Pneumococcal
Empyema: Toronto,
Ontario 1995-2006
Dr. Todd C. Lee
Karen Green, Dr. A. McGeer,
Dr. D. Low
for the Toronto Invasive Bacterial Diseases
Network
Presented Nov 15, 2007
What is Empyema?


Empyema is an infection of the normally sterile pleural
space
Can be diagnosed when pleural fluid is floridly purulent.
A complicated effusion is one that meets the criteria
below (CID Dec 1, 2007)

Microbiological diagnosis
 sputum
culture
 pleural fluid culture
 blood culture or in some studies
 molecular techniques such as pleural fluid
PCR or streptococcal antigen.
Development of Empyema
Why Study Empyema?

Within the past several years and co-incident with (but perhaps predating)
the introduction of the pneumococcal conjugate vaccine (PCV) in many
jurisdictions there has been a dramatic reduction in the overall incidence of
invasive pneumococcal disease (IPD). This is particularly noticeable for
vaccine strain serotypes and this effect has been seen on multiple
continents.

Simultaneous increase in the incidence of pneumococcal empyema (PEMP)


emergence of serotype 1 which is consistently associated with a disproportionate
percentage
The majority of studies have focussed on paediatric empyema. Ours would
represent one of the largest studies of an adult predominant cohort of
patients with empyema recently reported.
Methods



Population based surveillance for invasive pneumococcal disease
has been ongoing through TIDBN since 1995.
A database exists for the collection of clinical data from cases with
information obtained from the patients themselves, their treating
physicians, and retrospective chart review. This data is matched
with microbiological data obtained from the isolates.
Empyema in this study was defined as pleural fluid consistent with
complicated pleural effusion or empyema with:


(1) a positive pleural fluid culture for pneumococcus
(2) a clinical diagnosis of empyema with positive blood culture for
pneumococcus.
Demographics
Sex (no. % male)
Age gp
<15 yrs
15-64
>64
Institutionally acquired
Hospital-acquired
Nursing home acquired
No underlying chronic illness
Underlying illnesses
Cardiac
Lung
Renal
Diabetes mellitus
Alcohol abuse
HIV infection
Antibiotic exposure
Received any, last 3 mos
Failing AB at presentation
Outcome
ICU Admission
Mechanical Ventillation
Death
Non-empyema
N=4744
2604 (55%)
Empyema
N=154
91 (59%)
P value
1018
1740
1929
17
71
64
.004
204 (4.5%)
309 (6.8%)
2790/4671 (60%)
(N=4608)
932/3660 (26%)
761/3659 (21%)
241/3660 (6.6%)
663/3372 (20%)
497/3150 (16%)
214/3002 (7.1%)
9 (4.0%)
6 (6.0%)
100/154 (65%)
(N=117)
37/121 (31%)
37/121 (31%)
4/121 (3.3%)
17/114 (14.9%)
26/111 (23.4%)
5/110 (4.5%)
NS
NS
NS
1116/3531 (32%)
205/2235 (9.2%)
28/113 (25%)
15/75 (20%)
.12
.004
1044/4583 (22.8)
709/4560 (15.5)
889/4658 (19%)
59/153 (38.6)
45/152 (29.6)
31/154(20%)
<0.001
<0.001
NS
NS
.21
.01
.15
.21
.03
.29
1.4
Population Based Rate (See Legend)
1.2
1
0.8
0.6
0.4
0.2
0
1996
1997
1998
1999
2000
2001
Non Empyema Per 10,000
2002
2003
Empyema Per 100,000
2004
2005
2006
Rates per 100,000 – Age Adjusted
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
1996
1997
1998
1999
2000
2001
Age <15
Age 15-64
2002
Age >=65
2003
2004
2005
2006
Microbiology
Empyema as an Invasive
Pneumococcal Disease
Microbiology
Serotype 1
Blood Culture Positive
Pleural Fluid Culture Pos
Both Positive
Vaccine type causing
infection
Conjugate vaccine
Polysaccharide vaccine
Antibiotic resistance
Penicillin
TMP-SMX
Erythromycin
Ciprofloxacin
Levofloxacin
Moxifloxacin
MDR (>=2 classes)
Non-empyema
Empyema
P value
27/4309 (0.63)
4596/4772 (96.3)
NA
NA
6/136 (4.4%)
79/154(51.3%)
121/154 (78.5%)
46/121 (38%)
<.001
<.001
NA
NA
2456/4309 (57%)
3751/4309 (87%)
N=4330
168 (3.9%)
847 (19.6%)
497 (11.5%)
51 (1.2%)
31 (0.8%)
9 (0.2%)
24/130(18%)
58/136 (43%)
116/136 (85%)
N=137
7 (5.1%)
30 (21.9%)
24 (17.5%)
7 (5.3%)
6 (4.6%)
1 (0.8%)
501/4082(12%)
<.001
.54
.6
.5
.03
<.001
<.001
.21
.04
Isolate Serotypes
14
16%
OTHER
34%
3
11%
6B
7%
23F
4%
19F
4%
12F
4%
1
4%
9V
5%
6A
5%
7F
6%


Conjugate Vaccine
4,6B, 9V, 14, 18C,
19F, 23F


Polyvalent Vaccine
1 2 3 4 5 6B 7F 8 9N
9V 10A 11A 12F 14
15B 17F 18C 19F
19A 20 22F 23F 33F
Vaccine Strains by Year
100.0
80.0
Percentage
60.0
CONJUGATE VACCINE PERCENTAGE
POLYVALENT VACCINE PERCENTAGE
40.0
20.0
0.0
1996
1997
1998
1999
2000
2001
Year
2002
2003
2004
2005
2006
Clustering of Resistance
Penicillin
Erythromycin Resistant
TMP/SMX Resistant
Levofloxacin Resistant
Erythromycin
TMP/SMX Resistant
Levofloxacin Resistant
TMP/SMX
Levofloxacin Resistance
Conjugate Vaccine Serotypes
Penicillin Resistance
Erythromycin Resistance
TMP/SMX Resistance
Levofloxacin Resistance
Polyvalent Vaccine Serotypes
Penicillin Resistance
Erythromycin Resistance
TMP/SMX Resistance
Levofloxacin Resistance
Resistant
Not-Resistant
P value
11/20(55%)
15/20(75%)
0/20(0%)
13/117(11%)
15/117(13%)
6/111(5.4%)
<.001
<.001
0.59
14/24 (58%)
1/24(4.2%)
16/116(14%)
5/107(4.7%)
<.001
1
1/30(3.3%)
5/101(5.0%)
1
13/20 (65%)
15/24(63%)
19/30(63%)
1/6(17%)
45/116(39%)
43/112(39%)
39/106(37%)
53/124(43%)
0.048
0.04
0.01
0.4
18/20(90%)
21/24(88%)
23/30(77%)
3/6(50%)
98/116(85%)
95/112(85%)
93/106(88%)
108/124(87%)
0.7
1
0.015
0.04
Resistance to Multiple Agents
Resistance to Multiple Agents
MDR
12/24 (50%)
NOT MDR
65/107 (61%)
P value
.36
4/24 (17%)
12/24 (50%)
8/24 (33%)
3/24 (13%)
0/24 (0%)
9/24 (38%)
13/106 (13%)
47/106 (44%)
46/106 (43%)
3/103 (3%)
8/103 (7.8%)
39/107 (36%)
.6
ICU
Ventilation
Death
10/24 (42%)
5/24 (21%)
2/24 (8.3%)
41/106 (39%)
33/105 (31%)
26/107 (24%)
.8
.45
.1
Positive Blood Culture
13/24 (54%)
56/107 (52%)
1
Conjugate Vaccine Serotypes
Polyvalent Vaccine Serotypes
16/24 (67%)
20/24 (83%)
38/106 (36%)
91/106 (86%)
0.01
0.75
Male
Age
<15
15-64
>=65
Nursing Home
Nosocomial
Any Chronic Illness
.08
.35
1
Resistance over Time
Percentage of Resistant Isolates vs Time
45.0
40.0
35.0
30.0
25.0
Year
PCN-R RATE
LEV-R RATE
MDR RATE
20.0
15.0
10.0
5.0
0.0
1996
1997
1998
1999
2000
2001
Percentage
2002
2003
2004
2005
2006
Outcomes
Survival
Deceased
21/31 (68%)
Survived
70/123 (57%)
P value
.31
1/30 (3.3%)
8/30 (27%)
21/30 (70%)
5/29 (17%)
2/29 (6.9%)
5/31 (16%)
13/26 (50%)
10/31 (32%)
2/26 (7.7%)
10/26 (39%)
16/122 (13%)
63/122 (52%)
43/122 (35%)
1/120 (0.8%)
7/120 (5.8%)
49/123 (39%)
24/95 (25%)
17/123 (14%)
15/88 (17%)
16/85 (19%)
.002
ICU
Ventilation
17/30 (57%)
17/30 (57%)
42/123 (34%)
28/122 (23%)
.04
.001
Positive Blood Culture
21/31 (68%)
58/123 (47%)
.046
Conjugate Vaccine Serotypes
Polyvalent Vaccine Serotypes
Penicillin Resistant
Erythromycin Resistant
TMP/SMX Resisitant
Levofloxacin Resistant
MDR
8/28 (29%)
21/28 (75%)
4/28 (14%)
1/28 (3.6%)
3/28 (11%)
0/28 (0%)
2/28 (7.1%)
50/108 (46%)
95/108 (88%)
16/109 (15%)
23/109 (21%)
27/109 (25%)
6/103 (5.8%)
22/103 (21%)
0.13
0.13
1
.03
0.13
0.34
.1
Male
Age
<15
15-64
>=65
Nursing Home
Nosocomial
No Chronic Illness
Lung Disease
Cardiac Disease
Diabetes
Alcohol
.001
.69
.02
.03
.03
.35
.06
ICU Admissions and Deaths By
Year
Complications by Year
60.0
50.0
40.0
ICU Admission
30.0
Case Fatality Rate
20.0
10.0
0.0
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
Limitations
 Culture
negative pneumococcal empyema and
patients with sputum cultures only would not be
captured by our surveillance.

Eltringham G, Kearns A, Freeman R, Clark J, Spencer D,
Eastham K, et al. Culture-negative childhood empyema is
usually due to penicillin-sensitive Streptococcus pneumoniae
capsular serotype 1. J Clin Microbiol 2003 Jan;41(1):521-2.

~70% of culture negative were pneumoccoccus according to
PCR assays. ~60% of these were serotype 1
 Examining
complicated pleural effusion and
empyema rather than empyema exclusively
 Limited access (at this point) to patient specific data
Conclusions
In our cohort of patients with pneumococcal empyema:




Population based rates were highest in patients older than 65
Cases more likely to be alcohol abusers or have underlying lung
disease
Cases were more likely to be failing outpatient therapy
There was a high morbidity (40% ICU admission) and mortality
(20% death) associated with pneumococcal empyema



Death associated with underlying disease states and more severe
illness
Serotype 1 was more common in empyema than in other IPD
Isolates found in empyema were more likely to be resistant to
macrolides, ciprofloxacin (not shown) and levofloxacin but not
penicillin or moxifloxacin
Acknowledgements
Refik Saskin
 Karen Green
 Dr. Allison McGeer
 Dr. D. Low
 Toronto Invasive Bacterial Diseases
Network

References
1. Aspa J, Rajas O, Rodriguez de Castro F, Blanquer J, Zalacain R, Fenoll A, et al. Drug-resistant pneumococcal pneumonia: clinical relevance
and related factors. Clin Infect Dis 2004 Mar 15;38(6):787-98.
2. Barnes NP, Hull J, Thomson AH. Medical management of parapneumonic pleural disease. Pediatr Pulmonol 2005 Feb;39(2):127-34.
3. Buckingham SC, King MD, Miller ML. Incidence and etiologies of complicated parapneumonic effusions in children, 1996 to 2001. Pediatr
Infect Dis J 2003 Jun;22(6):499-504.
4. Byington CL, Korgenski K, Daly J, Ampofo K, Pavia A, Mason EO. Impact of the pneumococcal conjugate vaccine on pneumococcal
parapneumonic empyema. Pediatr Infect Dis J 2006 Mar;25(3):250-4.
5. Byington CL, Samore MH, Stoddard GJ, Barlow S, Daly J, Korgenski K, et al. Temporal trends of invasive disease due to Streptococcus
pneumoniae among children in the intermountain west: emergence of nonvaccine serogroups. Clin Infect Dis 2005 Jul 1;41(1):21-9.
6. Byington CL, Spencer LY, Johnson TA, Pavia AT, Allen D, Mason EO, et al. An epidemiological investigation of a sustained high rate of
pediatric parapneumonic empyema: risk factors and microbiological associations. Clin Infect Dis 2002 Feb 15;34(4):434-40.
7. Calbo E, Diaz A, Canadell E, Fabrega J, Uriz S, Xercavins M, et al. Invasive pneumococcal disease among children in a health district of
Barcelona: early impact of pneumococcal conjugate vaccine. Clin Microbiol Infect 2006 Sep;12(9):867-72.
8. Carratala J, Martin-Herrero JE, Mykietiuk A, Garcia-Rey C. Clinical experience in the management of community-acquired pneumonia:
lessons from the use of fluoroquinolones. Clin Microbiol Infect 2006 May;12 Suppl 3:2-11.
9. Eltringham G, Kearns A, Freeman R, Clark J, Spencer D, Eastham K, et al. Culture-negative childhood empyema is usually due to penicillinsensitive Streptococcus pneumoniae capsular serotype 1. J Clin Microbiol 2003 Jan;41(1):521-2.
10. Fletcher M, Leeming J, Cartwright K, Finn A, South West of England Invasive Community Acquired Infection Study,Group. Childhood
empyema: limited potential impact of 7-valent pneumococcal conjugate vaccine. Pediatr Infect Dis J 2006 Jun;25(6):559-60.
11. Giachetto G, Pirez MC, Nanni L, Martinez A, Montano A, Algorta G, et al. Ampicillin and penicillin concentration in serum and pleural fluid of
hospitalized children with community-acquired pneumonia. Pediatr Infect Dis J 2004 Jul;23(7):625-9.
12. Liapakis IE, Kottakis I, Tzatzarakis MN, Tsatsakis AM, Pitiakoudis MS, Ypsilantis P, et al. Penetration of newer quinolones in the empyema
fluid. Eur Respir J 2004 Sep;24(3):466-70.
13. Le Monnier A, Carbonnelle E, Zahar JR, Le Bourgeois M, Abachin E, Quesne G, et al. Microbiological diagnosis of empyema in children:
comparative evaluations by culture, polymerase chain reaction, and pneumococcal antigen detection in pleural fluids. Clin Infect Dis 2006
Apr 15;42(8):1135-40.
14. Obando I, Arroyo LA, Sanchez-Tatay D, Moreno D, Hausdorff WP, Brueggemann AB. Molecular typing of pneumococci causing
parapneumonic empyema in Spanish children using multilocus sequence typing directly on pleural fluid samples.comment. Pediatr Infect
Dis J 2006 Oct;25(10):962-3.
15. Paganini H, Guinazu JR, Hernandez C, Lopardo H, Gonzalez F, Berberian G. Comparative analysis of outcome and clinical features in
children with pleural empyema caused by penicillin-nonsusceptible and penicillin-susceptible Streptococcus pneumoniae. Int J Infect Dis
2001;5(2):86-8.
16. Schultz KD, Fan LL, Pinsky J, Ochoa L, Smith EO, Kaplan SL, et al. The changing face of pleural empyemas in children: epidemiology and
management. Pediatrics 2004 Jun;113(6):1735-40.
17. Tan TQ, Mason EO,Jr, Wald ER, Barson WJ, Schutze GE, Bradley JS, et al. Clinical characteristics of children with complicated pneumonia
caused by Streptococcus pneumoniae. Pediatrics 2002 Jul;110(1 Pt 1):1-6.