Treatment of Legionnaires’ Disease

Dr. J. RoigPulmonary Division

Hospital N Sra MeritxellANDORRA

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)

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

1Edelstein PH. In: Legionella, Ch. 32; ASM Press 2002; 2Bognar C, ERS Congress, P2203; 2002; 3 Plouffe JF. 2003

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%)

GROUP 1(Macrolides)

N=76

GROUP 2(Fluoroquinolones)

N=54

p

TIME TO APYREXIA (range) h 77.1 (24-408) 48 (24-192) 0.000BREAKDOWN 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%) 0.2EMPYEMA 1 (1.3%) 0 (0%) 1MECHANICAL VENTILATION 5 (6.5%) 3 (5.5%) 1SEPTIC 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.

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)

Recommended therapy in legionellosisAntimicrobial agent

Dosage Route

Macro-azalides Azithromycin1

Clarithromycin500 mg every 24 hours500 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 hours400 mg every 24 hours320 mg every 24 hours200-400 mg every 24 hours400-750 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 immunocompromised2 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)

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

1Gacouin 2002; 2Lettinga 2002; 3Navarro, Eurosurveillance Weekly 2001; 4Garcia-Fulgueiras 2003

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

Effect of nicotine on L. pneumophila growth in alveolar macrophages

02

4

control nicotine 0.1 nicotine 1 nicotine 10

24h afterinfection48h afterinfection

Rel

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of L

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Matsunaga K et al. J Immunol 2001

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

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

1Matute AJ, 2000; 2Schindel C, 2000; 3Morley JN, 1994; 4O’Reilly K, 2005; 5Tan JS, 2001; 6Gacouin A,2002; 7Roig J, 1998; 8Johnson KM, 1997; 9Nzerue C, 2001

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. InfluenzaeP. aeruginosa MS S. aureus MR S. aureusGNB*Pneumocystis M. tuberculosis Varicella zosterAspergillus 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%)

Yield of diagnostic tests in 23 cases of severe LD

TEST No. performed

No. positive result

Percentage

Urine antigenSputum cultureFOB samplesPleural fluidSerology

2215143

13

194418

82.617.417.44.3

34.8

Basal homogeneity: baseline analysis

Legionella Pneumococcus Other p

Age, mean ± SDAge score ± SDSex, male Smoking habitAlcohol habitImmunocompromisedPrior antibiotic COPD CardiopathyNeurological illnessDiabetes APACHE ± SD

52.8 ± 13.53.13 ± 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 ± 16.54.47 ± 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 ± 15.94.32 ± 1.49254 (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

0.020.0100.170.810.380.980.0030.120.220.800.980.76

Basal homogeneity: baseline analysis - 2

Legionella Pneumococcus Other p

Malignancy IV addictionHIVAspirationObesity Mechanical vent Days of MV 1st dosage time (h)Ventilator pneumoniaShock 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 ± 3.34 (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 ± 156.6 ± 12.39 (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 ± 12.635 (9.6%)183 (50.3%)164 (45.7%)

0.110.510.490.660.1020.230.080.820.180.610.04

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

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

120100806040200

DAYS

1,0

0,8

0,6

0,4

0,2

0,0

Cum

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ed s

urvi

val

PNEUMOCOCCUS-censured

OTHER-censured

LEGIONELLA-censured

PNEUMOCOCCUSOTHERLEGIONELLA

Kaplan-Meier survival curve

P=0.395(Log Rank)

Severe LD: prognostic factors of death

Death n=6 Survive n=17

Odds ratio p

Age > 60 yearsAPACHE score >15Sex, male Smoking habitAlcohol habitImmunocompromiseShock 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)

1.00.051.00.371.00.010.040.53

Severe LD: prognostic factors of death

Death n=6

Survive n=17

Odds ratio p

CardiopathyNeurological illnessDiabetes Mechanical vent.Ventilator pneumoniaAcute renal failureMonotherapy1st 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)

0.620.620.080.090.530.0080.161.0

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

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

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

1Roig J, Drugs 1993; 2Hubbard RB, QJMed 1993; 3Martin SJ, AAC 1996; 4Dournon E, JAC 1990; 5Gacouin A, Inten Care Med 2002

806040200

DAYS

1,0

0,8

0,6

0,4

0,2

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censured

COMBINED-censured

MONOTHERAPYCOMBINED RX

Kaplan – Meier survival curve

P=0.203(Log Rank)

Antimicrobial therapy against L. pneumophila administered in severe legionellosis

Treatment Nº patients

Deaths Ventilation(days)

MV- late pneumonia

MONOTHERAPY

LevofloxacinClarithromycinErithromycinCiprofloxacin

9

3411

4 (44%)

3 100

4–30 5-29 49 19

No1*

No No

COMBINED THERAPY 14 2 (14.2%) 3-81 3**

* Pseudomonas aeruginosa ** Pseudomonas , MRSA , Haemophilus

Types of combination therapy

MACROLIDES

Erithromycin X X 2Clarithromycin X X X X X X X X 9

QUINOLONES

Levofloxacin X X X X X X 6Ciprofloxacin 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

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

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

• 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.

Extrapulmonary legionellosisCardiovascular 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 2004. Morgan J 2004.

Potential role of steroid therapy in legionellosisPROLIFERATIVE PHASE OF DIFFUSE ALVEOLAR DAMAGE (ARDS)

Controversial use, as happens in other types of pneumonia with adult respiratory distress syndrome

REACTIVE EXTRAPULMONARY MANIFESTATIONS

ArthritisMyocarditisSome neurological manifestationsSome renal manifestationsSome hematological manifestations

INFLAMMATORY PATTERN IN LUNG TISSUE BIOPSY *

Plasma-cell interstitial pneumonia Chronic interstitial pneumonia Lymphocytic interstitial pneumoniaNon-specific interstitial pneumonia BOOP

Roig J, Rello J. JAC 2003; Conn’s Therapy (in press)

* Representative samples of lung tissue are mandatory

Rhabdomyolysis: other agents

• Streptococcus pneumoniae 1

• Mycoplasma pneumoniae 2

• Adenovirus 3

• HIV infection 4

• Influenza A 5

• Miscellaneous6 : other virus, S. aureus, Salmonella

1Garcia MC. Tenn Med 2002; 2Berger R. Pediatrics 2000; 3Klinger JR. AJRCCM 1998; 4Rastegar D. CID 2001; 5Morton S. South Med J 2001; 6Sauret JM. Am Fam Phys 2002

• 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

LD – Pregnancy associated manifestations

• Intrauterine fetal demise

• Risk of premature delivery

• Septic shock

• Azithromycin: first line therapy

• Clarithromycin: risk of aborptionRoig J. JAC 2003; Vimercati A. J Perinat Med 2000; Tewari K. Am J Obstet Gynecol 1997; Eisenberg VH. Eur J Obstet Gynecol 1997

PROTRACTED LEGIONELLOSIS

FOB

NEGATIVE MICRO COINFECTION

LUNG BIOPSY?

INFLAMMATION

ONLY LEGIONELLA

STEROIDS

SEARCH

Roig J, Rello J. JAC 2003

SUPERINFECTION

IDENTIFICATIONOF ANY AGENT

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 tuberculosisVirus Herpes virus, Influenza, CytomegalovirusFungus Aspergillus, CryptococcusParasites Pneumocystis jiroveci, Leishmania

Roig J. Curr Op Infect Dis 2003