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
; 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?
1. Pseudomonas aeruginosa
2. Escherichia coli
3. Staphylococcus aureus
4. Coagulase negative Staphylococci
5. viridans streptococci
6. fungi

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

5. Clin Infect Dis 2003;36:1103-10
Epidemiology, US [SCOPE] Project

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. Korean J Intern Med 2011;26:220-52
Infect Chemother 2011;43:285-321
NA09-013

10. 초기 항균요법 (2)
No. (%)
Reference Rho et al. Rhee et al. Choi et al. Kim et al. Park et al.
Period (year) 1996-2001 1996-2003 1998-1999 1999-2000 2001-2002
Hospital A B C D C
Patients leukemia allo-HSCT acute
leukemia
cancer HSCT
Prophylaxis NA Cotrimazole
Nystatin
gargle
Ciprofloxacin,
roxithromycin,
fluconazole
NA 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 4 (14.8) - 13 (8.2) 3 (7.1) 2 (2.8)
Enterococcus 2 (7.4) - 14 (8.9) 2 (4.8) 6 (8.3)
Gram (-) bacteria 16 (59.3) 42 (53.8) 83 (52.5) 31 (73.8) 47 (65.3)
Escherichia coli 4 (14.8) - 43 (27.2) 2 (4.8) 32 (44.4)
Pseudomonas
aeruginosa
1 (3.7) - 12 (7.6) 5 (11.9) 4 (5.6)
Klebsiella pneumoniae 6 (22.2) - 12 (7.6) 8 (19.0) 4 (5.6)
Enterobacter - - 5 (3.2) 4 (9.5) 3 (4.2)
Acinetobacter baumanii 2 (7.4) - - 2 (4.8) 2 (2.8)
Aeromonas hydrophila 1 (3.7) - 6 (3.8) - -
Citrobacter freundii - - - 2 (4.8) 1 (1.4)
Salmonella - - - 4 (9.5) -
Epidemiology, Korea

11. Catholic HSCT Center (Pre-engraftment)
’83 ~ ’88 ’89 ~ ’92 ’93 ~ ’96 ’98 ~ ’99 ’01 ~ ’02
No. of isolates
13
14 8 24 25
G (+)
CNS (6) 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) E. faecalis (2)
Micrococcus (1)
15 12 24 40 47
G (-)
P. aeruginosa
(11)
P. aeruginosa
(8)
P. aeruginosa
(6)
E. coli (32) 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) Klebsiella (3) P. aeruginosa (1) Enterobacter (3)
Others (5) Others (2) A. baumanii (2)
Epidemiology, Catholic BMT Center
(Pre-engraftment Period)
J Korean Med Sci 2006;21:199-207

12. ’83 ~ ’
88 ’89 ~ ’
92 ’93 ~ ’
96 ’98 ~ ’
99 ’01 ~ ’
02
Others
Enterobacter spp.
K. pneumoniae
E. coli
P. aeruginosa
0
10
20
30
40
50
60
70
80
GNB
Catholic HSCT Center (Pre-engraftment)
Epidemiology, Catholic BMT Center

13. Catholic HSCT Center (Pre-engraftment)
’83 ~ ’88
’89 ~ ’92
’93 ~ ’96
’98 ~ ’99
’01 ~ ’02
Enterococcus spp.
Streptococcus spp.
S. aureus
CNS
0
10
20
30
40
50
GPC
Epidemiology, Catholic BMT Center

14. 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 0 14 (5.8) 0.227
Viridans streptococci
39
(18.6)
5 (15.2) 44 (18.1) 0.635
S. pneumonia 2 0 2 (0.8)
Rothia mucilaginosa 5 0 5 (2.1)
Enterococcus spp. 27 7 34 (14.0) 0.198
Corynebacterium spp. 4 0 4 (1.6)
Bacillus spp. 3 0 3 (1.2)
Others† 5 0 5 (2.1)
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. 5 1 6 (2.5)
Enterobacter spp. 3 1 4 (1.6)
Stenotrophomonas
maltophilia
4 0 4 (1.6)
Others* 2 0 2 (0.8)
Fungus (n=2)
Candida tropicalis 1 0 1 (0.4)
No. of microorganims
Epidemiology, Catholic BMT Center
(‘09-’10)

15. 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 5/11 - - 4/11 6/11 0/11 - -
CoNS (14) 14/14
12/1
3
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) 0/2 - - 2/2 0/2 - - 0/2 0/2 - -
Enterococcus faecium
(19)
19/19 - 19/19 17/19 - - - 19/19 7/19 19/19 19/19
Enterococcus faecalis
(15)
6/15 - 15/15 12/15 - - - 14/15 0/15 0/15 5/15
Gamella mibiliform (1) 1/1 - 0/1 0/1 0/1 0/1 - - 0/1 - -
Total no. of G (+)
75/10
8
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
Resistance Patterns (GPC)
Resistance Pattern, GPC

16. 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 64/72 30/72 33/72 24/72 65/70 40/72 23/72 0/72 0/72
K. pneumoniae (31) 22/31 31/31 27/31 18/31 21/31 22/31 24/29 20/31 22/31 0/31 0/31
Pseudomonas spp.
(6)
- - 0/6 0/6 0/5 2/6 3/5 4/4 2/6 4/6 0/6
Enterobacter spp.
(4)
- 4/4 4/4 0/4 0/4 1/4 1/4 3/4 1/4 0/4 0/4
S. maltophilia (4) - - - - - - 0/4 0/4 - - -
B. cepacia (1) - - - - - 0/1 0/1 0/1 - - 0/1
C. indologenes (1) - - 1/1 1/1 1/1 1/1 1/1 0/1 1/1 1/1 1/1
Total no. of G (-) 44/94 99/107 96/114 49/114 55/113 50/115 94/114 67/117 49/114 5/114 1/115
% of resistance 46.8 92.5 84.2 43.0 48.7 43.5 82.3 57.3 43.0 4.4 0.9
Resistance Pattern, GNB

17. 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 140 (100.0) 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]
Viridans Streptococci Bacteremia in
NF

18. 초기 항균요법 (1)
 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.
What is the major etiologic agents of neutropenic feverWhat is the major etiologic agents of neutropenic fever
in Asia?in Asia?

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

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

21. J Antimicrob Chemother 2012;67:1311-20
Mortality: ESBL vs. Non-ESBL BSI

22. Ann Hematol 2013; [in press]
ESBL vs. Non-ESBL BSI in NF
No. (%)
E. coli K. pneumoniae
ESBL
(n=15)
Non-ESBL
(n=72)
ESBL
(n=11)
Non-ESBL
(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)
2 (13.3)
33 (45.8)
31 (43.1)
4 (5.6)
4 (5.6)
5 (45.5)
4 (36.4)
0 (0.0)
2 (18.1)
1 (33.3)
0 (0.0)
0 (0.0)
2 (66.6)
Undergoing therapy
Chemotherapy
HSCT
10 (66.7)
5 (33.3)
59 (81.9)
13 (18.1)
8 (72.7)
3 (27.3)
3 (100.0)
0 (0.0)
1st
set fever†
13 (86.7) 72 (100.0) 4 (36.3) 3 (100.0)
Empirical therapy
3rd
generation cephalosporin
Cefepime
Piperacillin-tazobactam
Carbapenem
Aminoglycoside combination
13 (87.0)
2 (13.0)
0 (0.0)
0 (0.0)
14 (93.3)
60 (83.0)
3 (4.0)
8 (11.1)
1 (1.4)
71 (98.6)
4 (36.0)
1 (9.0)
0 (0.0)
6 (54.5)
5 (45.5)
1 (33.3)
0 (0.0)
1 (33.3)
1 (33.3)
3
(100.0)

23. Ann Hematol 2013; [in press]
Susceptibility

24. Characteristics
Unadjusted OR (95% CI) p-
value
Adjusted OR (95%
CI)
p-
value
Disease status, non-remitted
3.569 (1.375-9.263) 0.009
- 0.110
History of ICU admission within prior 3 months 13.455 (1.429-126.686) 0.023
- 0.162
Hospital stay for >2 weeks within the preceding 3 months 7.874 (2.177-28.475) 0.002
5.887 (1.572-22.041) 0.008
Previous antibiotics use within the preceding 4 weeks
Broad-spectrum cephalosporins
9.397 (2.584-34.179) 0.001
6.186 (1.616-23.683) 0.008
β-lactam/β-lactamase inhibitors
4.226 (1.040-17.173) 0.044
- 0.083
Aminoglycosides
6.088 (1.906-19.447) 0.002
- 0.565
Glycopeptides
8.690 (1.572-48.056) 0.013
- 0.436
Factors associated with ESBL BSI
Ann Hematol 2013; [in press]

25. No. (%)
E. coli K. pneumoniae
ESBL
(n=15)
Non-
ESBL
(n=72)
P
ESBL
(n=11)
Non-ESBL
(n=3)
P
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)
NS
Mortality
Overall
at 7 day
at 30 day
Bacteremia attributable
0 (0.0)
1 (6.7)
1 (6.7)
1 (1.4)
3 (4.2)
3 (4.2)
NS
NS
NS
0 (0.0)
2 (20.0)
2 (22.0)
0 (0.0)
1 (33.3)
0 (0.0)
NS
NS
SAnn Hematol 2013; [in press]
Factors associated with Mortality

26. Factors associated with Mortality
Characteristics Unadjusted OR (95% CI) p-value Adjusted OR (95% CI) *
p-value
ESBL production 3.227 (0.745-13.982) 0.117 0.735 (0.231-2.338) 0.602
Inappropriate empirical antimicrobial therapy 4.286 (0.393-46.785) 0.233 1.401 (0.254-7.722) 0.699
Disease status, non-remitted 4.843 (1.131-20.735)*
0.034 1.990 (0.534-7.416) 0.305
Duration of neutropenia >3 weeks 7.731 (1.465-40.787) 0.016 1.757 (0.675-4.570) 0.248
Septic shock at presentation 43.500 (7.180-263.552) <0.001 2.946 (1.075-8.073) 0.036
Infecting organism, Klebsiella pneumoniae 8.300 (1.791-38.459) 0.007 3.593 (1.023-12.628) 0.046
Copathogen 7.731 (1.465-40.787) 0.016 1.335 (0.513-3.471) 0.554
Ann Hematol 2013; [in press]

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

28. Role of Aminoglycoside in NF (2)
Ann Hematol 2012;91:1161-74
[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;41:90-101 [Australian Guideline]

30. 초기 항균요법 (1)
 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…
in high incidence of ESBL producingin high incidence of ESBL producing
Enterobacteriaceae area…Enterobacteriaceae area…

31. Question (4)
What do you use mainly
for MRSA bacteremia in NF?
1. Vancomycin
2. Teicoplanin
3. Arbekacin
4. Linezolid
5. Fusidic acid
6. 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. Lancet Infect Dis 2008;8:612-20
PK of Glycopeptides in
Neutropenia

34. What can we learn from studies
comparing Linezolid with
Vancomycin in neutropenic patients
when vancomycin doses are not
optimized?
Clin Infect Dis 2006;42:1813-4
1. 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

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

36. Antimicrob Agents Chemother 2001;45:2460-7
Continuous vs. Intermittent
Infusion of Vancomycin in
Severe Staphylococcal
InfectionFrance, Prospective study, CIV (plateau 20-25 mg/L), IIV (trough 15-20 mg/L)
N= 119, Hospital acquired infection, bacteremia 35%, pneumonia 45%

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

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

39. Teicoplanin Dose in Acute Leukemia
and Febrile Neutropenia
Clin Pharmacokinet 2004;43:405-15
H : q12h, 800-400-600-400-400-400
S : 400 mg q12hrs (×3), 400 mg q24h

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

41. 초기 항균요법 (1)
 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 15-20 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.
When using glycopeptide to NF patients, Consider…When using glycopeptide to NF patients, Consider…

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