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S54 Parenteral colistin: finally a useful drug?
S12 serotypes. In particular, multiresistant global clones of serotype 19A are now dominant in the USA and a 13-valent vaccine formulation including serotype 19A is under development. The implementation of immunisation programmes including conjugate pneumococcal vaccine to infants in European countries affords the opportunity to monitor the impact on all of these health outcomes in both children and adults.
Infective endocarditis – time for change? S50 Treatment options for infective endocarditis: new drugs for bad bugs? R. Corey (Durham, US) In the USA infections due to both hospital and community-acquired methicillin resistant Staphylococcus aureus (MRSA) are increasing rapidly in both frequency and severity. As a result new treatment options are badly needed. This presentation will first address the role of traditional therapy focusing on the gradual development of increasing resistance to vancomycin among MRSA. Next it will focus on alternative oral therapies such as clindamycin, cotrimoxazole and minocycline and their role in the treatment of community-acquired MRSA, an organism that has displaced “traditional” MRSA in many venues. The efficacy of the newly approved antibiotics linezolid, daptomycin, and tigecycline will be addressed through the presentation of the results of large phase 3 clinical trials in complicated skin and skin structure infections, hospital-acquired pneumonia, and bacteraemia. Discussion will focus on the efficacy of these agents in the MRSA subgroups. Finally, the efficacy of antibiotics in development will be presented again focusing on the MRSA subgroups from phase 2 and 3 studies. These antibiotics will include dalbavancin, telavancin, oritavancin, iclaprim, ceftobiprole and ceftaroline. As the epidemiology of staphylococcal infections changes new therapeutic agents are becoming available to clinicians. Therapeutic utility will depend on understanding the unique characteristics and efficacy of the new agents in clinical trials in order to clearly understand their role in the new therapeutic paradigms.
New tricks for old drugs S53 Recent and emerging uses of long-acting tetracyclines H.M. Lode (Berlin, DE) Antimicrobial resistance is a serious problem with increasing strains of bacteria becoming resistant to many or all available antibiotics. Tetracyclines were already introduced 50 years ago but have undergone a considerable resistance development in nosocomial and communityacquired pathogens. In June 2005, a minocycline derivative, the new glycylcycline antimicrobial tygecycline, was approved by the FDA for treatment of complicated intra-abdominal and complicated skin and skinstructure infections. Tigecycline, a bacteriostatic agent, binds to the 30S ribosome unit, blocks entry of amino-acyl tRNA molecules, and prevents protein synthesis; it has a broad antibacterial spectrum with activity against Gram-positive and Gram-negative pathogens, including multidrug-resistant organisms and anaerobes. The modification of the basic tetracycline molecule has overcome the two resistance mechanisms seen with tetracyclines (efflux, ribosome protection). Tigecycline exhibits linear pharmacokinetics, has a long half-life (24−48 hours), is highly protein bound (71−89%), and has a large volume of distribution (7−9 L/kg). Tigecycline is not extensively metabolised; the primary route of elimination is biliary excretion (59%) and 33% is excreted unchanged in urine. The recommended dosing regimen is an initial dose of 100 mg, followed by 50 mg every 12 hours. Time above MIC and AUC/MIC ratio are the most important pharmacodynamic parameters. In two double-blind studies the safety and efficacy of tigecycline versus aztreonam plus vancomycin were compared in hospitalised adults with
17th ECCMID / 25th ICC, Oral presentations complicated skin and skin-structure infections. Over 1000 patients were randomised and the results of the pooled analysis determined that tigecycline monotherapy was as effective and statistically non-inferior to aztreonam plus vancomycin. Two double-blind studies including more than 1000 patients analysed safety and efficacy of tigecycline versus imipenem/cilastatin in adults with complicated intra-abdominal infections. Results of the pooled analysis determined that tigecycline was efficacious and statistically noninferior to imipenem. Nausea (20−30%) and vomiting (15−20%) are the most common adverse effects observed in clinical trials. They usually occur within the first two days of therapy, are more common in women (48%) than in men (24%), and may also be age related. Tigecycline is an important addition to the antimicrobial armentarium. It has a broad spectrum of activity and its ability to evade numerous mechanisms of resistance makes it a promising solution to the treatment of multi-drug resistant organisms. This is very helpful in selected patients in the ICU. S54 Parenteral colistin: finally a useful drug? F. Jacobs (Brussels, BE) The increasing resistance of Gram-negative bacteria and particularly amongst Pseudomonas aeruginosa and Acinetobacter baumannii, raises a major therapeutic problem. The lack of new effective agents in the near future has revived interest in the re-use of some molecules, abandoned because of their toxicities. Colistin (colistimethate sodium) is a polymyxin antibiotic available in parenteral formulation and used for intravenous, aerosolised and intrathecal/intraventricular administration. The bactericidal activity of colistin is due to a detergent effect on the cell membrane and therefore not dependent upon bacterial metabolic activity. Because this drug was developed during the 1950s, only little pharmacokinetic and pharmacodynamic information are available and the optimal daily dose for severely ill patients is still unknown. Colistin, used both intravenously and by inhalation, was used until last decade mainly in cystic fibrosis patients. Recently, colistin has been used in non cystic fibrosis patients as a salvage therapy for the treatment of infections with Gram-negative bacteria resistant to all other antibiotics. Clinical reports on the efficacy of intravenous colistin in these patients are not randomised studies and in most of them, colistin was frequently associated with other antimicrobial agents with a lack of a control group. A good outcome occurred in most infections (52−75%) but with the poorest results observed in pneumonia (25%). In vitro studies have shown synergistic effect between colistin and rifampin but no clinical study has been designed to confirm this synergy. Nephrotoxicity and neurotoxicity are the most common toxicities of colistin. However recent studies demonstrated a reduced toxicity as compared with previous studies, even if a higher dosage is used. This low renal toxicity rate was observed in both critically ill patients and patients treated with prolonged courses of colistin. There are also recent clinical reports on the use of colistin in continuous intravenous infusion to minimise potential toxicity. This reduction of toxicity without impairment of efficacy (concentration-dependent killing in in-vitro timekill studies) should be confirmed by further studies. Neurotoxicity has also been more frequently reported in case of renal dysfunction. Development of resistance to colistin is a major problem, especially in A. baumannii. This highlights the urgent need to preserve this molecule by the best appropriate dose regimen and by an optimal synergistic combination with other antibiotics. S55 Facts and myths about fosfomycin F. Gudiol (Barcelona, ES) Fosfomycin is a phosphonic broad spectrum antibiotic discovered in Spain in 1969, licensed in many countries since then, but used only sporadically in the clinical setting. In fact, It is not mentioned specifically in the current editions of the most prestigious textbooks of internal
Infective endocarditis – time for change? S50 Treatment options for infective endocarditis: new drugs for bad bugs? R. Corey (Durham, US) In the USA infections due to both hospital and community-acquired methicillin resistant Staphylococcus aureus (MRSA) are increasing rapidly in both frequency and severity. As a result new treatment options are badly needed. This presentation will first address the role of traditional therapy focusing on the gradual development of increasing resistance to vancomycin among MRSA. Next it will focus on alternative oral therapies such as clindamycin, cotrimoxazole and minocycline and their role in the treatment of community-acquired MRSA, an organism that has displaced “traditional” MRSA in many venues. The efficacy of the newly approved antibiotics linezolid, daptomycin, and tigecycline will be addressed through the presentation of the results of large phase 3 clinical trials in complicated skin and skin structure infections, hospital-acquired pneumonia, and bacteraemia. Discussion will focus on the efficacy of these agents in the MRSA subgroups. Finally, the efficacy of antibiotics in development will be presented again focusing on the MRSA subgroups from phase 2 and 3 studies. These antibiotics will include dalbavancin, telavancin, oritavancin, iclaprim, ceftobiprole and ceftaroline. As the epidemiology of staphylococcal infections changes new therapeutic agents are becoming available to clinicians. Therapeutic utility will depend on understanding the unique characteristics and efficacy of the new agents in clinical trials in order to clearly understand their role in the new therapeutic paradigms.
New tricks for old drugs S53 Recent and emerging uses of long-acting tetracyclines H.M. Lode (Berlin, DE) Antimicrobial resistance is a serious problem with increasing strains of bacteria becoming resistant to many or all available antibiotics. Tetracyclines were already introduced 50 years ago but have undergone a considerable resistance development in nosocomial and communityacquired pathogens. In June 2005, a minocycline derivative, the new glycylcycline antimicrobial tygecycline, was approved by the FDA for treatment of complicated intra-abdominal and complicated skin and skinstructure infections. Tigecycline, a bacteriostatic agent, binds to the 30S ribosome unit, blocks entry of amino-acyl tRNA molecules, and prevents protein synthesis; it has a broad antibacterial spectrum with activity against Gram-positive and Gram-negative pathogens, including multidrug-resistant organisms and anaerobes. The modification of the basic tetracycline molecule has overcome the two resistance mechanisms seen with tetracyclines (efflux, ribosome protection). Tigecycline exhibits linear pharmacokinetics, has a long half-life (24−48 hours), is highly protein bound (71−89%), and has a large volume of distribution (7−9 L/kg). Tigecycline is not extensively metabolised; the primary route of elimination is biliary excretion (59%) and 33% is excreted unchanged in urine. The recommended dosing regimen is an initial dose of 100 mg, followed by 50 mg every 12 hours. Time above MIC and AUC/MIC ratio are the most important pharmacodynamic parameters. In two double-blind studies the safety and efficacy of tigecycline versus aztreonam plus vancomycin were compared in hospitalised adults with
17th ECCMID / 25th ICC, Oral presentations complicated skin and skin-structure infections. Over 1000 patients were randomised and the results of the pooled analysis determined that tigecycline monotherapy was as effective and statistically non-inferior to aztreonam plus vancomycin. Two double-blind studies including more than 1000 patients analysed safety and efficacy of tigecycline versus imipenem/cilastatin in adults with complicated intra-abdominal infections. Results of the pooled analysis determined that tigecycline was efficacious and statistically noninferior to imipenem. Nausea (20−30%) and vomiting (15−20%) are the most common adverse effects observed in clinical trials. They usually occur within the first two days of therapy, are more common in women (48%) than in men (24%), and may also be age related. Tigecycline is an important addition to the antimicrobial armentarium. It has a broad spectrum of activity and its ability to evade numerous mechanisms of resistance makes it a promising solution to the treatment of multi-drug resistant organisms. This is very helpful in selected patients in the ICU. S54 Parenteral colistin: finally a useful drug? F. Jacobs (Brussels, BE) The increasing resistance of Gram-negative bacteria and particularly amongst Pseudomonas aeruginosa and Acinetobacter baumannii, raises a major therapeutic problem. The lack of new effective agents in the near future has revived interest in the re-use of some molecules, abandoned because of their toxicities. Colistin (colistimethate sodium) is a polymyxin antibiotic available in parenteral formulation and used for intravenous, aerosolised and intrathecal/intraventricular administration. The bactericidal activity of colistin is due to a detergent effect on the cell membrane and therefore not dependent upon bacterial metabolic activity. Because this drug was developed during the 1950s, only little pharmacokinetic and pharmacodynamic information are available and the optimal daily dose for severely ill patients is still unknown. Colistin, used both intravenously and by inhalation, was used until last decade mainly in cystic fibrosis patients. Recently, colistin has been used in non cystic fibrosis patients as a salvage therapy for the treatment of infections with Gram-negative bacteria resistant to all other antibiotics. Clinical reports on the efficacy of intravenous colistin in these patients are not randomised studies and in most of them, colistin was frequently associated with other antimicrobial agents with a lack of a control group. A good outcome occurred in most infections (52−75%) but with the poorest results observed in pneumonia (25%). In vitro studies have shown synergistic effect between colistin and rifampin but no clinical study has been designed to confirm this synergy. Nephrotoxicity and neurotoxicity are the most common toxicities of colistin. However recent studies demonstrated a reduced toxicity as compared with previous studies, even if a higher dosage is used. This low renal toxicity rate was observed in both critically ill patients and patients treated with prolonged courses of colistin. There are also recent clinical reports on the use of colistin in continuous intravenous infusion to minimise potential toxicity. This reduction of toxicity without impairment of efficacy (concentration-dependent killing in in-vitro timekill studies) should be confirmed by further studies. Neurotoxicity has also been more frequently reported in case of renal dysfunction. Development of resistance to colistin is a major problem, especially in A. baumannii. This highlights the urgent need to preserve this molecule by the best appropriate dose regimen and by an optimal synergistic combination with other antibiotics. S55 Facts and myths about fosfomycin F. Gudiol (Barcelona, ES) Fosfomycin is a phosphonic broad spectrum antibiotic discovered in Spain in 1969, licensed in many countries since then, but used only sporadically in the clinical setting. In fact, It is not mentioned specifically in the current editions of the most prestigious textbooks of internal