Neutropenic Fever: Challenges and

TreatmentDong-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 Staphylococci5. viridans streptococci6. 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;26:220-52Infect 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 2001-2002Hospital A B C D CPatients leukemia allo-HSCT acute

leukemiacancer 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

aureus4 (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

aeruginosa1 (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

baumanii2 (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 ~ ’02No. 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. coliP. aeruginosa

01020304050607080

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 streptococci 39

(18.6) 5 (15.2) 44 (18.1) 0.635S. 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. 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) 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

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 12/13 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 19/19Enterococcus 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 64/72 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(susceptibility)

Adults (≥ 20 years old)

(n=140)

Children (< 20 years

old)(n=61)

Penicillin 57 (40.7) 22 (36.1) 0.535Cefotaxime 127 (90.7) 39 (65.0) < 0.001Cefepime 120 (85.7) 39 (66.1) 0.002

Vancomycin 140 (100.0) 61 (100.0) NALinezolid 140 (100.0) 60 (98.4) 0.303Clindamycin 121 (86.4) 51 (83.6) 0.601Erythromycin 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

monotherapy2. Broad spectrum Penicillin monotherapy3. Carbapenem monotherapy4. Beta-lactam + Aminoglycoside5. Beta-lactam + Quinolone6. Double Beta-lactams

Question (3)

Do you think ESBL producing organisms show higher mortality?

1. YES2. 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 NFNo. (%)

E. coli K. pneumoniaeESBL

(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 3:0Underlying 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)

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)

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. Vancomycin2. Teicoplanin3. Arbekacin4. Linezolid5. Fusidic acid6. 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 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:

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 removal3. 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…

SummaryEtiology 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