Old Drugs for Bad Bugs—Aerosolized Antibiotics in Ventilator-Associated Pneumonia* Katy McAllister, MBChB Department of Intensive Care Medicine Ninewells Hospital Dundee, United Kingdom James D. Chalmers, MBChB, PhD Tayside Respiratory Research Group University of Dundee Dundee, United Kingdom
V
entilator-associated pneumonia (VAP) is the most common healthcare-associated infection in mechanically ventilated patients and occurs in 9–27% of ICU admitted patients (1). It carries a high morbidity and mortality rate, extending length of ICU stay and placing a high ecological burden in terms of antibiotic use, with about half of antibiotics used in ICUs being for suspected VAP (2). Most cases of VAP are bacterial. Classically, the microbiology of VAP is divided into early (< 4 d of intubation) and late onset. Although microbiology is highly dependent on casemix, the type of ICU, and patient comorbidities, in early-onset VAP, the most common bacteria are those typically found in the community, such as Haemophilus species, Streptococcus pneumoniae, and methicillin-sensitive Staphylococcus aureus (3). Late-onset VAP, however, is typically caused by pathogens such as Pseudomonas aeruginosa, Acinetobacter species, Enterobacteriaceae, and methicillin-resistant S. aureus. Increasingly, these organisms are multidrug resistant, and as antibiotic resistance increases inexorably worldwide, the burden of VAP due to multidrug-resistant (MDR) pathogens increases (3). There is no single optimal regimen for the treatment of VAP, and even more so in cases of MDR VAP. Antibiotic regimes are selected in close liaison with microbiologists, taking into account antibiotic sensitivity data and the adverse effects associated with certain classes of antibiotics (4). As bacteria become increasingly resistant to existing antibiotic options, there is a need to expand the antibiotic development pipeline (5). Several influential reports have noted the paucity of new antibiotics being developed. An attractive option, therefore, has been the repurposing of existing antibiotics, including aerosolizing drugs that are less frequently used systemically (6). Colistin is a polymyxin antibiotic produced by certain strains of Bacillus polymyxa subspecies colistinus. Discovered
*See also p. 527. Key Words: antibiotics; critical illness; inhalation; resistance; ventilatorassociated pneumonia The authors have disclosed that they do not have any potential conflicts of interest. Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000000840
Critical Care Medicine
in 1949 and introduced into clinical practice in Europe and United States in the 1950s, it was gradually abandoned in the 1980s due to unacceptable nephrotoxicity (7). It has broadspectrum activity against most Gram-negative bacilli including P. aeruginosa, leading to its development as an inhalational antibiotic and ultimately its licensing for chronic treatment in cystic fibrosis (8). Inhalation/aerosol delivery allows administration of much higher doses of antibiotics to the airway while reducing the risks of systemic toxicity. This old drug may now have an emerging role as an aerosolized therapy in VAP. In this issue of Critical Care Medicine, Valachis et al (9) report a systematic review and meta-analysis on the effectiveness and safety of aerosolized colistin, primarily as adjunctive therapy with IV antimicrobials in patients with VAP. The analysis included seven observational studies and could identify only one randomized controlled trial (RCT) (10). The overall level of evidence was very low and assessed to be at high risk of bias, but suggested more rapid clinical response, better microbiological eradication, and reduced infection-related mortality in patients receiving adjunctive aerosolized colistin (9). The one identified RCT studied 100 patients, comparing nebulized colistin with aerosolized normal saline in addition to systemic antibiotics in patients with Gram-negative VAP. This study found a clear advantage in terms of microbiological eradication in the colistin group but no significant advantage in clinical recovery (10). In these relatively short studies, no safety issues were identified and rates of acquired colistin resistance were low. Bronchospasm has been a particular issue in administration of aerosolized antibiotics in a number of diseases, and although this was not analyzed by Valachis et al (9), it was noted in 7.8% of colistin-treated patients in the previously mentioned RCT (10). Together, these studies suggest a potential advantage in the use of aerosolized colistin compared with IV colistin, but studies are small and the quality of evidence is low (9). Colistin is not the only “old” antibiotic that may be repurposed in this way. A number of antibiotics that have important systemic toxicity have been adapted for aerosol use, particularly aminoglycosides but also glycopeptides, are being used in mechanically ventilated patients (11, 12). As with colistin, we need high-quality randomized trials to establish the safety and efficacy and these new approaches. A further key question not yet answered is whether using aerosolized antimicrobials alone is a viable option in VAP, instead of using them as an adjunct to systemic therapy. Finally, this approach to treatment needs to be set in context of recent data suggested that aerosolized antibiotics (other than colistin) can eradicate MDR pathogens and reduce bacterial resistance when used prophylactically in patients at high risk of acquiring MDR pathogens (13). At present, aerosolized antibiotics are rarely used in clinical practice in the United Kingdom or United States for the treatment of VAP. The 2005 guidelines from the American Thoracic www.ccmjournal.org
697
Editorials
Society/Infectious Diseases Society of America stated that they may be considered as adjunctive therapy in patients with MDR VAP not responding to systemic therapy (4). The committee noted, however, a lack of quality evidence and recommended further prospective trials. Nine years on, the evidence base remains extremely weak. The repurposing of old drugs for inhalation therapy offers a potentially important therapeutic option in the battle against MDR VAP. This now needs to be tested in high-quality multicenter trials.
REFERENCES
1. Chastre J, Fagon JY: Ventilator-associated pneumonia. Am J Respir Crit Care Med 2002; 165:867–903 2. Vincent JL, Bihari DJ, Suter PM, et al: The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. EPIC International Advisory Committee. JAMA 1995; 274:639–644 3. Park DR: The microbiology of ventilator-associated pneumonia. Respir Care 2005; 50:742–763; discussion 763–765 4. 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; 171:388–416
5. Peterson LR: Bad bugs, no drugs: No ESCAPE revisited. Clin Infect Dis 2009; 49:992–993 6. Koyama Y, Kurosasa A, Tsuchiya A, et al: A new antibiotic “colistin” produced by spore-forming soil bacteria. J Antibiot (Tokyo) 1950; 3:457–458 7. Falagas ME, Kasiakou SK: Colistin: The revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis 2005; 40:1333–1341 8. Máiz L, Girón RM, Olveira C, et al: Inhaled antibiotics for the treatment of chronic bronchopulmonary Pseudomonas aeruginosa infection in cystic fibrosis: Systematic review of randomised controlled trials. Expert Opin Pharmacother 2013; 14:1135–1149 9. Valachis A, Samonis G, Kofteridis DP: The Role of Aerosolized Colistin in the Treatment of Ventilator-Associated Pneumonia: A Systematic Review and Metaanalysis. Crit Care Med 2015; 43:527–533 10. Rattanaumpawan P, Lorsutthitham J, Ungprasert P, et al: Randomized controlled trial of nebulized colistimethate sodium as adjunctive therapy of ventilator-associated pneumonia caused by Gram-negative bacteria. J Antimicrob Chemother 2010; 65:2645–2649 11. Hallal A, Cohn SM, Namias N, et al: Aerosolized tobramycin in the treatment of ventilator-associated pneumonia: A pilot study. Surg Infect (Larchmt) 2007; 8:73–82 12. Hayes D Jr, Murphy BS, Mullett TW, et al: Aerosolized vancomycin for the treatment of MRSA after lung transplantation. Respirology 2010; 15:184–186 13. Palmer LB, Smaldone GC: Reduction of bacterial resistance with inhaled antibiotics in the intensive care unit. Am J Respir Crit Care Med 2014; 189:1225–1233
What Is Old Is New Again: Acetaminophen as a Novel Approach to Treating Sepsis* Abdurrahman A. Husain, MBBS Greg S. Martin, MD, MSc Pulmonary, Allergy and Critical Care Department of Medicine Emory University Atlanta, GA
S
epsis is among the most common conditions encountered in adult critical care, occurring in approximately 2% of all hospitalizations and in some hospitals occurring in more than 50% of all ICU admissions (1, 2). The past three decades have seen tremendous advances in understanding the pathophysiology of sepsis. However, some core elements of sepsis pathophysiology that remain unchanged include the general *See also p. 534. Key Words: acetaminophen; hemoglobin; sepsis Dr. Martin served as a board member for Cumberland Pharmaceuticals, Pulsion Medical Systems, the Society of Critical Care Medicine, the National Institutes of Health (NIH), the Food and Drug Administration (FDA) (data safety monitoring boards), and Medscape (Critical care editor); consulted for Grifols; and received support for article research from the NIH. His institution received grant support from the NIH, FDA, Baxter Healthcare, and Abbott Laboratories. Mr. Husain has disclosed that he does not have any potential conflicts of interest. Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000000782
698
www.ccmjournal.org
processes of oxidative stress, inflammation, and endothelial dysfunction, among other factors that advance along a common pathway toward multiple organ dysfunction (3). These contributors are most apparent in critically ill patients with severe sepsis and septic shock, where multiple organ dysfunction is the major cause of death (4, 5). The underlying instigators of reactive oxygen species (ROS) and endothelial injury are myriad and unlikely to be from a single cause in all patients. Hemolysis occurs in many diseases, producing cell-free hemoglobin (CFH) as a result. Increased quantities of circulating CFH have been reported in a variety of diseases, including sickle cell disease, blood transfusion, malaria, and sepsis, among other conditions. Two of the predominant effects of CFH are depletion of nitric oxide (NO) and generation of ROS (6). A primary effector for NO is reduced oxyhemoglobin that rapidly reacts with it to form methemoglobin and nitrate. This reaction accounts for the vasoconstrictor response known to occur with CFH and hemoglobin-based oxygen carriers (i.e., one class of artificial blood substitutes). In addition, oxidation reactions are catalyzed by hemoglobin, heme, and iron to generate ROS, subsequently leading to lipid peroxidation and cellular injury (7). Although free heme can amplify some innate immune responses in sepsis, free iron can amplify a deleterious inflammatory response. Fortunately, there is an efficient biological system to scavenge hemoglobin and heme, using haptoglobin, CD163, and hemopexin, which effectively sequesters March 2015 • Volume 43 • Number 3
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
V
entilator-associated pneumonia (VAP) is the most common healthcare-associated infection in mechanically ventilated patients and occurs in 9–27% of ICU admitted patients (1). It carries a high morbidity and mortality rate, extending length of ICU stay and placing a high ecological burden in terms of antibiotic use, with about half of antibiotics used in ICUs being for suspected VAP (2). Most cases of VAP are bacterial. Classically, the microbiology of VAP is divided into early (< 4 d of intubation) and late onset. Although microbiology is highly dependent on casemix, the type of ICU, and patient comorbidities, in early-onset VAP, the most common bacteria are those typically found in the community, such as Haemophilus species, Streptococcus pneumoniae, and methicillin-sensitive Staphylococcus aureus (3). Late-onset VAP, however, is typically caused by pathogens such as Pseudomonas aeruginosa, Acinetobacter species, Enterobacteriaceae, and methicillin-resistant S. aureus. Increasingly, these organisms are multidrug resistant, and as antibiotic resistance increases inexorably worldwide, the burden of VAP due to multidrug-resistant (MDR) pathogens increases (3). There is no single optimal regimen for the treatment of VAP, and even more so in cases of MDR VAP. Antibiotic regimes are selected in close liaison with microbiologists, taking into account antibiotic sensitivity data and the adverse effects associated with certain classes of antibiotics (4). As bacteria become increasingly resistant to existing antibiotic options, there is a need to expand the antibiotic development pipeline (5). Several influential reports have noted the paucity of new antibiotics being developed. An attractive option, therefore, has been the repurposing of existing antibiotics, including aerosolizing drugs that are less frequently used systemically (6). Colistin is a polymyxin antibiotic produced by certain strains of Bacillus polymyxa subspecies colistinus. Discovered
*See also p. 527. Key Words: antibiotics; critical illness; inhalation; resistance; ventilatorassociated pneumonia The authors have disclosed that they do not have any potential conflicts of interest. Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000000840
Critical Care Medicine
in 1949 and introduced into clinical practice in Europe and United States in the 1950s, it was gradually abandoned in the 1980s due to unacceptable nephrotoxicity (7). It has broadspectrum activity against most Gram-negative bacilli including P. aeruginosa, leading to its development as an inhalational antibiotic and ultimately its licensing for chronic treatment in cystic fibrosis (8). Inhalation/aerosol delivery allows administration of much higher doses of antibiotics to the airway while reducing the risks of systemic toxicity. This old drug may now have an emerging role as an aerosolized therapy in VAP. In this issue of Critical Care Medicine, Valachis et al (9) report a systematic review and meta-analysis on the effectiveness and safety of aerosolized colistin, primarily as adjunctive therapy with IV antimicrobials in patients with VAP. The analysis included seven observational studies and could identify only one randomized controlled trial (RCT) (10). The overall level of evidence was very low and assessed to be at high risk of bias, but suggested more rapid clinical response, better microbiological eradication, and reduced infection-related mortality in patients receiving adjunctive aerosolized colistin (9). The one identified RCT studied 100 patients, comparing nebulized colistin with aerosolized normal saline in addition to systemic antibiotics in patients with Gram-negative VAP. This study found a clear advantage in terms of microbiological eradication in the colistin group but no significant advantage in clinical recovery (10). In these relatively short studies, no safety issues were identified and rates of acquired colistin resistance were low. Bronchospasm has been a particular issue in administration of aerosolized antibiotics in a number of diseases, and although this was not analyzed by Valachis et al (9), it was noted in 7.8% of colistin-treated patients in the previously mentioned RCT (10). Together, these studies suggest a potential advantage in the use of aerosolized colistin compared with IV colistin, but studies are small and the quality of evidence is low (9). Colistin is not the only “old” antibiotic that may be repurposed in this way. A number of antibiotics that have important systemic toxicity have been adapted for aerosol use, particularly aminoglycosides but also glycopeptides, are being used in mechanically ventilated patients (11, 12). As with colistin, we need high-quality randomized trials to establish the safety and efficacy and these new approaches. A further key question not yet answered is whether using aerosolized antimicrobials alone is a viable option in VAP, instead of using them as an adjunct to systemic therapy. Finally, this approach to treatment needs to be set in context of recent data suggested that aerosolized antibiotics (other than colistin) can eradicate MDR pathogens and reduce bacterial resistance when used prophylactically in patients at high risk of acquiring MDR pathogens (13). At present, aerosolized antibiotics are rarely used in clinical practice in the United Kingdom or United States for the treatment of VAP. The 2005 guidelines from the American Thoracic www.ccmjournal.org
697
Editorials
Society/Infectious Diseases Society of America stated that they may be considered as adjunctive therapy in patients with MDR VAP not responding to systemic therapy (4). The committee noted, however, a lack of quality evidence and recommended further prospective trials. Nine years on, the evidence base remains extremely weak. The repurposing of old drugs for inhalation therapy offers a potentially important therapeutic option in the battle against MDR VAP. This now needs to be tested in high-quality multicenter trials.
REFERENCES
1. Chastre J, Fagon JY: Ventilator-associated pneumonia. Am J Respir Crit Care Med 2002; 165:867–903 2. Vincent JL, Bihari DJ, Suter PM, et al: The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. EPIC International Advisory Committee. JAMA 1995; 274:639–644 3. Park DR: The microbiology of ventilator-associated pneumonia. Respir Care 2005; 50:742–763; discussion 763–765 4. 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; 171:388–416
5. Peterson LR: Bad bugs, no drugs: No ESCAPE revisited. Clin Infect Dis 2009; 49:992–993 6. Koyama Y, Kurosasa A, Tsuchiya A, et al: A new antibiotic “colistin” produced by spore-forming soil bacteria. J Antibiot (Tokyo) 1950; 3:457–458 7. Falagas ME, Kasiakou SK: Colistin: The revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis 2005; 40:1333–1341 8. Máiz L, Girón RM, Olveira C, et al: Inhaled antibiotics for the treatment of chronic bronchopulmonary Pseudomonas aeruginosa infection in cystic fibrosis: Systematic review of randomised controlled trials. Expert Opin Pharmacother 2013; 14:1135–1149 9. Valachis A, Samonis G, Kofteridis DP: The Role of Aerosolized Colistin in the Treatment of Ventilator-Associated Pneumonia: A Systematic Review and Metaanalysis. Crit Care Med 2015; 43:527–533 10. Rattanaumpawan P, Lorsutthitham J, Ungprasert P, et al: Randomized controlled trial of nebulized colistimethate sodium as adjunctive therapy of ventilator-associated pneumonia caused by Gram-negative bacteria. J Antimicrob Chemother 2010; 65:2645–2649 11. Hallal A, Cohn SM, Namias N, et al: Aerosolized tobramycin in the treatment of ventilator-associated pneumonia: A pilot study. Surg Infect (Larchmt) 2007; 8:73–82 12. Hayes D Jr, Murphy BS, Mullett TW, et al: Aerosolized vancomycin for the treatment of MRSA after lung transplantation. Respirology 2010; 15:184–186 13. Palmer LB, Smaldone GC: Reduction of bacterial resistance with inhaled antibiotics in the intensive care unit. Am J Respir Crit Care Med 2014; 189:1225–1233
What Is Old Is New Again: Acetaminophen as a Novel Approach to Treating Sepsis* Abdurrahman A. Husain, MBBS Greg S. Martin, MD, MSc Pulmonary, Allergy and Critical Care Department of Medicine Emory University Atlanta, GA
S
epsis is among the most common conditions encountered in adult critical care, occurring in approximately 2% of all hospitalizations and in some hospitals occurring in more than 50% of all ICU admissions (1, 2). The past three decades have seen tremendous advances in understanding the pathophysiology of sepsis. However, some core elements of sepsis pathophysiology that remain unchanged include the general *See also p. 534. Key Words: acetaminophen; hemoglobin; sepsis Dr. Martin served as a board member for Cumberland Pharmaceuticals, Pulsion Medical Systems, the Society of Critical Care Medicine, the National Institutes of Health (NIH), the Food and Drug Administration (FDA) (data safety monitoring boards), and Medscape (Critical care editor); consulted for Grifols; and received support for article research from the NIH. His institution received grant support from the NIH, FDA, Baxter Healthcare, and Abbott Laboratories. Mr. Husain has disclosed that he does not have any potential conflicts of interest. Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000000782
698
www.ccmjournal.org
processes of oxidative stress, inflammation, and endothelial dysfunction, among other factors that advance along a common pathway toward multiple organ dysfunction (3). These contributors are most apparent in critically ill patients with severe sepsis and septic shock, where multiple organ dysfunction is the major cause of death (4, 5). The underlying instigators of reactive oxygen species (ROS) and endothelial injury are myriad and unlikely to be from a single cause in all patients. Hemolysis occurs in many diseases, producing cell-free hemoglobin (CFH) as a result. Increased quantities of circulating CFH have been reported in a variety of diseases, including sickle cell disease, blood transfusion, malaria, and sepsis, among other conditions. Two of the predominant effects of CFH are depletion of nitric oxide (NO) and generation of ROS (6). A primary effector for NO is reduced oxyhemoglobin that rapidly reacts with it to form methemoglobin and nitrate. This reaction accounts for the vasoconstrictor response known to occur with CFH and hemoglobin-based oxygen carriers (i.e., one class of artificial blood substitutes). In addition, oxidation reactions are catalyzed by hemoglobin, heme, and iron to generate ROS, subsequently leading to lipid peroxidation and cellular injury (7). Although free heme can amplify some innate immune responses in sepsis, free iron can amplify a deleterious inflammatory response. Fortunately, there is an efficient biological system to scavenge hemoglobin and heme, using haptoglobin, CD163, and hemopexin, which effectively sequesters March 2015 • Volume 43 • Number 3
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
