- Email: [email protected]
Optimal Therapy for Methicillin-Resistant Staphylococcus aureus Pneumonia
jects, giving a 48% prevalence of CFTR mutations in this cohort, although elevated sweat chloride was only measured in 7 of these subjects. The subjects with CF were more likely to have mucus plugging on high-resolution CT scans, and the women with CF had a significantly lower body mass index than the non-CF subjects, but there appeared to be no other specific signs or symptoms that might be clues to the CF diagnosis. This important study provides new insight to the pathogenesis both of CF and of NTM disease. Considering that people with neuromuscular weakness and an inability to generate effective cough do not typically develop NTM infection, it seems much more likely that patients with Lady Windermere syndrome would have CF or be carriers of a CFTR mutation than develop NTM disease because of fastidiousness. This brings us back to the question, “Did Lady Windermere have CF”? It has become a cottage industry to diagnose “modern” diseases in historical figures who had unusual deaths, chronic illness, or physiognomy consistent with specific conditions. On the basis of extremely postmortem evaluations, Abraham Lincoln has been thought to have had Marfan syndrome,5 and to the point of this editorial, the PolishFrench composer, Frederick Chopin, may have had CF.6,7 Although, the diagnosis of chronic illness in the long dead is an interesting blend of medicine and history, diagnosing disease in fictional characters falls under the realm of creative imagination. As the librarian, Emily Drew, pointed out in a letter to CHEST in December 2002, in Wilde’s play, Lady Windermere was a vivacious young women, married only 2 years who never coughs or displays any other signs of illness.8 She not only appears to have excellent health, but she does not seem exceptionally prissy. Thus, it is not such a Wilde assumption that Lady Windermere most certainly does not appear to have either CF or even her eponymous syndrome. While I mourn the passing of a literary eponym, I applaud the contribution to our understanding of this disease by Ziedalski and colleagues.4 The diagnosis of CF has profound implications for medical therapy, genetic counseling, male fertility, insurance, etc. Therefore, this article would present a strong argument that all adults with bronchiectasis of unknown ideology or NTM without documented immunodeficiency should be tested for CF by sweat chloride and CFTR genetic analysis. Bruce K. Rubin, MEngr, MD, MBA, FCCP Winston Salem, NC Dr. Rubin is Professor and Vice-Chair, Department of Pediatrics, and Professor of Biomedical Engineering, Physiology, and Pharmacology, Wake Forest University School of Medicine. 938
The author has no conflicts of interest to declare. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Bruce K. Rubin, MEngr, MD, MBA, FCCP, Professor and Vice-Chair, Department of Pediatrics, Professor of Biomedical Engineering, Physiology, and Pharmacology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1081; e-mail: [email protected]. DOI: 10.1378/chest.130.4.937
References 1 Reich JM, Johnson RE. Mycobacterium avium complex pulmonary disease presenting as an isolated lingular or middle lobe pattern: the Lady Windermere syndrome. Chest 1992; 101:1605–1609 2 Chbeir E, Casas L, Toubia N, et al. Adult cystic fibrosis presenting with recurrent non-tuberculous mycobacterial infections. Lancet 2006; 367:1952 3 Nick JA. Nontuberculous mycobacteria in cystic fibrosis. Semin Respir Crit Care Med 2003; 24:693–702 4 Ziedalski T, Kao P, Henig N, et al. Prospective analysis of cystic fibrosis transmembrane regulator mutations in adults with bronchiectasis or pulmonary nontuberculous mycobacterial infection. Chest 2006; 130:995–1002 5 McKusick VA. The defect in Marfan syndrome. Nature 1991; 25:352:279 –281 6 Majka L, Gozdzik J, Witt M. Cystic fibrosis: a probable cause of Frederic Chopin’s suffering and death. J Appl Genet 2003; 44:77– 84 7 Kubba AK, Young M. The long suffering of Frederic Chopin. Chest 1998; 113:210 –216 8 Drew EW. Have you read Lady Windermere’s fan by Oscar Wilde? Chest e-letter December 11, 2002. Available at: http://www.chestjournal.org/cgi/eletters/101/6/1605. Accessed August 30, 2006
Optimal Therapy for Methicillin-Resistant Staphylococcus aureus Pneumonia What Is the Best Dosing Regimen? of antimicrobial prescription in pneumoT heniagoal is to achieve effective active drug concentra-
tions that result in clinical cure while avoiding antibiotic-associated toxicity or emergence of resistances. Until recently, the in vitro susceptibility of microorganism was considered the reference aspect for antibiotic efficacy for pneumonia1 and defined the concept of appropriate therapy. Pinder et al2 emphasized that standard antimicrobial dosing regimens are based on research often performed decades ago and for the most part with patients who were not critically ill. At the present time, other factors and circumstances should be considered to achieve what we call appropriate, adequate, or optiEditorials
mal therapy for pneumonia and to determine what is the best dosing regimen for a specific patient. Appropriate (or concordant) antimicrobial therapy is only based on the in vitro susceptibility of the organisms. Timely administration of appropriate antimicrobial therapy, particularly in the subset of patients with highest severity, is a crucial factor to improve survival and ensure prompt clinical resolution.3,4 However, a multicenter study5 demonstrated that despite appropriate therapy with glycopeptides, an increased attributable mortality occurred in patients with ventilator-associated pneumonia (VAP) due to methicillin-resistant Staphylococcus aureus (MRSA), compared with matched intubated control subjects without VAP-MRSA. Therefore, adequate antimicrobial therapy should take in account the interaction between the bacterial pathogen and the antimicrobial agent at the minimal inhibitory concentration (MIC). Effective drug concentration levels at the infectious site (alveolar macrophages for intracellular organisms and epithelial lining fluid [ELF] for extracellular pathogens) are also required. Moreover, antimicrobials may exhibit significantly different behavior in the lung consistent with their hydrophilic or lipophilic characteristics.1 Lipophilic compounds (macrolides, fluoroquinolones, rifampin, or linezolid) may achieve higher levels in ELF, compared with hydrophilic agents (-lactams, aminoglycosides, or vancomycin) and are the only compounds able to accumulate in alveolar macrophages. Optimal therapy for pneumonia should take in to consideration additional factors ahead of the in vitro susceptibility and penetration to the infectious site. For example, several studies6,7 suggest that combination therapy with a macrolide might be preferred above monotherapy with a -lactam or combination therapy with a fluoroquinolone in specific subsets of patients with severe community-acquired pneumonia, such as those with severe pneumococcal bacteremic episodes. The determination of the best dosing regimen for specific patients is probably the most complex issue. To ensure optimal pharmacodynamic exposure at the infection site, we should prescribe higher doses than those traditionally recommended, and a loading dose should be considered. The maximal bacterial burden and individual patients’ conditions, such as an enhanced renal blood flow or an increased volume of distribution in hyperdynamic patients, who are receiving mechanical ventilation or have severe sepsis, may lead to underdosing. The most recent advances in research on pneumonia are focusing on improving our understanding of the patterns of clinical resolution, and many opportunities exist to improve resolution and reduce clinwww.chestjournal.org
ical failure. Ensuring clinical cure and prevention of resistance to the antimicrobial agents should take in account the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of the agents. Therefore, different dosing regimens may be preferred for time-dependent agents (eg, vancomycin) compared with concentration-dependent agents (eg, fluoroquinolones). Finally, the presence of postantibiotic effect in some agents is another factor influencing the prescription regimen. Clinical failures and mortality rates of patients with S aureus pneumonia treated with vancomycin have been consistently reported ⬎ 50%.8 A key PK/PD determinant of outcome is the percentage of time that the drug levels in the alveolar space exceed the MIC (time greater than MIC), and this can be optimized using continuous infusion.5 The area under the 24-h curve (AUC) to MIC dosing is a second key element.9 One possible option to ensure an adequate AUC-MIC value is to increase the dose of vancomycin, although this decision might be associated with higher rates of ear and kidney toxicity. Among patients with community-acquired staphylococcal pneumonia,10 clinical and bacteriological responses were best when the area under the inhibitory curve (AUIC, a surrogate for AUC-MIC) was ⬎ 400. A second study11 that involved 70 patients, including 35 patients with MRSA, reported a success rate of 76% for episodes with AUIC ⬎ 345 and only 22% for AUIC ⬍ 345. Therefore, some researchers12 have suggested that the dose of vancomycin should be adjusted to reach these values. Moreover, in some cases, concentrations needed for effective therapy should be considerably higher because of the effect of protein binding, increase in volume of distribution in hyperdynamic patients with severe sepsis, presence of some virulence factors, or a high bacterial inoculum. In this scenario, metaanalyses13,14 concluded that linezolid was superior to vancomycin for therapy of MRSA pneumonia. Differences in MIC, tissue penetration, or the degree of protein binding may explain these discrepancies. In addition, the label dose of vancomycin administered in the trials might be suboptimal,2 and many experts have advocated that when increasing the dose, the differences in outcome might not be significant. In this context, the study by Kollef et al15 in this issue of CHEST (see page 947) adds an additional piece to the puzzle of the best antimicrobial therapy.1 Their findings suggest that time to apyrexia was shorter in the AUIC ⬎ 400 group. However, a disappointing finding was that greater vancomycin trough concentrations failed to increase the hospital survival of patients with health-care associated pneumonia. CHEST / 130 / 4 / OCTOBER, 2006
939
Efforts to improve survival in patients with MRSA pneumonia should concentrate on alternative agents to glycopeptides rather than in adjusting what is the best antimicrobial dose. In our opinion, the challenge to define what is optimal therapy for MRSA pneumonia should focus as a target in the 5% attributable mortality associated with methicillinsensitive S aureus VAP treated with -lactams. This should be the objective of the ongoing clinical trials for MRSA pneumonia with newer agents with strong anti-MRSA activity such as tigecycline, ceftobiprole, telavancin, iclaprim, or garenoxacin. Jordi Rello, MD, PhD Tarragona, Spain Jordi Mallol, MD, PhD Reus, Spain Dr. Rello is chief of the Critical Care Department, Joan XXIII University Hospital. Dr. Mallol is Chairman of the Pharmacology Department, School of Medicine and Health Sciences, Universitat Rovira & Virgili. Supported in part by FISS05/2410 and CIRIT SGR-05/920. Dr. Rello has served in the Speakers Bureau and is a consultant for Pfizer, Wyeth Pharmaceuticals, Arpida, Basilea, Johnson & Johnson, and Schering Plough, and he has received research grants from Lilly and Pfizer. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Jordi Rello, MD, PhD, Critical Care Department, Joan XXIII University Hospital, Carrer Mallafre Guasch 4, 43007 Tarragona, Spain; e-mail: [email protected] DOI: 10.1378/chest.130.4.938
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References 1 Pea F, Viale P. The antimicrobial therapy puzzle: could pharmacokinetic-pharmacodynamic relationships be helpful in addressing the issue of appropriate pneumonia treatment in critically ill patients? Clin Infect Dis 2006; 42:1764 –1771 2 Pinder M, Bellomo R, Lipman J. Pharmacological principles of antibiotic prescription in the critically ill. Anaesth Intensive Care 2002; 30:134 –144 3 Iregui M, Ward S, Sherman G, et al. Clinical importance of
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delays in the initiation of appropriate antibiotic treatment for ventilator-associated pneumonia. Chest 2002; 122:262–268 Rello J, Gallego M, Mariscal D, et al. The value of routine microbial investigation in ventilator-associated pneumonia. Am J Respir Crit Care Med 1997; 156:196 –200 Rello J, Sole-Violan J, Sa-Borges M, et al. Pneumonia caused by oxacillin-resistant Staphylococcus aureus treated with glycopeptides. Crit Care Med 2005; 33:1983–1987 Lujan M, Gallego M, Rello J. Optimal therapy for pneumococcal pneumonia. Intensive Care Med 2006; 32:971–980 Baddour LM, Yu VL, Klugman KP, et al. Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia. Am J Respir Crit Care Med 2004; 170:440 – 444 Rello J, Torres A, Ricart M, et al. Ventilator-associated pneumonia by Staphylococcus aureus: comparison of methicillin-resistant and methicillin-sensitive episodes. Am J Respir Crit Care Med 1994; 150:1545–1549 Nathwani D, Tillotson G. Vancomycin for Staphylococcus aureus therapy of respiratory infections: the end of an era? Int J Antimicrob Agents 2003; 21:521–524 Moise-Broder PA, Forrest A, Birmingham MC, et al. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet 2004; 43:925–942 Moise PA, Forrest A, Bhavnani SM, et al. Area under the inhibitory curve and a pneumonia scoring system for predicting outcomes of vancomycin therapy for respiratory infections by Staphylococcus aureus. Am J Health Syst Pharm 2000; 43:925–942 Kiem S, Schentag JJ. Relationship of minimal inhibitory concentration and bactericidal activity to efficacy of antibiotics for treatment of ventilator-associated pneumonia. Semin Respir Crit Care Med 2006; 27:51– 67 Wunderink RG, Rello J, Cammarata SK, et al. Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia. Chest 2003; 124:1789 –1797 Kollef MH, Rello J, Cammarata SK, et al. Clinical cure and survival in Gram positive ventilator-associated pneumonia: retrospective analysis of two double-blind studies comparing linezolid with vancomycin. Intensive Care Med 2004; 30: 388 –394 Kollef MH, Isakow W, Jeffres M, et al. Predictors of mortality for methicillin-resistant Staphylococcus aureus healthcareassociated pneumonia. Chest 2006; 130:947–955
Editorials
The author has no conflicts of interest to declare. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Bruce K. Rubin, MEngr, MD, MBA, FCCP, Professor and Vice-Chair, Department of Pediatrics, Professor of Biomedical Engineering, Physiology, and Pharmacology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1081; e-mail: [email protected]. DOI: 10.1378/chest.130.4.937
References 1 Reich JM, Johnson RE. Mycobacterium avium complex pulmonary disease presenting as an isolated lingular or middle lobe pattern: the Lady Windermere syndrome. Chest 1992; 101:1605–1609 2 Chbeir E, Casas L, Toubia N, et al. Adult cystic fibrosis presenting with recurrent non-tuberculous mycobacterial infections. Lancet 2006; 367:1952 3 Nick JA. Nontuberculous mycobacteria in cystic fibrosis. Semin Respir Crit Care Med 2003; 24:693–702 4 Ziedalski T, Kao P, Henig N, et al. Prospective analysis of cystic fibrosis transmembrane regulator mutations in adults with bronchiectasis or pulmonary nontuberculous mycobacterial infection. Chest 2006; 130:995–1002 5 McKusick VA. The defect in Marfan syndrome. Nature 1991; 25:352:279 –281 6 Majka L, Gozdzik J, Witt M. Cystic fibrosis: a probable cause of Frederic Chopin’s suffering and death. J Appl Genet 2003; 44:77– 84 7 Kubba AK, Young M. The long suffering of Frederic Chopin. Chest 1998; 113:210 –216 8 Drew EW. Have you read Lady Windermere’s fan by Oscar Wilde? Chest e-letter December 11, 2002. Available at: http://www.chestjournal.org/cgi/eletters/101/6/1605. Accessed August 30, 2006
Optimal Therapy for Methicillin-Resistant Staphylococcus aureus Pneumonia What Is the Best Dosing Regimen? of antimicrobial prescription in pneumoT heniagoal is to achieve effective active drug concentra-
tions that result in clinical cure while avoiding antibiotic-associated toxicity or emergence of resistances. Until recently, the in vitro susceptibility of microorganism was considered the reference aspect for antibiotic efficacy for pneumonia1 and defined the concept of appropriate therapy. Pinder et al2 emphasized that standard antimicrobial dosing regimens are based on research often performed decades ago and for the most part with patients who were not critically ill. At the present time, other factors and circumstances should be considered to achieve what we call appropriate, adequate, or optiEditorials
mal therapy for pneumonia and to determine what is the best dosing regimen for a specific patient. Appropriate (or concordant) antimicrobial therapy is only based on the in vitro susceptibility of the organisms. Timely administration of appropriate antimicrobial therapy, particularly in the subset of patients with highest severity, is a crucial factor to improve survival and ensure prompt clinical resolution.3,4 However, a multicenter study5 demonstrated that despite appropriate therapy with glycopeptides, an increased attributable mortality occurred in patients with ventilator-associated pneumonia (VAP) due to methicillin-resistant Staphylococcus aureus (MRSA), compared with matched intubated control subjects without VAP-MRSA. Therefore, adequate antimicrobial therapy should take in account the interaction between the bacterial pathogen and the antimicrobial agent at the minimal inhibitory concentration (MIC). Effective drug concentration levels at the infectious site (alveolar macrophages for intracellular organisms and epithelial lining fluid [ELF] for extracellular pathogens) are also required. Moreover, antimicrobials may exhibit significantly different behavior in the lung consistent with their hydrophilic or lipophilic characteristics.1 Lipophilic compounds (macrolides, fluoroquinolones, rifampin, or linezolid) may achieve higher levels in ELF, compared with hydrophilic agents (-lactams, aminoglycosides, or vancomycin) and are the only compounds able to accumulate in alveolar macrophages. Optimal therapy for pneumonia should take in to consideration additional factors ahead of the in vitro susceptibility and penetration to the infectious site. For example, several studies6,7 suggest that combination therapy with a macrolide might be preferred above monotherapy with a -lactam or combination therapy with a fluoroquinolone in specific subsets of patients with severe community-acquired pneumonia, such as those with severe pneumococcal bacteremic episodes. The determination of the best dosing regimen for specific patients is probably the most complex issue. To ensure optimal pharmacodynamic exposure at the infection site, we should prescribe higher doses than those traditionally recommended, and a loading dose should be considered. The maximal bacterial burden and individual patients’ conditions, such as an enhanced renal blood flow or an increased volume of distribution in hyperdynamic patients, who are receiving mechanical ventilation or have severe sepsis, may lead to underdosing. The most recent advances in research on pneumonia are focusing on improving our understanding of the patterns of clinical resolution, and many opportunities exist to improve resolution and reduce clinwww.chestjournal.org
ical failure. Ensuring clinical cure and prevention of resistance to the antimicrobial agents should take in account the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of the agents. Therefore, different dosing regimens may be preferred for time-dependent agents (eg, vancomycin) compared with concentration-dependent agents (eg, fluoroquinolones). Finally, the presence of postantibiotic effect in some agents is another factor influencing the prescription regimen. Clinical failures and mortality rates of patients with S aureus pneumonia treated with vancomycin have been consistently reported ⬎ 50%.8 A key PK/PD determinant of outcome is the percentage of time that the drug levels in the alveolar space exceed the MIC (time greater than MIC), and this can be optimized using continuous infusion.5 The area under the 24-h curve (AUC) to MIC dosing is a second key element.9 One possible option to ensure an adequate AUC-MIC value is to increase the dose of vancomycin, although this decision might be associated with higher rates of ear and kidney toxicity. Among patients with community-acquired staphylococcal pneumonia,10 clinical and bacteriological responses were best when the area under the inhibitory curve (AUIC, a surrogate for AUC-MIC) was ⬎ 400. A second study11 that involved 70 patients, including 35 patients with MRSA, reported a success rate of 76% for episodes with AUIC ⬎ 345 and only 22% for AUIC ⬍ 345. Therefore, some researchers12 have suggested that the dose of vancomycin should be adjusted to reach these values. Moreover, in some cases, concentrations needed for effective therapy should be considerably higher because of the effect of protein binding, increase in volume of distribution in hyperdynamic patients with severe sepsis, presence of some virulence factors, or a high bacterial inoculum. In this scenario, metaanalyses13,14 concluded that linezolid was superior to vancomycin for therapy of MRSA pneumonia. Differences in MIC, tissue penetration, or the degree of protein binding may explain these discrepancies. In addition, the label dose of vancomycin administered in the trials might be suboptimal,2 and many experts have advocated that when increasing the dose, the differences in outcome might not be significant. In this context, the study by Kollef et al15 in this issue of CHEST (see page 947) adds an additional piece to the puzzle of the best antimicrobial therapy.1 Their findings suggest that time to apyrexia was shorter in the AUIC ⬎ 400 group. However, a disappointing finding was that greater vancomycin trough concentrations failed to increase the hospital survival of patients with health-care associated pneumonia. CHEST / 130 / 4 / OCTOBER, 2006
939
Efforts to improve survival in patients with MRSA pneumonia should concentrate on alternative agents to glycopeptides rather than in adjusting what is the best antimicrobial dose. In our opinion, the challenge to define what is optimal therapy for MRSA pneumonia should focus as a target in the 5% attributable mortality associated with methicillinsensitive S aureus VAP treated with -lactams. This should be the objective of the ongoing clinical trials for MRSA pneumonia with newer agents with strong anti-MRSA activity such as tigecycline, ceftobiprole, telavancin, iclaprim, or garenoxacin. Jordi Rello, MD, PhD Tarragona, Spain Jordi Mallol, MD, PhD Reus, Spain Dr. Rello is chief of the Critical Care Department, Joan XXIII University Hospital. Dr. Mallol is Chairman of the Pharmacology Department, School of Medicine and Health Sciences, Universitat Rovira & Virgili. Supported in part by FISS05/2410 and CIRIT SGR-05/920. Dr. Rello has served in the Speakers Bureau and is a consultant for Pfizer, Wyeth Pharmaceuticals, Arpida, Basilea, Johnson & Johnson, and Schering Plough, and he has received research grants from Lilly and Pfizer. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Jordi Rello, MD, PhD, Critical Care Department, Joan XXIII University Hospital, Carrer Mallafre Guasch 4, 43007 Tarragona, Spain; e-mail: [email protected] DOI: 10.1378/chest.130.4.938
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References 1 Pea F, Viale P. The antimicrobial therapy puzzle: could pharmacokinetic-pharmacodynamic relationships be helpful in addressing the issue of appropriate pneumonia treatment in critically ill patients? Clin Infect Dis 2006; 42:1764 –1771 2 Pinder M, Bellomo R, Lipman J. Pharmacological principles of antibiotic prescription in the critically ill. Anaesth Intensive Care 2002; 30:134 –144 3 Iregui M, Ward S, Sherman G, et al. Clinical importance of
940
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delays in the initiation of appropriate antibiotic treatment for ventilator-associated pneumonia. Chest 2002; 122:262–268 Rello J, Gallego M, Mariscal D, et al. The value of routine microbial investigation in ventilator-associated pneumonia. Am J Respir Crit Care Med 1997; 156:196 –200 Rello J, Sole-Violan J, Sa-Borges M, et al. Pneumonia caused by oxacillin-resistant Staphylococcus aureus treated with glycopeptides. Crit Care Med 2005; 33:1983–1987 Lujan M, Gallego M, Rello J. Optimal therapy for pneumococcal pneumonia. Intensive Care Med 2006; 32:971–980 Baddour LM, Yu VL, Klugman KP, et al. Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia. Am J Respir Crit Care Med 2004; 170:440 – 444 Rello J, Torres A, Ricart M, et al. Ventilator-associated pneumonia by Staphylococcus aureus: comparison of methicillin-resistant and methicillin-sensitive episodes. Am J Respir Crit Care Med 1994; 150:1545–1549 Nathwani D, Tillotson G. Vancomycin for Staphylococcus aureus therapy of respiratory infections: the end of an era? Int J Antimicrob Agents 2003; 21:521–524 Moise-Broder PA, Forrest A, Birmingham MC, et al. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet 2004; 43:925–942 Moise PA, Forrest A, Bhavnani SM, et al. Area under the inhibitory curve and a pneumonia scoring system for predicting outcomes of vancomycin therapy for respiratory infections by Staphylococcus aureus. Am J Health Syst Pharm 2000; 43:925–942 Kiem S, Schentag JJ. Relationship of minimal inhibitory concentration and bactericidal activity to efficacy of antibiotics for treatment of ventilator-associated pneumonia. Semin Respir Crit Care Med 2006; 27:51– 67 Wunderink RG, Rello J, Cammarata SK, et al. Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia. Chest 2003; 124:1789 –1797 Kollef MH, Rello J, Cammarata SK, et al. Clinical cure and survival in Gram positive ventilator-associated pneumonia: retrospective analysis of two double-blind studies comparing linezolid with vancomycin. Intensive Care Med 2004; 30: 388 –394 Kollef MH, Isakow W, Jeffres M, et al. Predictors of mortality for methicillin-resistant Staphylococcus aureus healthcareassociated pneumonia. Chest 2006; 130:947–955
Editorials