in Nanjing, China, this compound showed effectiveness against M. abscessus and M. intracellulare in vitro, although resistant strains were observed. nih.gov The MIC ranges of this compound were the same for M. abscessus and M. intracellulare in this study, with 8 strains of M. abscessus and 38 strains of M. intracellulare showing this compound resistance. nih.gov this compound exhibited strong antibacterial activity against Slowly Growing Mycobacteria (SGM) and relatively better activity against Rapidly Growing Mycobacteria (RGM) in a study in Southwest China. frontiersin.org

Clonal Spread vs. Horizontal Gene Transfer

This compound resistance can spread through two primary mechanisms: clonal expansion of resistant strains and horizontal gene transfer (HGT) of resistance determinants between bacteria. Resistance to this compound can arise from mutations, particularly in the 23S ribosomal RNA (rRNA) gene (most commonly G2576T), or through the acquisition of mobile resistance genes such as cfr, optrA, and poxtA. microbiologyjournal.orgmdpi.comfrontiersin.orgresearchgate.netmdpi.com

The cfr gene encodes a 23S rRNA methyltransferase that confers resistance to several antibiotic classes, including oxazolidinones. mdpi.comfrontiersin.org The optrA and poxtA genes encode ABC-F proteins that can also lead to decreased susceptibility to oxazolidinones and phenicols. mdpi.comresearchgate.net These acquired resistance genes are often located on plasmids or transposons, facilitating their transfer between different bacterial isolates and species. mdpi.comfrontiersin.orgresearchgate.netmdpi.com

Studies have shown that both clonal dissemination and horizontal gene transfer contribute to the spread of this compound resistance. For instance, the optrA gene has been found on both chromosomes and plasmids, indicating its potential for both mechanisms of spread. mdpi.com The presence of resistance genes like optrA and cfr(D) on mobile genetic elements highlights the risk of their dissemination through HGT. mdpi.comfrontiersin.org The co-occurrence of multiple resistance genes on the same plasmid can further enhance the risk of HGT. mdpi.com

Sequence Types (STs) Associated with Resistance (e.g., ST16, ST150 for E. faecalis)

Specific sequence types (STs) within bacterial species, particularly Enterococcus faecalis and Enterococcus faecium, have been associated with this compound resistance. Multilocus sequence typing (MLST) is a tool used to characterize the genetic lineages of bacteria.

For E. faecalis, ST16 has been identified as a prevalent sequence type among this compound-resistant isolates. researchgate.netmdpi.comresearchgate.net Another ST, ST150, has also been linked to this compound resistance in E. faecalis, with studies reporting its emergence in clinical settings. nih.gov While ST16 is a major lineage associated with this compound resistance in E. faecalis, other STs are also observed. mdpi.com

In E. faecium, clonal complex (CC) 17 is commonly associated with resistance. researchgate.net However, this compound resistance mechanisms, such as the presence of the optrA gene, have been observed across various STs in E. faecalis and E. faecium, suggesting that resistance is not limited to a few specific lineages and can be acquired by genetically diverse strains. mdpi.com

Previous Carbapenem Exposure

Exposure to carbapenem antibiotics has been identified as a risk factor for this compound-resistant infections, particularly those caused by Enterococcus faecalis. researchgate.netdovepress.comdovepress.com Studies have shown a significant association between prior carbapenem use and the development of this compound-resistant E. faecalis infections, with multivariate analysis identifying it as an independent risk factor. dovepress.comdovepress.com While the exact mechanisms linking carbapenem exposure to this compound resistance are still being investigated, it is hypothesized that the selective pressure from carbapenem use may favor the emergence or selection of strains with co-resistance mechanisms or facilitate the acquisition of resistance genes. oup.comjidc.org

Long-term this compound Therapy

Prolonged exposure to this compound is a well-established risk factor for the development of resistance. oup.comfrontiersin.org Extended treatment courses provide a selective pressure that can lead to the emergence and outgrowth of resistant subpopulations. oup.com Studies have shown that patients receiving longer durations of this compound treatment are more likely to develop this compound-resistant infections compared to those receiving shorter courses. oup.com The median duration of this compound treatment has been found to be significantly longer in patients with resistant isolates. oup.com While the risk of resistance increases with treatment duration, some patients on prolonged therapy may not develop resistance, particularly if trough levels remain within the therapeutic range. frontiersin.org

Presence of Foreign Bodies or Deep Organ Infections

Infections involving foreign bodies or deep organ sites can be more challenging to treat and are associated with an increased risk of this compound resistance. oup.com The presence of foreign material can provide a niche for bacteria to form biofilms, which can reduce antibiotic penetration and promote the development of resistance. Deep-seated infections may also have reduced antibiotic exposure due to poor vascularization, contributing to treatment failure and the selection of resistant strains. oup.com While the search results mention infected foreign bodies and deep organ infections as potential concerns regarding this compound use and resistance, specific detailed research findings directly linking these solely as independent risk factors for this compound resistance emergence were not extensively detailed within the provided snippets. However, the context suggests that these sites may be associated with challenging infections where resistance is more likely to emerge or be selected for due to suboptimal drug exposure or biofilm formation. oup.com

Nosocomial Outbreaks

Nosocomial outbreaks, or healthcare-associated outbreaks, play a significant role in the spread of this compound-resistant organisms. oup.commicrobiologyjournal.orgnih.govcambridge.org The healthcare setting, with its high density of vulnerable patients, frequent antibiotic use, and potential for patient-to-patient transmission, provides an environment conducive to the dissemination of resistant strains. nih.govcambridge.org Outbreaks of this compound-resistant Enterococcus faecium and other resistant Gram-positive bacteria have been reported in hospitals, highlighting the importance of infection control measures in preventing their spread. oup.comnih.govcambridge.org Patient-to-patient transmission and the presence of resistant strains in the hospital environment contribute to the occurrence of nosocomial outbreaks. nih.gov Prior colonization or infection with resistant organisms, such as MRSA, has also been identified as a risk factor for acquiring Linezoid-resistant enterococci, potentially serving as a marker for increased susceptibility to nosocomial transmission. nih.govresearchgate.net

Association with Indwelling Catheters

The presence of indwelling medical devices, such as central venous catheters and urinary catheters, has been identified as a risk factor for this compound-resistant bacterial infections and colonization. Some reports indicate that patients who developed this compound resistance during therapy often had indwelling prosthetic devices and received extended courses of this compound treatment. nih.gov

Studies have investigated the association between indwelling catheters and this compound-resistant Enterococcus faecalis infections, particularly in urinary tract infections (UTIs). Research in China, for instance, identified indwelling catheters as an independent predictor for this compound-resistant or intermediate E. faecalis infections in patients with UTIs. frontiersin.orgresearchgate.netnih.gov The study found a notable frequency of this compound-resistant/intermediate E. faecalis isolates in UTI patients, with indwelling catheters being a significant risk factor alongside the presence of resistance genes like erm(A) or optrA. frontiersin.orgresearchgate.net

While the exact mechanisms linking indwelling catheters to this compound resistance are complex, the presence of a catheter can facilitate biofilm formation, which may contribute to reduced antibiotic susceptibility and provide a niche for the selection and persistence of resistant strains.

Interaction with Adrenergic Agents (e.g., Pseudoephedrine, Epinephrine, Dopamine)

Influence on P-glycoprotein Substrates

The interaction between this compound and P-glycoprotein (P-gp) substrates is a subject of investigation. Some studies suggest that this compound may be a substrate of P-glycoprotein, an efflux transporter highly expressed in tissues like the intestine, liver, and kidney. nih.govresearchgate.netersnet.org Inhibition of P-gp by co-administered drugs could potentially lead to increased this compound concentrations. Conversely, P-gp inducers might decrease this compound levels. nih.govresearchgate.net While some research points to this compound being a P-gp substrate, there is no definitive evidence, and some data suggest its metabolism is independent of certain cytochrome P450 enzymes. researchgate.netersnet.org

Effects on Drugs with Narrow Therapeutic Index

This compound's potential to interact with drugs possessing a narrow therapeutic index is a significant clinical consideration. nih.govresearchgate.net This is particularly relevant due to this compound's activity as a reversible and non-selective inhibitor of monoamine oxidase enzymes. drugbank.comnih.gov This MAO inhibition can lead to interactions with adrenergic and serotonergic agents, potentially causing conditions like hypertensive crisis or serotonin syndrome. drugbank.comresearchgate.netrxlist.com Therefore, caution and close monitoring are recommended when this compound is co-administered with such medications or with other drugs that have a narrow therapeutic window. nih.govresearchgate.netrxlist.com

Rifampicin and this compound Concentration Reduction

Co-administration of rifampicin with this compound has been shown to decrease this compound plasma concentrations. nih.govresearchgate.netidstewardship.comfrontiersin.org Studies in healthy volunteers have demonstrated reductions in this compound concentrations at various time points after co-administration with rifampicin. researchgate.netdrugs.com For instance, one study reported reductions of 10%, 20%, and 35% at 6, 9, and 12 hours post-dose, respectively, when a single intravenous dose of this compound was given with rifampicin compared to this compound alone. drugs.com The exact mechanism of this interaction is not fully elucidated but is proposed to involve the induction of P-glycoprotein by rifampicin, which could increase this compound clearance. researchgate.netidstewardship.comfrontiersin.org Some research also suggests a potential role for increased expression of CYP3A4, although its contribution to this compound clearance is typically small. researchgate.netersnet.org This interaction could potentially lead to reduced this compound efficacy, and therapeutic drug monitoring is recommended when these drugs are used together. nih.govidstewardship.comfrontiersin.org

Here is a table summarizing the effect of Rifampicin on this compound concentrations:

Clarithromycin and this compound Concentration Increase

Conversely, clarithromycin has been shown to increase this compound exposure. ersnet.orgnih.goversnet.orgresearchgate.netnih.gov A study in patients with multidrug-resistant tuberculosis showed a significant increase in this compound serum exposure when co-administered with clarithromycin. nih.goversnet.orgresearchgate.net Specifically, co-administration of 500 mg clarithromycin daily resulted in a median increase of 44% in this compound AUC (area under the concentration-time curve) compared to baseline. nih.goversnet.org The proposed mechanism for this interaction is the inhibition of P-glycoprotein by clarithromycin, which is a known P-gp inhibitor. ersnet.orgersnet.org Inhibition of P-gp efflux pumps could lead to increased this compound levels. ersnet.orgersnet.org

Here is a table summarizing the effect of Clarithromycin on this compound concentrations:

Interactions Affecting Hypoglycemic Agents

Postmarketing reports have indicated cases of symptomatic hypoglycemia in diabetic patients receiving insulin or oral hypoglycemic agents when treated with this compound. rxlist.comdrugs.com this compound, being a reversible, nonselective MAO inhibitor, may potentiate the hypoglycemic effects of these agents. rxlist.comdrugs.comdrugs.com While a definitive causal relationship has not been fully established, diabetic patients should be aware of the potential for hypoglycemic reactions when receiving this compound, and close monitoring is recommended. rxlist.comdrugs.comdrugs.com

Interactions Affecting Anticoagulants and Antiplatelet Agents (e.g., Aspirin)

The interaction between this compound and anticoagulants or antiplatelet agents, such as aspirin, is an area of clinical interest, particularly in patients with cardiovascular diseases. rxlist.commims.comnih.govfrontierspartnerships.org While this compound is not known to significantly interact with the cytochrome P450 system, which is involved in the metabolism of many anticoagulants, there can be other mechanisms of interaction. nih.govnih.gov Some research suggests a potential association between this compound-induced thrombocytopenia and the concomitant use of aspirin. nih.govfrontierspartnerships.org However, the relationship between this compound-induced thrombocytopenia and the use of antiplatelet/anticoagulant medications is not extensively studied. nih.govfrontierspartnerships.org It is important to consider the potential for increased bleeding risk when this compound is used with agents that affect coagulation or platelet function. drugbank.comrxlist.commedscape.com

Thrombocytopenia: Incidence, Risk Factors and Proposed Mechanisms

This compound-induced thrombocytopenia (LIT) is one of the most frequently reported hematologic toxicities, with incidence rates varying considerably across studies dovepress.comfrontiersin.org. Reported incidence rates in hospitalized patients have ranged from 18.2% to 41.5% dovepress.com. A systematic review and meta-analysis indicated a 37% incidence of LIT in patients across 40 observational studies cambridge.org.

Several risk factors for LIT have been identified through research:

Duration of Therapy: Treatment exceeding 14 days is consistently reported as a significant risk factor mdpi.comjidc.org. Some studies suggest increased risk even with treatment durations of 7 days or more mdpi.com.

Renal Impairment: Impaired kidney function, often defined by creatinine clearance (CrCl) below a certain threshold (e.g., < 60 mL/min or < 30 mL/min), is a major risk factor dovepress.comfrontiersin.orgmdpi.comjidc.org. Patients with renal insufficiency may have higher this compound trough concentrations, increasing the incidence of adverse reactions frontiersin.orgjidc.org.

Low Body Weight: Lower body weight has been associated with an increased risk of thrombocytopenia dovepress.commdpi.comjidc.org.

Low Baseline Platelet Count: Patients with lower platelet counts before starting this compound therapy are at higher risk dovepress.commdpi.comjidc.org.

Increased this compound Trough Concentration: Higher plasma trough concentrations of this compound are significantly correlated with an increased incidence of thrombocytopenia jidc.org. A critical trough concentration value of 6.94 μg/mL has been suggested for thrombocytopenia jidc.org.

Co-medication: Concurrent use of carbapenems has been identified as a risk factor in some studies jidc.org.

Other Factors: Advanced age, chronic liver disorder, respiratory tract infections, bacteremia, and shock have also been reported as potential risk factors mdpi.comjidc.orgjidc.org.

Proposed mechanisms for LIT include:

Mitochondrial Toxicity: this compound is thought to inhibit mitochondrial protein synthesis by binding to the mitochondrial 16S rRNA, which shares structural homology with bacterial 23S rRNA researchgate.netnih.gov. This can impair mitochondrial function, potentially affecting megakaryocyte maturation and platelet production dovepress.com.

Direct Bone Marrow Suppression: Some research suggests a direct suppressive effect on bone marrow researchgate.net. Evidence includes findings of increased bone marrow iron saturation, erythroid aplasia, and vacuolated erythroblasts in patients receiving this compound turkarchpediatr.org.

Immune-Mediated Destruction: Immune-mediated mechanisms have also been proposed, with reports of this compound-related antibodies and response to immune globulin therapy in some cases turkarchpediatr.orgresearchgate.net.

Here is a summary of reported risk factors for this compound-Induced Thrombocytopenia:

Anemia and Leukopenia

Anemia and leukopenia are also recognized hematologic toxicities associated with this compound, although they may be less frequent than thrombocytopenia nih.govfrontiersin.orgjidc.org. Research indicates that poor renal function (CrCl < 50 mL/min/1.73 m²) and this compound plasma trough concentration > 7 μg/mL are significantly correlated with this compound-induced anemia jidc.org. The mechanisms underlying this compound-induced anemia and leukopenia are thought to overlap with those of thrombocytopenia, including mitochondrial toxicity and bone marrow suppression nih.govturkarchpediatr.org.

Peripheral Neuropathy: Incidence, Reversibility, and Underlying Mechanisms

This compound-induced peripheral neuropathy (LIPN) is a known complication, with reported incidence rates varying. A systematic review and meta-analysis of studies on this compound use for multidrug-resistant tuberculosis (MDR-TB) reported a pooled incidence of 26%, with rates ranging from 6.7% to 60% cambridge.org. An open-label study in patients with other chronic infections found an LIPN incidence of 12.5% with a median treatment duration of 80.5 days cambridge.org. LIPN symptoms commonly include pain, numbness, tingling, burning, and allodynia, often in a glove-and-stocking distribution frontiersin.org.

The reversibility of LIPN is often described as limited frontiersin.org. While some studies have reported partial recovery upon discontinuation of this compound, others have noted persistent symptoms, highlighting the risk of irreversible damage jcdr.net. The onset of LIPN can vary, with symptoms appearing after several months of therapy, although reports of earlier onset exist jcdr.net.

Underlying mechanisms of LIPN are being investigated. Research suggests that this compound may impair autophagy flux in Schwann cells, which are crucial for nerve repair nih.govjcdr.netresearchgate.net. Animal studies have shown that this compound can cause sparse sciatic nerve arrangements, neuronal and myelin sheath damage, and downregulation of autophagic structural proteins nih.govresearchgate.net. Additionally, this compound may decrease the mitochondrial membrane potential of sensory axons and induce excessive calcium influx, contributing to mitochondrial toxicity and axonal damage nih.gov. Genetic factors, such as mtDNA haplotypes, might also influence susceptibility to peripheral neuropathy nih.gov.

Optic Neuropathy: Incidence, Potential Irreversibility, and Pathophysiology

This compound-induced optic neuropathy (LION) is a serious but less common adverse effect compared to peripheral neuropathy cambridge.org. Incidence rates of LION in patients treated for MDR-TB have been reported between 8% and 19% in systematic reviews and meta-analyses cambridge.org. LION typically presents with blurry vision, loss of visual acuity, color vision defects, or photophobia cambridge.org.

While LION has been considered potentially irreversible in some earlier reports, more recent studies and reviews suggest that it is often reversible upon discontinuation of this compound, with visual improvement typically occurring within 1 to 3 months cambridge.orguspharmacist.comnih.govmdpi.comnih.gov. However, complete visual recovery is not always achieved nih.gov. LION is generally associated with prolonged this compound use, with symptom onset often occurring after treatment durations of 28 days or longer, and the mean time to onset reported around 8.5 months cambridge.orgnih.gov. Cases of LION following shorter treatment durations have also been reported nih.gov.

The pathophysiology of LION is thought to involve the alteration of mitochondrial oxidative metabolism in the optic nerve cambridge.org. Similar to peripheral neuropathy, this is likely due to this compound's inhibition of mitochondrial protein synthesis uspharmacist.comnih.gov. This mechanism can theoretically mimic the respiratory chain dysfunction seen in Leber's Hereditary Optic Neuropathy (LHON), where Complex I is commonly affected mdpi.com. The selective degeneration of the papillomacular bundle of retinal ganglion cells, a feature of mitochondrial optic neuropathies, is also observed in LION, suggesting a common pathway mdpi.com. This compound's good penetration into the central nervous system and eye may contribute to its neurotoxic effects uspharmacist.com.

Mitochondrial Toxicity as a Proposed Mechanism

A significant body of research suggests that this compound's adverse effects, including lactic acidosis, myelosuppression, and neuropathies (peripheral and optic), are linked to the inhibition of mitochondrial protein synthesis. researchgate.netoup.comasm.orgasm.orgcambridge.org This mechanism is analogous to this compound's action on bacterial ribosomes, as human mitochondrial ribosomes share structural similarities with bacterial ribosomes. researchgate.netoup.com By binding to the 16S ribosomal RNA (rRNA) of the mitochondrial ribosome, this compound can impair the synthesis of essential proteins required for mitochondrial respiration and function. oup.com This disruption leads to decreased mitochondrial enzymatic activity and can result in mitochondrial dysfunction. asm.orgnih.gov Studies have shown reduced protein expression for mitochondrially coded subunits, such as COX-II, alongside decreased cytochrome c oxidase (COX) activity during this compound-induced hyperlactatemia. asm.org

Experimental studies using human cell lines and rat tissues have demonstrated decreased rates of mitochondrial protein synthesis upon treatment with this compound. asm.org This inhibition can lead to a reduction in mitochondrial respiratory chain complex activity and mitochondrial mass. asm.org Interestingly, some studies have observed an increase in mitochondrial DNA content and elevated mitochondrial RNA and ATPase-α levels following this compound treatment, potentially representing a compensatory cellular response to impaired mitochondrial protein synthesis. asm.org

Clinical Presentation and Monitoring

The clinical presentation of this compound-induced mitochondrial toxicity can include lactic acidosis, myelosuppression (anemia, thrombocytopenia, leukopenia, pancytopenia), and neurological complications such as peripheral and optic neuropathies. researchgate.netasm.orgcambridge.orgnih.govdovepress.comresearchgate.nethres.ca The risk and severity of these adverse effects are often associated with the duration of treatment and this compound exposure levels. asm.orgcambridge.orgdovepress.com

Studies have highlighted a correlation between this compound trough concentrations and the risk of mitochondrial toxicity-related adverse events. aphrc.orgnih.govnih.gov Research in patients treated for chronic extensively drug-resistant tuberculosis showed that increasing mean this compound trough concentrations were associated with lower mitochondrial function levels. aphrc.orgnih.govnih.gov Specifically, all patients with mean this compound trough concentrations above 2 μg/ml developed an adverse event related to mitochondrial toxicity, regardless of the dosage. aphrc.orgnih.govnih.gov This finding underscores the potential utility of therapeutic drug monitoring (TDM) in mitigating the risk of mitochondrial toxicity, particularly during long-term this compound therapy. cambridge.orgaphrc.orgnih.govnih.gov TDM allows for the adjustment of this compound dosage to maintain concentrations within a range associated with efficacy while minimizing the risk of toxicity. cambridge.org

Data from clinical studies indicate that this compound plasma concentrations are associated with hematological toxicity, with heightened concentrations posing an increased risk of adverse hematological effects. tandfonline.com For example, patients experiencing thrombocytopenia have demonstrated significantly higher this compound plasma concentrations compared to those without this condition. tandfonline.com

Suppression of Phagocytic Ability and Cytokine Synthesis

In vitro and pre-clinical evidence suggests that this compound can suppress the phagocytic ability and cytokine synthesis and secretion of immune cells when stimulated by endotoxins or pathogens. nih.govresearchgate.netfrontiersin.orgnih.gov Studies using peripheral blood mononuclear cells (PBMCs) from volunteers have shown that this compound can suppress the synthesis of pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α, and IL-1ra in a concentration-dependent manner. nih.govfrontiersin.org A similar inhibitory effect has been observed in LPS-stimulated cytokine production in peripheral venous whole blood. nih.govfrontiersin.org While some studies indicated no direct effect of this compound on the phagocytosis of unstimulated polymorphonuclear neutrophils (PMNs), it could suppress phagocytic ability activated by lipopolysaccharide (LPS). nih.govfrontiersin.org

Impact on Inflammatory Response during Infections

The immunomodulatory effects of this compound can influence the inflammatory response during bacterial infections. By reducing the production of pro-inflammatory cytokines, this compound may help to mitigate the inflammatory damage caused by an exaggerated or prolonged immune response. nih.govresearchgate.netfrontiersin.orgnih.gov Animal models of bacterial pneumonia have demonstrated that this compound can effectively reduce the concentration of pro-inflammatory cytokines in lung tissue or bronchoalveolar lavage fluid (BALF) and ameliorate tissue inflammatory damage, even when its antibacterial efficacy is similar to other antibiotics. nih.govfrontiersin.org Studies comparing this compound with other antibiotics like vancomycin have shown that this compound treatment can lead to significantly attenuated pro-inflammatory cytokine responses (e.g., TNF-α and IL-6) and reduced acute lung damage. nih.govfrontiersin.org This anti-inflammatory effect may contribute to improved outcomes, such as earlier defervescence, observed in some this compound-treated patients with severe infections. asm.org

Some research suggests that the suppression of inflammatory cytokines by this compound administration might be due to the inhibition of bacterial virulence factors by sub-inhibitory concentrations of this compound rather than a direct modulation of host inflammatory responses. asm.org However, other in vitro studies point towards a direct effect on host immune cells. nih.govfrontiersin.org

Potential Application in Non-infectious Inflammatory Conditions

The observed immunomodulatory effects of this compound, particularly its ability to suppress pro-inflammatory cytokine production, suggest a potential for its application in alleviating the symptoms of non-infectious inflammatory conditions. nih.govresearchgate.netfrontiersin.orgnih.govresearchgate.net While the primary indication for this compound is bacterial infections, its influence on the inflammatory cascade opens avenues for further research into its therapeutic potential in conditions where excessive inflammation plays a significant role. However, further research is necessary to explore the molecular mechanisms involved and confirm these potential applications in clinical practice. nih.govresearchgate.netfrontiersin.orgnih.gov

Incorporation of Novel Heterocyclic Rings (e.g., Pyrimidine substituted Piperazine, Triazolyl-oxazolidinone)

Improved Pharmacokinetic Profiles (e.g., Bioavailability, Half-life)

Optimizing the pharmacokinetic profile of this compound derivatives is a key area of research to improve drug exposure at the site of infection and potentially reduce dosing frequency. This compound itself exhibits excellent oral bioavailability, approximately 100% in healthy volunteers, which allows for a convenient switch from intravenous to oral administration. nih.govoup.com Its plasma half-life ranges from 3.4 to 7.4 hours. nih.govoup.com

Studies on novel oxazolidinone derivatives have investigated their pharmacokinetic properties. For instance, a comparative pharmacokinetic study in rabbits evaluated this compound and two novel oxazolidinone antibacterial agents, PH027 and PH051. mdpi.comnih.govresearchgate.net The study found that PH027 and PH051 had longer elimination half-lives (68.7 ± 12.1 min and 175 ± 46.1 min, respectively) compared to this compound (52.4 ± 6.3 min). mdpi.comnih.govresearchgate.net However, their oral bioavailability when administered as a suspension was lower than that of this compound (38.7% for this compound, 22.1% for PH027, and 4.73% for PH051). mdpi.comnih.govresearchgate.net This lower bioavailability was identified as a potential reason for discrepancies between their in vitro and in vivo activities. mdpi.comnih.govresearchgate.net The bioavailability of PH027 and PH051 significantly increased when administered as a microemulsion (72.9% for PH027 and 13.9% for PH051), suggesting that formulation plays a crucial role in their oral absorption. mdpi.comnih.govresearchgate.net Plasma protein binding also varied among the compounds, with PH051 showing significantly higher binding (90–91%) compared to this compound (32–34%) and PH027 (37–38%). mdpi.comnih.govresearchgate.net Tissue distribution for PH027 and PH051 was higher in all investigated tissues compared to this compound. mdpi.comnih.govresearchgate.net

Tedizolid phosphate (Tedizolid), another oxazolidinone approved for clinical use, has a longer half-life than this compound, allowing for once-daily oral administration. mdpi.comnih.gov This extended half-life contributes to its favorable pharmacokinetic profile and suitability for prolonged treatment courses, such as those required for mycobacterium infections. nih.gov

Reduced Propensity for Resistance Development

The emergence of resistance is a significant challenge in the continued effectiveness of this compound. Resistance is primarily associated with mutations in the 23S rRNA genes and, less commonly, mutations in ribosomal proteins L3 and L4. researchgate.netmdpi.comnih.govnih.gov The Cfr gene, encoding an RNA methyltransferase, also confers resistance to this compound and other antimicrobial classes. mdpi.commdpi.com

Research into novel derivatives aims to reduce the potential for resistance development. This involves designing compounds that bind differently to the ribosome or are less susceptible to existing resistance mechanisms like efflux pumps, which are particularly relevant for Gram-negative bacteria. mdpi.comnih.gov

Studies have explored the structure-activity relationship (SAR) of this compound analogs to understand how modifications affect activity and resistance. For instance, modifying the C-5 position of the oxazolidine ring has been investigated. acs.orgkcl.ac.uk One study synthesized a this compound analogue, 10f, with comparable antimicrobial activity to this compound. nih.gov However, resistance to 10f in Staphylococcus aureus was associated with a mutation in the ribosomal protein L3, suggesting that targeting the specific binding cavity of this analogue could be a strategy for developing derivatives with a lower propensity for resistance. nih.gov

Another approach involves combining this compound with other agents that can suppress the development of resistance. Studies have shown that low levels of other antibiotics, particularly rifampin and fusidic acid, can delay the emergence of this compound resistance in Staphylococcus aureus by suppressing the recombination-based acquisition of resistance. nih.gov

Novel oxazolidinones like tedizolid have shown potent activity against Gram-positive organisms, including those resistant to this compound, suggesting a potential to overcome some existing resistance mechanisms. mdpi.comnih.gov

Improved Safety Profiles and Reduced Adverse Effects

This compound therapy, especially prolonged use, can lead to significant adverse effects, including myelosuppression (anemia, thrombocytopenia, leukopenia), peripheral neuropathy, and optic neuropathy. asm.orgnih.govdovepress.comwho.int These toxicities can limit treatment duration and patient compliance. nih.govdovepress.com

A major focus in developing new oxazolidinones is improving the safety profile and reducing the incidence and severity of adverse effects. researchgate.netasm.orgtoku-e.com Novel derivatives are being designed with attenuated myelotoxicity and reduced monoamine oxidase (MAO) inhibition, which is linked to serotonergic toxicity. acs.orgtoku-e.com

MRX-I, a novel oxazolidinone, was developed with the specific aim of reducing myelotoxicity and MAO inhibition. toku-e.com It has shown success in clinical trials with no reported adverse events. toku-e.com

Contezolid (CZD) is another analog of this compound that has demonstrated a safer side-effect profile while maintaining potent activity against tuberculosis. dovepress.com An early bactericidal activity study comparing contezolid and this compound in pulmonary TB patients found that contezolid exhibited comparable efficacy to this compound and had a superior safety profile, suggesting it could be a viable alternative. dovepress.com

Tedizolid is also reported to offer better tolerance and safety profiles for long-term treatment compared to this compound, particularly in mycobacterium infections. nih.gov Sutezolid, a thiomorpholinyl analog, also appears to cause less bone marrow suppression and QT-interval prolongation than this compound, although concerns about potential neurotoxicity and hepatotoxicity remain. nih.gov

Bioisosteres of this compound with modifications at the C-5 position have been designed to balance antibacterial activity with reduced serotonergic toxicity. acs.org One such bioisostere, R7, demonstrated greater effectiveness against M. tuberculosis while being significantly less toxic towards MAO-A and MAO-B enzymes compared to this compound, indicating a substantial improvement in its safety profile. acs.org

Antifungal and Antitubercular Activities

While primarily known for its activity against Gram-positive bacteria, research has also explored the potential of this compound derivatives to exhibit antifungal and antitubercular activities.

This compound itself has shown in vitro antimycobacterial action against Mycobacterium tuberculosis (Mtb), including multidrug-resistant strains. acs.org It is included in some regimens for treating drug-resistant TB. dovepress.comwho.int

Novel this compound-based oxazolidinones have been synthesized and evaluated for their antifungal and antitubercular potential. Some oxazolidinone-sulphonamide and oxazolidinone-amide conjugates have demonstrated enhanced potency against Bacillus subtilis and Staphylococcus aureus. mdpi.com Notably, some novel this compound-based oxazolidinones have shown better antifungal activity against Candida species compared to standard antifungal agents like miconazole and fluconazole. mdpi.com

Studies have also focused specifically on developing this compound analogs with improved antitubercular activity. AZD5847, a novel oxazolidinone, has shown improved in vitro anti-tuberculosis activity, both intracellularly and extracellularly, compared to this compound. toku-e.com This increased potency could potentially lead to shorter treatment durations for TB. toku-e.com

Sutezolid, a thiomorpholinyl analog of this compound, has demonstrated superior efficacy against M. tuberculosis in preliminary studies. nih.gov Novel azaspiro analogs of this compound have also been reported to exhibit antitubercular activity. researchgate.nettandfonline.com

Anti-biofilm Activity

Bacterial biofilms are structured communities of bacteria encased in a self-produced matrix, which confer increased resistance to antibiotics and host immune responses. mdpi.com Research is exploring the ability of this compound derivatives to inhibit or eradicate bacterial biofilms.

Studies have investigated the anti-biofilm activity of oxazolidinones against Gram-positive bacteria, including Staphylococcus aureus and Enterococcus faecalis. nih.govmdpi.comresearchgate.netoup.com While this compound has shown some inherent anti-biofilm activity, its effectiveness in eradicating established biofilms, particularly MRSA biofilms, can be limited. mdpi.comresearchgate.net

Novel this compound derivatives are being developed with enhanced anti-biofilm properties. Oxazolidinone-sulphonamide/amide conjugates have shown good antibiofilm activity against Bacillus subtilis and Pseudomonas aeruginosa. mdpi.com

A this compound-nitroxide hybrid (compound 11) demonstrated greater effectiveness in eradicating MRSA biofilms compared to this compound. researchgate.net This suggests that hybridization strategies can improve the anti-biofilm potential of oxazolidinones.

Other oxazolidinones like tedizolid and radezolid have also been evaluated for their anti-biofilm activity against this compound-resistant Enterococcus faecalis. nih.gov Radezolid showed greater antimicrobial activity against planktonic cells of these resistant strains compared to tedizolid and this compound, and both tedizolid and radezolid showed differential activity on biofilm inhibition and eradication. nih.gov Ranbezolid has also shown the ability to eradicate MRSA biofilms, and its activity was synergistically enhanced when combined with a biofilm dispersal agent. mdpi.com

These findings highlight the ongoing efforts to develop this compound derivatives with improved activity against bacterial biofilms, addressing a critical aspect of persistent and difficult-to-treat infections.

Dosing Strategies in TB Regimens and Impact on Efficacy

Research into linezolid dosing strategies for tuberculosis (TB), particularly multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB), aims to balance efficacy and potential toxicity frontiersin.orgfoliamedica.bg. Studies have explored different daily doses, including 300 mg, 600 mg, and 1200 mg, as well as intermittent dosing schedules frontiersin.orgnih.govtballiance.org.zaasm.org.

Early bactericidal activity trials have indicated that higher daily doses of this compound demonstrate greater activity during the initial treatment period tballiance.org.zatballiance.org. For instance, a study found that activity increased with increasing doses, with the highest activity observed at 1200 mg daily, followed by 600 mg and then 300 mg tballiance.org.zatballiance.org. The distribution of the total daily dose (once daily versus divided doses) did not appear to significantly impact activity in this context tballiance.org.zatballiance.org.

Pharmacokinetic (PK) studies in patients with MDR-TB have investigated the probability of target attainment (PTA) for different this compound doses based on minimum inhibitory concentrations (MICs) frontiersin.org. Simulations suggest that a 300 mg daily dose may be effective for strains with MICs ≤ 0.25 mg/L, but a 600 mg daily dose may be more appropriate for higher MIC levels (0.5–1 mg/L) to achieve a higher PTA frontiersin.org. One study in Indian patients with MDR-TB predicted that while 300 mg daily could achieve effective targets for the majority, it failed for a notable percentage of participants, whereas 600 mg daily had a PTA over 90% for susceptible samples frontiersin.org. However, achieving higher efficacy targets with increased doses can also correlate with a higher likelihood of exceeding toxicity thresholds frontiersin.org.

Studies evaluating this compound-containing regimens for XDR-TB have shown favorable outcomes foliamedica.bg. One multicenter study indicated that patients receiving this compound (initially 1200 mg daily, potentially reduced thereafter) had better treatment outcomes compared to a control group foliamedica.bg. The treatment success rate was significantly higher in the this compound therapy group foliamedica.bg. Some research suggests that doses ≤ 600 mg daily in MDR-TB and XDR-TB treatment may offer a good balance of efficacy and tolerability foliamedica.bg. However, the administration of higher doses, such as 1200 mg daily, has been associated with a high incidence of adverse events foliamedica.bg.

Further research is ongoing to optimize this compound dosing strategies in TB, including the role of therapeutic drug monitoring (TDM) to individualize doses and balance effectiveness with minimizing adverse events who.intasm.orgrjptonline.org. Studies are also exploring alternative dosing schedules, such as intermittent dosing, to potentially maintain efficacy while reducing toxicity asm.org.

This compound vs. Vancomycin in Specific Infections

This compound and vancomycin are both utilized for treating Gram-positive bacterial infections, including those caused by resistant strains like methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) nih.govalixarx.comseq.es. Comparative studies have assessed their efficacy in various infection types.

Meta-analyses and randomized controlled trials have compared this compound to vancomycin in treating complicated skin and soft tissue infections (cSSTIs) nih.govportlandpress.com. Some analyses have found this compound to be significantly more effective than vancomycin in achieving clinical and microbiological cure rates in SSTIs portlandpress.com. For infections specifically caused by MRSA, this compound has also demonstrated superiority over vancomycin in clinical and microbiological cure rates in some studies portlandpress.comnih.gov.

For pneumonia, particularly nosocomial pneumonia and MRSA pneumonia, comparisons between this compound and vancomycin (or other glycopeptides) have yielded varied results nih.govplos.org. Some meta-analyses have found no significant difference in efficacy between this compound and comparator drugs for Gram-positive pneumonia or nosocomial pneumonia nih.gov. However, other studies, including an updated trial, have suggested that this compound may be more effective than vancomycin for treating MRSA nosocomial pneumonia plos.org.

Here is a summary of comparative efficacy findings:

Real-World Effectiveness Data from Observational Studies

Real-world effectiveness data from observational studies provide insights into how this compound performs in routine clinical practice seq.esmednexus.orgjmcp.orgnih.govdovepress.com. These studies complement data from controlled clinical trials by reflecting the heterogeneity of patient populations and clinical settings.

Observational studies in critically ill patients with Gram-positive bacterial infections have reported favorable clinical success rates with this compound treatment mednexus.org. One multi-center, observational study found that clinical success was achieved in a high percentage of evaluated ICU patients treated with this compound for Gram-positive infections, with the most common pathogens being Staphylococcus aureus (including MRSA) and Enterococci mednexus.org. The primary infection sites included the lung, skin and soft tissue, and blood mednexus.org.

Real-world data has also been used to compare this compound-containing regimens with other treatments in specific scenarios. For instance, an observational study investigating empirical therapy for spontaneous bacterial peritonitis (SBP) found that combination therapy with piperacillin/tazobactam plus this compound was associated with fewer treatment failures compared to piperacillin/tazobactam monotherapy, although there was no impact on short-term survival nih.govkarger.com.

Post-marketing surveillance and real-world data analysis, such as using databases like the FDA Adverse Event Reporting System (FAERS), are utilized to monitor the use and outcomes of this compound in broader populations medsafe.govt.nznih.gov. These efforts contribute to understanding the effectiveness and safety profile in real-world settings as the indications for this compound expand, including its use in drug-resistant TB nih.gov.

Optimization of Treatment Regimens

Future research directions for this compound include continued efforts to optimize treatment regimens to maximize efficacy and minimize potential limitations, such as toxicity and the development of resistance asm.orgrjptonline.orgtandfonline.comnih.govnih.govoup.com.

Pharmacokinetic/pharmacodynamic (PK/PD) analyses and modeling, including Monte Carlo simulations, are valuable tools for optimizing this compound dosing strategies for various infections and pathogens asm.orgtandfonline.comnih.govnih.govoup.comnih.gov. These approaches help determine the probability of achieving specific PK/PD targets associated with favorable clinical outcomes for different bacterial MICs and infection sites tandfonline.comnih.gov. Studies using these methods have investigated optimal dosing regimens for Gram-positive infections, including those caused by staphylococci and enterococci tandfonline.comnih.gov. For instance, while 600 mg every 12 hours may be suitable for staphylococcal infections with lower MICs, higher doses or more frequent administration (e.g., 600 mg every 8 hours) may be required for enterococcal infections with elevated MICs to achieve better efficacy tandfonline.comnih.gov.

Research is also focused on optimizing this compound use in combination therapies, particularly for difficult-to-treat infections like drug-resistant TB and infections caused by resistant Enterococcus species nih.govnih.govresearchgate.net. In vitro PK/PD models are being used to explore the synergistic effects of this compound with other antibiotics, such as fosfomycin, to identify combinations and dosing strategies that enhance bacterial killing and potentially reduce the risk of resistance development nih.govnih.govresearchgate.net. These studies aim to provide a quantitative basis for optimizing combination regimens in simulated human conditions nih.govnih.gov.

Further research is needed to refine TDM strategies for this compound to allow for individualized dosing adjustments based on patient-specific PK characteristics, which can vary significantly who.intasm.orgrjptonline.org. This personalized approach aims to ensure adequate drug exposure for efficacy while avoiding concentrations associated with toxicity who.intasm.org.

Integration into Antimicrobial Stewardship Programs

This compound is recognized as a valuable antimicrobial, particularly for treating infections caused by resistant Gram-positive pathogens like MRSA and VRE alixarx.comalbertahealthservices.caajol.info. Given its importance and the need to preserve its effectiveness, integration into antimicrobial stewardship programs (ASPs) is a key future direction alixarx.comajol.infonih.govnih.govpaho.orgsapg.scotmdpi.com.

ASPs aim to promote the appropriate use of antimicrobial agents to improve patient outcomes, reduce the development of drug resistance, and minimize healthcare costs alixarx.comajol.infoniinfectioncontrolmanual.net. Within ASPs, strategies for this compound often include restricting its use to specific indications or based on culture and susceptibility results, particularly for resistant organisms alixarx.comalbertahealthservices.caajol.infopaho.orgsapg.scotniinfectioncontrolmanual.net. This helps ensure that this compound is used when it is most needed and is likely to be effective alixarx.com.

Recommendations for ASPs often include educating clinical staff on appropriate prescribing, making up-to-date guidelines readily available, and reviewing antibiotic prescriptions within a set timeframe, especially for empirical therapy niinfectioncontrolmanual.net. This compound is often categorized as a restricted or "alert" antibiotic within hospital formularies, requiring authorization or review by infectious disease specialists or an antimicrobial management team albertahealthservices.caajol.infopaho.orgsapg.scotmdpi.com.

Integrating this compound into ASPs involves monitoring its usage, tracking resistance patterns, and implementing policies to guide its appropriate selection, dosing, and duration of therapy alixarx.comajol.infoniinfectioncontrolmanual.net. This is particularly crucial for potent agents like this compound to safeguard their continued efficacy against challenging resistant bacteria ajol.infosapg.scot. Real-world studies evaluating the impact of ASPs have shown success in reducing the consumption of targeted antimicrobials, including this compound, and curbing the prevalence of multidrug-resistant organisms mdpi.com.

Exploring Efficacy in Non-Approved or Off-Label Indications (Research Only)

Research into the off-label uses of this compound has investigated its effectiveness in various challenging infections where approved therapies may be limited or have failed. These investigations often stem from in vitro activity data or clinical observations suggesting potential benefit. ersnet.orgamegroups.org

One significant area of research for off-label this compound use is in the treatment of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). Despite the absence of large randomized controlled trials specifically for this indication, this compound is used off-label in several countries for MDR-TB due to limited alternative antibiotics. ersnet.orgamegroups.org Studies, including systematic reviews and meta-analyses, have evaluated the efficacy of this compound-containing regimens in treating MDR-TB and XDR-TB. A meta-analysis of 12 studies involving 121 patients with definite treatment outcomes reported that 81.8% of patients treated with individualized regimens containing this compound were successfully treated. ersnet.org The pooled rate of sputum culture conversion among evaluable patients in studies was reported as 89%. amegroups.org Another study in China evaluating this compound therapy for XDR-TB reported a treatment success rate of 69.7%, significantly higher than a control group. ersnet.org this compound has also been observed to accelerate cavity closure and sputum culture conversion rates in these patients. ersnet.org

This compound's penetration into the central nervous system (CNS) has led to its investigation for the treatment of CNS infections, although this is considered an off-label use and approved indications exclude bacterial meningitis. oup.comnih.gov Retrospective studies in adult populations have suggested that this compound may be noninferior to vancomycin in clinical response and pathogen clearance for Gram-positive CNS infections and has shown promise as salvage therapy in cases of vancomycin allergy or treatment failure, with one report indicating an 83.3% cure rate in such cases. oup.com However, pediatric data on this compound for CNS infections are primarily limited to retrospective case reports. oup.com

In compassionate use programs, where this compound was provided for the treatment of multidrug-resistant, Gram-positive infections, including those not covered by approved indications, high rates of clinical cure and microbiological success were observed. oup.com In a compassionate use program involving 796 patients with 828 treatment courses for multidrug-resistant Gram-positive infections, including bacteremia, endocarditis, line-related infections, intraabdominal infections, complicated skin and skin-structure infections, and osteomyelitis, clinical cure rates in evaluable patients reached 91.5%, and microbiological success rates were 85.8%. oup.com For a subset of patients with S. aureus infections treated under a compassionate use protocol, clinical success rates in the clinically evaluable population were 83.9%, and bacteriological eradication rates were 76.9% in the bacteriologically evaluable population. capes.gov.br

Research has also explored this compound's efficacy in bone and joint infections, such as osteomyelitis. A retrospective look at oral this compound therapy for osteomyelitis showed a clinical cure rate of 55% in patients who received at least 6 weeks of therapy. nih.gov In a compassionate use program, this compound treatment for osteomyelitis in 22 evaluable patients resulted in an 82% clinical cure rate. nih.gov

While not strictly off-label in all contexts depending on the specific pathogen, studies have also compared this compound's efficacy to other agents like vancomycin in complicated skin and soft tissue infections (cSSTIs) and in critically ill patients with Gram-positive infections, sometimes including conditions that might fall outside initial narrow indications or in specific patient populations. For instance, this compound demonstrated comparable clinical efficacy to dalbavancin in complicated SSTIs (91.2% vs 88.9% success). nih.gov In a study comparing this compound to vancomycin in patients with proven or suspected MRSA cSSTIs, this compound was found to be more effective in patients with abscesses and those with MRSA infections. nih.gov A meta-analysis comparing this compound to vancomycin for SSTIs indicated that this compound was associated with significantly better clinical and microbiological cure rates. portlandpress.com In critically ill patients with Gram-positive infections, an observational study suggested this compound was associated with microbiological eradication of the infecting organism at the seventh day of treatment. seq.es

The exploration of this compound in these non-approved or off-label indications highlights its potential utility in challenging clinical scenarios, particularly those involving multidrug-resistant Gram-positive pathogens and infections in sites with limited antibiotic penetration.

Research Findings on Off-Label this compound Use

Note: This table summarizes efficacy findings from research studies on off-label or investigational uses of this compound. It does not include information on approved indications, dosage, administration, or safety/adverse effects.