ru-66647 and Gram-Positive-Bacterial-Infections

Vancomycin is considered the workhorse for the treatment of most drug-resistant gram-positive bacterial infections. However, concerns have been raised regarding the increasing rates of vancomycin-resistant enterococci and the clinical shortcomings of vancomycin in the treatment of invasive Staphylococcus aureus infections. Resources have been committed to the development of antimicrobial agents with activity against these organisms. This review will focus on the newer antibacterial agents that have been developed for the treatment of resistant gram-positive pathogens. Included in this review are the agents: quinupristin-dalfopristin, linezolid, daptomycin, telithromycin, and tigecycline.

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Gram-Positive Bacterial Infections; Humans; Ketolides; Minocycline; Peptides, Cyclic; Tigecycline

Topics: Acetamides; Anti-Bacterial Agents; Drug Resistance, Bacterial; Germany; Gram-Positive Bacterial Infections; Humans; Ketolides; Linezolid; Macrolides; Oxazolidinones

Macrolides, ketolides and streptogramins are three families of antibiotics with different chemical structures, sharing the same mechanism of action. All three bind to distinct bases of the peptidyl transferase center of ARNr 23S. Their antibacterial spectrum practically overlaps, but dissimilarities in affinity and/or number of binding sites determine differences in the intensity of their antibacterial effects (bacteriostatic or bactericidae) and in their activity against strains with acquired resistance mechanisms. These agents are active against the majority of gram-positive microorganisms and many intracellular microorganisms for growth. Over the last five years in our country, the percentage of macrolide-resistant pneumococci and S. pyogenes strains has increased substantially. Telithromycin (ketolide) and Synercid (streptogramin) have shown maintained activity against these strains. Macrolides, ketolides and streptogramins are metabolized in the liver through CYP 3A4 and they can partially block the activity of the enzyme, interfering with the metabolism of other drugs that use the same metabolic pathway. There is little elimination through the urine, with the exception of clarithromycin. High concentrations are reached in the cellular cytoplasm, but they do not diffuse to the CSF. These agents are included among class B drugs for use during pregnancy. Tolerance to macrolides and telithromycin is good and they have few associated adverse effects. The main clinical indication for these drugs is in empirical treatment of mild to moderate, community-acquired, upper and lower respiratory tract infections. Synercid is indicated in the treatment of infections due to methicillin-resistant staphylococci and glycopeptide-resistant enterococci.

Topics: Anti-Bacterial Agents; Biotransformation; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Drug Resistance; Gastrointestinal Diseases; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Hearing Loss, Sensorineural; Humans; Ketolides; Macrolides; Microsomes, Liver; Protein Synthesis Inhibitors; RNA, Bacterial; RNA, Ribosomal, 23S; Streptogramins

CHANGING RESISTANCE OF GRAM-POSITIVE COCCI: Several new families of antibiotics are under development in response to the changing resistance of Gram-positive cocci. Linezolide, the leading member of the oxazolidinone family and telithromycin and ABT-773, leading members of the ketolide family have reached an advanced stage of development. INHIBITION OF PROTEIN SYNTHESIS: Oxazolidinones and ketolides inhibit protein synthesis at different levels. Oxazolidinones inhibit formation of the 70S initiation complex and ketolides block the protein elongation step by inhibiting peptidyl transferase. MECHANISMS OF RESISTANCE: To date, no cross resistance of linezolide with other antibiotic families used for the treatment of Gram-positive bacteria has been observed. It is quite difficult to obtain resistant mutants in the laboratory but two point mutations on the 23S ribosome fraction have been described in vivo. Resistance of Gram-positive cocci to macrolides occur via mechanisms altering the target (methylation of 23S rRNA or ribosome protein mutations) or via mechanisms involving active efflux. LINEZOLIDE: Linezolide is highly active in vitro against meticillin-resistant Staphylococcus aureus (MRSA), against Streptococcus including resistant pneumococcal strains, and against glycopeptide-resistant E. faecium and E. faecalis strains. TELITHROMYCIN AND ABT-773: These ketolides are active against Streptococcus and Pneumococcus strains exhibiting erythromycin-inducible resistance and resistance by active efflux. In addition, these antibiotics are highly active against other bacteria causing respiratory tract infections (Moraxella and Haemophilus), anaerobic germs and intracellular germs (Legionella).

Topics: Acetamides; Anti-Bacterial Agents; Erythromycin; Gram-Positive Bacterial Infections; Humans; Ketolides; Linezolid; Macrolides; Microbial Sensitivity Tests; Oxazolidinones; Respiratory Tract Infections; Streptococcus; Structure-Activity Relationship

The antibacterial activities of clindamycin, synercid, telithromycin, linezolid and mupirocin were evaluated against erythromycin-resistant Gram-positive coccal clinical isolates collected in Korean hospitals. In Staphylococcus aureus, synercid, linezolid and mupirocin were the most active agents. Against coagulase-negative staphylococci (CNS), synercid, linezolid and mupirocin were also active. Telithromycin and synercid resistance was common against enterococci, only linezolid and mupirocin were active. The reason of low activity of telithromycin against staphylococci and enterococci is because most of the isolates were constitutively resistant to erythromycin. Synercid, telithromycin, linezolid and mupirocin were active against streptococci.

Topics: Acetamides; Anti-Bacterial Agents; Clindamycin; Drug Resistance, Bacterial; Erythromycin; Gram-Positive Bacterial Infections; Gram-Positive Cocci; Humans; Ketolides; Korea; Linezolid; Microbial Sensitivity Tests; Mupirocin; Oxazolidinones; Virginiamycin