The present report provides a detailed assessment of Oxazolidinone (OZE) resistance: geographical dissemination and horizontal gene transfer in Gram-positive bacteria. It is a class of synthetic antimicrobial agents discovered in 1987 to treat multi-drug resistant gram-positive and gram-negative bacteria. OZEs are mainly used in intensive care units and have been effective against these bacteria. OZEs inhibit protein biosynthesis by preventing the formation of a functional 70S initiation complex composed of the 30S ribosomal subunit initiation factors. OZEs resistance mechanisms include point mutations in the 23S rRNA, mutations in L3 and L4 ribosomal proteins, and the acquisition of different genes, namely cfr, optrA, and poxtA. Chromosomal mutations to linezolid, an antibiotic, have been identified, with the G2576U mutation in 23S rRNA being the most common. The first resistant strain was S. aureus (2001), and these mutations are typically developed during treatment and spread through clonal dissemination.
The cfr gene is an RNA methyltransferase first identified in a bovine Mammalicoccus sciuri isolate from Germany. It confers resistance to linezolid, lincosamides, pleuromutilins, and streptogramin A but susceptibility to Tedizolid and phenicols. It is found in bacteria from eight different genera and is commonly located on mobile genetic elements. The gene has been identified in isolates from humans, animals, food, and the environment. The optrA gene, found on a plasmid in a human E. faecalis isolates in China, provides resistance to phenicols via the ABC-F protein mechanism, which protects ribosomes. It is prevalent in Enterococcus spp and has over 69 variants, which may have varying resistance levels. The PoxtA gene was discovered in Italy in 2018 and provided resistance to certain antibiotics through an efflux pump mechanism. It differs from the OptrA gene and is found on various mobile genetic elements. PoxtA has only been found in Enterococcus and Staphylococcus isolates from human clinical settings.
Three studies on antibiotic-resistant bacteria were conducted. The first one found an outbreak of an antibiotic-resistant in Russia caused by mutations in 23s rRNA and L3 protein, with related isolates across different regions. The second study revealed that a strain of antibiotic-resistant bacteria had increased growth rates in higher antibiotic concentrations due to adaptations in the ribosome. The third investigation compared environmental and clinical isolates of MRSA from the US and Pakistan with different clonal types and resistance mechanisms. According to animal studies, animals may be functioning as a reservoir for antibiotic-resistance genes that affect humans. The development of antibiotic resistance is a significant problem, mainly due to cross-resistance with other antibiotics. The use of amphenicols in animal consumption has been identified as a source of selective pressure for antibiotic resistance. A study in catfish production found that treatment with florfenicol increased the number of antibiotic-resistance genes, including those that confer resistance to OZE. While the frequency of OZE resistance is still low, it is increasing due to the transfer and spread of genetic elements and clonal spread. In addition, the use of non-OZE antibiotics also promotes OZE resistance. Some measures must be implemented to address this issue, such as reducing antibiotic use in humans and animals, forbidding antibiotics as growth promoters, and continuing surveillance.
Oxazolidinones in the Management of Gram-Positive Infections
The challenges in gram-positive infections include the need for effective oral agents for skin and soft tissue infections, pneumonia caused by MRSA and streptococcus pneumoniae that are resistant to beta-lactams or macrolides in the community setting. In the hospital setting, there is a demand for agents to treat bloodstream infections, hospital-acquired infections, and ventilator-associated pneumonia caused by MRSA and Vancomycin-resistant enterococcus. Now, new drugs are available to combat gram-positive infections, including new cephalosporins and new oxazolidinones, like tedizolid.
In 1978, the first oxazolidinones were developed and used as agents against plant pathogens. In 1996, two synthetic oxazolidinones were developed, which are more stable against resistances. Linezolid was approved for clinical use in 2000, and Tedizolid was approved by FDA in 2014 and by the European Medicines Agency in 2015. These antimicrobials are effective against gram-positive k bacteria, multi-susceptible and multi-drug-resistant strains, and certain pathogens like Listeria and Nocardia. They also work well against both gram-positive and gram-negative anaerobes and exhibit strong activity against Mycobacterium, including drug-resistant strains.
The MIC (minimum inhibitory concentration) breakpoints defined by EUCAST differ for Linezolid and Tedizolid, as well as for different types of bacteria such as staphylococcus, enterococcus, and different groups of streptococcus A, B, C, and G. Tedizolid shows 100% probability of achieving the pharmacokinetic-pharmacodynamic (PK-PD) target only for strains with a MIC lower than 0.5 µg/ml, which is why the breakpoints are different for the two drugs. Tedizolid has a dosing of 200 mg/day, while Linezolid is dosed at 600 milligrams every 12 hours. Linezolid has a higher maximum concentration after administration, resulting in a larger area under the curve. Tedizolid has a longer half-life, making once-daily dosing appropriate. The AUC to MIC ratio of 100 is the target for optimal activity of oxazolidinones.
In patients with sepsis, the concentration of Linezolid in the lung is higher than in plasma, both after the initial dose and in the steady state. Similarly, Tedizolid also shows higher concentrations in the lung and alveolar macrophages compared to plasma 24 hours after administration. The lipophilic nature of oxazolidinone drugs allows them to penetrate deep tissues, including the central nervous system (CNS). The mean serum to cerebrospinal fluid (CSF) ratio of Linezolid is around 70%, indicating its ability to reach the CNS. This makes oxazolidinones attractive for treating meningitis, central nervous system infections, and neurosurgical infections.
Adverse effects of oxazolidinone drugs include gastrointestinal symptoms, bone marrow suppression, neurological adverse events (which can be irreversible, especially in those treatments which are longer than 28 days), and other potential side effects such as hypoglycemia, lactic acidosis, arterial hypertension, pancreatitis, hyponatremia, or Clostridium difficile-associated diarrhoea. Despite these, they are generally well tolerated. Bone marrow suppression, specifically thrombocytopenia, is a known risk associated with oxazolidinone drugs. Studies have shown that the likelihood of developing thrombocytopenia increases with prolonged treatment, and risk factors include renal insufficiency and high Linezolid concentrations. Close monitoring of haematological parameters, including weekly monitoring, is typically recommended in patients with these risk factors.
Tedizolid, compared to Linezolid in ESTABLISH 1 and ESTABLISH 2 studies for gram-positive infections, showed similar early response, side effects, and MRSA efficacy. However, a recent pneumonia study did not find differences in mortality, but Tedizolid did not demonstrate non-inferiority in clinical cure rate Clinical outcomes of Linezolid showed cure rates of more than 75% in most cases, though bone infections had slightly lower success rates. In the treatment of Periprosthetic joint infections, Linezolid was mainly used as a second-line option after the failure of previous treatments. Combination therapy with rifampin was used in half of the patients, but it was associated with higher rates of relapse and failure, likely due to interactions. Linezolid and Tedizolid are effective treatments for CNS infections, osteoarticular infections, and related conditions, particularly in patients who have failed glycopeptide therapy. Tedizolid shows high cure rates in various infections, including gram-positive resistant osteoarticular infections. Studies have demonstrated favorable clinical outcomes with prolonged Tedizolid treatment in 75% of patients.
Oxazolidinones are potent antibacterial drugs that inhibit specific bacteria. Tedizolid has better in vitro activity than Linezolid, and the AUC to MIC ratio is the key pharmacodynamic parameter for oxazolidinones. Oxazolidinones exhibit excellent tissue penetration, including the CNS, but Linezolid requires caution due to its interaction with P-glycoprotein. Therapeutic drug monitoring (TDM) may be helpful for Linezolid dosing. Oxazolidinones' toxicity may be related to impaired mitochondrial protein synthesis, and high Linezolid levels may cause bone marrow suppression. Serotonin syndrome is a risk with Linezolid co-administration, and long-term tedizolid treatment is generally well-tolerated with lower rates of toxicity compared to Linezolid.
European Congress of Clinical Microbiology and Infectious Disease 2023, 15th April - 18th April 2023, Copenhagen, Denmark
