Intensive Care Medicine

, Volume 36, Issue 4, pp 612–620 | Cite as

Combination antibiotic therapy with macrolides improves survival in intubated patients with community-acquired pneumonia

  • I. Martin-Loeches
  • T. Lisboa
  • A. Rodriguez
  • C. Putensen
  • D. Annane
  • J. Garnacho-Montero
  • M. I. Restrepo
  • J. Rello



To assess the effect on survival of macrolides or fluoroquinolones in intubated patients admitted to the intensive care unit (ICU) with severe community-acquired pneumonia (severe CAP).


Prospective, observational cohort, multicenter study conducted in 27 ICUs of 9 European countries. Two hundred eighteen consecutive patients requiring invasive mechanical ventilation for an admission diagnosis of CAP were recruited.


Severe sepsis and septic shock were present in 165 (75.7%) patients. Microbiological documentation was obtained in 102 (46.8%) patients. ICU mortality was 37.6% (n = 82). Non-survivors were older (58.6 ± 16.1 vs. 63.4 ± 16.7 years, P < 0.05) and presented a higher score on the simplified Acute Physiology Score II at admission (45.6 ± 15.4 vs. 50.8 ± 17.5, P < 0.05). Monotherapy was given in 43 (19.7%) and combination therapy in 175 (80.3%) patients. Empirical antibiotic therapy was in accordance with the 2007 Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) guidelines in 100 (45.9%) patients (macrolides in 46 patients and fluoroquinolones in 54). In this cohort, a Cox regression analysis adjusted by severity identified that macrolide use was associated with lower ICU mortality (hazard ratio, HR 0.48, confidence intervals, 95% CI 0.23–0.97, P = 0.04) when compared to the use of fluoroquinolones. When more severe patients presenting severe sepsis and septic shock were analyzed (n = 92), similar results were obtained (HR 0.44, 95% CI 0.20–0.95, P = 0.03).


Patients with severe community-acquired pneumonia had a low adherence with the 2007 IDSA/ATS guidelines. Combination therapy with macrolides should be preferred in intubated patients with severe CAP.


Severe community-acquired pneumonia Macrolides Critical care Mortality 



The EU-VAP/CAP Study is endorsed by the European Critical Care Research Network (ECCRN). This study has been supported in part by grants from CIBER Enfermedades Respiratorias (CIBERES 37706/06/0036) by Carlos III Health Institute and FISS 04/1500. Dr. Restrepo is supported by a Department of Veteran Affairs Veterans Integrated Service Network 17 new faculty grant and National Health Institute grant KL2 RR025766.

Conflict of interest statement

The authors declare no conflict of interest regarding this manuscript.


  1. 1.
    Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 29:1303–1310CrossRefPubMedGoogle Scholar
  2. 2.
    Bodi M, Rodriguez A, Sole-Violan J, Gilavert MC, Garnacho J, Blanquer J, Jimenez J, de la Torre MV, Sirvent JM, Almirall J, Doblas A, Badia JR, Garcia F, Mendia A, Jorda R, Bobillo F, Valles J, Broch MJ, Carrasco N, Herranz MA, Rello J (2005) 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 41:1709–1716CrossRefPubMedGoogle Scholar
  3. 3.
    Shorr AF, Bodi M, Rodriguez A, Sole-Violan J, Garnacho-Montero J, Rello J, for the CAPUCI Study Investigators (2006) Impact of antibiotic guideline compliance on duration of mechanical ventilation in critically ill patients with community-acquired pneumonia. Chest 130:93–100CrossRefPubMedGoogle Scholar
  4. 4.
    Rodríguez A, Mendia A, Sirvent JM, Barcenilla F, de la Torre-Prados MV, Solé-Violán J, Rello J, CAPUCI Study Group (2007) Combination antibiotic therapy improves survival in patients with community-acquired pneumonia and shock. Crit Care Med 35:1493–1498CrossRefPubMedGoogle Scholar
  5. 5.
    Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM Jr, Musher DM, Niederman MS, Torres A, Whitney CG (2007) 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 44(Suppl 2):S27–S72CrossRefPubMedGoogle Scholar
  6. 6.
    Restrepo MI, Mortensen EM, Waterer GW, Wunderink RG, Coalson JJ, Anzueto A (2009) Impact of macrolide therapy on mortality for patients with severe sepsis due to pneumonia. Eur Respir J 33:153–159CrossRefPubMedGoogle Scholar
  7. 7.
    Giamarellos-Bourboulis EJ, Adamis T, Laoutaris G, Sabracos L, Koussoulas V, Mouktaroudi M, Perrea D, Karayannacos PE, Giamarellou H (2004) Immunomodulatory clarithromycin treatment of experimental sepsis and acute pyelonephritis caused by multidrug-resistant pseudomonas aeruginosa. Antimicrob Agents Chemother 48:93–99CrossRefPubMedGoogle Scholar
  8. 8.
    Garcia Vazquez E, Mensa J, Martinez JA, Marcos MA, Puig J, Ortega M, Torres A (2005) 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 24:190–195CrossRefPubMedGoogle Scholar
  9. 9.
    Houck PM, MacLehose RF, Niederman MS, Lowery JK (2001) Empiric antibiotic therapy and mortality among medicare pneumonia inpatients in ten western states: 1993, 1995, and 1997. Chest 119:1420–1426CrossRefPubMedGoogle Scholar
  10. 10.
    Mortensen EM, Restrepo M, Anzueto A, Pugh J (2004) Effects of guideline-concordant antimicrobial therapy on mortality among patients with community-acquired pneumonia. Am J Med 117:726–731CrossRefPubMedGoogle Scholar
  11. 11.
    Koulenti D, Lisboa T, Brun-Buisson C, Krueger W, Macor A, Sole-Violan J, Diaz E, Topeli A, DeWaele J, Carneiro A, Martin-Loeches I, Armaganidis A, Rello J (2009) The spectrum of practice in the diagnosis of nosocomial pneumonia in patients requiring mechanical ventilation in European ICUs. Crit Care Med 37:2360–2368CrossRefPubMedGoogle Scholar
  12. 12.
    de Castro FR, Torres A (2003) Optimizing treatment outcomes in severe community-acquired pneumonia. Am J Respir Med 2:39–54PubMedGoogle Scholar
  13. 13.
    Rello J, Bodi M, Mariscal D, Navarro M, Diaz E, Gallego M, Valles J (2003) Microbiological testing and outcome of patients with severe community-acquired pneumonia. Chest 123:174–180CrossRefPubMedGoogle Scholar
  14. 14.
    Bartlett JG, Dowell SF, Mandell LA, File TM Jr, Musher DM, Fine MJ (2000) Practice guidelines for the management of community-acquired pneumonia in adults. Infectious Diseases Society of America. Clin Infect Dis 31:347–382CrossRefPubMedGoogle Scholar
  15. 15.
    Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS.CCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 31:1250-1256Google Scholar
  16. 16.
    Bone RC (1996) Why sepsis trials fail. JAMA 276:565–566CrossRefPubMedGoogle Scholar
  17. 17.
    Dambrava PG, Torres A, Vallès X, Mensa J, Marcos MA, Peñarroja G, Camps M, Estruch R, Sánchez M, Menéndez R, Niederman MS (2008) Adherence to guidelines’ empirical antibiotic recommendations and community-acquired pneumonia outcome. Eur Respir J 32:892–901CrossRefPubMedGoogle Scholar
  18. 18.
    Weiss K, Low DE, Cortes L, Beaupre A, Gauthier R, Gregoire P, Legare M, Nepveu F, Thibert D, Tremblay C, Tremblay J (2004) Clinical characteristics at initial presentation and impact of dual therapy on the outcome of bacteremic Streptococcus pneumoniae pneumonia in adults. Can Respir J 11:589–593PubMedGoogle Scholar
  19. 19.
    Sollet JP (2006) Respiratory tract infections: at-risk patients, who are they? Implications for their management with levofloxacin. Int J Antimicrob Agents 28 Suppl 2:S113–S114CrossRefPubMedGoogle Scholar
  20. 20.
    Baddour LM, Yu VL, Klugman KP, Feldman C, Ortkvist A, Rello J, Morris AJ, Luna CM, Snydman DR, Ko WC, Chedid BF, Hui DS, Andremont A, Chiou CCC, the International Pneumococcal Study Group (2004) Combination antibiotic therapy may lower mortality in severely ill patients with Streptococcus pneumoniae bacteremia. Am J Respir Crit Care Med 170:400–404CrossRefGoogle Scholar
  21. 21.
    Martinez JA, Horcajada JP, Almela M, Marco F, Soriano A, Garcia E, Marco MA, Torres A, Mensa J (2003) 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 36:389–395CrossRefPubMedGoogle Scholar
  22. 22.
    Waterer GW, Somes GW, Wunderink RG (2001) Monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia. Arch Intern Med 161:1837–1842CrossRefPubMedGoogle Scholar
  23. 23.
    Tessmer A, Welte T, Martus P, Schnoor M, Marre R, Suttorp N (2009) Impact of intravenous β-lactam/macrolide versus β-lactam monotherapy on mortality in hospitalized patients with community-acquired pneumonia. J Antimicrob Chemother 63:1025–1033CrossRefPubMedGoogle Scholar
  24. 24.
    Tamaoki J, Kadota J, Takizawa H (2004) Clinical implications of the immunomodulatory effects of macrolides. Am J Med 117(Suppl 9A):5S–11SPubMedGoogle Scholar
  25. 25.
    Healy DP (2007) Macrolide immunomodulation of chronic respiratory diseases. Curr Infect Dis Rep 9:7–13CrossRefPubMedGoogle Scholar
  26. 26.
    Vanaudenaerde BM, Wuyts WA, Geudens N, Dupont LJ, Schoofs K, Smeets S, Van Raemdonck DE, Verleden GM (2007) Macrolides inhibit IL17-induced IL8 and 8-isoprostane release from human airway smooth muscle cells. Am J Transplant 7:76–82CrossRefPubMedGoogle Scholar
  27. 27.
    Wunderink RG (2009) Adjunctive therapy in community-acquired pneumonia. Semin Respir Crit Care Med 30:146–153CrossRefPubMedGoogle Scholar
  28. 28.
    Brown RB, Iannini P, Gross P, Kunkel M (2003) Impact of initial antibiotic choice on clinical outcomes in community-acquired pneumonia: análisis of a hospital claims-made database. Chest 123:1503–1511CrossRefPubMedGoogle Scholar
  29. 29.
    Gleason PP, Meehan TP, Fine JM, Galusha DH, Fine MJ (1999) Associations between initial antimicrobial therapy and medical outcomes for hospitalized elderly patients with pneumonia. Arch Intern Med 159:2562–2572CrossRefPubMedGoogle Scholar
  30. 30.
    Metersky ML, Ma A, Houck PM, Bratzler DW (2007) Antibiotics for bacteremic pneumonia: improved outcomes with macrolides but not fluoroquinolones. Chest 131:466–473CrossRefPubMedGoogle Scholar
  31. 31.
    Mortensen EM, Restrepo MI, Anzueto A, Pugh J (2006) The impact of empiric antimicrobial therapy with a β-lactam and fluoroquinolone on mortality for patients hospitalized with severe pneumonia. Crit Care 10:R8CrossRefGoogle Scholar
  32. 32.
    Capelastegui A, Espana PP, Quintana JM, Areitio I, Gorordo I, Egurrola M, Bilbao A (2006) Validation of a predictive rule for the management of community-acquired pneumonia. Eur Respir J 27:151–157CrossRefPubMedGoogle Scholar
  33. 33.
    Dremsizov T, Clermont G, Kellum JA, Kalassian KG, Fine MJ, Angus DC (2006) Severe sepsis in community-acquired pneumonia: when does it happen, and do systemic inflammatory response syndrome criteria help predict course? Chest 129:968–978CrossRefPubMedGoogle Scholar
  34. 34.
    Shorr AF, Wunderink R (2008) There is no “CAP” on the importance of community acquired pneumonia in the ICU. Chest 133:590–592CrossRefPubMedGoogle Scholar
  35. 35.
    Roberts JA, Lipman J (2006) Antibacterial dosing in intensive care: pharmacokinetics, degree of disease, and pharmacodynamics of sepsis. Clin Pharmacokinet 45:755–773CrossRefPubMedGoogle Scholar
  36. 36.
    Pea F, Viale P (2009) Bench-to-bedside review: appropriate antibiotic therapy in severe sepsis and septic shock—does the dose matter? Crit Care 13:214CrossRefPubMedGoogle Scholar
  37. 37.
    Roberts JA, Lipman J, Blot S, Rello J (2008) Better outcomes through continuous infusion of time-dependent antibiotics to critically ill patients? Curr Opin Crit Care 14:390–396CrossRefPubMedGoogle Scholar
  38. 38.
    Murphy TF (2008) Placebo-controlled trials of treatments for community acquired pneumonia: review of the literature and discussion of feasibility and potential value. Clin Infect Dis 47:S145–S149CrossRefPubMedGoogle Scholar

Copyright information

© Copyright jointly hold by Springer and ESICM 2009

Authors and Affiliations

  • I. Martin-Loeches
    • 1
    • 2
  • T. Lisboa
    • 2
  • A. Rodriguez
    • 2
  • C. Putensen
    • 3
  • D. Annane
    • 4
  • J. Garnacho-Montero
    • 5
  • M. I. Restrepo
    • 6
  • J. Rello
    • 2
  1. 1.Critical Care DepartmentMater Misericordiae University HospitalDublinIreland
  2. 2.Critical Care Department, Joan XXIII University HospitalUniversity Rovira i Virgili, IISPV, CIBER Enfermedades Respiratorias (CIBERES)TarragonaSpain
  3. 3.Department of Anesthesiology and Intensive Care MedicineUniversity of BonnBonnGermany
  4. 4.Service de Réanimation, Hôpital Raymond Poincaré (AP-HP)Université de Versailles SQYParisFrance
  5. 5.Critical Care and Emergency DepartmentHospital Universitario Virgen del RocioSevillaSpain
  6. 6.Department of Medicine, Division of Pulmonary and Critical Care Medicine, VERDICT, South Texas Veterans Health Care System, Audie L Murphy DivisionUniversity of Texas Health Science Center at San AntonioSan AntonioUSA

Personalised recommendations