The Oxazolidinones: Past, Present, and Future
Trius Therapeutics, Inc., Department of Biology, San Diego, California 92121, USA.Annals of the New York Academy of Sciences (Impact Factor: 4.38). 12/2011; 1241(1):48-70. DOI: 10.1111/j.1749-6632.2011.06330.x
The success of linezolid stimulated significant efforts to discover new agents in the oxazolidinone class. Over a dozen oxazolidinones have reached the clinic, but many were discontinued due to lack of differentiated potency, inadequate pharmacokinetics, and safety risks that included myelosuppression. Four oxazolidinones are currently undergoing clinical evaluation. The Trius Therapeutics compound tedizolid phosphate (formerly known as torezolid phosphate, TR-701, DA-7218), the most advanced, is in phase 3 clinical trials for acute bacterial skin and skin structure infections. Rib-X completed two phase 2 studies for radezolid (Rx-01_667, RX-1741) in uncomplicated skin and skin structure infections and community-acquired pneumonia. Pfizer and AstraZeneca have each identified antitubercular compounds that have completed phase 1 studies: sutezolid (PNU-100480, PF-02341272) and AZD5847 (AZD2563), respectively. The oxazolidinones share a relatively low frequency of resistance largely due to the requirement of mutations in 23S ribosomal RNA genes. However, maintaining potency against strains carrying the mobile cfr gene poses a challenge for the oxazolidinone class, as well as other 50S ribosome inhibitors that target the peptidyl transferase center.
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- "Resistance to linezolid was first reported in a MRSA isolate from a patient who received linezolid treatment in 2001 (Tsiodras et al., 2001). The prevalence of linezolid resistance among staphylococci is relatively low, presumably because mutationmediated resistance develops slowly and is not transmissible (Shaw and Barbachyn, 2011; Witte and Cuny, 2011). However , the emergence of transferable linezolid resistance mediated by cfr is a global concern and poses a significant challenge to the clinical treatment of this infection. "
ABSTRACT: Bacteria harboring cfr, a multidrug resistance gene, have high prevalence in livestock in China and might be transmitted to humans through direct contact or via contaminated food products. To better understand the epidemiology of cfr producers in the food chain, the prevalence and genetic analysis of Staphylococcus isolates recovered from pigs, workers, and meat-handling facilities (a slaughterhouse and a hog market in Guangzhou, China) were examined. Twenty (4.5%) cfr-positive Staphylococcus isolates (18 Staphylococcus simulans, 1 S. cohnii, and 1 S. aureus) were derived from pigs (16/312), the environment (2/52), and workers (2/80). SmaI pulsed-field gel electrophoresis of 26 staphylococcal strains (22 S. simulans and 4 S. cohnii), including previously reported cfr-carrying staphylococci of animal food origin, exhibited 19 major pulsed-field gel electrophoresis patterns (A-S). Clonal spread of cfr-carrying staphylococci among pigs, workers, and meat products was detected. The genetic contexts of cfr in plasmids (pHNKF3, pHNZT2, and pHNCR35) obtained from S. simulans of swine or human origin were similar to that of Staphylococcus species isolated from human clinics and animal-derived food. The cfr-carrying S. aureus strain isolated from floor swabs of the hog market was spa-type t889 and belonged to the ST9 clonal lineage. In summary, both clonal spread and horizontal transmission via mobile elements contributed to cfr dissemination among staphylococcal isolates obtained from different sources. To monitor potential outbreaks of cfr-positive bacteria, continued surveillance of this gene in animals at slaughter and in animal-derived food is warranted.
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- "Mutations in the drug target site (23S rRNA or ribosomal proteins L3 and L4) are the most common mechanisms of linezolid resistance. Due to the low frequency of target mutation, the frequency of linezolid resistance is also relatively low . However, emergence of the transferable linezolid resistance gene, cfr, in clinical isolates poses a challenge in linezolid treatment. "
ABSTRACT: Background The emergence and wide distribution of the transferable gene for linezolid resistance, cfr, in staphylococci of human and animal origins is of great concern as it poses a serious threat to the public health. In the present study, we investigated the emergence and presence of the multiresistance gene, cfr, in retail meat sourced from supermarkets and free markets of Guangzhou, China. Results A total of 118 pork and chicken samples, collected from Guangzhou markets, were screened by PCR for cfr. Twenty-two Staphylococcus isolates obtained from 12 pork and 10 chicken samples harbored cfr. The 22 cfr-positive staphylococci isolates, including Staphylococcus equorum (n = 8), Staphylococcus simulans (n = 7), Staphylococcus cohnii (n = 4), and Staphylococcus sciuri (n = 3), exhibited 17 major SmaI pulsed-field gel electrophoresis (PFGE) patterns. In 14 isolates, cfr was located on the plasmids. Sequence analysis revealed that the genetic structures (including ΔtnpA of Tn558, IS21-558, ΔtnpB, and tnpC of Tn558, orf138, fexA) of cfr in plasmid pHNTLD18 of a S. sciuri strain and in the plasmid pHNLKJC2 (including rep, Δpre/mob, cfr, pre/mob and partial ermC) of a S. equorum strain were identical or similar to the corresponding regions of some plasmids in staphylococcal species of animal and human origins. Conclusions To the best of our knowledge, this is the first study to report the presence of the multiresistance gene, cfr, in animal meat. A high occurrence of cfr was observed in the tested retail meat samples. Thus, it is important to monitor the presence of cfr in animal foods in China.
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- "Radezolid was selected for further advancement with two phase 2 clinical trials completed to date: the first in CAP and the second trial in cSSSI . "
ABSTRACT: Bacterial resistance to antibiotics is growing up day by day in both community and hospital setting, with a significant impact on the mortality and morbidity rates and the financial burden that is associated. In the last two decades multi drug resistant microorganisms (both hospital- and community-acquired) challenged the scientific groups into developing new antimicrobial compounds that can provide safety in use according to the new regulation, good efficacy patterns, and low resistance profile. In this review we made an evaluation of present data regarding the new classes and the new molecules from already existing classes of antibiotics and the ongoing trends in antimicrobial development. Infectious Diseases Society of America (IDSA) supported a proGram, called "the [prime]10 x 20[prime] initiative", to develop ten new systemic antibacterial drugs within 2020. The microorganisms mainly involved in the resistance process, so called the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and enterobacteriaceae) were the main targets. In the era of antimicrobial resistance the new antimicrobial agents like fifth generation cephalosporins, carbapenems, monobactams, beta-lactamases inhibitors, aminoglycosides, quinolones, oxazolidones, glycopeptides, and tetracyclines active against Gram-positive pathogens, like vancomycin-resistant S. aureus (VRSA) and MRSA, penicillin-resistant streptococci, and vancomycin resistant Enterococcus (VRE) but also against highly resistant Gram-negative organisms are more than welcome. Of these compounds some are already approved by official agencies, some are still in study, but the need of new antibiotics still does not cover the increasing prevalence of antibiotic-resistant bacterial infections. Therefore the management of antimicrobial resistance should also include fostering coordinated actions by all stakeholders, creating policy guidance, support for surveillance and technical assistance.
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