Adjunctive Therapy in Community-Acquired Pneumonia

ABSTRACT

Despite potent antibiotics, community-acquired pneumonia (CAP) remains the most common cause of death from infection and the seventh overall leading cause of death in the United States. For this reason, interest has been redirected into nonantibiotic therapeutic measures. Despite theoretical benefits, the existing literature does not suggest a clear benefit for corticosteroid treatment, but large prospective randomized trials are needed. Nonsteroidal antiinflammatory drugs may benefit oxygenation but have no documented effect on mortality. Activation of the coagulation system appears to be a major pathophysiological event in severe pneumonia, possibly even more so than for sepsis in general. The CAP subgroup in phase III sepsis trials of both drotrecogin alfa (activated) and tifacogin (recombinant tissue factor pathway inhibitor) demonstrated the greatest benefit. The immunomodulatory effects of macrolide antibiotics may play a significant role in management of severe CAP. Exogenous surfactant replacement is being explored as adjunctive therapy for acute lung injury due to CAP. 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. Other therapies have theoretical benefit but are not yet in the stage of clinical trials.

KEYWORDS

Corticosteroids - immunomodulation - drotrecogin alfa (activated)

REFERENCES

• 1 Dowling H F, Lepper M H. 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;  222 396-403
• 2 Anderson R N, Smith B L. Deaths: leading causes for 2002.  Natl Vital Stat Rep. 2005;  53 1-89
• 3 Fine M J, Smith M A, Carson C A et al.. Prognosis and outcomes of patients with community-acquired pneumonia: a meta-analysis.  JAMA. 1996;  275 134-141
• 4 Watanakunakorn C, Bailey T A. Adult bacteremic pneumococcal pneumonia in a community teaching hospital, 1992–1996: a detailed analysis of 108 cases.  Arch Intern Med. 1997;  157 1965-1971
• 5 Burman L A, Norrby R, Trollfors B. Invasive pneumococcal infections: incidence, predisposing factors, and prognosis.  Rev Infect Dis. 1985;  7 133-142
• 6 Gillet Y, Issartel B, Vanhems P et al.. Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients.  Lancet. 2002;  359 753-759
• 7 Francis J S, Doherty M C, Lopatin U et al.. Severe community-onset pneumonia in healthy adults caused by methicillin-resistant Staphylococcus aureus carrying the Panton-Valentine leukocidin genes.  Clin Infect Dis. 2005;  40 100-107
• 8 Whitney C G, Farley M M, Hadler J et al.. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine.  N Engl J Med. 2003;  348 1737-1746
• 9 Crowley M R, Katz R W, Kessler R et al.. Successful treatment of adults with severe Hantavirus pulmonary syndrome with extracorporeal membrane oxygenation.  Crit Care Med. 1998;  26 409-414
• 10 Gagnon S, Boota A M, Fischl M A, Baier H, Kirksey O W, 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 1444-1450
• 11 Bozzette S A, Sattler F R, Chiu J et al.. A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. California Collaborative Treatment Group.  N Engl J Med. 1990;  323 1451-1457
• 12 Lau L G. Adult varicella pneumonia that responded to combined acyclovir and steroid therapy.  Med J Malaysia. 1999;  54 270-272
• 13 Adhami N, Arabi Y, Raees A, Al-Shimemeri A, Ur-Rahman M, Memish Z A. Effect of corticosteroids on adult varicella pneumonia: cohort study and literature review.  Respirology. 2006;  11 437-441
• 14 Ahmed R, Ahmed Q A, Adhami N A, Memish Z A. Varicella pneumonia: another “steroid responsive” pneumonia?.  J Chemother. 2002;  14 220-222
• 15 Mer M, Richards G A. Corticosteroids in life-threatening varicella pneumonia.  Chest. 1998;  114 426-431
• 16 Popara M, Pendle S, Sacks L, Smego Jr R A, Mer M. Varicella pneumonia in patients with HIV/AIDS.  Int J Infect Dis. 2002;  6 6-8
• 17 Goldman M, Johnson P C, Sarosi G A. Fungal pneumonias: the endemic mycoses.  Clin Chest Med. 1999;  20 507-519
• 18 Bradsher R W. Histoplasmosis and blastomycosis.  Clin Infect Dis. 1996;  22(Suppl 2) S102-S111
• 19 Lahm T, Neese S, Thornburg A T, Ober M D, Sarosi G A, Hage C A. Corticosteroids for blastomycosis-induced ARDS: a report of two patients and review of the literature.  Chest. 2008;  133 1478-1480
• 20 Marik P, Kraus P, Bribante J et al.. Hydrocortisone and tumour necrosis factor in severe community acquired pneumonia.  Chest. 1993;  104 389-392
• 21 Montón C, Ewig S, Torres A et al.. Role of glucocorticoids on inflammatory response in nonimmunosuppressed patients with pneumonia: a pilot study.  Eur Respir J. 1999;  14 218-220
• 22 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;  171 242-248
• 23 Confalonieri M, Potena A, Carbone G, Porta R D, Tolley E A, Meduri G U. 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
• 24 Sprung C L, Annane D, Keh D et al.. Hydrocortisone therapy for patients with septic shock.  N Engl J Med. 2008;  358 111-124
• 25 Salluh J I, Bozza F A, Soares M et al.. Adrenal response in severe community-acquired pneumonia: impact on outcomes and disease severity.  Chest. 2008;  134 947-954
• 26 Light R B. Indomethacin and acetylsalicylic acid reduce intrapulmonary shunt in experimental pneumococcal pneumonia.  Am Rev Respir Dis. 1986;  134 520-525
• 27 Hanly P J, Roberts D, Dobson K, Light R B. Effect of indomethacin on arterial oxygenation in critically ill patients with severe bacterial pneumonia.  Lancet. 1987;  1 351-354
• 28 Ferrer M, Torres A, Baer R, Hernandez 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 1094-1100
• 29 Bernard G R, Wheeler A P, Russell J A et al.. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group.  N Engl J Med. 1997;  336 912-918
• 30 Arons M M, Wheeler A P, Bernard G R et al.. Effects of ibuprofen on the physiology and survival of hypothermic sepsis. Ibuprofen in Sepsis Study Group.  Crit Care Med. 1999;  27 699-707
• 31 Dhainaut J F, Yan S B, Joyce D E et al.. Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation.  J Thromb Haemost. 2004;  2 1924-1933
• 32 Choi G, Hofstra J J, Roelofs J J et al.. Antithrombin inhibits bronchoalveolar activation of coagulation and limits lung injury during Streptococcus pneumoniae pneumonia in rats.  Crit Care Med. 2008;  36 204-210
• 33 Bernard G R, Vincent J L, Laterre P F et al.. Efficacy and safety of recombinant human activated protein C for severe sepsis.  N Engl J Med. 2001;  344 699-709
• 34 Laterre P F, Garber G, Levy H et al.. Severe community-acquired pneumonia as a cause of severe sepsis: data from the PROWESS study.  Crit Care Med. 2005;  33 952-961
• 35 Roson B, Fernandez-Sabe N, Carratala J et al.. Contribution of a urinary antigen assay (Binax NOW) to the early diagnosis of pneumococcal pneumonia.  Clin Infect Dis. 2004;  38 222-226
• 36 Smith M D, Derrington P, Evans R et al.. Rapid diagnosis of bacteremic pneumococcal infections in adults by using the Binax NOW Streptococcus pneumoniae urinary antigen test: a prospective, controlled clinical evaluation.  J Clin Microbiol. 2003;  41 2810-2813
• 37 Abraham E, Laterre P F, Garg R et al.. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death.  N Engl J Med. 2005;  353 1332-1341
• 38 Ely E W, Laterre P F, Angus D C et al.. Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis.  Crit Care Med. 2003;  31 12-19
• 39 Mandell L A, Wunderink R G, Anzueto A et al.. 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 2) S27-S72
• 40 Abraham E, Reinhart K, Opal S et al.. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial.  JAMA. 2003;  290 238-247
• 41 Laterre P F, Opal S M, 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;  , in press
• 42 Ramirez J, Aliberti S, Mirsaeidi M et al.. Acute myocardial infarction in hospitalized patients with community-acquired pneumonia.  Clin Infect Dis. 2008;  47 182-187
• 43 Geerts W H, Bergqvist D, Pineo G F 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
• 44 Tamaoki J. The effects of macrolides on inflammatory cells.  Chest. 2004;  125(2, Suppl) 41S-50S
• 45 Yamasawa H, Oshikawa K, Ohno S, Sugiyama Y. Macrolides inhibit epithelial cell-mediated neutrophil survival by modulating granulocyte macrophage colony-stimulating factor release.  Am J Respir Cell Mol Biol. 2004;  30 569-575
• 46 Labro M T, el Benna J, Babin-Chevaye C. Comparison of the in-vitro effect of several macrolides on the oxidative burst of human neutrophils.  J Antimicrob Chemother. 1989;  24 561-572
• 47 Joone G K, Van Rensburg C E, Anderson R. Investigation of the in-vitro uptake, intraphagocytic biological activity and effects on neutrophil superoxide generation of dirithromycin compared with erythromycin.  J Antimicrob Chemother. 1992;  30 509-523
• 48 Mitsuyama T, Tanaka T, Hidaka K, Abe M, Hara N. Inhibition by erythromycin of superoxide anion production by human polymorphonuclear leukocytes through the action of cyclic AMP-dependent protein kinase.  Respiration.. 1995;  62 269-273
• 49 Reato G, Cuffini A M, Tullio V et al.. Immunomodulating effect of antimicrobial agents on cytokine production by human polymorphonuclear neutrophils.  Int J Antimicrob Agents. 2004;  23 150-154
• 50 Koch C C, Esteban D J, Chin A C et al.. Apoptosis, oxidative metabolism and interleukin-8 production in human neutrophils exposed to azithromycin: effects of Streptococcus pneumoniae.  J Antimicrob Chemother. 2000;  46 19-26
• 51 Imamura Y, Yanagihara K, Mizuta Y et al.. Azithromycin inhibits MUC5AC production induced by the Pseudomonas aeruginosa autoinducer N-(3-Oxododecanoyl) homoserine lactone in NCI-H292 Cells.  Antimicrob Agents Chemother. 2004;  48 3457-3461
• 52 Tamaoki J, Takeyama K, Yamawaki I, Kondo M, Konno K. Lipopolysaccharide-induced goblet cell hypersecretion in the guinea pig trachea: inhibition by macrolides.  Am J Physiol. 1997;  272(1 Pt 1) L15-L19
• 53 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
• 54 Amsden G W. 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 10-21
• 55 Brown R B, 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 1503-1511
• 56 Martinez J A, Horcajada J P, 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;  36 389-395
• 57 Waterer G W, Somes G W, Wunderink R G. Monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia.  Arch Intern Med. 2001;  161 1837-1842
• 58 Weiss K, Low D E, 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;  11 589-593
• 59 Mufson M A, Stanek R J. Bacteremic pneumococcal pneumonia in one American City: a 20-year longitudinal study, 1978–1997.  Am J Med. 1999;  107 34S-43S
• 60 Baddour L M, Yu V L, Klugman K P et al.. Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia.  Am J Respir Crit Care Med. 2004;  170 440-444
• 61 Harbarth S, Garbino J, Pugin J, Romand J A, Pittet D. Lack of effect of combination antibiotic therapy on mortality in patients with pneumococcal sepsis.  Eur J Clin Microbiol Infect Dis. 2005;  24 688-690
• 62 Aspa J, Rajas O, Rodriguez de Castro F et al.. Impact of initial antibiotic choice on mortality from pneumococcal pneumonia.  Eur Respir J. 2006;  27 1010-1019
• 63 Metersky M L, Ma A, Houck P M, Bratzler D W. Antibiotics for bacteremic pneumonia: Improved outcomes with macrolides but not fluoroquinolones.  Chest. 2007;  131 466-473
• 64 Lonks J R, 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;  35 556-564
• 65 Waterer G W, Somes G W, Wunderink R G. Monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia.  Arch Intern Med. 2001;  161 1837-1842
• 66 Giamarellos-Bourboulis E J, Pechere J C, Routsi C et al.. Effect of clarithromycin in patients with sepsis and ventilator-associated pneumonia.  Clin Infect Dis. 2008;  46 1157-1164
• 67 Taut F J, Rippin G, Schenk P et al.. A search for subgroups of patients with ARDS who may benefit from surfactant replacement therapy: a pooled analysis of five studies with recombinant surfactant protein-C surfactant (Venticute).  Chest. 2008;  134 724-732
• 68 Willson D F, Thomas N J, Markovitz B P et al.. Effect of exogenous surfactant (calfactant) in pediatric acute lung injury: a randomized controlled trial.  JAMA. 2005;  293 470-476
• 69 Lin Z, Pearson C, Chinchilli V et al.. Polymorphisms of human SP-A, SP-B, and SP-D genes: association of SP-B Thr131Ile with ARDS.  Clin Genet. 2000;  58 181-191
• 70 Quasney M W, Waterer G W, Dahmer M K et al.. Association between surfactant protein B + 1580 polymorphism and the risk of respiratory failure in adults with community-acquired pneumonia.  Crit Care Med. 2004;  32 1115-1119
• 71 Almog Y, Shefer A, Novack V et al.. Prior statin therapy is associated with a decreased rate of severe sepsis.  Circulation. 2004;  110 880-885
• 72 Thomsen R W, Hundborg H H, Johnsen S P et al.. Statin use and mortality within 180 days after bacteremia: a population-based cohort study.  Crit Care Med. 2006;  34 1080-1086
• 73 Kruger P, Fitzsimmons K, Cook D, Jones M, Nimmo G. Statin therapy is associated with fewer deaths in patients with bacteraemia.  Intensive Care Med. 2006;  32 75-79
• 74 Fernandez R, De Pedro V J, Artigas A. Statin therapy prior to ICU admission: protection against infection or a severity marker?.  Intensive Care Med. 2006;  32 160-164
• 75 Hackam D G, Mamdani M, Li P, Redelmeier D A. Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis.  Lancet. 2006;  367 413-418
• 76 Liappis A P, Kan V L, Rochester C G, Simon G L. The effect of statins on mortality in patients with bacteremia.  Clin Infect Dis. 2001;  33 1352-1357
• 77 Mortensen E M, Restrepo M I, 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
• 78 Thomsen R W, Riis A, Kornum J B, Christensen S, Johnsen S P, Sorensen H T. Preadmission use of statins and outcomes after hospitalization with pneumonia: population-based cohort study of 29,900 patients.  Arch Intern Med. 2008;  168 2081-2087
• 79 Majumdar S R, McAlister F A, Eurich D T, Padwal R S, Marrie T J. Statins and outcomes in patients admitted to hospital with community acquired pneumonia: population based prospective cohort study.  BMJ. 2006;  333 999
• 80 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;  12 778-783
• 81 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 1353-1359
• 82 van de Garde E M, Souverein P C, van den Bosch J M, Deneer V H, Leufkens H G. Angiotensin-converting enzyme inhibitor use and pneumonia risk in a general population.  Eur Respir J. 2006;  27 1217-1222
• 83 Etminan M, Zhang B, Fitzgerald M, Brophy J M. 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;  26 479-482
• 84 Turgeon A F, Hutton B, Fergusson D A et al.. Meta-analysis: intravenous immunoglobulin in critically ill adult patients with sepsis.  Ann Intern Med. 2007;  146 193-203
• 85 El-Nawawy A, El-Kinany H, Hamdy El-Sayed M, Boshra N. Intravenous polyclonal immunoglobulin administration to sepsis syndrome patients: a prospective study in a pediatric intensive care unit.  J Trop Pediatr. 2005;  51 271-278
• 86 Klimek J J, Ajemian E, Fontecchio S, Gracewski J, Klemas B, Jimenez L. Community-acquired bacterial pneumonia requiring admission to hospital.  Am J Infect Control. 1983;  11 79-82
• 87 Aubertin J, Dabis F, Fleurette J et al.. Prevalence of legionellosis among adults: a study of community-acquired pneumonia in France.  Infection. 1987;  15 328-331
• 88 Fang G D, Fine M, Orloff J et al.. New and emerging etiologies for community-acquired pneumonia with implications for therapy: a prospective multi-center study of 359 cases.  Medicine. 1990;  69 307-316
• 89 Lieberman D, Porath A, Schlaeffer F, Lieberman D, Boldur I. Legionella species community-acquired pneumonia: a review of 56 hospitalized adult patients.  Chest. 1996;  109 1243-1249
• 90 Tateda K, Matsumoto T, Ishii Y et al.. Serum cytokines in patients with Legionella pneumonia: relative predominance of Th1-type cytokines.  Clin Diagn Lab Immunol. 1998;  5 401-403
• 91 Friedman H, Yamamoto Y, Newton C, Klein T. Immunologic response and pathophysiology of Legionella infection.  Semin Respir Infect. 1998;  13 100-108
• 92 Murray H W. Interferon-gamma, the activated macrophage, and host defense against microbial challenge.  Ann Intern Med. 1988;  108 595-608
• 93 Nathan C F, Prendergast T J, Wiebe M E et al.. Activation of human macrophages: comparison of other cytokines with interferon-gamma.  J Exp Med. 1984;  160 600-605
• 94 Skerrett S J, Martin T R. Intratracheal interferon-gamma augments pulmonary defenses in experimental legionellosis.  Am J Respir Crit Care Med. 1994;  149 50-58