Legionnaires International Congress, Chicago 2006

1. Treatment of Legionnaires’
Disease
Dr. J. Roig
Pulmonary Division
Hospital N Sra Meritxell
ANDORRA

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. • 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. 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. 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. 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. • 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. 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. 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. 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