Foreword
Bad Bugs, No Drugs: Are We Part of the Problem, or Leaders in Developing Solutions? Brooke Decker, MD University of Pittsburgh Henry Masur, MD NIH-Clinical Center
A
s critical care professionals, we are acutely aware of the challenges that infectious diseases present to our patients. In the current era, 21% of patients entering the ICU have an infectious disease as their primary reason for admission and 10% of initially non-infected patients will develop an infection after 24 hours of intensive care (1). The rate of infection for patients in intensive care for more than 7 days may be as high as 70%. At any point in time, 51% of ICU patients are considered to be infected and 71% are receiving antibiotics (2). Thus, preventing and managing infections is part of the everyday challenge for all critical care professionals. A disturbing trend that virtually all ICUs are encountering is the increasing fraction of infections caused by organisms that are resistant to some, many, or all of our currently available antimicrobial agents. This abundance of extremely resistant pathogens is not theoretical, and is not a problem solely in “someone else’s ICU.” Most of us deal regularly with cases or outbreaks of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and multidrug-resistant Pseudomonas, Acinetobacter, Burkholderia, Serratia, and Stenotrophomonas. Azole-resistant Candida and acyclovir-resistant herpes simplex virus are increasingly common. Recently, the University of California, Los Angeles (UCLA) has experienced an outbreak of carbapenem-resistant Enterobacteriaceae (CRE), transmitted via incompletely cleaned duodenoscope channels (3). Other major medical centers have reported CRE outbreaks, for example, in Charlottesville (4), Denver (5), Chicago (6), and at the National Institutes of Health (NIH)-Clinical Center (7). As of February 2015, the Centers for Disease Control map of CRE epidemiology shows that 48 states have reported CRE isolates, excluding only Idaho and Maine (http://www.cdc.gov/hai/organisms/cre/ TrackingCRE.html, accessed March 11, 2015). The percentage of hospitals reporting a CRE hospital-associated infection increased from 1.2% in 2001 to 4.6% in 2012 (8). Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000001039
Critical Care Medicine
Either infection with CRE or mere colonization with CRE is associated with an increased risk of death and increased length of hospital stay (9). CRE also increase overall hospital costs. CRE infections are examples of microbial diseases due to highly resistant pathogens which elicit substantial consequences from regulatory bodies and payers. As UCLA and the NIH-Clinical Center have learned, such outbreaks can also provoke unfavorable media attention that can substantially erode the community goodwill and the market place dynamics that medical centers appropriately acquire over years of good work. Ironically, this attention is often the result of dutiful investigation and reporting as well as responsible acceptance of complicated inter-hospital transfers rather than poor performance. What more can we as critical care professionals do to protect our patients from the morbidity of highly resistant pathogens under “our watch”? While the hospital epidemiologists and infectious disease practitioners have special expertise and acknowledged accomplishments in the prevention and management of such infections, the critical care team has the most influence on the conduct and performance of medical care in the ICU. If a medical facility is to reduce the impact of such pathogens in the ICU, the leadership needs to come from the critical care team. We set the tone and influence practice far more than hand hygiene monitors, antibiotic review programs, or front office “carrot and stick” policies. There are three major areas to focus on: infection prevention, antibiotic stewardship, and public policy. Infection Prevention Intensivists are best positioned to improve ICU performance in measures of infection prevention. Although it may be preferable to blame the environment rather than ourselves, the hands of healthcare providers are the usual vehicle of travel when resistant organisms are transmitted between patients (10). Transmission risk is magnified in the ICU compared with other healthcare settings because an average ICU patient has been estimated to receive 178 interactions with providers daily (11). Despite data showing greater efficacy reducing transmission with improvements in hand hygiene as compared with other prevention measures (12), hand hygiene rates in the ICU are reprehensibly poor, with a median compliance between 30% to 40% (13). Scrupulous adherence to hand hygiene is critical as every interaction is a potential source of transmission. As leaders in the critical care community, we must demand adherence to hand hygiene policy and we must set the standard with uniform adherence to policies. Measuring adherence, initiating www.ccmjournal.org
Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
1153
Foreword
programs to educate staff, and developing and enforcing consequences for missed hygiene opportunities should be the responsibility of critical care medicine leadership, and not left solely to hospital epidemiologists and administrators. Should our ICUs begin screening patients or staff for highly resistant pathogens, and if so, how should they be screened, how often should they be screened, and what should we do with the data we collect? The issue of screening patients or staff is in flux: we need to be sure that if we institute this plausible approach, we have data to demonstrate conclusively that effective interventions will result and that the cost and staff disruptions that occur will be justified. There is little consensus as to when screening improves outcomes. Patients known to harbor resistant organisms are frequently identified and separated by additional distance and protective equipment. Nasal or perirectal cultures can identify many more asymptomatically colonized patients, over and above patients identified by clinically indicated cultures, who can still act as reservoirs of transmission (7). Identification of silent carriers may be relevant to their own care, and will allow isolation measures to be augmented. In the setting of ongoing transmission, or an outbreak, intensivists should collaborate with hospital epidemiology to develop a rational strategy of active surveillance such as universal patient screening for MRSA, VRE, or CRE that fits the patient population and microbial epidemiology in their facility. However, one strategy does not fit all facilities. Rapid recognition and response to highly resistant pathogens may reduce the number of patients exposed, saving lives, but we need more studies to prove that such measures consistently improve measurable outcomes. Antibiotic Stewardship We all know the basic principles of antibiotic stewardship: avoid unnecessary antibiotics and limit the duration of empirical antibiotic therapy and prophylaxis to “what is necessary.” While such platitudes make for good rhetoric, can we institute quality improvement projects that accomplish specific goals with measurable and worthwhile outcomes? Critical care units have published dramatic examples of how they have reduced antibiotic exposure for their patients, reduced the incidence of Clostridium difficile infections (14), reduced the incidence of highly resistant infections, all while shortening length of stay and reducing nosocomial infection rates (15−17). However, other such studies have also been completed without affecting duration of stay, or mortality (16, 18). Proving that such interventions reduce the development of resistance or improve clinical outcome has been difficult given the superimposition of antibiotic policies in hospital units outside the ICU. Programs that reduce antibiotic use will reduce costs, toxicities, and drug-drug interactions related to antibiotics, but we need to measure the results of our policies to be sure that our efforts yield desired, quantifiable endpoints. Opportunities to reduce antibiotic use in the ICU abound. Examples include: reducing perioperative prophylaxis to guideline-specified regimens, narrowing antimicrobials once an organism is identified or after 48 hours, eliminating the use of combination regimens for definitive therapy (as opposed to initial empirical regimens), and limiting excessive antibiotic 1154
www.ccmjournal.org
duration. For example, consensus recommendations on perioperative prophylaxis recommend limiting antibiotics to a single dose or 24 hours for most surgeries (48 hours in the setting of sternotomy) (19). Blood cultures, as another example, now have a median time to positivity of 13.7 hours and a negative predictive value of 99.8 at 48 hours, and may be appropriate for rapid molecular screening for resistance mutations, thus permitting faster antimicrobial deescalation than was feasible in an earlier era of clinical microbiology (20). Limiting antibiotic duration may be complicated by senior leadership who may have trained in an era when 10−14 or 10−21 days regimens were routine (21), and who have not adapted to newer evidence (22). Public Policy Following a call for antimicrobial drug development incentives in 2004, the Infectious Diseases Society of America released in 2009 their seminal treatise “Bad Bugs, No drugs: No ESKAPE” illustrating the continued lack of new antimicrobial agents for resistant organism (23, 24). Pharmaceutical companies have little incentive to develop new antibiotics given the regulatory difficulty of getting such drugs approved, and the slim profit margins for such drugs compared to other endeavors which promise life-long regimens for large groups of individuals. Six years after the 2009 report, only the “S” in ESKAPE has seen new drugs. For MRSA, the Food and Drug Administration (FDA) approved telavancin in 2009; ceftaroline in 2010; and dalbavancin, oritavancin, and tedizolid in 2014. Clinical data indicating whether these agents are effective against VRE are lacking. Ceftolozane/tazobactam, approved in 2014, targets Gramnegative bacteria. Unfortunately ceftolozone/tazobactam, while useful against many highly resistant Gram-negative bacilli has no activity against CRE. The eagerly awaited ceftazidime/avibactam (approved by the FDA in 2015) has activity against KPC-producing CRE, but may be less effective against NDM-1 producers (25), ineffective against CRE (26), and effluxed by archived clinical strains of Pseudomonas (27). Lacking other options, clinicians have turned back to the polymixins. Prescriptions for colistin have nearly tripled in the last decade (28), mirroring the tripling of acute care hospitals reporting a CRE hospital-associated infection (8). It is a sad state of modern medicine that we must turn to relatively ineffective and toxic drugs such as tigecycline and colistin, discarded for other indications, in our search for regimens effective against these highly resistant organisms. It is our responsibility as critical care professionals to support and to lead efforts that influence public policy to the benefit of our patients. We should be proud of the contributions of our society, The Society of Critical Care Medicine, with other organizations such as the Infectious Diseases Society of America, in bringing the reality of antibiotic-resistant pathogens to the forefront of policy and funding decisions for federal and state authorities and by other funding organizations. We need to be willing to have our professional societies expend funds on lobbying and other public awareness programs. Initiatives such as providing incentives to pharmaceutical companies to respond to vitally needed but not very profitable opportunities may help refill the antibiotic June 2015 • Volume 43 • Number 6
Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Foreword
pipeline. Professional societies have previously encouraged the authorization of tax or patent incentives to stimulate the interest of small and large pharmaceutical companies in reentering the market for developing new antimicrobials (24). We desperately need more ideas, and more funding, to revitalize our discovery and development of preventive and therapeutic strategies that will reduce the impact of highly resistant pathogens on our patients. The release in March 2015 of the White House’s “National Action Plan for Combating Antibiotic-Resistant Bacteria” offers hope that more Federal funding will be available for research and implementation of strategies to reduce morbidity due to highly resistant pathogens including MRSA, CRE, and extended spectrum beta-lactamase-producing organisms (https://www. whitehouse.gov/sites/default/files/docs/national_action_plan_ for_combating_antibotic-resistant_bacteria.pdf). This plan has five major goals: 1) to slow the mergence of resistant bacteria; 2) to strengthen national surveillance; 3) to advance the development and use of rapid diagnostic tests; 4) to accelerate research; and 5) to improve international collaboration. Most of us are already facing the threat of “superbugs” in our ICUs. As intensivists, we cannot simply look to our colleagues in infectious disease and hospital epidemiology to “fix” these problems. We alone have the credibility to affect cultural changes in our ICU team. We all must make certain that we invest in hospital surveillance programs, in local and national epidemiologic monitoring and in sound scientific research to develop better strategies for both prevention and management. We need to make certain that we act based on knowledge and that we promptly introduce into our practices sound initiatives that have been proven to provide our patients with better outcomes using clinically meaningful endpoints. There is much to be done!
References
1. Alberti C, Brun-Buisson C, Burchardi H, et al: Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study. Intensive Care Med 2002; 28(2):108–121 2. Vincent JL, Rello J, Marshall J, et al: International study of the prevalence and outcomes of infection in intensive care units. JAMA 2009;302(21):2323−2329 3. Centers for Disease Control and Prevention (CDC): CDC Statement: Los Angeles County/UCLA investigation of CRE transmission and duodenoscopes, 2015 4. Mathers AJ, Cox HL, Kitchel B, et al: Molecular dissection of an outbreak of carbapenem-resistant enterobacteriaceae reveals Intergenus KPC carbapenemase transmission through a promiscuous plasmid. MBio 2011; 2(6):e00204–e00211 5. Centers for Disease Control and Prevention (CDC): Notes from the field: hospital outbreak of carbapenem-resistant Klebsiella pneumoniae producing New Delhi metallo-beta-lactamase--Denver, Colorado, 2012. MMWR Morb Mortal Wkly Rep 2013;62(6):108 6. Centers for Disease Control and Prevention (CDC): Notes from the Field: New Delhi metallo-beta-lactamase-producing Escherichia coli associated with endoscopic retrograde cholangiopancreatography Illinois, 2013. MMWR Morb Mortal Wkly Rep 2014;62(51−52):1051 7. Snitkin ES, Zelazny AM, Thomas PJ, et al: Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneumoniae with whole-genome sequencing. Sci Transl Med 2012;4(148):148ra116 8. Centers for Disease Control and Prevention (CDC): Vital signs: carbapenem-resistant Enterobacteriaceae. MMWR Morb Mortal Wkly Rep 2013;62(9):165−170
Critical Care Medicine
9. Dautzenberg MJD, Wekesa AN, Gniadkowski M, et al: The association between colonization with carbapenemase-producing Enterobacteriaceae and overall intensive care unit mortality: an observational cohort study. Crit Care Med 2015; 43: 1170–1177 10. Barbolla RE, Centrón D, Maimone S, et al: Molecular epidemiology of Acinetobacter baumannii spread in an adult intensive care unit under an endemic setting. Am J Infect Control 2008; 36(6):444–452 11. Donchin Y, Gopher D, Olin M, et al: A look into the nature and causes of human errors in the intensive care unit. Crit Care Med 1995; 23(2):294–300 12. Barnes SL, Morgan DJ, Harris AD, et al: Preventing the transmission of multidrug-resistant organisms: modeling the relative importance of hand hygiene and environmental cleaning interventions. Infect Control Hosp Epidemiol 2014; 35(9):1156–1162 13. Erasmus V, Daha TJ, Brug H, et al: Systematic review of studies on compliance with hand hygiene guidelines in hospital care. Infect Control Hosp Epidemiol 2010; 31(3):283–294 14. Feazel LM, Malhotra A, Perencevich EN, et al: Effect of antibiotic stewardship programmes on Clostridium difficile incidence: a systematic review and meta-analysis. J Antimicrob Chemother 2014; 69(7):1748–1754 15. Pugh R, Grant C, Cooke RP, et al: Short-course versus prolongedcourse antibiotic therapy for hospital-acquired pneumonia in critically ill adults. Cochrane Database Syst Rev 2011(10):CD007577 16. Wang HY, Chiu CH, Huang CT, et al: Blood culture-guided de-escalation of empirical antimicrobial regimen for critical patients in an online antimicrobial stewardship programme. Int J Antimicrob Agents 2014; 44(6):520–527 17. Zhang YZ, Singh S: Antibiotic stewardship programmes in intensive care units: Why, how, and where are they leading us. World J Crit Care Med 2015; 4(1):13–28 18. Kaki R, Elligsen M, Walker S, et al: Impact of antimicrobial stewardship in critical care: a systematic review. J Antimicrob Chemother 2011; 66(6):1223–1230 19. Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm 2013;70(3):195–283. 20. Pardo J, Klinker KP, Borgert SJ, et al: Time to positivity of blood cultures supports antibiotic de-escalation at 48 hours. Ann Pharmacother 2014; 48(1):33–40 21. Singh N, Rogers P, Atwood CW, et al: Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med 2000; 162(2 Pt 1):505–511 22. American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005;171(4):388–416. 23. Boucher HW, Talbot GH, Bradley JS, et al: Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 2009; 48(1):1–12 24. Infectious Diseases Society of America (IDSA): Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates, a Public Health Crisis Brews. Alexandria, VA: Infectious DIseases Society of America, 2004 25. Castanheira M, Farrell SE, Krause KM, et al: Contemporary diversity of β-lactamases among Enterobacteriaceae in the nine U.S. census regions and ceftazidime-avibactam activity tested against isolates producing the most prevalent β-lactamase groups. Antimicrob Agents Chemother 2014; 58(2):833–838 26. Yoshizumi A, Ishii Y, Aoki K, et al: In vitro susceptibility of characterized β-lactamase-producing Gram-negative bacteria isolated in Japan to ceftazidime-, ceftaroline-, and aztreonam-avibactam combinations. J Infect Chemother 2015; 21(2):148–151 27. Winkler ML, Papp-Wallace KM, Hujer AM, et al: Unexpected challenges in treating multidrug-resistant Gram-negative bacteria: resistance to ceftazidime-avibactam in archived isolates of Pseudomonas aeruginosa. Antimicrob Agents Chemother 2015; 59(2):1020–1029 28. Kadri SS, Hohmann SF, Orav EJ, et al: Tracking colistin-treated patients to monitor the incidence and outcome of carbapenem-resistant Gram-negative infections. Clin Infect Dis 2015; 60(1):79–87 www.ccmjournal.org
Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
1155
Bad Bugs, No Drugs: Are We Part of the Problem, or Leaders in Developing Solutions? Brooke Decker, MD University of Pittsburgh Henry Masur, MD NIH-Clinical Center
A
s critical care professionals, we are acutely aware of the challenges that infectious diseases present to our patients. In the current era, 21% of patients entering the ICU have an infectious disease as their primary reason for admission and 10% of initially non-infected patients will develop an infection after 24 hours of intensive care (1). The rate of infection for patients in intensive care for more than 7 days may be as high as 70%. At any point in time, 51% of ICU patients are considered to be infected and 71% are receiving antibiotics (2). Thus, preventing and managing infections is part of the everyday challenge for all critical care professionals. A disturbing trend that virtually all ICUs are encountering is the increasing fraction of infections caused by organisms that are resistant to some, many, or all of our currently available antimicrobial agents. This abundance of extremely resistant pathogens is not theoretical, and is not a problem solely in “someone else’s ICU.” Most of us deal regularly with cases or outbreaks of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and multidrug-resistant Pseudomonas, Acinetobacter, Burkholderia, Serratia, and Stenotrophomonas. Azole-resistant Candida and acyclovir-resistant herpes simplex virus are increasingly common. Recently, the University of California, Los Angeles (UCLA) has experienced an outbreak of carbapenem-resistant Enterobacteriaceae (CRE), transmitted via incompletely cleaned duodenoscope channels (3). Other major medical centers have reported CRE outbreaks, for example, in Charlottesville (4), Denver (5), Chicago (6), and at the National Institutes of Health (NIH)-Clinical Center (7). As of February 2015, the Centers for Disease Control map of CRE epidemiology shows that 48 states have reported CRE isolates, excluding only Idaho and Maine (http://www.cdc.gov/hai/organisms/cre/ TrackingCRE.html, accessed March 11, 2015). The percentage of hospitals reporting a CRE hospital-associated infection increased from 1.2% in 2001 to 4.6% in 2012 (8). Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000001039
Critical Care Medicine
Either infection with CRE or mere colonization with CRE is associated with an increased risk of death and increased length of hospital stay (9). CRE also increase overall hospital costs. CRE infections are examples of microbial diseases due to highly resistant pathogens which elicit substantial consequences from regulatory bodies and payers. As UCLA and the NIH-Clinical Center have learned, such outbreaks can also provoke unfavorable media attention that can substantially erode the community goodwill and the market place dynamics that medical centers appropriately acquire over years of good work. Ironically, this attention is often the result of dutiful investigation and reporting as well as responsible acceptance of complicated inter-hospital transfers rather than poor performance. What more can we as critical care professionals do to protect our patients from the morbidity of highly resistant pathogens under “our watch”? While the hospital epidemiologists and infectious disease practitioners have special expertise and acknowledged accomplishments in the prevention and management of such infections, the critical care team has the most influence on the conduct and performance of medical care in the ICU. If a medical facility is to reduce the impact of such pathogens in the ICU, the leadership needs to come from the critical care team. We set the tone and influence practice far more than hand hygiene monitors, antibiotic review programs, or front office “carrot and stick” policies. There are three major areas to focus on: infection prevention, antibiotic stewardship, and public policy. Infection Prevention Intensivists are best positioned to improve ICU performance in measures of infection prevention. Although it may be preferable to blame the environment rather than ourselves, the hands of healthcare providers are the usual vehicle of travel when resistant organisms are transmitted between patients (10). Transmission risk is magnified in the ICU compared with other healthcare settings because an average ICU patient has been estimated to receive 178 interactions with providers daily (11). Despite data showing greater efficacy reducing transmission with improvements in hand hygiene as compared with other prevention measures (12), hand hygiene rates in the ICU are reprehensibly poor, with a median compliance between 30% to 40% (13). Scrupulous adherence to hand hygiene is critical as every interaction is a potential source of transmission. As leaders in the critical care community, we must demand adherence to hand hygiene policy and we must set the standard with uniform adherence to policies. Measuring adherence, initiating www.ccmjournal.org
Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
1153
Foreword
programs to educate staff, and developing and enforcing consequences for missed hygiene opportunities should be the responsibility of critical care medicine leadership, and not left solely to hospital epidemiologists and administrators. Should our ICUs begin screening patients or staff for highly resistant pathogens, and if so, how should they be screened, how often should they be screened, and what should we do with the data we collect? The issue of screening patients or staff is in flux: we need to be sure that if we institute this plausible approach, we have data to demonstrate conclusively that effective interventions will result and that the cost and staff disruptions that occur will be justified. There is little consensus as to when screening improves outcomes. Patients known to harbor resistant organisms are frequently identified and separated by additional distance and protective equipment. Nasal or perirectal cultures can identify many more asymptomatically colonized patients, over and above patients identified by clinically indicated cultures, who can still act as reservoirs of transmission (7). Identification of silent carriers may be relevant to their own care, and will allow isolation measures to be augmented. In the setting of ongoing transmission, or an outbreak, intensivists should collaborate with hospital epidemiology to develop a rational strategy of active surveillance such as universal patient screening for MRSA, VRE, or CRE that fits the patient population and microbial epidemiology in their facility. However, one strategy does not fit all facilities. Rapid recognition and response to highly resistant pathogens may reduce the number of patients exposed, saving lives, but we need more studies to prove that such measures consistently improve measurable outcomes. Antibiotic Stewardship We all know the basic principles of antibiotic stewardship: avoid unnecessary antibiotics and limit the duration of empirical antibiotic therapy and prophylaxis to “what is necessary.” While such platitudes make for good rhetoric, can we institute quality improvement projects that accomplish specific goals with measurable and worthwhile outcomes? Critical care units have published dramatic examples of how they have reduced antibiotic exposure for their patients, reduced the incidence of Clostridium difficile infections (14), reduced the incidence of highly resistant infections, all while shortening length of stay and reducing nosocomial infection rates (15−17). However, other such studies have also been completed without affecting duration of stay, or mortality (16, 18). Proving that such interventions reduce the development of resistance or improve clinical outcome has been difficult given the superimposition of antibiotic policies in hospital units outside the ICU. Programs that reduce antibiotic use will reduce costs, toxicities, and drug-drug interactions related to antibiotics, but we need to measure the results of our policies to be sure that our efforts yield desired, quantifiable endpoints. Opportunities to reduce antibiotic use in the ICU abound. Examples include: reducing perioperative prophylaxis to guideline-specified regimens, narrowing antimicrobials once an organism is identified or after 48 hours, eliminating the use of combination regimens for definitive therapy (as opposed to initial empirical regimens), and limiting excessive antibiotic 1154
www.ccmjournal.org
duration. For example, consensus recommendations on perioperative prophylaxis recommend limiting antibiotics to a single dose or 24 hours for most surgeries (48 hours in the setting of sternotomy) (19). Blood cultures, as another example, now have a median time to positivity of 13.7 hours and a negative predictive value of 99.8 at 48 hours, and may be appropriate for rapid molecular screening for resistance mutations, thus permitting faster antimicrobial deescalation than was feasible in an earlier era of clinical microbiology (20). Limiting antibiotic duration may be complicated by senior leadership who may have trained in an era when 10−14 or 10−21 days regimens were routine (21), and who have not adapted to newer evidence (22). Public Policy Following a call for antimicrobial drug development incentives in 2004, the Infectious Diseases Society of America released in 2009 their seminal treatise “Bad Bugs, No drugs: No ESKAPE” illustrating the continued lack of new antimicrobial agents for resistant organism (23, 24). Pharmaceutical companies have little incentive to develop new antibiotics given the regulatory difficulty of getting such drugs approved, and the slim profit margins for such drugs compared to other endeavors which promise life-long regimens for large groups of individuals. Six years after the 2009 report, only the “S” in ESKAPE has seen new drugs. For MRSA, the Food and Drug Administration (FDA) approved telavancin in 2009; ceftaroline in 2010; and dalbavancin, oritavancin, and tedizolid in 2014. Clinical data indicating whether these agents are effective against VRE are lacking. Ceftolozane/tazobactam, approved in 2014, targets Gramnegative bacteria. Unfortunately ceftolozone/tazobactam, while useful against many highly resistant Gram-negative bacilli has no activity against CRE. The eagerly awaited ceftazidime/avibactam (approved by the FDA in 2015) has activity against KPC-producing CRE, but may be less effective against NDM-1 producers (25), ineffective against CRE (26), and effluxed by archived clinical strains of Pseudomonas (27). Lacking other options, clinicians have turned back to the polymixins. Prescriptions for colistin have nearly tripled in the last decade (28), mirroring the tripling of acute care hospitals reporting a CRE hospital-associated infection (8). It is a sad state of modern medicine that we must turn to relatively ineffective and toxic drugs such as tigecycline and colistin, discarded for other indications, in our search for regimens effective against these highly resistant organisms. It is our responsibility as critical care professionals to support and to lead efforts that influence public policy to the benefit of our patients. We should be proud of the contributions of our society, The Society of Critical Care Medicine, with other organizations such as the Infectious Diseases Society of America, in bringing the reality of antibiotic-resistant pathogens to the forefront of policy and funding decisions for federal and state authorities and by other funding organizations. We need to be willing to have our professional societies expend funds on lobbying and other public awareness programs. Initiatives such as providing incentives to pharmaceutical companies to respond to vitally needed but not very profitable opportunities may help refill the antibiotic June 2015 • Volume 43 • Number 6
Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Foreword
pipeline. Professional societies have previously encouraged the authorization of tax or patent incentives to stimulate the interest of small and large pharmaceutical companies in reentering the market for developing new antimicrobials (24). We desperately need more ideas, and more funding, to revitalize our discovery and development of preventive and therapeutic strategies that will reduce the impact of highly resistant pathogens on our patients. The release in March 2015 of the White House’s “National Action Plan for Combating Antibiotic-Resistant Bacteria” offers hope that more Federal funding will be available for research and implementation of strategies to reduce morbidity due to highly resistant pathogens including MRSA, CRE, and extended spectrum beta-lactamase-producing organisms (https://www. whitehouse.gov/sites/default/files/docs/national_action_plan_ for_combating_antibotic-resistant_bacteria.pdf). This plan has five major goals: 1) to slow the mergence of resistant bacteria; 2) to strengthen national surveillance; 3) to advance the development and use of rapid diagnostic tests; 4) to accelerate research; and 5) to improve international collaboration. Most of us are already facing the threat of “superbugs” in our ICUs. As intensivists, we cannot simply look to our colleagues in infectious disease and hospital epidemiology to “fix” these problems. We alone have the credibility to affect cultural changes in our ICU team. We all must make certain that we invest in hospital surveillance programs, in local and national epidemiologic monitoring and in sound scientific research to develop better strategies for both prevention and management. We need to make certain that we act based on knowledge and that we promptly introduce into our practices sound initiatives that have been proven to provide our patients with better outcomes using clinically meaningful endpoints. There is much to be done!
References
1. Alberti C, Brun-Buisson C, Burchardi H, et al: Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study. Intensive Care Med 2002; 28(2):108–121 2. Vincent JL, Rello J, Marshall J, et al: International study of the prevalence and outcomes of infection in intensive care units. JAMA 2009;302(21):2323−2329 3. Centers for Disease Control and Prevention (CDC): CDC Statement: Los Angeles County/UCLA investigation of CRE transmission and duodenoscopes, 2015 4. Mathers AJ, Cox HL, Kitchel B, et al: Molecular dissection of an outbreak of carbapenem-resistant enterobacteriaceae reveals Intergenus KPC carbapenemase transmission through a promiscuous plasmid. MBio 2011; 2(6):e00204–e00211 5. Centers for Disease Control and Prevention (CDC): Notes from the field: hospital outbreak of carbapenem-resistant Klebsiella pneumoniae producing New Delhi metallo-beta-lactamase--Denver, Colorado, 2012. MMWR Morb Mortal Wkly Rep 2013;62(6):108 6. Centers for Disease Control and Prevention (CDC): Notes from the Field: New Delhi metallo-beta-lactamase-producing Escherichia coli associated with endoscopic retrograde cholangiopancreatography Illinois, 2013. MMWR Morb Mortal Wkly Rep 2014;62(51−52):1051 7. Snitkin ES, Zelazny AM, Thomas PJ, et al: Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneumoniae with whole-genome sequencing. Sci Transl Med 2012;4(148):148ra116 8. Centers for Disease Control and Prevention (CDC): Vital signs: carbapenem-resistant Enterobacteriaceae. MMWR Morb Mortal Wkly Rep 2013;62(9):165−170
Critical Care Medicine
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