Neutropenic fever : Challenges and Treatment

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

Contents
• Epidemiology Focus in Asia
; Etiologic microorganisms & Resistance
• ESBL producing Enterobacteriaceae
• Glycopeptides

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

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

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

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

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

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

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

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

’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

’83 ~ ’88
’89 ~ ’92
’93 ~ ’96
’98 ~ ’99
’01 ~ ’02
Enterococcus spp.
Streptococcus spp.
S. aureus
CNS
0
10
20
30
40
50
GPC

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
Viridians 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
(‘09-’10)

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

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

Antibiotics 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

 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?

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

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)

Susceptibility

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

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
at EOT
0 (0.0)
1 (6.7)
5
1 (1.4)
3 (4.2)
30 (41.7)
NS
NS
NS
0 (0.0)
2 (20.0)
9 (81.8)
0(0.0)
1 (33.3)
2 (66.7)
NS
NS
NS
Factors associated with Mortality

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

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

Ann Hematol 2012;91:1161-74
[DGHO]

 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]

 We 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…

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

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

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

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

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%

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

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

Teicoplanin Dose in Acute Leukemia
and Febrile Neutropenia
Clin Pharmacokinet 2004;43:405-15

 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…

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

Neutropenic fever : Challenges and Treatment

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