1. M A T T H E W R O S E N F E L D
S T . J O H N ’ S U N I V E R S I T Y
D O C T O R O F P H A R M A C Y C A N D I D A T E
C / O 2 0 1 6
Legionnaires’ Disease

2. OBJECTIVES
 Background
 Epidemiology
 Symptoms and risk factors
 Treatment
 Complications
 Prevention

3. BACKGROUND
 Legionnaires' disease is a form of atypical
community-acquired pneumonia (CAP)
 Caused by any type of Legionella bacteria
 > 90% caused by Legionella pneumophila.
 Thin, aerobic, pleomorphic, flagellated, non-spore forming,
Gram-negative bacteria
 Organism was first recognized in 1976 during an
outbreak at an American Legion Convention in
Philadelphia.
1

4. EPIDEMIOLOGY
 Estimated 8,000-
18,000 hospitalized
cases occur in the U.S.
each year.
Accomodation sites per destination country associated with cases of travel-associated
Legionnaires’ disease, EU Member States and neighbouring countries (2010)
2

5. LEGIONNAIRES’ IN THE NEWS

8. DISEASE TRANSMISSION
 Disease usually contracted from inhalation of aerosolized
water droplets, NOT from person-to-person contact
 More likely to come from indoor than outdoor legionella
bacteria
 More outbreaks occur in large buildings (i.e. hotels and apartment
complexes)
 Potentially due to more complex plumbing systems?
 Bacteria thrive in warm water and damp sources
 i.e. showers, faucets, hot tubs, swimming pools, cooling towers
 Other means of transmission:
 Aspiration
 Soil 3

9. SYMPTOMS
 Legionnaires' disease usually develops two to 10 days after
exposure to legionella bacteria.
 Initial signs and symptoms:
 Headache
 Muscle pain
 Chills
 Fever (≥104 F)
 Potential subsequent signs and symptoms:
 Cough (with or without mucus/blood)
 Shortness of breath
 Chest pain
 Gastrointestinal symptoms
 Nausea, vomiting and diarrhea
 Confusion or other mental changes
 The legionella bacterium also causes Pontiac fever, a milder
illness resembling the flu. 4

10. LEGIONNAIRES’ vs. PONTIAC FEVER
Legionnaires’
Disease
Pontiac Fever
Attack rate < 5% > 90%
Respiratory complaints Yes No
Incubation period 2-10 days 36 hours
Treatment Antibiotic therapy Self-limiting;
antibiotics not given
Outcome Hospitalization likely;
fatality rate: 10-30%
Hospitalization
unlikely; fatality rate of
0%
5

11. RISK FACTORS
 Not everyone exposed to legionella
bacteria becomes sick.
 In outbreaks, fewer than 5 % of people
exposed to contaminated water develop
Legionnaires' disease
 More likely to develop the infection
in patients who:
 Smoke
 Have a weakened immune system
 HIV/AIDS
 Cancer
 Have a chronic lung disease
 Emphysema
 COPD
 Asthma
 Are 50 years of age or older
6

12. *preferred
Test Advantages Disadvantages
Culture*
•Clinical & environmental
isolates can be compared
•Detects all species & serogroups
•100% specific
•Technically difficult
•Slow (>5 days to grow)
•May be affected by antibiotic
treatment
Urine Antigen*
•100% specific...
•Rapid (same day)
•Only for L. pneumophila
serogroup 1 (Lp1)
•Does not allow for molecular
comparison to environmental
isolates
Serology
•Less affected by antibiotic
treatment
•80-90% sensitive; 99% specific
•Must have paired sera
•5-10% of population has titer
Direct Flourescent Antibody
(DFA)
•Can be performed on pathologic
specimens
•>95% specific
•25-75% sensitive
Polymerase Chain Reaction
(PCR)
•Rapid
•Assays vary by laboratory
•Not FDA-approved
DIAGNOSTIC TESTS
7

13. TREATMENT
 Pleural effusion in a patient with community-acquired
pneumonia (CAP) and extra-pulmonary manifestations
should suggest Legionella infection.
 i.e. mental confusion, myalgia, abdominal pain, diarrhea, rash
 Follow Infectious Disease Society of America (IDSA)
treatment guidelines for CAP
 Need antibiotics with good intracellular penetration
8

14. OVERVIEW OF CAP
• Estimates of the
incidence of CAP
range from 4-5
million cases per
year
• Approximately
25% require
hospitalization

15. GUIDELINES
• Macrolides are 1st line
• Azithromycin > clarithromycin>erythromycin
• Fluoroquinolones are 2nd line
• Levofloxacin > moxifloxacin
*Doxycycline may be used as an alternative to a macrolide, but there is stronger evidence to support the use of a macrolide than doxycycline for CAP.
9

16. GUIDELINES
Table extracted from www.uptodate.com

17. ANTIBIOTIC COMPARISONS
Azithromycin Clarithromycin Levofloxacin Moxifloxacin Doxycycline
Abx Class Macrolide Macrolide 3rd gen FQ 4th gen FQ Tetracycline
CAP Dosing Oral: 500 mg PO
day 1; 250 mg PO
daily on days 2-5
IV: 500 mg single
dose x 2 days,
followed by PO
therapy
500 mg PO bid or
1000 mg ER PO
q24h
750 mg PO
q24h
(IV->PO 1:1)
400 mg PO
q24h
(IV -> PO 1:1)
100 mg PO
BID
Adjustments N/A CrCl <30
mL/minute:
Decrease
clarithromycin
dose by 50%
CrCl 20-49
mL/minute:
Administer
750 mg q 48
hours
CrCl 10-19
mL/minute:
Administer
750 mg initial
dose, followed
by 500 mg
q 48 hours
N/A N/A
10

18. ANTIBIOTIC COMPARISONS
Azithromycin Clarithromycin Levofloxacin Moxifloxacin Doxycycline
Contra-
indications
Hypersensitivity to
azithromycin or
other macrolides ;
history of
cholestatic
jaundice/hepatic
dysfunction
associated with
prior azithromycin
use
Concurrent use
with pimozide (per
pimozide PI)
Hypersensitivity to
clarithromycin, or
other macrolides ;
history of
cholestatic
jaundice/hepatic
dysfunction;
history of QT
prolongation;
concomitant use
with cisapride,
pimozide,
ergotamine,
dihydroergotamine,
statins;
concomitant use
with colchicine in
patients with renal
or hepatic
impairment
Hypersensitivity
to levofloxacin or
other FQs
Hypersensitivity
to moxifloxacin
or other FQs
Hypersensitivity to
doxycycline or
tetracyclines;
Use during second
or third trimester of
pregnancy (cat D)
Adverse
events
Diarrhea Diarrhea, increased
BUN
Tendon rupture,
myasthenia gravis
(US BBW)
Tendon rupture,
myasthenia
gravis (US BBW)
Diarrhea, increased
BUN, tooth
discoloration,
photosensitivity,
Steven Johnson’s
Syndrome,
Increased LFT
(rare) 10

19. ANTIBIOTIC COMPARISONS
Azithromycin Clarithromycin Levofloxacin Moxifloxacin Doxycycline
Drug-Drug
Interactions
(Risk X:
AVOID
combination)
Amiodarone:
may enhance the
QTc-prolonging
effect
Quinine:
Macrolide
antibiotics may
increase the serum
concentration of
Quinine.
P-glycoprotein
/ABCB1
Inhibitors: may
increase the serum
concentration of
Pazopanib and
Silodosin
CYP 3A4
inhibitors;
increases serum
concentration of:
Ado-Trastuzumab
Emtansine,
Alfuzosin,
Astemizole,
Avanafil, Axitinib,
Bosutinib,
Cabozantinib,
Ceritinib, Crizotinib,
Domperidone,
Dronedarone,
Eletriptan,
Everolimus,
Irinotecan,
Pazopanib,
Pimozide, Quinine,
Qunidine,
Ranolazine,
Salmeterol,
Simvastatin,
Tamsulosin
BCG
(Intravesical):
may diminish the
therapeutic effect
of BCG
(Intravesical)
Ivabradine,
Mifepristone:
May enhance QTc-
prolonging effect
Strontium
Ranelate: May
decrease the
serum
concentration of
Quinolone
Antibiotics
BCG
(Intravesical):
may diminish the
therapeutic effect
of BCG
(Intravesical)
Ivabradine,
Mifepristone:
May enhance
QTc-prolonging
effect
Strontium
Ranelate: May
decrease the
serum
concentration of
Quinolone
Antibiotics
Mequitazine:
Moxifloxacin
may enhance the
arrhythmogenic
effect of
Mequitazine.
BCG
(Intravesical):
may diminish the
therapeutic effect of
BCG (Intravesical)
Mecamylamine:
may enhance the
neuromuscular-
blocking effect of
Mecamylamine
Retinoic Acid
Derivatives*: may
enhance the
adverse/toxic effect
of Retinoic Acid
Derivatives.
*Exceptions: Adapalene;
Bexarotene (Topical);
Tretinoin (Topical)
Strontium
Ranelate: May
decrease the serum
concentration of
Doxycycline
10

20. DURATION OF THERAPY
 Few well-controlled studies have evaluated the optimal
duration of therapy for patients with CAP
 Duration is difficult to determine; Affected by T ½
 i.e. Azithromycin T ½ (Oral, IV): 68-72 hours IR formulation
 Most patients become clinically stable within three to
four days of starting antibiotic treatment
 IDSA guidelines suggest that patients with CAP should
be treated for a minimum of five days
11
10
9

21. PREVIOUS STUDY
 Open, prospective, multicenter trial evaluated azithromycin for the
treatment of legionnaires disease
 Included twenty-five (25) hospitalized patients with community-acquired
pneumonia and a positive result of a L. pneumophila serogroup 1 urinary antigen
assay
 Patients received monotherapy with intravenous azithromycin (500 mg/day) for 2-7
days, followed by oral azithromycin (1500 mg administered over the course of 3 or 5
days)
 The mean total duration of intravenous plus oral therapy was 7.92
days.
 Overall cure rate among clinically evaluable patients:
 95% (20 of 21 patients) at 10-14 days after therapy
 96% (22 of 23 patients) at 4-6 weeks after therapy
12

22. COMPLICATIONS
 Fatal complications can occur if not treated
appropriately and in a timely manner
 Respiratory failure
 pO2 <60 mm Hg, pCO2 >50 mm Hg, and pH <7.35
 Septic shock
 Severe sepsis + refractory hypotension (systolic BP <90 mm Hg)
 Acute kidney injury
 Increase in SCr by ≥0.3 mg/dl within 48 hours; or increase in SCr
to ≥1.5 times baseline; or urine volume < 0.5 ml/kg/h for 6 hours.
11
15
14
13

23. PREVENTION
 Need to improve the design and maintenance of
cooling towers and plumbing systems
 Water supply systems should be cooled below 68 F or heated
above 140 F
 Newer methods of controlling and eliminating
Legionella growth
 Copper-silver ionization, super heating, and monochloramine
disinfection
 Hyperchlorination tends to be ineffective
 No vaccination currently available
16

24. SUMMARY
http://www.medindia.net/health-infographics/images/legionnaires-disease.jpg

25. REFERENCES
1.) Ryan, Kenneth J., C. George Ray, and John C. Sherris. Sherris Medical Microbiology: An
Introduction to Infectious Diseases. New York: McGraw-Hill, 2004. Print.
2.) “Fast Facts." Centers for Disease Control and Prevention. 1600 Clifton Road Atlanta, GA
30329-4027 ; 05 Feb. 2013. Web.
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infection: Current Status and Emerging Perspectives. American Society for Microbiology,
Washington, DC 1993. p.30.
4.) Lowry PW, Tompkins LS. Nosocomial legionellosis: a review of pulmonary and
extrapulmonary syndromes. Am J Infect Control 1993; 21:21.
5.) Roig J, Aguilar X, Ruiz J, et al. Comparative study of Legionella pneumophila and other
nosocomial-acquired pneumonias. Chest 1991; 99:344.
6.) Den Boer JW, Nijhof J, Friesema I. Risk factors for sporadic community-acquired
Legionnaires' disease: A 3-year national case-control study; Public Health. 2006;120(6):566.
7.) Zuravleff JJ, Yu VL, Shonnard JW, et. al. Diagnosis of Legionnaires' disease: an update of
laboratory methods with new emphasis on isolation by culture. JAMA 1983;250:1981-5.
8.) Cunha BA. Diagnostic Significance in Legionnaires' Disease. Am J Med. 2006. 119:5-6

26. REFERENCES
9.) Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, 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 Mar 1. 44
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10.) Lexicomp Online® , Azithromycin, Clarithromycin, Levofloxacin, Moxifloxacin,
Doxycycline drug monographs, Hudson, Ohio: Lexi-Comp, Inc.; Oct 15, 2015
11.) Halm EA, Fine MJ, Marrie TJ, Coley CM, Kapoor WN, Obrosky DS, Singer DE . Time to
clinical stability in patients hospitalized with community-acquired pneumonia: implications
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12.) Plouffe Jf, Breiman RF, et. al. Azithromycin in the treatment of Legionella pneumonia
requiring hospitalization. Clin Infect Dis. 2003 Dec 1;37(11):1475-80
13.) Burt, Christiana C.; Arrowsmith, Joseph E. (1 November 2009). "Respiratory failure".
Surgery (Oxford) 27 (11): 475–479
14.) Angus, Derek C.; van der Poll, Tom (2013). "Severe Sepsis and Septic Shock". New
England Journal of Medicine 369 (9): 840–851
15.) Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group.
KDIGO Clinical Practice Guideline for Acute Kidney Injury.
16.) Flanery, B., et al. "Reducing Legionella Colonization in Water Systems With
Monochloramine." Emerg Infect Dis 12 (2006): 588.

27. QUESTIONS