1. Neutropenic Fever: Challenges and Treatment
Dong-Gun Lee
Div. of Infectious Diseases,
Dept. of Internal Medicine,
The Catholic Univ. of Korea

2. Contents Epidemiology Focus in Asia ESBL producing Enterobacteriaceae
; Etiologic microorganisms & Resistance
ESBL producing Enterobacteriaceae
; Empirical therapy as 1st onset of NF
When using Glycopeptides…

3. Question (1)
What is the most common pathogen during neutropenia in your institution in these days?
Pseudomonas aeruginosa
Escherichia coli
Staphylococcus aureus
Coagulase negative Staphylococci
viridans streptococci
fungi

4. Epidemiology, EU
Clin Infect Dis 2005;40:S240-5

5. Epidemiology, US [SCOPE] Project
Clin Infect Dis 2003;36:

6. Epidemiology, Malaysia (2004)
Int J Infect Dis
2007;11:513-7

7. Epidemiology, Taiwan (‘99-02)
Chemotherapy
2005;51:147-53

8. Epidemiology, Taiwan (‘02-06)
Epidemiol Infect 2010;138:1044;51

9. NA09-013 Korean J Intern Med 2011;26:220-52
Infect Chemother 2011;43:

10. Epidemiology, Korea 초기 항균요법 (2) No. (%) Reference Rho et al.
Rhee et al.
Choi et al.
Kim et al.
Park et al.
Period (year)
Hospital A B C D
Patients
leukemia
allo-HSCT
acute leukemia
cancer
HSCT
Prophylaxis NA
Cotrimazole
Nystatin gargle
Ciprofloxacin, roxithromycin, fluconazole
Ciprofloxacin, fluconazole/ itraconazole,
TMP/SMX
No. of MDI
27 (100)
78 (100)
158 (100)
42 (100)
72 (100)
Gram (+) bacteria
11 (40.7)
36 (46.2)
75 (47.5)
11 (26.2)
25 (34.7)
Streptococcus
1 (3.7) -
24 (15.2)
2 (4.8)
9 (12.5)
CoNS
4 (14.8)
15 (19.2)
20 (12.7)
4 (9.5)
7 (9.7)
Staphylococcus aureus
13 (8.2)
3 (7.1)
2 (2.8)
Enterococcus
2 (7.4)
14 (8.9)
6 (8.3)
Gram (-) bacteria
16 (59.3)
42 (53.8)
83 (52.5)
31 (73.8)
47 (65.3)
Escherichia coli
43 (27.2)
32 (44.4)
Pseudomonas aeruginosa
12 (7.6)
5 (11.9)
4 (5.6)
Klebsiella pneumoniae
6 (22.2)
8 (19.0)
Enterobacter
5 (3.2)
3 (4.2)
Acinetobacter baumanii
Aeromonas hydrophila
6 (3.8)
Citrobacter freundii
1 (1.4)
Salmonella

11. Epidemiology, Catholic BMT Center (Pre-engraftment Period)
Catholic HSCT Center (Pre-engraftment)
Epidemiology, Catholic BMT Center
(Pre-engraftment Period)
’83 ~ ’88
’89 ~ ’92
’93 ~ ’96
’98 ~ ’99
’01 ~ ’02
No. of isolates 14 8 24 25
G (+)
CNS (6)
S. aureus (4)
S. epidermidis (10)
Streptococcus (9)
S. aureus (2)
S. aureus (3)
S. epidermidis (3)
Streptococcus (5)
CNS (7)
Enterococcus (3)
Enterococcus (2)
E. faecalis (1)
Staphylococcus (3)
S.aureus (2)
Streptococcus (2)
Streptococcus (3)
E. faecium (4)
E. faccium (4)
E. faecalis (2)
Micrococcus (1) 15 12 40 47
G (-)
P. aeruginosa (11)
P. aeruginosa (8)
P. aeruginosa (6)
E. coli (32)
Klebsiella (2)
Klebsiella (1)
E. coli (5)
Klebsiella (3)
K. pneumoniae (4)
E. coli (1)
E. coli (1)
Enterobacter (5)
Enterobacter (2)
P. aeruginosa (4)
Other (1)
Others (2)
P. aeruginosa (1)
Enterobacter (3)
Others (5)
A. baumanii (2)
J Korean Med Sci 2006;21:

12. Epidemiology, Catholic BMT Center
Catholic HSCT Center (Pre-engraftment)
Epidemiology, Catholic BMT Center
GNB

13. Epidemiology, Catholic BMT Center
Catholic HSCT Center (Pre-engraftment)
Epidemiology, Catholic BMT Center
GPC

14. Epidemiology, Catholic BMT Center (‘09-’10)
No. of microorganims
Epidemiology, Catholic BMT Center (‘09-’10)
Organisms (n=243)
Ward A
Ward B
Total (%)
P value
Gram (+) (n=122)
(n=108)
(n=14)
S. aureus 9 2
11 (4.5)
0.649
CoNS 14
14 (5.8)
0.227
Viridans streptococci
39 (18.6)
5 (15.2)
44 (18.1)
0.635
S. pneumonia
2 (0.8)
Rothia mucilaginosa 5
5 (2.1)
Enterococcus spp. 27 7
34 (14.0)
0.198
Corynebacterium spp. 4
4 (1.6)
Bacillus spp. 3
3 (1.2)
Others†
Gram (-) (n=119)
(n=100)
(n=17)
E. coli
58 (27.6)
14 (42.4)
72 (29.6)
0.083
K. pneumonia
28 (13.3)
3 (9.1)
31 (12.8)
Pseudomonas spp. 1
6 (2.5)
Enterobacter spp.
Stenotrophomonas maltophilia
Others*
Fungus (n=2)
Candida tropicalis
1 (0.4)
Trichosporon asahii
Infect Chemother 2013;45: [in press]

15. Resistance Patterns (GPC) Resistance Pattern, GPC
Pathogens
(No. of isolates)
No. of isolates resistant to antibiotics/no. of isolates tested
PCV
OXAC
CLM EM
CFTX
CFPM GM
CPFX or LVX
VAN
IMPM
AMP
S. aureus (11)
11/11
7/11
5/11 -
4/11
6/11
0/11
CoNS (14)
14/14
12/13
8/14
9/14
10/14
13/14
0/14
Streptococci other than pneumococcus (46)
24/46
11/45
21/46
4/45
17/45
0/1
0/45
0/2
S. pneumonia (2)
2/2
Enterococcus faecium (19)
19/19
17/19
7/19
Enterococcus faecalis (15)
6/15
15/15
12/15
14/15
0/15
5/15
Gamella mibiliform (1)
1/1
Total no. of G (+)
75/108
19/24
58/105
66/108
4/48
17/46
14/25
52/62
7/107
19/34
24/36
% of resistance
69.4
79.2
55.2
61.1
8.3
37.0
56.0
83.9
6.5
55.9
66.7

16. Resistance Pattern, GNB
Pathogens
(No. of isolates)
No. of isolates resistant to antibiotics/no. of isolates tested
ESBL
AMC
PIPC GM
TOB
CAZ
LVX
SXT
AZTN
IMPM
MRPN
E. coli (72)
22/63
64/72
30/72
33/72
24/72
65/70
40/72
23/72
0/72
K. pneumoniae (31)
22/31
31/31
27/31
18/31
21/31
24/29
20/31
0/31
Pseudomonas spp. (6) -
0/6
0/5
2/6
3/5
4/4
4/6
Enterobacter spp. (4)
0/4
1/4
3/4
S. maltophilia (4)
B. cepacia (1)
0/1
C. indologenes (1)
1/1
Total no. of G (-)
44/94
99/107
96/114
49/114
55/113
50/115
94/114
67/117
5/114
1/115
% of resistance
46.8
92.5
84.2
43.0
48.7
43.5
82.3
57.3
4.4
0.9

17. Viridans Streptococci Bacteremia in NF
Antibiotics
(susceptibility)
Adults
(≥ 20 years old)
(n=140)
Children
(< 20 years old)
(n=61)
Penicillin
57 (40.7)
22 (36.1)
0.535
Cefotaxime
127 (90.7)
39 (65.0)
< 0.001
Cefepime
120 (85.7)
39 (66.1)
0.002
Vancomycin
140 (100.0)
61 (100.0) NA
Linezolid
60 (98.4)
0.303
Clindamycin
121 (86.4)
51 (83.6)
0.601
Erythromycin
78 (55.7)
21 (34.4)
0.006
Data from Catholic BMT Center [in press]

18. What is the major etiologic agents of neutropenic fever in Asia?
초기 항균요법 (1)
What is the major etiologic agents of neutropenic fever in Asia?
In contrast to western countries, Gram-negative bacteria are the prevailing etiological agents of infections in neutropenic fever patients in Asia.
Because of the reported etiologic bacteria and their antimicrobial resistance rates causing neutropenic fever vary widely by times, area, even wards, every hospital should continue to monitor the changing patterns of etiology and adjustment of empirical antibiotics may be necessary.

19. Question (2)
What is your strategy for the empirical Tx in 1st onset of neutropenic fever?
Broad spectrum Cephalosporin monotherapy
Broad spectrum Penicillin monotherapy
Carbapenem monotherapy
Beta-lactam + Aminoglycoside
Beta-lactam + Quinolone
Double Beta-lactams

20. Do you think ESBL producing organisms show higher mortality?
Question (3)
Do you think ESBL producing organisms show higher mortality?
YES NO

21. Mortality: ESBL vs. Non-ESBL BSI
J Antimicrob Chemother 2012;67:

22. ESBL vs. Non-ESBL BSI in NF
E. coli
K. pneumoniae
ESBL
(n=15)
Non-ESBL
(n=72)
(n=11)
(n=3)
Age, median (range), yr
44 (15-64)
42 (17-74)
39 (16-59)
31 (23-42)
Sex, M:F
9:6
39:33
6:5
3:0
Underlying disease
AML
ALL MM
Others*
10 (66.7)
2 (13.3)
1 (6.7)
33 (45.8)
31 (43.1)
4 (5.6)
5 (45.5)
4 (36.4)
0 (0.0)
2 (18.1)
1 (33.3)
2 (66.6)
Undergoing therapy
Chemotherapy
HSCT
5 (33.3)
59 (81.9)
13 (18.1)
8 (72.7)
3 (27.3)
3 (100.0)
1st set fever†
13 (86.7)
72 (100.0)
4 (36.3)
Empirical therapy
3rd generation cephalosporin
Cefepime
Piperacillin-tazobactam
Carbapenem
Aminoglycoside combination
13 (87.0)
2 (13.0)
14 (93.3)
60 (83.0)
3 (4.0)
8 (11.1)
1 (1.4)
71 (98.6)
4 (36.0)
1 (9.0)
6 (54.5)
Ann Hematol 2013; [in press]

23. Susceptibility
Ann Hematol 2013; [in press]

24. Factors associated with ESBL BSI
Characteristics
Unadjusted OR (95% CI)
p-value
Adjusted OR (95% CI)
Disease status, non-remitted
3.569 ( )
0.009 -
0.110
History of ICU admission within prior 3 months
( )
0.023
0.162
Hospital stay for >2 weeks within the preceding 3 months
7.874 ( )
0.002
5.887 ( )
0.008
Previous antibiotics use within the preceding 4 weeks
Broad-spectrum cephalosporins
9.397 ( )
0.001
6.186 ( )
β-lactam/β-lactamase inhibitors
4.226 ( )
0.044
0.083
Aminoglycosides
6.088 ( )
0.565
Glycopeptides
8.690 ( )
0.013
0.436
Ann Hematol 2013; [in press]

25. Factors associated with Mortality
No. (%)
E. coli
K. pneumoniae
ESBL
(n=15)
Non-ESBL
(n=72) P
(n=11)
(n=3)
Early response (72hr) CR PR
Treatment failure
5 (33.3)
9 (60.0)
1 (6.7)
29 (40.3)
41 (56.9)
2 (2.8) NS
2 (18.2)
6 (54.5)
3 (27.3)
1 (33.3)
2 (66.7)
0 (0.0)
Mortality
Overall
at 7 day
at 30 day
Bacteremia attributable
1 (1.4)
3 (4.2)
2 (20.0)
2 (22.0) S
Ann Hematol 2013; [in press]

26. Factors associated with Mortality
Characteristics
Unadjusted OR (95% CI)
p-value
Adjusted OR (95% CI) *
ESBL production
3.227 ( )
0.117
0.735 ( )
0.602
Inappropriate empirical antimicrobial therapy
4.286 ( )
0.233
1.401 ( )
0.699
Disease status, non-remitted
4.843 ( )*
0.034
1.990 ( )
0.305
Duration of neutropenia >3 weeks
7.731 ( )
0.016
1.757 ( )
0.248
Septic shock at presentation
( )
<0.001
2.946 ( )
0.036
Infecting organism, Klebsiella pneumoniae
8.300 ( )
0.007
3.593 ( )
0.046
Copathogen
1.335 ( )
0.554
따라서, 이번연구에서는 ESBL production이 mortality에는 관련이 없었다. 아마도 aminoglycoside combination 때문이 아닐까??
Ann Hematol 2013; [in press]

27. Role of Aminoglycoside in NF (1)
EJC Suppl 2007;5:13-22 [ECIL-1]

28. Role of Aminoglycoside in NF (2)
Ann Hematol 2012;91:
[DGHO]

29. Role of Aminoglycoside in NF (3)
While the addition of an aminoglycoside has not been shown to be of clinical advantage compared with beta-lactam monotherapy in systematic reviews, there are particular circumstances where the choice of aminoglycoside may be important. These include severe sepsis where there is a risk of resistance in Gram-negative bacilli and in Pseudomonas infection.
Intern Med 2011;41: [Australian Guideline]

30. in high incidence of ESBL producing Enterobacteriaceae area…
초기 항균요법 (1)
in high incidence of ESBL producing Enterobacteriaceae area…
We may still use the beta-lactam + aminoglycoside combination strategy for empirical therapy of NF. When ESBL is not proven, aminoglycoside is only used for 3-5 days.
Adjustment for inadequate empirical therapy can lead to a reduction of mortality. For example, combination therapy with aminoglycoside…

31. for MRSA bacteremia in NF?
Question (4)
What do you use mainly
for MRSA bacteremia in NF?
Vancomycin
Teicoplanin
Arbekacin
Linezolid
Fusidic acid
Others

32. PKs in Neutropenia
Reduced serum, tissue, and body fluid concentrations of antibacterial agents have been reported in neutropenic patients and animal models, potentially reducing the bactericidal activities of these agents.
PK changes in neutropenic patients are probably not only related to neutropenia per se, but also to the severity of sepsis, as has been in ICU patients.  host defense mechanism…
Lancet Infect Dis 2008;8:612-20

33. PK of Glycopeptides in Neutropenia
Lancet Infect Dis 2008;8:612-20

34. What can we learn from studies comparing Linezolid with Vancomycin in neutropenic patients when vancomycin doses are not optimized?
PK of vancomycin therapy in neutropenic patients is different.
; 3-fold increases of initial Vd, shorted half-life (vs. healthy
volunteer)
2. Achievement of trough serum conc. ≥15 mg/L?
3. T>MIC 100%
4. 1 g iv q12hrs fixed dose  30 mg/kg/day
Clin Infect Dis 2006;42:1813-4

35. Vancomycin TDM Consensus
Am J Health Syst Pharm 2009;66:82-98

36. N= 119, Hospital acquired infection, bacteremia 35%, pneumonia 45%
Continuous vs. Intermittent Infusion of Vancomycin in Severe Staphylococcal Infection
France, Prospective study, CIV (plateau mg/L), IIV (trough mg/L)
N= 119, Hospital acquired infection, bacteremia 35%, pneumonia 45%
Antimicrob Agents Chemother 2001;45:2460-7

37. Empirical Teicoplanin in Neutropenic Fever in Korea: Comments
TPV 400 mg qd and then 200 mg qd
; is that enough?
Only one strains of S. aureus,
CNS can be affected by catheter removal
Four out of 6 strains of E. faecium were vancomycin resistant.
Viridans streptococci would be susceptible with cefepime.
Infect Chemother 2004;36:83-91

38. Loading Dose of Teicoplanin
J Antimicrob Chemother 2003;51:971-5

39. Teicoplanin Dose in Acute Leukemia and Febrile Neutropenia
H : q12h,
S : 400 mg q12hrs (×3), 400 mg q24h
Clin Pharmacokinet 2004;43:405-15

40. Yonsei Med J 2011;52:616-23

41. When using glycopeptide to NF patients, Consider…
초기 항균요법 (1)
When using glycopeptide to NF patients, Consider…
PK of glycopeptides in neutropenic patients is different with that of normal volunteers. We need their PK data!!!
may need higher doses than usual
Vancomycin trough concentrations mg/L or AUC/MIC >400 would be required in neutropenic fever as well as in severe staphylococcal infection.
Teicoplanin PK/PD magnitude for neutropenic fever is not established yet (trough >10 or 20 mg/L, AUC/MIC >345??). However, TDM would be needed for monitoring TAR. Teicoplanin dose would be needed more than we usually prescribe.

42. Summary
Etiology of NF is different according to the area, time, even the wards in the same hospital.  We need to continue monitoring the changing patterns.
ESBL producing organisms are common. High index of suspicion (prior use of beta-lactams, Hx of long hospital stay…) is important. For empirical Tx against ESBL organisms, consider the susceptibility patterns and adjust for inadequate antibiotics…
PK of glycopeptides in neutropenic patients is different with that of normal volunteers.  We need their PK data!!! Population PK

43. Thank You for Your Attention