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New Agents on the Horizon

　　Naomi O'Grady, MD,[14] of the National Institutes of Health in Bethesda, Maryland, summarized features of newer antibiotic agents for Gram-positive cocci. Gram-positive cocci are becoming the predominant causes of nosocomial infections, replacing Gram-negative bacilli. Thus, newer agents for Gram-positive cocci have increasing importance.
　　Linezolid was approved in 2000. It is a bacteriostatic agent against both Staphylococci and Enterococci. It is not cross-resistant with vancomycin or dalfopristin-quinupristin. It is available intravenously or orally and does not need dose adjustment with renal or hepatic disease. Thus, the drug is relatively easy to administer and is well tolerated, although thrombocytopenia can occur (usually during the second week of therapy), as can granulocytopenia.
　　Linezolid is active against both MRSA and vancomycin-resistant Enterococcus fecium. Clinical trials have been impressive with skin and soft tissue infections and with pneumonia. However, linezolid-resistant isolates of Staphylococcus and Enterococci have been reported. Caution should be used when considering the use of this drug for endocarditis since the agent is bacteriostatic, not bactericidal. Linezolid is a weak inhibitor of monoamine oxidase; thus, there are drugs that may have increased areas-under-the-curve when administered with linezolid, such as pseudoephedrine and the serotonin uptake inhibitors.
　　Quinupristin-dalfopristin was approved for use in 1999. This synergistic combination is bactericidal. This drug causes sclerosis of veins and, therefore, must be given through a central line. Its dose must be adjusted in hepatic failure. Quinupristin-dalfopristin is active against Staphylococci and Enterococcus fecium. It is important to note that it is not active against Enterococcus fecalis. This drug is well tolerated, but arthralgias and myalgias can be limiting factors in patients who are not deeply sedated. Quinupristin-dalfopristin interacts with drugs metabolized by the hepatic cytochrome p450 system.
　　What new drugs are likely to become available? There are several new drugs for Gram-positive organisms close to US Food and Drug Administration approval. These include daptomycin, oritavancin, dalbavancin, telithromycin, and ramoplanin.
　　Daptomycin is likely to be approved during the next year. This drug is rapidly bactericidal against Staphylococci, Enterococci, and Pneumococci. Daptomycin is well tolerated. With the current dosing regimen, elevations in serum muscle enzymes are uncommon. Trials looking at skin and soft tissue infections and urinary tract infections are promising.
The rising number of Gram-positive cocci that are resistant to beta lactam drugs, vancomycin, and even linezolid and quinupristin-dalfopristin raises concerns about the adequacy of our current antimicrobial armamentarium. The new agents with novel mechanisms of action will be welcome additions to our antibiotic armamentarium.
　　Dr. O'Grady concluded by lamenting the fact that the pharmaceutical industry is no longer developing new antibiotics as actively as in the past. While there is a huge clinical need for new drugs with new mechanisms of action, the financial incentives are discouraging for developing drugs that will be used for short courses rather than life long. Incentives are needed to assure our ability to have agents available that can stay ahead of the ability of pathogens to circumvent antimicrobial agents.