neutropenic fever: challenges and treatment
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Neutropenic Fever:
Challenges and
Treatment
Dong-Gun Lee
Div. of Infectious Diseases,
Dept. of Internal Medicine,
The Catholic Univ. of Korea
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
; Empirical therapy as 1st onset of NF
• When using Glycopeptides…
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
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 CotrimazoleNystatin gargle
Ciprofloxacin, roxithromycin, fluconazole
NA Ciprofloxacin, fluconazole/ itraconazole,
TMP/SMXNo. 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)
Others (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
0102030
4050
60
70
80
GNB
Catholic HSCT Center (Pre-engraftment)Epidemiology, Catholic BMT
Center
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
Organisms (n=243) Ward A Ward B Total (%) P valueGram (+) (n=122) (n=108) (n=14) S. aureus 9 2 11 (4.5) 0.649 CoNS 14 0 14 (5.8) 0.227
Viridans streptococci39
(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) 0.198Corynebacterium 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. coli58
(27.6)14
(42.4)72 (29.6) 0.083
K. pneumonia28
(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) Trichosporon asahii 1 0 1 (0.4)
No. of microorganims
Infect Chemother 2013;45: [in press]
Epidemiology, Catholic BMT Center (‘09-’10)
Pathogens(No. of isolates)
No. of isolates resistant to antibiotics/no. of isolates tested
PCVOXAC
CLM EM CFTX CFPM GMCPFX or LVX
VAN IMPM AMP
S. aureus (11) 11/11 7/11 5/11 5/11 - - 4/11 6/11 0/11 - -
CoNS (14) 14/1412/13
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) 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 (+)75/108
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
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 64/7264/72
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 (-) 44/9499/107
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
(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
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 What is the major etiologic agents of neutropenic fever in Asia?fever in Asia?
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
Question (3)
Do you think ESBL producing organisms show higher mortality?
1. YES
2. NO
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), yr44 (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)
Ann Hematol 2013; [in press]
Susceptibility
CharacteristicsUnadjusted 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 cephalosporins9.397 (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]
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)
NS2 (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)
NSNSNS
0 (0.0) 2
(20.0) 2
(22.0)
0 (0.0) 1 (33.3) 0 (0.0)
NSNSSAnn Hematol 2013; [in press]
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)
<0.00
1
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) 0.554Ann Hematol 2013; [in press]
EJC Suppl 2007;5:13-22 [ECIL-1]
Role of Aminoglycoside in NF (1)
Role of Aminoglycoside in NF (2)
Ann Hematol 2012;91:1161-74
[DGHO]
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]
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 producing in high incidence of ESBL producing Enterobacteriaceae area…Enterobacteriaceae area…
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
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 Infection
France, 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:
CommentsTPV 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
H : q12h, 800-400-600-400-400-400S : 400 mg q12hrs (×3), 400 mg q24h
Yonsei Med J 2011;52:616-23
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, When using glycopeptide to NF patients, Consider…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
Thank You for Your Attention
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