Download PDF
Semin Respir Crit Care Med 2012; 33(03): 311-318
DOI: 10.1055/s-0032-1315643
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Adjunctive Therapy in Community-Acquired Pneumonia

Richard G. Wunderink
1   Department of Medicine, Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
,
Lionel Mandell
2   Department of Medicine, Division of Infectious Diseases, McMaster University, Hamilton, Ontario, Canada.
3   Juravinski Hospital, Hamilton, Ontario, Canada.
› Author Affiliations
Further Information

Publication History

Publication Date:
20 June 2012 (online)

    Permissions and Reprints

Abstract

Despite potent antibiotics, community-acquired pneumonia (CAP) remains the most common cause of death from infection and the eighth overall leading cause of death in the United States. For this reason, adjunctive therapeutic measures directed at the host response rather than the pathogen are attractive. The immunomodulatory effects of macrolide antibiotics may play a significant role in management of severe CAP. The existing literature does not demonstrate a clear benefit for corticosteroids, but larger prospective randomized trials are needed. Nonsteroidal antiinflammatory drugs may benefit oxygenation but have no documented effect on mortality. Statin use before CAP diagnosis is associated with improved outcome but requires further research to determine if initiation at the time of diagnosis will affect outcome positively. Activation of the coagulation system appears to be a major pathophysiological event in severe pneumonia, but neither drotrecogin alfa activated nor tifacogin (recombinant tissue factor pathway inhibitor) have demonstrated a survival benefit. Other therapies have theoretical benefit but are not yet in the stage of clinical trials.

Keywords

corticosteroids - immunomodulation - macrolides - community-acquired pneumonia
 

  • References

  • 1 Xu J, Kochanek K, Murphy SL, Tejada-Vera B. Deaths: final data for 2007. Natl Vital Stat Rep 2010; 58: 1-135
    PubMedGoogle Scholar
  • 2 Whitney CG, Farley MM, Hadler J , et al; Active Bacterial Core Surveillance of the Emerging Infections Program Network. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med 2003; 348 (18) 1737-1746
    CrossrefPubMedGoogle Scholar
  • 3 Simpson JC, Macfarlane JT, Watson J, Woodhead MA ; British Thoracic Society Research Committee and Public Health Laboratory Service. A national confidential enquiry into community acquired pneumonia deaths in young adults in England and Wales. Thorax 2000; 55 (12) 1040-1045
    CrossrefPubMedGoogle Scholar
  • 4 Rivers E, Nguyen B, Havstad S , et al; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345 (19) 1368-1377
    CrossrefPubMedGoogle Scholar
  • 5 Giamarellos-Bourboulis EJ. Macrolides beyond the conventional antimicrobials: a class of potent immunomodulators. Int J Antimicrob Agents 2008; 31 (1) 12-20
    CrossrefPubMedGoogle Scholar
  • 6 Amsden GW. Anti-inflammatory effects of macrolides—an underappreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflammatory pulmonary conditions?. J Antimicrob Chemother 2005; 55 (1) 10-21
    CrossrefPubMedGoogle Scholar
  • 7 Reato G, Cuffini AM, Tullio V , et al. Immunomodulating effect of antimicrobial agents on cytokine production by human polymorphonuclear neutrophils. Int J Antimicrob Agents 2004; 23 (2) 150-154
    CrossrefPubMedGoogle Scholar
  • 8 Koch CC, Esteban DJ, Chin AC , et al. Apoptosis, oxidative metabolism and interleukin-8 production in human neutrophils exposed to azithromycin: effects of Streptococcus pneumoniae. J Antimicrob Chemother 2000; 46 (1) 19-26
    CrossrefPubMedGoogle Scholar
  • 9 Kudoh S, Azuma A, Yamamoto M, Izumi T, Ando M. Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin. Am J Respir Crit Care Med 1998; 157 (6 Pt 1) 1829-1832
    CrossrefPubMedGoogle Scholar
  • 10 Majumdar SR, McAlister FA, Eurich DT, Padwal RS, Marrie TJ. Statins and outcomes in patients admitted to hospital with community acquired pneumonia: population based prospective cohort study. BMJ 2006; 333 (7576) 999
    CrossrefPubMedGoogle Scholar
  • 11 Mortensen EM, Pugh MJ, Copeland LA , et al. Impact of statins and angiotensin-converting enzyme inhibitors on mortality of subjects hospitalised with pneumonia. Eur Respir J 2008; 31 (3) 611-617
    CrossrefPubMedGoogle Scholar
  • 12 Schlienger RG, Fedson DS, Jick SS, Jick H, Meier CR. Statins and the risk of pneumonia: a population-based, nested case-control study. Pharmacotherapy 2007; 27 (3) 325-332
    CrossrefPubMedGoogle Scholar
  • 13 Waterer GW, Somes GW, Wunderink RG. Monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia. Arch Intern Med 2001; 161 (15) 1837-1842
    CrossrefPubMedGoogle Scholar
  • 14 Weiss K, Low DE, Cortes L , et al. Clinical characteristics at initial presentation and impact of dual therapy on the outcome of bacteremic Streptococcus pneumoniae pneumonia in adults. Can Respir J 2004; 11 (8) 589-593
    PubMedGoogle Scholar
  • 15 Restrepo MI, Mortensen EM, Waterer GW, Wunderink RG, Coalson JJ, Anzueto A. Impact of macrolide therapy on mortality for patients with severe sepsis due to pneumonia. Eur Respir J 2009; 33 (1) 153-159
    CrossrefPubMedGoogle Scholar
  • 16 Mufson MA, Stanek RJ. Bacteremic pneumococcal pneumonia in one American City: a 20-year longitudinal study, 1978-1997. Am J Med 1999; 107 (1A) 34S-43S
    PubMedGoogle Scholar
  • 17 Martínez JA, Horcajada JP, Almela M , et al. Addition of a macrolide to a beta-lactam-based empirical antibiotic regimen is associated with lower in-hospital mortality for patients with bacteremic pneumococcal pneumonia. Clin Infect Dis 2003; 36 (4) 389-395
    CrossrefPubMedGoogle Scholar
  • 18 Baddour LM, Yu VL, Klugman KP , et al; International Pneumococcal Study Group. Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia. Am J Respir Crit Care Med 2004; 170 (4) 440-444
    CrossrefPubMedGoogle Scholar
  • 19 García Vázquez E, Mensa J, Martínez JA , et al. Lower mortality among patients with community-acquired pneumonia treated with a macrolide plus a beta-lactam agent versus a beta-lactam agent alone. Eur J Clin Microbiol Infect Dis 2005; 24 (3) 190-195
    CrossrefPubMedGoogle Scholar
  • 20 Meehan TP, Fine MJ, Krumholz HM , et al. Quality of care, process, and outcomes in elderly patients with pneumonia. JAMA 1997; 278 (23) 2080-2084
    CrossrefPubMedGoogle Scholar
  • 21 Brown RB, Iannini P, Gross P, Kunkel M. Impact of initial antibiotic choice on clinical outcomes in community-acquired pneumonia: analysis of a hospital claims-made database. Chest 2003; 123 (5) 1503-1511
    CrossrefPubMedGoogle Scholar
  • 22 Aspa J, Rajas O, Rodriguez de Castro F , et al; Pneumococcal Pneumonia in Spain Study Group. Impact of initial antibiotic choice on mortality from pneumococcal pneumonia. Eur Respir J 2006; 27 (5) 1010-1019
    PubMedGoogle Scholar
  • 23 Harbarth S, Garbino J, Pugin J, Romand JA, Pittet D. Lack of effect of combination antibiotic therapy on mortality in patients with pneumococcal sepsis. Eur J Clin Microbiol Infect Dis 2005; 24 (10) 688-690
    CrossrefPubMedGoogle Scholar
  • 24 Dwyer R, Ortqvist A, Aufwerber E , et al. Addition of a macrolide to a ss-lactam in bacteremic pneumococcal pneumonia. Eur J Clin Microbiol Infect Dis 2006; 25 (8) 518-521
    CrossrefPubMedGoogle Scholar
  • 25 Houck PM, MacLehose RF, Niederman MS, Lowery JK. Empiric antibiotic therapy and mortality among Medicare pneumonia inpatients in 10 western states: 1993, 1995, and 1997. Chest 2001; 119 (5) 1420-1426
    CrossrefPubMedGoogle Scholar
  • 26 Metersky ML, Ma A, Houck PM, Bratzler DW. Antibiotics for bacteremic pneumonia: Improved outcomes with macrolides but not fluoroquinolones. Chest 2007; 131 (2) 466-473
    CrossrefPubMedGoogle Scholar
  • 27 Lonks JR, Garau J, Gomez L , et al. Failure of macrolide antibiotic treatment in patients with bacteremia due to erythromycin-resistant Streptococcus pneumoniae. Clin Infect Dis 2002; 35 (5) 556-564
    CrossrefPubMedGoogle Scholar
  • 28 Rodríguez A, Mendia A, Sirvent JM , et al; CAPUCI Study Group. Combination antibiotic therapy improves survival in patients with community-acquired pneumonia and shock. Crit Care Med 2007; 35 (6) 1493-1498
    CrossrefPubMedGoogle Scholar
  • 29 Giamarellos-Bourboulis EJ, Pechère JC, Routsi C , et al. Effect of clarithromycin in patients with sepsis and ventilator-associated pneumonia. Clin Infect Dis 2008; 46 (8) 1157-1164
    CrossrefPubMedGoogle Scholar
  • 30 Mandell LA, Wunderink RG, Anzueto A , et al; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44 (Suppl. 02) S27-S72
    CrossrefPubMedGoogle Scholar
  • 31 Bodí M, Rodríguez A, Solé-Violán J , et al; Community-Acquired Pneumonia Intensive Care Units (CAPUCI) Study Investigators. Antibiotic prescription for community-acquired pneumonia in the intensive care unit: impact of adherence to Infectious Diseases Society of America guidelines on survival. Clin Infect Dis 2005; 41 (12) 1709-1716
    CrossrefPubMedGoogle Scholar
  • 32 Dean NC, Silver MP, Bateman KA, James B, Hadlock CJ, Hale D. Decreased mortality after implementation of a treatment guideline for community-acquired pneumonia. Am J Med 2001; 110 (6) 451-457
    CrossrefPubMedGoogle Scholar
  • 33 Wagner Jr HN, Bennett Jr IL, Lasagna L, Cluff LE, Rosenthal MB, Mirick GS. The effect of hydrocortisone upon the course of pneumococcal pneumonia treated with penicillin. Bull Johns Hopkins Hosp 1956; 98 (3) 197-215
    PubMedGoogle Scholar
  • 34 Meijvis SC, Hardeman H, Remmelts HH , et al. Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial. Lancet 2011; 377 (9782) 2023-2030
    CrossrefPubMedGoogle Scholar
  • 35 Snijders D, Daniels JM, de Graaff CS, van der Werf TS, Boersma WG. Efficacy of corticosteroids in community-acquired pneumonia: a randomized double-blinded clinical trial. Am J Respir Crit Care Med 2010; 181 (9) 975-982
    CrossrefPubMedGoogle Scholar
  • 36 Confalonieri M, Urbino R, Potena A , et al. Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med 2005; 171 (3) 242-248
    CrossrefPubMedGoogle Scholar
  • 37 Confalonieri M, Potena A, Carbone G, Porta RD, Tolley EA, Umberto Meduri G. Acute respiratory failure in patients with severe community-acquired pneumonia. A prospective randomized evaluation of noninvasive ventilation. Am J Respir Crit Care Med 1999; 160 (5 Pt 1) 1585-1591
    CrossrefPubMedGoogle Scholar
  • 38 Fernández-Serrano S, Dorca J, Garcia-Vidal C , et al. Effect of corticosteroids on the clinical course of community-acquired pneumonia: a randomized controlled trial. Crit Care 2011; 15 (2) R96
    CrossrefPubMedGoogle Scholar
  • 39 Marik P, Kraus P, Sribante J, Havlik I, Lipman J, Johnson DW. Hydrocortisone and tumour necrosis factor in severe community-acquired pneumonia. A randomized controlled study. Chest 1993; 104 (2) 389-392
    CrossrefPubMedGoogle Scholar
  • 40 Sprung CL, Annane D, Keh D , et al; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008; 358 (2) 111-124
    CrossrefPubMedGoogle Scholar
  • 41 Salluh JI, Bozza FA, Soares M , et al. Adrenal response in severe community-acquired pneumonia: impact on outcomes and disease severity. Chest 2008; 134 (5) 947-954
    CrossrefPubMedGoogle Scholar
  • 42 Garcia-Vidal C, Calbo E, Pascual V, Ferrer C, Quintana S, Garau J. Effects of systemic steroids in patients with severe community-acquired pneumonia. Eur Respir J 2007; 30 (5) 951-956
    CrossrefPubMedGoogle Scholar
  • 43 Weiss AK, Hall M, Lee GE, Kronman MP, Sheffler-Collins S, Shah SS. Adjunct corticosteroids in children hospitalized with community-acquired pneumonia. Pediatrics 2011; 127 (2) e255-e263
    CrossrefPubMedGoogle Scholar
  • 44 Gagnon S, Boota AM, Fischl MA, Baier H, Kirksey OW, La Voie L. Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A double-blind, placebo-controlled trial. N Engl J Med 1990; 323 (21) 1444-1450
    CrossrefPubMedGoogle Scholar
  • 45 Bozzette SA, Sattler FR, Chiu J , et al; California Collaborative Treatment Group. A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 1990; 323 (21) 1451-1457
    CrossrefPubMedGoogle Scholar
  • 46 Roberts C, Nirmalan M, O'Shea S. Steroid-sensitive post-viral inflammatory pneumonitis (PVIP). Am J Respir Crit Care Med 2010; 182 (8) 1089-1090
    PubMedGoogle Scholar
  • 47 Kim SH, Hong SB, Yun SC , et al; Korean Society of Critical Care Medicine H1N1 Collaborative. Corticosteroid treatment in critically ill patients with pandemic influenza A/H1N1 2009 infection: analytic strategy using propensity scores. Am J Respir Crit Care Med 2011; 183 (9) 1207-1214
    CrossrefPubMedGoogle Scholar
  • 48 Martin-Loeches I, Lisboa T, Rhodes A , et al; ESICM H1N1 Registry Contributors. Use of early corticosteroid therapy on ICU admission in patients affected by severe pandemic (H1N1)v influenza A infection. Intensive Care Med 2011; 37 (2) 272-283
    CrossrefPubMedGoogle Scholar
  • 49 Brun-Buisson C, Richard JC, Mercat A, Thiébaut AC, Brochard L ; REVA-SRLF A/H1N1v 2009 Registry Group. Early corticosteroids in severe influenza A/H1N1 pneumonia and acute respiratory distress syndrome. Am J Respir Crit Care Med 2011; 183 (9) 1200-1206
    CrossrefPubMedGoogle Scholar
  • 50 Light RB. Indomethacin and acetylsalicylic acid reduce intrapulmonary shunt in experimental pneumococcal pneumonia. Am Rev Respir Dis 1986; 134 (3) 520-525
    PubMedGoogle Scholar
  • 51 Hanly PJ, Roberts D, Dobson K, Light RB. Effect of indomethacin on arterial oxygenation in critically ill patients with severe bacterial pneumonia. Lancet 1987; 1 (8529) 351-354
    PubMedGoogle Scholar
  • 52 Ferrer M, Torres A, Baer R, Hernández C, Roca J, Rodriguez-Roisin R. Effect of acetylsalicylic acid on pulmonary gas exchange in patients with severe pneumonia: a pilot study. Chest 1997; 111 (4) 1094-1100
    CrossrefPubMedGoogle Scholar
  • 53 Bernard GR, Wheeler AP, Russell JA , et al; The Ibuprofen in Sepsis Study Group. The effects of ibuprofen on the physiology and survival of patients with sepsis. N Engl J Med 1997; 336 (13) 912-918
    CrossrefPubMedGoogle Scholar
  • 54 Voiriot G, Dury S, Parrot A, Mayaud C, Fartoukh M. Nonsteroidal antiinflammatory drugs may affect the presentation and course of community-acquired pneumonia. Chest 2011; 139 (2) 387-394
    CrossrefPubMedGoogle Scholar
  • 55 Arons MM, Wheeler AP, Bernard GR , et al; Ibuprofen in Sepsis Study Group. Effects of ibuprofen on the physiology and survival of hypothermic sepsis. Crit Care Med 1999; 27 (4) 699-707
    CrossrefPubMedGoogle Scholar
  • 56 Mortensen EM, Restrepo MI, Anzueto A, Pugh J. The effect of prior statin use on 30-day mortality for patients hospitalized with community-acquired pneumonia. Respir Res 2005; 6: 82
    CrossrefPubMedGoogle Scholar
  • 57 Frost FJ, Petersen H, Tollestrup K, Skipper B. Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins. Chest 2007; 131 (4) 1006-1012
    CrossrefPubMedGoogle Scholar
  • 58 Chalmers JD, Singanayagam A, Murray MP, Hill AT. Prior statin use is associated with improved outcomes in community-acquired pneumonia. Am J Med 2008; 121 (11) 1002-1007 , e1
    CrossrefPubMedGoogle Scholar
  • 59 Thomsen RW, Riis A, Kornum JB, Christensen S, Johnsen SP, Sørensen HT. Preadmission use of statins and outcomes after hospitalization with pneumonia: population-based cohort study of 29,900 patients. Arch Intern Med 2008; 168 (19) 2081-2087
    CrossrefPubMedGoogle Scholar
  • 60 Liappis AP, Kan VL, Rochester CG, Simon GL. The effect of statins on mortality in patients with bacteremia. Clin Infect Dis 2001; 33 (8) 1352-1357
    CrossrefPubMedGoogle Scholar
  • 61 Thomsen RW, Hundborg HH, Johnsen SP , et al. Statin use and mortality within 180 days after bacteremia: a population-based cohort study. Crit Care Med 2006; 34 (4) 1080-1086
    CrossrefPubMedGoogle Scholar
  • 62 Myles PR, Hubbard RB, McKeever TM, Pogson Z, Smith CJ, Gibson JE. Risk of community-acquired pneumonia and the use of statins, ace inhibitors and gastric acid suppressants: a population-based case-control study. Pharmacoepidemiol Drug Saf 2009; 18 (4) 269-275
    CrossrefPubMedGoogle Scholar
  • 63 Douglas I, Evans S, Smeeth L.. Effect of statin treatment on short term mortality after pneumonia episode: cohort study. BMJ 2011; 342 :d1642.
    PubMedGoogle Scholar
  • 64 Yende S, Milbrandt EB, Kellum JA , et al. Understanding the potential role of statins in pneumonia and sepsis. Crit Care Med 2011; 39 (8) 1871-1878
    CrossrefPubMedGoogle Scholar
  • 65 Kruger PS, Harward ML, Jones MA , et al. Continuation of statin therapy in patients with presumed infection: a randomized controlled trial. Am J Respir Crit Care Med 2011; 183 (6) 774-781
    CrossrefPubMedGoogle Scholar
  • 66 Musher DM, Rueda AM, Kaka AS, Mapara SM. The association between pneumococcal pneumonia and acute cardiac events. Clin Infect Dis 2007; 45 (2) 158-165
    CrossrefPubMedGoogle Scholar
  • 67 Corrales-Medina VF, Serpa J, Rueda AM , et al. Acute bacterial pneumonia is associated with the occurrence of acute coronary syndromes. Medicine (Baltimore) 2009; 88 (3) 154-159
    CrossrefPubMedGoogle Scholar
  • 68 Ramirez J, Aliberti S, Mirsaeidi M , et al. Acute myocardial infarction in hospitalized patients with community-acquired pneumonia. Clin Infect Dis 2008; 47 (2) 182-187
    CrossrefPubMedGoogle Scholar
  • 69 Yende S, D'Angelo G, Mayr F , et al; GenIMS Investigators. Elevated hemostasis markers after pneumonia increases one-year risk of all-cause and cardiovascular deaths. PLoS ONE 2011; 6 (8) e22847
    CrossrefPubMedGoogle Scholar
  • 70 Winning J, Reichel J, Eisenhut Y , et al. Anti-platelet drugs and outcome in severe infection: clinical impact and underlying mechanisms. Platelets 2009; 20 (1) 50-57
    CrossrefPubMedGoogle Scholar
  • 71 Dowling HF, Lepper MH. The effect of antibiotics (penicillin, aureomycin, and terramycin) on the fatality rate and incidence of complications in pneumococcic pneumonia; a comparison with other methods of therapy. Am J Med Sci 1951; 222 (4) 396-403
    CrossrefPubMedGoogle Scholar
  • 72 Austrian R, Gold J. Pneumococcal bacteremia with special reference to bacteremic pneumococcal pneumonia. Ann Intern Med 1964; 60: 759-776
    CrossrefPubMedGoogle Scholar
  • 73 Turgeon AF, Hutton B, Fergusson DA , et al. Meta-analysis: intravenous immunoglobulin in critically ill adult patients with sepsis. Ann Intern Med 2007; 146 (3) 193-203
    CrossrefPubMedGoogle Scholar
  • 74 Deans KJ, Haley M, Natanson C, Eichacker PQ, Minneci PC. Novel therapies for sepsis: a review. J Trauma 2005; 58 (4) 867-874
    CrossrefPubMedGoogle Scholar
  • 75 Wunderink R, Leeper Jr K, Schein R , et al. Filgrastim in patients with pneumonia and severe sepsis or septic shock. Chest 2001; 119 (2) 523-529
    CrossrefPubMedGoogle Scholar
  • 76 Wunderink RG, Laterre PF, Francois B , et al; CAPTIVATE Trial Group. Recombinant tissue factor pathway inhibitor in severe community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med 2011; 183 (11) 1561-1568
    CrossrefPubMedGoogle Scholar
  • 77 Bernard GR, Vincent JL, Laterre PF , et al; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344 (10) 699-709
    CrossrefPubMedGoogle Scholar
  • 78 Choi G, Hofstra JJ, Roelofs JJ , et al. Antithrombin inhibits bronchoalveolar activation of coagulation and limits lung injury during Streptococcus pneumoniae pneumonia in rats. Crit Care Med 2008; 36 (1) 204-210
    CrossrefPubMedGoogle Scholar
  • 79 Brogly N, Devos P, Boussekey N, Georges H, Chiche A, Leroy O. Impact of thrombocytopenia on outcome of patients admitted to ICU for severe community-acquired pneumonia. J Infect 2007; 55 (2) 136-140
    CrossrefPubMedGoogle Scholar
  • 80 Querol-Ribelles JM, Tenias JM, Grau E , et al. Plasma d-dimer levels correlate with outcomes in patients with community-acquired pneumonia. Chest 2004; 126 (4) 1087-1092
    CrossrefPubMedGoogle Scholar
  • 81 Laterre PF, Garber G, Levy H , et al; PROWESS Clinical Evaluation Committee. Severe community-acquired pneumonia as a cause of severe sepsis: data from the PROWESS study. Crit Care Med 2005; 33 (5) 952-961
    CrossrefPubMedGoogle Scholar
  • 82 Ely EW, Laterre PF, Angus DC , et al; PROWESS Investigators. Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis. Crit Care Med 2003; 31 (1) 12-19
    CrossrefPubMedGoogle Scholar
  • 83 Abraham E, Reinhart K, Opal S , et al; OPTIMIST Trial Study Group. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 2003; 290 (2) 238-247
    Google Scholar
  • 84 Laterre PF, Opal SM, Abraham E , et al. A clinical evaluation committee assessment of recombinant human tissue factor pathway inhibitor (tifacogin) in patients with severe community-acquired pneumonia. Crit Care 2009; 13 (2) R36
    CrossrefPubMedGoogle Scholar
  • 85 Ranieri VM, Thompson BT, Barie PS , et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 2012; [epub ahead of print]. PMID 22616830
    PubMedGoogle Scholar
  • 86 Jaimes F, De La Rosa G, Morales C , et al. Unfractioned heparin for treatment of sepsis: A randomized clinical trial (The HETRASE Study). Crit Care Med 2009; 37 (4) 1185-1196
    CrossrefPubMedGoogle Scholar
  • 87 Geerts WH, Bergqvist D, Pineo GF , et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (6 Suppl) 381S-453S
    CrossrefPubMedGoogle Scholar
  • 88 Okaishi K, Morimoto S, Fukuo K , et al. Reduction of risk of pneumonia associated with use of angiotensin I converting enzyme inhibitors in elderly inpatients. Am J Hypertens 1999; 12 (8 Pt 1) 778-783
    CrossrefPubMedGoogle Scholar
  • 89 Takahashi T, Morimoto S, Okaishi K , et al. Reduction of pneumonia risk by an angiotensin I-converting enzyme inhibitor in elderly Japanese inpatients according to insertion/deletion polymorphism of the angiotensin I-converting enzyme gene. Am J Hypertens 2005; 18 (10) 1353-1359
    CrossrefPubMedGoogle Scholar
  • 90 Rafailidis PI, Matthaiou DK, Varbobitis I, Falagas ME. Use of ACE inhibitors and risk of community-acquired pneumonia: a review. Eur J Clin Pharmacol 2008; 64 (6) 565-573
    CrossrefPubMedGoogle Scholar
  • 91 Mortensen EM, Restrepo MI, Anzueto A, Pugh J. The impact of prior outpatient ACE inhibitor use on 30-day mortality for patients hospitalized with community-acquired pneumonia. BMC Pulm Med 2005; 5: 12
    CrossrefPubMedGoogle Scholar
  • 92 van de Garde EM, Souverein PC, van den Bosch JM, Deneer VH, Leufkens HG. Angiotensin-converting enzyme inhibitor use and pneumonia risk in a general population. Eur Respir J 2006; 27 (6) 1217-1222
    CrossrefPubMedGoogle Scholar
  • 93 Etminan M, Zhang B, Fitzgerald M, Brophy JM. Do angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers decrease the risk of hospitalization secondary to community-acquired pneumonia? A nested case-control study. Pharmacotherapy 2006; 26 (4) 479-482
    CrossrefPubMedGoogle Scholar
  • 94 van de Garde EM, Souverein PC, Hak E, Deneer VH, van den Bosch JM, Leufkens HG. Angiotensin-converting enzyme inhibitor use and protection against pneumonia in patients with diabetes. J Hypertens 2007; 25 (1) 235-239
    CrossrefPubMedGoogle Scholar
  • 95 Mukamal KJ, Ghimire S, Pandey R, O'Meara ES, Gautam S. Antihypertensive medications and risk of community-acquired pneumonia. J Hypertens 2010; 28 (2) 401-405
    CrossrefPubMedGoogle Scholar
  • 96 Mortensen EM, Restrepo MI, Copeland LA, Pugh JA, Anzueto A. Association of hydrophilic versus lipophilic angiotensin-converting enzyme inhibitor use on pneumonia-related mortality. Am J Med Sci 2008; 336 (6) 462-466
    CrossrefPubMedGoogle Scholar
  • 97 Akram AR, Singanayagam A, Choudhury G, Mandal P, Chalmers JD, Hill AT. Incidence and prognostic implications of acute kidney injury on admission in patients with community-acquired pneumonia. Chest 2010; 138 (4) 825-832
    CrossrefPubMedGoogle Scholar
  • 98 Singh S, Loke YK, Furberg CD. Long-term use of thiazolidinediones and the associated risk of pneumonia or lower respiratory tract infection: systematic review and meta-analysis. Thorax 2011; 66 (5) 383-388
    CrossrefPubMedGoogle Scholar
  • 99 Koh GC, Maude RR, Schreiber MF , et al. Glyburide is anti-inflammatory and associated with reduced mortality in melioidosis. Clin Infect Dis 2011; 52 (6) 717-725
    CrossrefPubMedGoogle Scholar
  • 100 Fedson DS. Confronting the next influenza pandemic with anti-inflammatory and immunomodulatory agents: why they are needed and how they might work. Influenza Other Respir Viruses 2009; 3 (4) 129-142
    CrossrefPubMedGoogle Scholar