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Treatment of Legionnaires’ Disease

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Legionnaires International Congress, Chicago 2006

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Treatment of Legionnaires’ Disease

  1. 1. Treatment of Legionnaires’ Disease Dr. J. Roig Pulmonary Division Hospital N Sra Meritxell ANDORRA
  2. 2. OBJECTIVES • Macrolides versus fluoroquinolones • Relapsing or persistent infection • Inflammation and steroid therapy • Extrapulmonary manifestations • What to do in non-responding patients • Mixed infections • Severe Legionnaires’ disease (ICU)
  3. 3. Macrolides vs quinolones as therapy of LD1 • Best overall intrinsic activity for new quinolones • Better activity for new macrolides • Azithromycin superior to other macrolides • New quinolones show best bacterial clearance • In vitro R-ciprofloxacin strains isolated in Hungary2 • Inflammation: lowest azithromycin and greater erythromycin • Azithromycin and quinolones: better PK and PD profile and irreversible inhibition3 1 Edelstein PH. In: Legionella, Ch. 32; ASM Press 2002; 2 Bognar C, ERS Congress, P2203; 2002; 3 Plouffe JF. 2003
  4. 4. Sabria et al. Fluoroquinolones vs macrolides in the treatment of LD. Chest 2005 • Observational study with homogeneous baseline analysis • Erythro (33) 500-1000 mg every 6 hours, IV or po • Clarithromycin (43) 500 mg q12h IV or po • Levofloxacin (50) 500 mg q12 hours IV to apyrexia → 500 mg po qd • Ofloxacin (4) 400 mg q12h to apyrexia → 400 mg qd po • Homogeneity on baseline analysis • MV: 5 in macrolide (6%); 3 in quinolone arm (5%) • Fatality: 6 in macrolide (7%); 3 in quinolone (5%)
  5. 5. GROUP 1 (Macrolides) N=76 GROUP 2 (Fluoroquinolones) N=54 p TIME TO APYREXIA (range) h 77.1 (24-408) 48 (24-192) 0.000 BREAKDOWN OF IV vs ORAL THERAPY (range) days 5.3 (3-19) 3.9 (3-10) 0.000 CLINICAL AND X-RAY COMPLICATIONS 18 (23.6%) 9 (16.6%) 0.4 PLEURAL EFFUSION 13 (17.1%) 5 (9.2%) 0.2 EMPYEMA 1 (1.3%) 0 (0%) 1 MECHANICAL VENTILATION 5 (6.5%) 3 (5.5%) 1 SEPTIC SHOCK 6 (7.8%) 3 (5.5%) 0.7 CAVITATION 0 0 MORTALITY 6 (7.8%) 3 (5.5%) 0.7 HOSPITAL STAY (range) days 9.9 (2-59) 7.6 (1-19) 0.09 Sabria M et al. Fluoroquinolones vs macrolides in the treatment of Legionnaire’s disease. Chest 2005;128:1401-1405.
  6. 6. Other comparative studies fluoroquinolones vs macrolides in the treatment of LD. Mykietiuk A, CID; Blazquez R, CID 2005 • Again just levofloxacin and no differences mortality • Blazquez study bias: all cases Murcia outbreak patients with an extremely low fatality rate (2 pts died, n=292), only 10 ICU pts and MV in 9 pts + no differences in mortality rate but in “severe” LD ↓complications (ARF or pleural effusion) with levo? • Mykietiuk study: no differences in fatality rate (overall 5%) or complications, only 7 ICU pts. MV not reported • Both studies: shorter LOS in levo arm: 8 vs 10 (Mykietiuk) and 5.5 vs 11.3 days in severe LD (Blazquez)
  7. 7. Recommended therapy in legionellosis Antimicrobial agent Dosage Route Macro-azalides Azithromycin1 Clarithromycin 500 mg every 24 hours 500 mg every 12 hour IV, p.o. IV, p.o. Tetracyclines Doxycycline 100 mg every 12-24 hours IV, p.o. Fluoroquinolones Levofloxacin1 Moxifloxacin1 Gemifloxacin2 Gatifloxacin2 Ciprofloxacin 500-750 mg every 24 hours 400 mg every 24 hours 320 mg every 24 hours 200-400 mg every 24 hours 400-750 mg every 12 hours IV, p.o. IV, p.o. p.o. IV, p.o. IV, p.o. Ketolides Telithromycin2 800 mg every 24 hours p.o. 1 Recommended in most severe cases, particularly in the immunocompromised 2 Because of short accumulated clinical experience their use is recommended only in mild to moderate cases.Roig J, Rello J. JAC 2003; Conn’s Therapy (in press)
  8. 8. Early recognition leads to prompt therapy and low mortality • Symptoms > 5 days: higher mortality1 in severe cases • Adequate Rx < 24 h ICU: 78% survival vs 54% (p=0.005)2 • Fatality rate11% in outbreaks if delayed recognition3 • Lower fatality rates (<2%) if early recognition, as reported in Australia and Murcia, Spain (n=449)3,4 1 Gacouin 2002; 2 Lettinga 2002; 3 Navarro, Eurosurveillance Weekly 2001; 4 Garcia-Fulgueiras 2003
  9. 9. Overall Prognostic Factors of Legionellosis • APACHE II score >15 or SAPS > 46, intubation • Advanced age, renal disease • Malignancy or immunosuppression • Chest X-ray progression • L. pneumophila serogroup 6 • Lack of initial appropriate treatment • Smoking Heath CH. Eur J Clin Microbiol Infect Dis 1996; Tkatch LS. Clin Infect Dis 1998; el-Ebiary M. Am J Resp Crit Care Med 1997; Lettinga KD. Emerg Infect Dis 2002; Gacouin A. Inten Care Med 2002
  10. 10. Effect of nicotine on L. pneumophila growth in alveolar macrophages 024 control nicotine 0.1 nicotine 1 nicotine 10 24h after infection 48h after infection RelativegrowthofL.pneumophilatocontrol Matsunaga K et al. J Immunol 2001
  11. 11. Legionellosis: Should We Worry About Radiographic Progression? • Radiographic progression identified as a negative prognostic factor in severe CAP caused by any etiologic agent Ewig S, Am J Respir Crit Care 1998 • In our experience just 30% incidence of progression in legionellosis if early, efficacious treatment is administered Domingo C, Thorax 1994 • Radiographic progression is a negative predictive factor in legionellosis, especially if severe clinical presentation Falcó ,V Chest 1991 ; El-Ebiary M, Am J Respir Crit Care 1997; Tkacht LS, Clin Infect Dis 1998; Roig J, Curr Top Rad 1998
  12. 12. Key points in treating recurrent or persisting Legionella infection • Avoid short therapy in immunocompromised patients1 • Longer treatment in endocarditis & immunosuppression2-4 • Patients with severe pneumonia may respond poorly5,6 • Need of drainage of any purulent collection7-9 • No development of resistance in well-documented cases 1 Matute AJ, 2000; 2 Schindel C, 2000; 3 Morley JN, 1994; 4 O’Reilly K, 2005; 5 Tan JS, 2001; 6 Gacouin A,2002; 7 Roig J, 1998; 8 Johnson KM, 1997; 9 Nzerue C, 2001
  13. 13. Etiology in immunocompetent patients with SCAP and microbiologic documentation: CAPUCI study Bodí M et al. Antibiotic prescription for CAP in ICU. CAPUCI study. CID 2005 Microorganisms Overall (N = 297) Immunocompetent patients (N = 248) S. pneumoniae Legionella sp. H. Influenzae P. aeruginosa MS S. aureus MR S. aureus GNB* Pneumocystis M. tuberculosis Varicella zoster Aspergillus sp. Nocardia sp. Other** 143 (48.1%) 23 (7.7%) 22 (7.4%) 20 (6.7%) 16 (5.4%) 3 (1.0%) 18 (6.1%) 10 (3.4%) 8 (2.7%) 8 (2.7%) 1 (0.3%) 1 (0.3% 24 (8.1%) 126 (50.8%) 20 (8.1%) 19 (7.7%) 16 (6.5%) 12 (4.8%) 3 (1.2%) 13 (5.2%) 6 (2.4%) 5 (2.0%) 8 (3.2%) 1 (0.4%) - 19 (7.7%)
  14. 14. Yield of diagnostic tests in 23 cases of severe LD TEST No. performed No. positive result Percentage Urine antigen Sputum culture FOB samples Pleural fluid Serology 22 15 14 3 13 19 4 4 1 8 82.6 17.4 17.4 4.3 34.8
  15. 15. Basal homogeneity: baseline analysis Legionella Pneumococcus Other p Age, mean ± SD Age score ± SD Sex, male Smoking habit Alcohol habit Immunocompromised Prior antibiotic COPD Cardiopathy Neurological illness Diabetes APACHE ± SD 52.8 ± 13.5 3.13 ± 1.25 16 (69.6%) 12 (52.2%) 7 (30.4%) 3 (13%) 6 (26.1%) 4 (17.4%) 8 (34.8%) 1 (4.3%) 5 (21.7%) 18.4 ± 5.97 60.2 ± 16.5 4.47 ± 1.49 110 (78%) 63 (45%) 41 (29.5%) 17 (12%) 19 (13.4%) 56 (39.4%) 34 (23.9%) 9 (6.3%) 33 (23.2%) 19.6 ± 7.35 60.2 ± 15.9 4.32 ± 1.49 254 (69.8%) 168 (46.3%) 87 (23.9%) 44 (12%) 101 (27.9%) 136 (37.4%) 114 (31.3%) 27 (7.4%) 83 (22.8%) 19.1 ± 7.0 0.02 0.010 0.17 0.81 0.38 0.98 0.003 0.12 0.22 0.80 0.98 0.76
  16. 16. Basal homogeneity: baseline analysis - 2 Legionella Pneumococcus Other p Malignancy IV addiction HIV Aspiration Obesity Mechanical vent Days of MV 1st dosage time (h) Ventilator pneumonia Shock Rapid X-ray spread 1 (4.3%) 0 (0%) 0 (0%) 0 (0%) 7 (30.4%) 17 (73.9%) 19.6 ± 18.1 4.3 ± 3.3 4 (17.4%) 14 (60.9%) 18 (81.8%) 5 (3.5%) 5 (3.5%) 5 (3.5%) 2 (1.4%) 21 (14.8%) 70 (49.3%) 13.5 ± 15 6.6 ± 12.3 9 (6.3%) 73 (51.4%) 68 (47.9%) 31 (8.6%) 8 (2.2%) 17 (4.7%) 8 (2.2%) 51 (14%) 200 (55.1%) 15.8 ± 13.8 7 ± 12.6 35 (9.6%) 183 (50.3%) 164 (45.7%) 0.11 0.51 0.49 0.66 0.102 0.23 0.08 0.82 0.18 0.61 0.04
  17. 17. Severe Legionellosis: baseline analysis n=23 • Most patients (20) were immunocompetent • Legionella patients trended to be younger • Legionella patients: prior antibiotic therapy significantly more frequently than those patients with SCAP caused by pneumococcus • Mechanical ventilation: 17 (74%) • Non-invasive ventilation: 4 (17.4%) • No ventilation: 2 (8.6%) • Mortality (MOF) was 26 % (6/23). 3 cases of death, one of them in an immunocompetent individual, occurred in patients with inadequate initial Rx
  18. 18. Severe Legionellosis (ICU): Gacouin A et al. Intensive Care Med 2002 • Outbreak cases were included • Nosocomial cases also included • < 5% of patients with diabetes mellitus • Mechanical ventilation: 20.9% • No ventilation: 79.1% • Mortality rate of 33 % • Use of old macrolides: erythromycin, spiramycin • Use of old quinolones: ofloxacin, pefloxacin, cipro • Use of rifampicin in only two cases • Monotherapy in 5 cases
  19. 19. 120100806040200 DAYS 1,0 0,8 0,6 0,4 0,2 0,0 Cumulatedsurvival PNEUMOCOCCUS- censured OTHER-censured LEGIONELLA- censured PNEUMOCOCCUS OTHER LEGIONELLA Kaplan-Meier survival curve P=0.395 (Log Rank)
  20. 20. Severe LD: prognostic factors of death Death n=6 Survive n=17 Odds ratio p Age > 60 years APACHE score >15 Sex, male Smoking habit Alcohol habit Immunocompromise Shock COPD 2 (33.3%) 6 (100%) 4 (66.7%) 2 (33.3%) 2 (33.3%) 3 (50%) 6 (100%) 0 (0%) 5 (29.4%) 10 (58.8%) 12 (70.6%) 10 (58.8%) 5 (29.4%) 0 (0%) 8 (47.1%) 4 (23.5%) 1.2 (0.16-8.8) 0.83 (0.1-6.1) 0.35 (0.05-2.4) 1.2 (0.16-8.8) 1.0 0.05 1.0 0.37 1.0 0.01 0.04 0.53
  21. 21. Severe LD: prognostic factors of death Death n=6 Survive n=17 Odds ratio p Cardiopathy Neurological illness Diabetes Mechanical vent. Ventilator pneumonia Acute renal failure Monotherapy 1st dosage > 6 hours 3 (50%) 3 (50%) 3 (50%) 6 (100%) 0 (0%) 5 (83.3%) 4 (66.7%) 2(40%) 5 (29.4%) 5 (29.4%) 2 (11.8%) 11 (64.7%) 4 (23.5%) 3 (17.6%) 5 (29.4%) 4(28.6%) 2.4 (0.36-16.2) 2.4 (0.36-16.2) 7.5 (0.8-66.1) 23.3 (1.9-279) 4.8 (0.65-35.2) 1.67(0.2-14.0) 0.62 0.62 0.08 0.09 0.53 0.008 0.16 1.0
  22. 22. Logistic regression analysis of variables associated with acute renal failure • UNIVARIATE MODEL – COPD p = 0.090 – Cardiopathy p= 0.013 – APACHE p= 0.081 • MULTIVARIATE MODEL – Cardiopathy
  23. 23. Logistic regression analysis of variables associated with death • UNIVARIATE MODEL – Diabetes mellitus p = 0.022 – APACHE p= 0.002 – Acute Physiologic Score p= 0.047 • MULTIVARIATE MODEL – APACHE
  24. 24. Combination Therapy ? • Macrolide + rifampicin was standard combined Rx1 • Risk of reversible liver toxicity with rifampin2 • Macrolides + quinolones: sinergistic activity in vitro3 • A retrospective study suggested a potential role for combined therapy with pefloxacin and erythromycin4 • Mortality rate of 33% in severe series using therapy with old macrolides + old quinolones5 1 Roig J, Drugs 1993; 2 Hubbard RB, QJMed 1993; 3 Martin SJ, AAC 1996; 4 Dournon E, JAC 1990; 5 Gacouin A, Inten Care Med 2002
  25. 25. 806040200 DAYS 1,0 0,8 0,6 0,4 0,2 0,0 CumulatedSurvival MONOTHERAPY- censured COMBINED- censured MONOTHERAPY COMBINED RX Kaplan – Meier survival curve P=0.203 (Log Rank)
  26. 26. Antimicrobial therapy against L. pneumophila administered in severe legionellosis Treatment Nº patients Deaths Ventilation (days) MV- late pneumonia MONOTHERAPY Levofloxacin Clarithromycin Erithromycin Ciprofloxacin 9 3 4 1 1 4 (44%) 3 1 0 0 4–30 5-29 49 19 No 1* No No COMBINED THERAPY 14 2 (14.2%) 3-81 3** * Pseudomonas aeruginosa ** Pseudomonas , MRSA , Haemophilus
  27. 27. Types of combination therapy MACROLIDES Erithromycin X X 2 Clarithromycin X X X X X X X X 9 QUINOLONES Levofloxacin X X X X X X 6 Ciprofloxacin X X X X X 5 RIFAMPICIN X X X X X X X X X X 11 DOXYCYCLINE X 1 2 pacients received the combination Clarithromycin + Rifampicin
  28. 28. Comparative trial between iv clarithromycin and erythromycin in hospitalized mild-to-moderate CAP EMLB n= 29 Clarithromycin n= 28 Significance Mean age 61.5 66.1 NS β- lactam 12 17 NS Gastrointestinal 15 (52%) 0 (0%) P< 0.001 Phlebitis 20 (65%) 33(81%) P< 0.05 EMLB: erythromycin lactobionate Celis G, Gea E, Roig J. Clin Drug Invest 2002
  29. 29. SUMMARY OF LEGIONELLA-CAPUCI STUDY • Rapid spread of X-ray infiltrates is very common (81%) in severe LD in the ICU setting • Severity markers (APACHE, MV) are predictive of death • Immunocompromise, shock and acute renal failure are associated with a high risk of death • No variables identified as associated with shock • COPD and heart disease are associated with acute renal failure: impact of preventive measures in these patients • Diabetes mellitus is also a potential marker of lethal LD • Combination therapy may be the best option in severe LD
  30. 30. • Animal model: potential role for gamma interferon1,2 • Endotoxin eliminating therapy (hemofiltration, exchange transfusion) in severe cases with DIC • ECMO in severe acute respiratory failure 3 • Animal model: hyperoxia exacerbates lung injury.4 • Experimental model: TNF-α has a protective role. 5 • Nitric oxide in experimental studies. 6,7 Severe legionellosis: other therapies? 1-Shinozawa Y. J Med Microbiol 2002. 2-Deng J. Infect Immun 2001 3-Ichiba S. CID 1999. 4-Tateda K. J Immun 2003. 5-Nara C. J Med Microbiol 2004. 6-Skerret S. Infect Immun 1996. 7-Summersgill L. J Leukoc Biol 1992.
  31. 31. Extrapulmonary legionellosis Cardiovascular Pericarditis, myocarditis*, endocarditis, aortic graft involvement, sinoatrial block Neurological Encephalitis that may mimic that caused by herpes, brain abscess, cerebellar ataxia*, corpus callosum involvement Digestive Colon involvement that may mimic ulcerative colitis, pancreatitis, digestive tract abscess, liver involvement, spleen rupture, severe diarrhea* Renal Kidney abscess, acute renal failure, interstitial nephritis* Blood* Thrombopenia, disseminated intravascular coagulation (DIC). Joint and bone Arthritis*, osteomyelitis Miscellaneous Wound infection, cellulitis, rhabdomyolisis, posttraumatic stress disorder Roig J 2003.Massey R 2003. Bemer P 2002. Karim A 2002. Linscott A 2004. Medarov B 2003, 2004. McClelland M 2004. Andereya S 2003. Shelburne S
  32. 32. Potential role of steroid therapy in legionellosis PROLIFERATIVE PHASE OF DIFFUSE ALVEOLAR DAMAGE (ARDS) Controversial use, as happens in other types of pneumonia with adult respiratory distress syndrome REACTIVE EXTRAPULMONARY MANIFESTATIONS Arthritis Myocarditis Some neurological manifestations Some renal manifestations Some hematological manifestations INFLAMMATORY PATTERN IN LUNG TISSUE BIOPSY * Plasma-cell interstitial pneumonia Chronic interstitial pneumonia Lymphocytic interstitial pneumonia Non-specific interstitial pneumonia BOOP Roig J, Rello J. JAC 2003; Conn’s Therapy (in press) * Representative samples of lung tissue are mandatory
  33. 33. Rhabdomyolysis: other agents • Streptococcus pneumoniae 1 • Mycoplasma pneumoniae 2 • Adenovirus 3 • HIV infection 4 • Influenza A 5 • Miscellaneous6 : other virus, S. aureus, Salmonella 1 Garcia MC. Tenn Med 2002; 2 Berger R. Pediatrics 2000; 3 Klinger JR. AJRCCM 1998; 4 Rastegar D. CID 2001; 5 Morton S. South Med J 2001; 6 Sauret JM. Am Fam Phys 2002
  34. 34. • Posttraumatic stress disorder in 15% of a Dutch outbreak disorder1 • Impaired HRQL in outbreak survivors (75% fatigue)1 • Well established lung fibrosis in ARDS survivors2 • Abnormal diffusion test one year after the episode3 • Clinical and therapeutic implications uncertain: mass media pressure 1 Lettinga KD, Clin Infect Dis, 2002 ; 2 Chastre J, Chest,1987; 3 Jonkers RE, Clin Infect Dis, 2004 Long term manifestations of LD
  35. 35. LD – Pregnancy associated manifestations • Intrauterine fetal demise • Risk of premature delivery • Septic shock • Azithromycin: first line therapy • Clarithromycin: risk of aborption Roig J. JAC 2003; Vimercati A. J Perinat Med 2000; Tewari K. Am J Obstet Gynecol 1997; Eisenberg VH. Eur J Obstet Gynecol 1997
  36. 36. PROTRACTED LEGIONELLOSIS FOB NEGATIVE MICROCOINFECTION LUNG BIOPSY? INFLAMMATION ONLY LEGIONELLA STEROIDS SEARCH Roig J, Rello J. JAC 2003 SUPER INFECTION IDENTIFICATION OF ANY AGENT
  37. 37. LEGIONELLA MIXED INFECTIONS Chlamydia and Mycoplasma pneumoniae reported on the basis on serology Other Legionella spp Dual infections by different species of Legionella and different serotypes of L. pneumophila Other bacteria St. pneumoniae, P. mirabilis, S. aureus, E. coli, Prevotella intermedia, E. facium, Enterobacter cloacae, K. pneumoniae, H. influenzae, S. mitis, N. meningitidis, Listeria monocytogenes, Nocardia asteroides. Mycobacteria Mycobacterium tuberculosis Virus Herpes virus, Influenza, Cytomegalovirus Fungus Aspergillus, Cryptococcus Parasites Pneumocystis jiroveci, Leishmania Roig J. Curr Op Infect Dis 2003

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