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S48 Recent discoveries in prevention of pneumococcal disease
Pathogenesis and epidemiology of invasive pneumococcal infections options include older agents, such as clindamycin, trimethoprimsulfamethoxazole, tetracyclines, and rifampin, and newer agents such as linezolid. In addition, new agents are in development.
Pathogenesis and epidemiology of invasive pneumococcal infections S45 Recent discoveries in the pathogenesis of pneumococcal pneumonia D.H. Dockrell (Sheffield, UK) Pneumococcal pneumonia is a pathogen of global significance and represents a leading cause of infection-related mortality at all ages. Recent developments in the field of pneumococcal pathogenesis reflect significant developments in both genomics and proteomics. The breadth of microbial genetic diversity is increasingly being recognized. Our understanding of the importance of traditional virulence factors such as polysaccharide capsule, pneumolysin and generation of hydrogen peroxide is evolving while important roles for factors such as pneumococcal pili are emerging. Genetic screens are identifying increasing roles for previously poorly characterised proteins involved in metabolism and transport of key molecules. The importance of the physical state of the bacteria in different tissue compartments is also becoming evident. An improved range of models of various aspects of infection ranging from colonisation and sub-clinical infection to fulminant pneumonia and invasive disease are allowing assessment of both microbial and host factors central to disease pathogenesis. The range of receptors involved in the innate response to pneumococci in the respiratory tract is starting to be appreciated and includes Tolllike receptors and receptors primarily involved in the phagocytosis of bacteria. The interaction between soluble factors and the resident phagocytes of the lung is being clarified and the complexity of cytokine networks involved in the innate host response is being elucidated. Important roles for T-lymphocytes, Natural Killer cells and dendritic cells in the response to pneumococci are being identified. Furthermore our understanding of the regulation of the inflammatory response and of the significant role of apoptosis in the regulation of the inflammatory response has lead to important insights into how cell survival and outcome of infection are closely linked. These observations are enabling a more scientific interpretation of many of the central clinical features of pneumococcal pneumonia and may encourage novel approaches to therapy to improve disease responses. S46 Invasive disease potential of pneumococcal clones carried by children H. de Lencastre, R. S´a-Le˜ao, M. Ramirez, J. Melo-Cristino (Oeiras, Lisbon, PT) Streptococcus pneumoniae (the pneumococcus) continues to be a leading cause of morbidity and mortality worldwide particularly among young children, the elderly and the immunocompromised of all ages. Infection is preceded by colonisation of the nasopharynx, which is the ecological niche of pneumococci. In most individuals colonisation is asymptomatic and does not evolve to disease. The carrier state is more frequent in young children and may reach over 70% in some populations such as those attending day-care centres. Indeed, this latter group has been found to be a major reservoir of pneumococci playing a key role on the amplification and transmission of the bacteria to other individuals. Of interest, several drug-resistant clones internationally disseminated have been found to be frequently carried by this population. In recent years, there has been some debate on the relative contribution of serotype and genetic background to the invasive disease potential of pneumococcal strains. We will present a study that addresses this question. The study was conducted in Portugal and results from the detailed comparison of two large collections of pneumococcal isolates: a group of over 450 invasive disease isolates and a group of over 750 colonisation isolates
S11 collected during the same time period which were characterised in detail by antibiogram, serotype, PFGE macro-restriction profiles, and multilocus sequence typing. The invasive disease potential of serotypes and clones will be discussed. S47 Epidemiology of invasive pneumococcal infections A. Brueggemann (Oxford, UK) Pneumococci cause a spectrum of diseases in humans, from reasonably mild diseases like sinusitis and conjunctivitis to potentially lifethreatening diseases like meningitis and bacteraemia. The current conjugate vaccines are ideally aimed at protecting against all pneumococcal disease, but have been very successful at preventing invasive pneumococcal disease. Understanding invasive disease epidemiology, both preceding vaccine implementation and after vaccine introduction, is crucial to the design and development of future vaccines. Several recent studies have shown that pneumococcal serotypes differ in their invasive disease potential, and this has particular relevance for the selection of serotypes to include in future conjugate vaccines. It is also essential to understand the serotype-specific changes that have occurred subsequent to conjugate vaccine implementation in the USA, as a model for what might occur post-vaccine implementation in other countries. S48 Recent discoveries in prevention of pneumococcal disease K. Klugman (Atlanta, US) The recent history of pneumococcal disease prevention is dominated by the development in the 1990’s of conjugate pneumococcal vaccine for administration to infants, and its implementation starting in 2000 in the USA. The vaccine as currently formulated affords protection against invasive pneumococcal disease (IPD) due to the 7 most common serotypes causing IPD among children less than 2 years of age prior to vaccine introduction in the USA. This formulation is not optimal for many developing countries where serotypes such as 1 and 5 are important. Global, second generation vaccines therefore include at least 10 serotypes. The importance of prevention of pneumococcal disease extends beyond IPD to pneumonia, meningitis, otitis media, prevention of antibiotic-resistant infections, and even prevention of mortality in young infants. Each of these presents specific challenges. The vaccine has been shown to prevent between 25% and 37% of all cause X-ray confirmed pneumonias and this implies a level of protection against pneumococcal pneumonia due to vaccine serotypes in excess of 70%. This reduction in pneumonia has translated into a reduction in allcause mortality due to the vaccine of 16% in rural Africa. The major preventable burden of disease in Africa may be among HIV infected children where the vaccine has also been shown to reduce pneumonia burden. An innovative aspect of the vaccine is the fact that it may reduce the pneumococcal super infections that follow viral respiratory infections, such as influenza, and conjugate vaccination of children may thus be a useful adjunct to pandemic influenza planning preparedness. The interruption of carriage of vaccine serotypes has been shown to reduce IPD in adults in the USA due to herd immunity so the population benefit in an influenza pandemic may extend beyond protection just of immunised children. Herd immunity has also recently been shown to protect young un-immunised infants from IPD. Conjugate vaccine has had little impact on all cause otitis media in randomised trials, but post-marketing studies in the USA suggest that healthcare utilisation for otitis episodes has reduced significantly post vaccine introduction suggesting a major role for herd immunity and allowing physicians to feel more comfortable in a “wait and see” attitude to otitis once the prospects of significant complications due to the pneumococcus are likely to be rare. The conjugation of pneumococcal polysaccharides to Haemophilus influenzae protein D has allowed the development of a more efficacious vaccine against otitis media. There has been a dramatic reduction in antibiotic resistance among vaccine serotypes causing IPD in the USA, in both children and adults, but resistance, driven by continuing high levels of antibiotic use, is now selecting resistance in non-vaccine
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
Pathogenesis and epidemiology of invasive pneumococcal infections S45 Recent discoveries in the pathogenesis of pneumococcal pneumonia D.H. Dockrell (Sheffield, UK) Pneumococcal pneumonia is a pathogen of global significance and represents a leading cause of infection-related mortality at all ages. Recent developments in the field of pneumococcal pathogenesis reflect significant developments in both genomics and proteomics. The breadth of microbial genetic diversity is increasingly being recognized. Our understanding of the importance of traditional virulence factors such as polysaccharide capsule, pneumolysin and generation of hydrogen peroxide is evolving while important roles for factors such as pneumococcal pili are emerging. Genetic screens are identifying increasing roles for previously poorly characterised proteins involved in metabolism and transport of key molecules. The importance of the physical state of the bacteria in different tissue compartments is also becoming evident. An improved range of models of various aspects of infection ranging from colonisation and sub-clinical infection to fulminant pneumonia and invasive disease are allowing assessment of both microbial and host factors central to disease pathogenesis. The range of receptors involved in the innate response to pneumococci in the respiratory tract is starting to be appreciated and includes Tolllike receptors and receptors primarily involved in the phagocytosis of bacteria. The interaction between soluble factors and the resident phagocytes of the lung is being clarified and the complexity of cytokine networks involved in the innate host response is being elucidated. Important roles for T-lymphocytes, Natural Killer cells and dendritic cells in the response to pneumococci are being identified. Furthermore our understanding of the regulation of the inflammatory response and of the significant role of apoptosis in the regulation of the inflammatory response has lead to important insights into how cell survival and outcome of infection are closely linked. These observations are enabling a more scientific interpretation of many of the central clinical features of pneumococcal pneumonia and may encourage novel approaches to therapy to improve disease responses. S46 Invasive disease potential of pneumococcal clones carried by children H. de Lencastre, R. S´a-Le˜ao, M. Ramirez, J. Melo-Cristino (Oeiras, Lisbon, PT) Streptococcus pneumoniae (the pneumococcus) continues to be a leading cause of morbidity and mortality worldwide particularly among young children, the elderly and the immunocompromised of all ages. Infection is preceded by colonisation of the nasopharynx, which is the ecological niche of pneumococci. In most individuals colonisation is asymptomatic and does not evolve to disease. The carrier state is more frequent in young children and may reach over 70% in some populations such as those attending day-care centres. Indeed, this latter group has been found to be a major reservoir of pneumococci playing a key role on the amplification and transmission of the bacteria to other individuals. Of interest, several drug-resistant clones internationally disseminated have been found to be frequently carried by this population. In recent years, there has been some debate on the relative contribution of serotype and genetic background to the invasive disease potential of pneumococcal strains. We will present a study that addresses this question. The study was conducted in Portugal and results from the detailed comparison of two large collections of pneumococcal isolates: a group of over 450 invasive disease isolates and a group of over 750 colonisation isolates
S11 collected during the same time period which were characterised in detail by antibiogram, serotype, PFGE macro-restriction profiles, and multilocus sequence typing. The invasive disease potential of serotypes and clones will be discussed. S47 Epidemiology of invasive pneumococcal infections A. Brueggemann (Oxford, UK) Pneumococci cause a spectrum of diseases in humans, from reasonably mild diseases like sinusitis and conjunctivitis to potentially lifethreatening diseases like meningitis and bacteraemia. The current conjugate vaccines are ideally aimed at protecting against all pneumococcal disease, but have been very successful at preventing invasive pneumococcal disease. Understanding invasive disease epidemiology, both preceding vaccine implementation and after vaccine introduction, is crucial to the design and development of future vaccines. Several recent studies have shown that pneumococcal serotypes differ in their invasive disease potential, and this has particular relevance for the selection of serotypes to include in future conjugate vaccines. It is also essential to understand the serotype-specific changes that have occurred subsequent to conjugate vaccine implementation in the USA, as a model for what might occur post-vaccine implementation in other countries. S48 Recent discoveries in prevention of pneumococcal disease K. Klugman (Atlanta, US) The recent history of pneumococcal disease prevention is dominated by the development in the 1990’s of conjugate pneumococcal vaccine for administration to infants, and its implementation starting in 2000 in the USA. The vaccine as currently formulated affords protection against invasive pneumococcal disease (IPD) due to the 7 most common serotypes causing IPD among children less than 2 years of age prior to vaccine introduction in the USA. This formulation is not optimal for many developing countries where serotypes such as 1 and 5 are important. Global, second generation vaccines therefore include at least 10 serotypes. The importance of prevention of pneumococcal disease extends beyond IPD to pneumonia, meningitis, otitis media, prevention of antibiotic-resistant infections, and even prevention of mortality in young infants. Each of these presents specific challenges. The vaccine has been shown to prevent between 25% and 37% of all cause X-ray confirmed pneumonias and this implies a level of protection against pneumococcal pneumonia due to vaccine serotypes in excess of 70%. This reduction in pneumonia has translated into a reduction in allcause mortality due to the vaccine of 16% in rural Africa. The major preventable burden of disease in Africa may be among HIV infected children where the vaccine has also been shown to reduce pneumonia burden. An innovative aspect of the vaccine is the fact that it may reduce the pneumococcal super infections that follow viral respiratory infections, such as influenza, and conjugate vaccination of children may thus be a useful adjunct to pandemic influenza planning preparedness. The interruption of carriage of vaccine serotypes has been shown to reduce IPD in adults in the USA due to herd immunity so the population benefit in an influenza pandemic may extend beyond protection just of immunised children. Herd immunity has also recently been shown to protect young un-immunised infants from IPD. Conjugate vaccine has had little impact on all cause otitis media in randomised trials, but post-marketing studies in the USA suggest that healthcare utilisation for otitis episodes has reduced significantly post vaccine introduction suggesting a major role for herd immunity and allowing physicians to feel more comfortable in a “wait and see” attitude to otitis once the prospects of significant complications due to the pneumococcus are likely to be rare. The conjugation of pneumococcal polysaccharides to Haemophilus influenzae protein D has allowed the development of a more efficacious vaccine against otitis media. There has been a dramatic reduction in antibiotic resistance among vaccine serotypes causing IPD in the USA, in both children and adults, but resistance, driven by continuing high levels of antibiotic use, is now selecting resistance in non-vaccine
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