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SY.7.2 MIC CREEP: DOES IT EXIST?
S6
Abstracts from 12th ISCVID / International Journal of Antimicrobial Agents 41S1 (2013) S1–S34
infection control problems – into a community pathogen with all the associated problems of massive diffusion. MRSA has recently become heteroresistant to both glycopeptides (hVISA and VISA); some of them are linezolid-resistant and strains with a profile of nonsusceptibility to daptomycin are emerging in clinical practice. With regard to enterococci, many studies in recent years have indicated that nosocomial strains have acquired traits involved in resistance and virulence, rendering these strains impervious to any antibiotic therapies. In conclusion, mechanisms of resistance are becoming even more complex and require a different view in terms of approaching the problem: continuous monitoring is necessary, but also studies on interactions with hosts and multidisciplinary strategies are absolutely necessary. SY.7.2 MIC CREEP: DOES IT EXIST? I.M. Gould *. Royal Infirmary, Aberdeen, UK E-mail address: [email protected] The term MIC creep commonly refers to vancomycin mean or modal MIC elevation, within the susceptible range over a number of years, in clinical isolates of Staphylococcus aureus (meticillin susceptible – MSSA, or resistant – MRSA) in a given population. It is a widely observed and published observation all around the world, but some papers do not describe it and it seems most likely that methodology of published studies is critical as to whether it is observed. Strain or clone type may also be a critical factor. There are many technical issues to be considered in measuring vancomycin MICs. The drug has a very narrow therapeutic window and with the recent reduction in breakpoint to 2 mg/L, this is only two doubling dilutions from the wild type MIC, so there isn’t much room for experimental variation. MIC is also method dependent, with gradient tests usually yielding higher results than the commonly used microbroth dilution methods, possibly due to a better ability to detect low numbers of cells with elevated MIC as gradient methods use a higher inoculum. Elevated MIC within the susceptible range certainly seems clinically important in yielding a poorer clinical response on vancomycin treatment. This is also true when a semisynthetic penicillin is used for MSSA, which suggests more changes are occurring in these organisms than just an elevated vancomycin MIC. These issues are heightened by the narrow therapeutic window of vancomycin and its poor activity, even for fully susceptible strains. So both the technical measurement of the vancomycin MIC and its therapeutic efficacy are on a knife edge, and hence the great debate about whether MIC creep really exists. Probably the most important issues in discussion at the moment are the influence of organism storage prior to measurement of MIC, the mechanisms of a raised MIC, and are these resistance mechanisms stable on storage. I am not aware of any work on the last point, although it is well described that VISA and hVISA strains can lose their reduced susceptibility on freezing over time. The mechanisms of elevated MIC to vancomycin are complex and many but basically seem to take the form of multiple mutations, sequentially acquired as the MIC elevates until ultimately perhaps, full VISA status may be obtained. SY.7.3 COMBINATION THERAPY FOR GRAM-POSITIVES – WHAT ARE THE ADVANTAGES? B. Barˇsic´ *. School of Medicine Zagreb, Hospital for Infectious Diseases, Croatia E-mail address: [email protected] Background: Severe, life-threatening infections often urge physicians to use a combination of antibiotics in order to increase the probability of a successful outcome. A number of contemporary guidelines suggest the use of such combinations without proper evidence for its utility. The objective of this presentation is to review recent papers on the clinical utility of combined treatment for Grampositive infections. Methods: Extensive review of papers reported on PubMed. Key words used are: combined treatment, Staphylococcus, Enterococcus,
Streptococcus, gentamycin, aminoglycosides, rifampicin, endocarditis, blood stream infections. Results: In the treatment of endocarditis even the newest guidelines suggest the use of gentamicin in the treatment of staphylococcal native-valve endocarditis admitting that such a suggestion is not supported by appropriate clinical trials. In recent years there has been an increase in the amount of data suggesting that the risk of nephrotoxicity might outweigh its potential benefits. Future guidelines will probably reconsider the value of addition of gentamycin to beta-lactams or glycopeptides in the treatment of staphylococcal endocarditis. Although combined ampicillin–gentamycin treatment is strongly recommended for the treatment of enterococcal endocarditis, new studies show that a combination of ampicillin and ceftriaxone improves outcome of patients with enterococcal endocarditis compared to an ampicillin combination with aminoglycosides, particularly in patients with a high level of aminoglycoside resistance. In the treatment of viridans streptococci associated IE aminoglycosides are recommended although the only clinical trial available did not support their use. However, numerous experimental data both in vitro and in vivo justify their administration. New combinations are emerging. Tygecycline combined with rifampicin for the treatment of infections associated with biofilm formation, and daptomycin plus rifampicin in the treatment of enterococcal and staphylococcal endocarditis are challenging. Conclusion: Although a number of suggested combinations is scarcely supported by evidence from clinical trials, we may expect that the use of combinations will in increase in the future due to the emergence of new resistance problems. Session 8 – Controversies in the prophylaxis of infective endocarditis SY.8.2 INCIDENCE OF INFECTIVE ENDOCARDITIS DUE TO VIRIDANS GROUP STREPTOCOCCI BEFORE AND AFTER PREVENTION GUIDELINES CHANGES L.M. Baddour *. Mayo Clinic, Division of Infectious Diseases, Rochester, MN, USA E-mail address: [email protected] Due to recent restrictions in antibiotic administration promulgated by guidelines that address the prevention of infective endocarditis, continued monitoring of the incidence of infective endocarditis was deemed warranted at the time of publication of the restrictions. To date, four investigations from three different countries have provided data on incidence of infective endocarditis, particularly that due to viridans group streptococci. Three of the four studies were population-based and involved cohorts in the United Kingdom, France, and the United States. Findings were consistent across the four surveys; no increase in infective endocarditis due to viridans group streptococci has been demonstrated. A major limitation of these studies is the lack of verification that antibiotic administration did not occur, particularly in high-risk patients (those with prosthetic valves), despite guidelines recommendations that recommend that no prophylaxis be given in the setting of dental procedures. Continued monitoring of the incidence of infective endocarditis is being done. SY.8.4 CAN WE REDUCE THE INCIDENCE OF HEALTH-CARE ASSOCIATED IE? J.M. Miro´ *, on behalf of the Hospital Clinic Endocarditis Study Group. Infectious Diseases Service, Hospital Cl´ınic, Institut d’Investigacions Biom`ediques Pi i Sunyer, University of Barcelona, Barcelona, Spain. E-mail address: [email protected] The incidence of health-care associated (HCA) native endocarditis (IE) in the largest available study from the International Collaboration on Endocarditis including the 2000–2005 period was 34% (Benito, Ann Intern Med. 2009). HCA IE patients had mainly S. aureus infections (half of them methicillin-resistant) and greater mortality rates. Fortysix percent of HCA IE were non-nosocomial. Most recent studies point to a notable progressive increase in the proportion of HCA IE. A third
Abstracts from 12th ISCVID / International Journal of Antimicrobial Agents 41S1 (2013) S1–S34
infection control problems – into a community pathogen with all the associated problems of massive diffusion. MRSA has recently become heteroresistant to both glycopeptides (hVISA and VISA); some of them are linezolid-resistant and strains with a profile of nonsusceptibility to daptomycin are emerging in clinical practice. With regard to enterococci, many studies in recent years have indicated that nosocomial strains have acquired traits involved in resistance and virulence, rendering these strains impervious to any antibiotic therapies. In conclusion, mechanisms of resistance are becoming even more complex and require a different view in terms of approaching the problem: continuous monitoring is necessary, but also studies on interactions with hosts and multidisciplinary strategies are absolutely necessary. SY.7.2 MIC CREEP: DOES IT EXIST? I.M. Gould *. Royal Infirmary, Aberdeen, UK E-mail address: [email protected] The term MIC creep commonly refers to vancomycin mean or modal MIC elevation, within the susceptible range over a number of years, in clinical isolates of Staphylococcus aureus (meticillin susceptible – MSSA, or resistant – MRSA) in a given population. It is a widely observed and published observation all around the world, but some papers do not describe it and it seems most likely that methodology of published studies is critical as to whether it is observed. Strain or clone type may also be a critical factor. There are many technical issues to be considered in measuring vancomycin MICs. The drug has a very narrow therapeutic window and with the recent reduction in breakpoint to 2 mg/L, this is only two doubling dilutions from the wild type MIC, so there isn’t much room for experimental variation. MIC is also method dependent, with gradient tests usually yielding higher results than the commonly used microbroth dilution methods, possibly due to a better ability to detect low numbers of cells with elevated MIC as gradient methods use a higher inoculum. Elevated MIC within the susceptible range certainly seems clinically important in yielding a poorer clinical response on vancomycin treatment. This is also true when a semisynthetic penicillin is used for MSSA, which suggests more changes are occurring in these organisms than just an elevated vancomycin MIC. These issues are heightened by the narrow therapeutic window of vancomycin and its poor activity, even for fully susceptible strains. So both the technical measurement of the vancomycin MIC and its therapeutic efficacy are on a knife edge, and hence the great debate about whether MIC creep really exists. Probably the most important issues in discussion at the moment are the influence of organism storage prior to measurement of MIC, the mechanisms of a raised MIC, and are these resistance mechanisms stable on storage. I am not aware of any work on the last point, although it is well described that VISA and hVISA strains can lose their reduced susceptibility on freezing over time. The mechanisms of elevated MIC to vancomycin are complex and many but basically seem to take the form of multiple mutations, sequentially acquired as the MIC elevates until ultimately perhaps, full VISA status may be obtained. SY.7.3 COMBINATION THERAPY FOR GRAM-POSITIVES – WHAT ARE THE ADVANTAGES? B. Barˇsic´ *. School of Medicine Zagreb, Hospital for Infectious Diseases, Croatia E-mail address: [email protected] Background: Severe, life-threatening infections often urge physicians to use a combination of antibiotics in order to increase the probability of a successful outcome. A number of contemporary guidelines suggest the use of such combinations without proper evidence for its utility. The objective of this presentation is to review recent papers on the clinical utility of combined treatment for Grampositive infections. Methods: Extensive review of papers reported on PubMed. Key words used are: combined treatment, Staphylococcus, Enterococcus,
Streptococcus, gentamycin, aminoglycosides, rifampicin, endocarditis, blood stream infections. Results: In the treatment of endocarditis even the newest guidelines suggest the use of gentamicin in the treatment of staphylococcal native-valve endocarditis admitting that such a suggestion is not supported by appropriate clinical trials. In recent years there has been an increase in the amount of data suggesting that the risk of nephrotoxicity might outweigh its potential benefits. Future guidelines will probably reconsider the value of addition of gentamycin to beta-lactams or glycopeptides in the treatment of staphylococcal endocarditis. Although combined ampicillin–gentamycin treatment is strongly recommended for the treatment of enterococcal endocarditis, new studies show that a combination of ampicillin and ceftriaxone improves outcome of patients with enterococcal endocarditis compared to an ampicillin combination with aminoglycosides, particularly in patients with a high level of aminoglycoside resistance. In the treatment of viridans streptococci associated IE aminoglycosides are recommended although the only clinical trial available did not support their use. However, numerous experimental data both in vitro and in vivo justify their administration. New combinations are emerging. Tygecycline combined with rifampicin for the treatment of infections associated with biofilm formation, and daptomycin plus rifampicin in the treatment of enterococcal and staphylococcal endocarditis are challenging. Conclusion: Although a number of suggested combinations is scarcely supported by evidence from clinical trials, we may expect that the use of combinations will in increase in the future due to the emergence of new resistance problems. Session 8 – Controversies in the prophylaxis of infective endocarditis SY.8.2 INCIDENCE OF INFECTIVE ENDOCARDITIS DUE TO VIRIDANS GROUP STREPTOCOCCI BEFORE AND AFTER PREVENTION GUIDELINES CHANGES L.M. Baddour *. Mayo Clinic, Division of Infectious Diseases, Rochester, MN, USA E-mail address: [email protected] Due to recent restrictions in antibiotic administration promulgated by guidelines that address the prevention of infective endocarditis, continued monitoring of the incidence of infective endocarditis was deemed warranted at the time of publication of the restrictions. To date, four investigations from three different countries have provided data on incidence of infective endocarditis, particularly that due to viridans group streptococci. Three of the four studies were population-based and involved cohorts in the United Kingdom, France, and the United States. Findings were consistent across the four surveys; no increase in infective endocarditis due to viridans group streptococci has been demonstrated. A major limitation of these studies is the lack of verification that antibiotic administration did not occur, particularly in high-risk patients (those with prosthetic valves), despite guidelines recommendations that recommend that no prophylaxis be given in the setting of dental procedures. Continued monitoring of the incidence of infective endocarditis is being done. SY.8.4 CAN WE REDUCE THE INCIDENCE OF HEALTH-CARE ASSOCIATED IE? J.M. Miro´ *, on behalf of the Hospital Clinic Endocarditis Study Group. Infectious Diseases Service, Hospital Cl´ınic, Institut d’Investigacions Biom`ediques Pi i Sunyer, University of Barcelona, Barcelona, Spain. E-mail address: [email protected] The incidence of health-care associated (HCA) native endocarditis (IE) in the largest available study from the International Collaboration on Endocarditis including the 2000–2005 period was 34% (Benito, Ann Intern Med. 2009). HCA IE patients had mainly S. aureus infections (half of them methicillin-resistant) and greater mortality rates. Fortysix percent of HCA IE were non-nosocomial. Most recent studies point to a notable progressive increase in the proportion of HCA IE. A third