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(1)

Current Guideline for Neutropenic Fever

Dong-Gun Lee

Div. of Infectious Diseases,

Dept. of Internal Medicine,

The Catholic Univ. of Korea

(2)

CONTENTS

 Prophylaxis

• Bacteria

• Fungi including Pneumocystis jirovecii

• Virus

 Empirical Anti-Bacterial Tx

 Persistent Neutropenic Fever & Empirical Anti-Fungal Tx

 Update on Invasive Candidiasis/Aspergillosis

(3)

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

NA09-013

(4)

Prophylaxis:

Bacteria

Fungi with PcP

Virus

(5)

예방적 항생제 (항균제)

1. 감염 발생의 위험이 중등도 이상인 환자에서는 세균에 대한 예방적 항균제 사

용을 권장한다(A-I).

2. 예방적 항균제로 fluoroquinolone 계열을 권장한다(A-I).

3. 예방적 항균제는 호중구감소증에서 회복될 때까지 사용을 고려한다(B-III).

(6)

Ann Hematol 2013;92:433-42

(7)

NCCN Guidelines, Vesion2.2017. Feb 21, 2017

(8)

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm513183.htm

(9)

Prophylaxis 1st Empirical 2nd

Empirical1) 3rd Empirical

Others No use of W-CF CAZV/IPMA TZV TNV

AML W-CF only in I/RI,

Others, no W-CF (including ASCT)

CFPV/IPMA TZV TNV

MM

ALL-M3- elderly AML

W-CF only in I/RI of ALL, Others, no W-CF (including ASCT)

CFPV/IPMA TZV MPNV

preBMT +

AA W-CF only in AlloHSCT from conditioning to engraftment,

Others, no W-CF

CFPV/IPMA TZV MPNV

postBMT S-BTR NF: CFPV/IPMA

Non-NF :

adapting Focus

TZV MPNV

1)It means persistent NF despite of 1st empirical antibiotics. If ESBL (+) bacteria is isolated, TNV or MPNV should be prescribed.

Prophylaxis & Empirical Tx Strategy

(From OCT/2016)

(10)

예방적 항균제 (항진균제)

4. 7일 이상 장기간 호중구 감소가 예상되는 환자에서 진균감염 예방을 위해 다음의 항진균제를 사용할 수 있다;

-Posaconazole (A-I) -Fluconazole (A-I)

-Itraconazole solution (B-I)

-Low dose amphotericin-B (B-I)

-Low dose liposomal amphotericin (C-II)

5. 조혈모세포 이식 환자에서 진균감염 예방을 위해 다음의 항진균제를 사용 할 수 있다; posaconazole (A-I), fluconazole (A-I), micafungin (B-I), 주사용 itraconazole 사용 후 경구액 변경(B-I).

6. 예방적 항진균제는 적어도 호중구감소증에서 회복될 때까지 사용을 고려 한다(B-III).

7. 동종 조혈모세포이식 후 면역억제제를 사용하는 경우 면역억제제를 중단 할 때까지 예방적 항진균제 사용을 고려한다(B-III).

(11)

Br J Haematol 2011;153:681-97

(12)

Clin Microbiol Infect 2012;18 (Suppl 2):1-15

(13)

In Catholic BMT Center … (June/2016)

AML/MDS Induction/

Reinduction CTx

Other

Chemotherapy (neutropenia

>7 days)

Auto-

BMT Allo-BMT (pre-

engraftment)

Allo-BMT (GVHD period)

Primary PCZ FCZ200 MICAFV ITZS

MICAFV PCZ

Alternati

ve PCZS

FCZ200 ITZS,

ITZ as 2ndary prophylaxis

FCZ400

ITZS VCZ (2ndary prophylaxis for post 3 m)

PCZSFCZ400 (GVHD

period only) Note, PCZ is now considered as post-alloBMT prophylaxis with GVHD because of reimbursement issues (Jul/2015)

Prophylaxis is done from D0 for chemotherapy to ANC >1,000/mm3

Anti-fungal Prophylaxis

(14)

Clinical outcomes

Outcomes (%) PCZ

(N = 140) FCZ

(N = 284) P

Proven/probable IFIs 4 (2.9%) 44 (15.5%) <0.001

Empirical antifungal Tx. 18 (12.9%) 130 (45.8%) <0.001

Duration of empirical antifungal Tx., days 10.8 ± 6.0 11.3 ± 6.8 0.717 Mortality until 100 days

Attributable 2 (1.4%) 6 (2.1%) 0.626

Overall 15 (10.7%) 36 (12.8%) 0.534

Fungus-free survival 112 (80.1%) 213 (74.7%) 0.003

Cho SY, Lee DG, et al. Mycoses 2015;58:565

(15)

Fungus-free survival & overall survival

Posaconazole Fluconazole

P = 0.584 P = 0.004

Cho SY, Lee DG, et al. Mycoses 2015;58:565

(16)

예방적 항균제 ( P. jirovecii )

8. 동종 조혈모세포이식 환자에서 P. jirovecii 예방을 권장한다(A-I).

9. 아래의 경우는 P. jirovecii 예방을 고려한다.

-자가 조혈모세포이식 받는 경우

-고농도의 부신피질호르몬제를 투여 받는 환자(4주 이상 하루에 Pd 20 mg이상)

-Fludarabine 등 T-세포 제거 약제를 투여 받는 경우 -급성백혈병(예, ALL)으로 항암치료를 받는 경우(B-III)

10. P. jirovecii 예방으로 항균제 TMP-SMX 사용을 권장한다(A-I). 약제 에 이상반응이 심한 경우 dapsone, 분무형 pentamidine 사용을 고려한 다(B-II).

(17)

Swiss Med Wkly 2016;146:w14281 Ann Hematol 2013;92:433-42

(18)

J Antimicrob Chemother 2016;71:2397-404

ECIL-5 Guideline for PcP Prophylaxis

(19)

11. HSV혈청 검사 양성이면서 동종 조혈모세포이식을 받는 경우(A-I), 자가 조혈모세포이식 후 점막염 발생 위험이 높은 경우(A-II), 급성백 혈병으로 관해 유도 혹은 재관해 유도요법을 받는 경우(B-I), 혹은 T- 세포 제거 단클론 항체(alemtuzumab 등)를 사용할 때(B-II) 예방적 항바이러스제를 사용할 수 있다.

12. 이전 항암치료 시에 HSV에 재활성화가 있었던 경우는 다음 항암치 료부터 예방적 항바이러스제 사용을 고려한다(B-III).

13. 항바이러스제는 acyclovir나 valacyclovir 사용을 권장한다(A-I).

예방적 항균제 (항바이러스제)

(20)

J Clin Oncol 2013;31:794-810

Antimicrobial Prophylaxis:

ASCO Guideline (1)

A-1a. FNE risk should be systematically assessed (in consultation with infectious disease specialists as needed), including patient-, cancer-, and treatment-related factors; G-CSF prophylaxis should be used before neutropenia develops for patients who meet criteria specified in the ASCO WBC growth factors guideline.

A-1b. Clinicians should consider antibacterial prophylaxis only for patients expected to experience profound neutropenia (defined as ANC <100/mm3) likely to last for ≥7 days; the Panel does not recommend routine antibacterial prophylaxis if neutropenia is less severe or of shorter duration, the usual course with current chemotherapy regimens for solid tumors; thus, the Panel does not recommend routine use of antibacterial prophylaxis for patients with solid tumors undergoing

conventional chemotherapy with or without biologics (eg, trastuzumab, bevacizumab, or cetuximab).

(21)

J Clin Oncol 2013;31:794-810

Antimicrobial Prophylaxis:

ASCO Guideline (2)

A-1c. Limit antifungal prophylaxis (for decreasing IFIs from opportunistic yeast or mold species) to patients receiving chemotherapy expected to cause profound neutropenia (ANC <100/L) for ≥7 days, which confers substantial risk (>6% to 10%) for IFI; antifungal prophylaxis is not recommended for patients with solid tumors receiving conventional-dose chemotherapy with or without

biologics (eg, trastuzumab, bevacizumab, or cetuximab).

A-1d. Patients receiving chemotherapy regimens associated with >3.5% risk for pneumonia from Pneumocystis jirovecii (eg, those with ≥20 mg of

prednisone equivalents daily for ≥1 month or those based on purine analogs) are eligible for prophylaxis.

(22)

J Clin Oncol 2013;31:794-810

Antimicrobial Prophylaxis:

ASCO Guideline (3)

A-1e. Antiviral prophylaxis should be considered for patients known to be at substantial risk for reactivation of HBV infection.

A-1f. Prophylaxis to prevent reactivation of infection from herpesviruses (HSV or VZV) is recommended for seropositive patients undergoing therapy for certain

hematologic malignancies (see details in the full guideline online).

A-1g. Seasonal influenza immunization is recommended for all patients receiving chemotherapy for malignancy and for all family and household contacts.

(23)

Neutropenic Fever:

Focus on Bacteria

(24)

Initial IV Antibiotics in Neutropenic Fever

20. Cefepime, imipenem/cilastatin, meropenem, or

piperacillin/tazobactam

is recommended as empirical monotherapy if the febrile neutropenic patients has no complications of infection (A-I).

21. Ceftazidime can be considered as empirical

monotherapy if the febrile neutropenic patient has no complications of infection, but clinicians should be aware of the possibility of breakthrough infections (from Gram-positive bacteria or drug-resistant

Gram-negative bacteria) (B-II).

Which IV antibiotics can be used as the

initial monotherapy for NF?

(25)
(26)

Ecthyma gangrenosum = Pseudomonas aeruginosa bacteremia?

(27)

Use of Glycopeptide (1)

29. Glycopeptide should not be routinely added to an initial empirical antibiotic regimen (A-I).

30. When fever persists or recurs 3-5 days after the initiation of the empirical treatment, glycopeptides should not be routinely added to the empirical

treatment (B-I).

Should glycopeptides be included in an empirical

antibioitc regimen?

(28)

Use of Glycopeptide (2)

31. The use of glycopeptides as empirical antimicrobial therapy is recommended,

if the patient’s blood cultures are positive for Gram

positive bacteria,

a catheter-related infection is suspected,

there is colonization with MRSA or a Hx of MRSA

infection,

the patients has severe sepsis or shock pending the results of cultures,

or the patient has a skin or soft tissue infection (A-II).

(29)

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 onset 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;92:533-41

(30)

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 Enterobacteriaceae BSI

Ann Hematol 2013;92:533-41

(31)

Factors associated with Mortality (ESBL vs. Non-ESBL)

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;92:533-41

(32)

Empirical Treatment of Enterobacteriaceae Bacteremia in Febrile Neutropenic Patient : Carbapenem May Not Improve Survival

Compared with Combination of Cefepime with Isepamicin

2016, IDweek, Poster 1054

Study design : Retrospective, and observational study.

Study site, observation period : Catholic HSCTC Korea, From June, 2009 to May, 2013.

Purpose : Comparison empirical antibiotics (Carbapenem vs Cefepime plus Isepamicin) in Enterobacteriacea BSI during first onset neutropenic fever

Inclusion criteria : Underlying hematology patient who had comfirmed Enterobacteriacea bacteremia

Exclusion criteria : Breakthrough bacteremia, Second onset neutropenic fever, Other empirical antibiotics use, Mixed infection of ESBL & non-ESBL strain

Statiscal analysis : inverse probability weighted analysis using propensity scores combined with regression adjustment.

Primary outcome : 7 day mortality, 30 day mortality

(33)
(34)

ESBL vs Non-ESBL

ESBL Non-ESBL P value

ESBL Non-ESBL P value

(n = 97) (n = 177) (n = 97) (n = 177)

Age, mean (SD), y 47.77 ±

13.78 48.12 ±

13.23 0.839 Charlson score (≥3) (%) 16 (16.5) 47 (26.6) 0.059 Male 52 (53.6) 98 (55.4) 0.780 Immunosuppressant (%) 17 (17.5) 32 (18.1) 0.909 Hematologic disease (%) 0.193 Steroid use (%) 13 (13.4) 34 (19.2) 0.223

AML 52 (53.6) 82 (46.3) Co-pathogen (Yes) (%) 21 (21.7) 46 (26.0) 0.424

ALL 36 (37.1) 68 (38.4) ICU admit (Yes) (%) 8 (8.3) 12 (6.8) 0.655

Lymphoma 2 (2.1) 11 (6.2) Duration of neutropenia 17.20 ±

8.31 17.22 ±

9.79 0.983 Myeloma 5 (5.2) 5 (2.8) Septic shock (Yes) (%) 28 (28.9) 66 (37.3) 0.160 Others 2 (2.1) 11 (6.2) Duration of bacteremia 13.96 ±

4.98 13.65 ±

5.71 0.654 Underlying disease (%) 0.405 SAPS score (SD) 28.00 ±

12.40 28.07 ±

11.80 0.961

CR or PR 61 (62.9) 97 (54.8) Empirical antibiotics (%) 0.003

Naïve 18 (18.6) 37 (20.9) Cefepime+ Isepamicin 79 (81.4) 165 (93.2) Refractory or relapse 18 (18.6) 43 (24.3) Carbapenem 18 (18.6) 12 (6.8)

Treatment (%) 0.929 7day mortality (%) 3 (3.09%) 9 (5.08%) 0.450 Allo SCT 17 (17.5) 28 (15.8) 30day mortality (%) 10 (10.30%) 18 (10.17%) 0.974 Auto SCT 4 (4.1) 8 (4.5)

CTx 76 (78.4) 141 (79.7)

(35)

Cefepime + Isepamicin vs Carbapenem

CFP+IPM Carbapenem P value

CFP+IPM Carbapenem P value

(n =244) (n =30) (n = 244) (n = 30)

Age, mean (SD), y 48.1± 12.7 46.8 ± 18.1 0.704 ESBL (yes) (%) 79 (32.4) 18 (60.0) 0.003 Sex : Male 135 (55.3) 15 (50.0) 0.58 Charlson score (≥3) (%) 56 (23.0) 7 (23.3) 0.963 Hematologic disease (%) 0.971 Steroid use (%) 40 (16.4) 7 (23.3) 0.341

AML 119 (48.8) 15 (50.0) Immunosupressant (%) 43 (17.6) 6 (20.0) 0.749

ALL 93 (38.1) 11 (36.7) Copathogen4 60 (24.6) 7 (23.3) 0.88

Lymphoma 12 (4.9) 1 (3.3) Admit to ICU (Yes) (%) 12 (4.9) 8 (26.7) <.001 Myeloma 9 (3.7) 1 (3.3) Duration of neutropenia 16.94 ±9.24 19.4 ± 9.45 0.171 Others¹ 11 (4.5) 2 (6.7) septic shock (Yes) (%) 76 (31.2) 18 (60.0) 0.002 Underlying disease (%) 0.077 Duration of bacteremia 13.6 ± 5.2 15.2 ± 6.9 0.232 CR or PR² 146 (59.8) 12 (40.0) SAPS II score (SD) 27.2 ± 11.1 35.1 ± 16.5 0.015

Naive 48 (19.7) 7 (23.3) Bacteria (%) 0.599

Refractory/relapse³ 50 (20.5) 11 (36.7) E. coli. 205 (84.0) 24 (80.0)

Treatment (%) 0.789 K. pneumoniae 36 (14.8) 6 (20.0)

Allo SCT 40 (16.4) 5 (16.7) 7day mortality 7 (2.87) 5 (16.67%) <.001 Auto SCT 10 (4.1) 2 (6.7) 30day mortality 19 (7.79%) 9 (30%) <.001

CTx 194 (79.5) 23 (76.7)

(36)

Factor associated 7 day Mortality

HR (95% CI) P value HR (95% CI) P value

Age 1.02 (0.98-1.07) 0.357 ESBL patients 1.64 (0.44-6.06) 0.458

Sex (Female) 2.44 (0.74-8.11) 0.145 Charlson score (≥3) 0.30 (0.04-2.31) 0.247

Hematologic disease 0.951 Steroid 3.62 (1.15-11.40) 0.028

AML 1 (Reference) Immunosuppressant 1.55 (0.42-5.73) 0.511

ALL 0.85 (0.24-3.03) 0.807 Co-pathogen 1.04 (0.28-3.83) 0.955

Lymphoma 1.69 (0.20-14.02) 0.628 ICU 56.32 (14.83-213.94) <.001 Myeloma N/A 0.993 Duration of neutropenia 0.92 (0.84-1.01) 0.095 Others 1.81 (0.22-15.02) 0.584 Septic shock 4.02 (1.21-13.34) 0.023 Underlying disease 0.191 Duration of bacteremia 1.11 (1.02-1.21) 0.020 CR or PR 1 (Reference) SAPS score (initial) 1.07 (1.04-1.10) <.001 Naïve 2.21 (0.49-9.85) 0.301 Antibiotics

Refractory or relapse 3.37 (0.91-12.57) 0.070 CEP+ITM 1 (Reference)

Treatment 0.998 Carbapenem 6.31 (2.00-19.91) 0.002

Allo SCT 1 (Reference) Bacteria 0.679

Auto SCT N/A 0.993 E coli 1 (Reference)

CTx 1.05 (0.23-4.77) 0.954 K. pneumoniae 1.80 (0.49-6.64) 0.379

E coli + KPA N/A 0.994

(37)

Factor associated 30 day Mortality

HR (95% CI) P value HR (95% CI) P value

Age 1.04 (1.01-1.08) 0.011 ESBL patients 0.99 (0.46-2.14) 0.974

Sex (Female) 1.43 (0.68-3.00) 0.349 Charlson score (≥3) 0.90 (0.36-2.21) 0.812

Hematologic disease 0.163 Steroid 3.42 (1.60-7.30) 0.002

AML 1 (Reference) Immunosuppressant 1.56 (0.67-3.68) 0.306

ALL 0.59 (0.24-1.46) 0.594 Co-pathogen 2.02 (0.94-4.30) 0.070

Lymphoma 1.35 (0.31-5.91) 0.690 ICU 35.07 (16.27-75.59) <.001 Myeloma N/A 0.991 Duration of neutropenia 0.99 (0.95-1.03) 0.686 Others 2.89 (0.96-8.70) 0.060 Septic shock 3.80 (1.75-8.23) 0.001 Underlying disease 0.001 Duration of bacteremia 1.07 (1.01-1.14) 0.034 CR or PR 1 (Reference) SAPS score (initial) 1.07 (1.05-1.09) <.001 Naïve 5.58 (2.07-15.10) 0.001 Antibiotics

Refractory or relapse 5.13 (1.90-13.86) 0.001 CEP+ITM 1 (Reference)

Treatment 0.915 Carbapenem 4.49 (2.03-9.92) <.001

Allo SCT 1 (Reference) Bacteria 0.768

Auto SCT N/A 0.989 E coli. 1 (Reference)

CTx 1.26 (0.44-3.62) 0.673 K. pneumoniae 0.64 (0.19-2.13) 0.468

E coli + KPA N/A 0.991

(38)

Mortality in ESBL group

Mortality

Unweighted Weighted*

CFP+IPM (N=79)

Carbapenem

(N=18) P value CFP+IPM

(N=91)

Carbapenem

(N=48) P value 7 day mortality 1 (1.3%) 2 (11.1%) 0.028 0.5 (0.01%) 0.8 (0.02%) 0.989 30 day mortality 5 (6.3%) 5 (27.8%) 0.004 8.3 (9.1%) 16.6 (34.6%) 0.057

CFP+IPM Carbapenem CFP+IPM

Carbapenem

* inverse probability weighted analysis using propensity scores combined with regression adjustment.

(39)

Mortality in Septic shock group*

CFP+IPM Carbapenem

CFP+IPM Carbapenem

Mortality

Unweighted Weighted**

CFP+IPM

(N=76) Carbapenem

(N=18) P value CFP+IPM

(N=88) Carbapenem

(N=30) P value 7day mortality 3 (3.9%) 3 (16.7%) 0.019 5.2 (5.9%) 3.5 (11.7%) 0.615 30day mortality 11 (14.5%) 7 (38.9%) 0.014 15.1 (17.2%) 9.2 (30.7%) 0.404

* Septic shock group (ESBL=28 (29.8%), Non-ESBL 66)

** inverse probability weighted analysis using propensity scores combined with regression adjustment.

(40)

Conclusion

• ESBL production is not associated with mortality in neutropenic patient

• Cefepime with isepamicin combination maybe effective as carbapenem at the initial empirical treatment of bloodstream infection of Enterobacteriaceae irrepsctive of ESBL production .

• Even though ESBL-producing Enterobacteriaceae increase steadily,

prompt antibiotics change by resistance pattern of blood culture,

and combination therapy can be successful to initial treatment.

(41)

BMC Infect Dis 2013;45:406-14

VSE vs. VRE BSI in NF

(42)

BMC Infect Dis 2013;45:406-14

Factors associated with Mortality

(Enterococcus BSI)

(43)

ECIL-4, Haematologica 2013;98:1826-35

Empirical Antibacterial Therapy

in the era of Growing Resistance

(44)

ECIL-4, Haematologica 2013;98:1826-35

Empirical Antibacterial Therapy

in the era of Growing Resistance

(45)

Empirical Anti-Fungal

Therapy

(46)

Persistent Neutropenic Fever

Non-bacterial infection

(fungal, viral, mycobacterial infection)

Resistance to antibiotics

Inadequate drug concentration

Drug fever

Bacteremia due to cell wall-deficient bacteria

Infection at an avascular site (such as abscess)

Fever related to underlying malignancy

Intravascular catheter related fever

Reasons of Persistent Fever 3-5 days

after Initiating Antibiotic Therapy

(47)

N Engl J Med 2002, 345:222-4 Fred Hutchinson Cancer Research Center

Causes of fever in pts with prolonged neutropenia who are receiving broad spectrum antibiotics

Empirical Antifungal Therapy

(48)

Empirical Antifungal Therapy

39. Empirical antifungal therapy is recommended in patients who are expected to maintain neutropenia for a longer period (>10 days), if the fever does not resolved within 3-5 days of initial empirical administration of antibacterial agents (A-II).

40. Regardless of fever, empirical antifungal therapy is

recommended in patients who have a history of invasive fungal infection, fungal colonization with neutropenia, symptoms

(pleuritic chest pain, blood tinged sputum, or hemoptysis) or signs that suggest newly developed pneumonia, tenderness, or edema around paranasal sinuses or orbital area, ulcerating

lesions or eschar in nose, etc. (A-II).

When do we start antifungal therapy?

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

(49)

What kinds of Antifungal agents can we use empirically?

41. The following antifungal agents are recommended or

can be considered as empirical antifungal therapy:

caspofungin (A-I), liposomal amphotericin B (A-I), amphotericin B deoxycholate (B-I), itraconazole (B-I), and voriconazole (B-II). Amphotericin B deoxycholate should not be considered in the presence of risk factors for nephrotoxicity (B-I).

42. Azoles may not be considered as empirical antifungals if prophylaxis with fluconazole or itraconazole has already been administered (B-II).

Empirical Antifungal Therapy

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

(50)

Empirical Tx Strategy, 2016, IA

74. Empiric antifungal therapy is recommended for high-risk patients with prolonged neutropenia who remain persistently febrile despite broad-spectrum antibiotic therapy.

Antifungal options include a lipid formulation of AmB (strong recommendation;

high-quality evidence), an echinocandin (caspofungin or micafungin) (strong

recommendation; high-quality evidence), or voriconazole (strong recommendation;

moderate quality evidence).

75. Not recommended for patients who are anticipated to have short durations of neutropenia (duration of neutropenia <10 days), unless other findings indicate a suspected invasive fungal infection (IFI) (strong recommendation; moderate-quality evidence).

78. Management of suspected or documented breakthrough IPA in the context of mold-active azole prophylaxis or empiric suppressive therapy is not defined by clinical trial data, but a switch to another drug class is suggested (weak

recommendation; low-quality evidence).

Clin Infect Dis 2016;63:e1-60

(51)

In Catholic BMT Center… (June/2016)

Empirical Anti-fungal Tx

• Neutropenic fever

• No Neutropenia

– Do not use CSFV, LABV!!

– No empirical Tx, But, Targeted Tx after Dx!!

– If empirically, Amphotericin B deoxycholate for mold infection – If empirically, Fluconazole or Echinocandins for yeast infection

Prophylaxis Empirical Empirical, Pneumonia (+)

CTx FCZ, PCZS CSFV LABV3

SCT ITZS, MICAF CSFV/LABV3 LABV3

Different ClassBroad Spectrum Initially

(52)

CANDIDIASIS

(53)

Clin Infect Dis 2016;62 (4):e1-50

Major change since 2009 guideline

1. An echinocandin is recommended as initial therapy for candidemia.

(54)

• Fluconazole, intravenous or oral, 800-mg (12 mg/kg)

loading dose, then 400 mg (6 mg/kg) daily is an acceptable alternative to an echinocandin as initial therapy in

– selected patients, including those who are not critically ill

– who are considered unlikely to have a fluconazole-resistant organism.

• Transition from an echinocandin to fluconazole (usually within 5–7 days) is recommended for

patients who are

– clinically stable

– have isolates that are susceptible to fluconazole (e.g., C. albicans),

– have not been previously exposed to triazoles,

– have negative repeat blood cultures following initiation of antifungal therapy

Clin Infect Dis 2016;62 (4):e1-50

Role of Fluconazole in Tx of Candidemia

(55)

ESCMID guideline for Candida, 2012

Clin Microbiol Infect 2012;18 (Suppl 7):19-37

(56)

Clin Microbiol Infect 2012;18 (Suppl 7):53-67

(57)

Morrell et al. Antimicrob Agents Chemother 2005;49:3640-5 Geary et al. Clin Infect Dis 2006;43:25-31

Retrospective cohort of 157

candidaemic patients (mixed ICU and non-ICU): single US centre

Retrospective cohort of 230

candidaemic patients (mixed ICU and non-ICU): 4 US centres

Delayed antifungal initiation is

associated with worse outcomes

(58)

Catheter Removal

 Intravenous catheter removal is strongly recommended for non-neutropenic patients with candidemia (A-II).

 Intravenous catheter removal should be considered (B-III).

(The management of intravascular catheters in neutropenic patients with candidemia is less straightfoward than in their nonneutropenic counterparts. Distinguishing gut-associated from vascular catheter- associated candidemia can be difficult in theses patients. The data for catheter removal is less

compelling, and the consequences of catheter removal often

create significant intravenous access problem)

(59)

Quality Improvement Issues

 Work up of metastatic focus

- fundoscopy to R/O endophthalmitis

- abscess, endocarditis, unremoved foreign body

 Daily blood cultures until clear

 Initiate antifungal therapy early

- within 1

st

24 hrs

 Minimun of 14 days after negative blood culture

- if no evidence of tissue or invasive candidiasis

(60)

Sanctuary in Candidiasis during Tx with Echinocandin

 Meningitis

 Endophthalmitis

 Urinary tract candidiasis

Echinocandins are limited by their PK.

Triazoles may be prefered.

N Engl J Med 2015;373:1145-56

(61)

ASPERGILLOSIS

(62)

Fauci AS at el. Harrison 17th Ed, p1258 Infect Dis Clin N Am 2016;30:125-42

Conditions at risk of IA

(63)

Patients given any antifungal regimens containing voriconazole, either alone (plain line) or in combination (dotted line), or any antifungal regimens without voriconazole (dashed line).

Clin Microbiol Infect 2011; 17: 1882–9 Clin Infect Dis 2008; 47:1176–84

Survival Rate in IA Tx

(64)

최재기 등. 2014년 대한감염학회 추계학술대회

Period 1; n = 193 Period 2; n = 81 1st/Apr/2013

Survival Improvement in Catholic BMT Center

(65)

Therapy

Condition Primary Alternative Comments

Invasive syndrome of Aspergillus IPA Voriconazole (6

mg/kg IV every 12 h for 1 d, followed by 4

mg/kg IV every 12 h;

oral therapy can be used at 200–300 mg every 12 h or weight based dosing on a mg/kg basis); see text for pediatric dosing

Primary: Liposomal AmB (3–5 mg/kg/day IV), isavuconazole 200

mg every 8 h for 6 doses, then 200 mg daily

Salvage: ABLC (5 mg/kg/day IV), caspofungin (70 mg/day IV × 1, then 50 mg/day IV thereafter), micafungin (100–

150 mg/day IV), posaconazole (oral suspension: 200 mg TID;

tablet: 300 mg BID on day 1, then 300 mg daily, IV: 300 mg BID on day 1, then 300 mg daily, itraconazole suspension (200 mg PO every 12 h)

Primary combination therapy is not routinely recommended;

addition of another agent or switch to another drug class for salvage therapy may be considered in individual patients; dosage in pediatric patients for voriconazole and for caspofungin is different than that of adults; limited clinical experience is reported with

anidulafungin; dosage of

posaconazole in pediatric patients has not been defined

Clin Infect Dis 2016;63:e1-60

(66)

CONCLUSION

 Infectious Cx is still the most common and significant cause of morbidity & mortality after HSCT.

 Infection is varied according to period of

immunocompromised status and immune-recovery.

 Updating knowledge about infection due to Bacteria,

Fungus, and Virus & approach strategies are important to

management from prophylaxis, empirical, pre-emptive, to

targeted therapy.

(67)

1) 67세 남자, CLL로 R-FC 항암치료

2) 37세 남자, DLBCL로 R-CHOP 항암치료 3회째 3) 50세 여자, breast cancer로 수술 후 방사선 치료

4) 65세 남자, colon cancer, 간전이, FOLFOX 항암치료 5) 40세 여자, AML로 타인간 동종조혈모세포이식으로 전

처치

문제 1

다음 중 ciprofloxacin 예방 항생제가 가장 필요한 환자는?

(68)

1) 67세 여자, DLBLC로 R-CHOP 2) 23세 남자, ALL로 관해유도요법 3) 34세 여자, AML로 1차 공고요법 4) 54세 남자, AML로 재관해유도요법

5) 40세 남자, Burkitt lymphoma로 자가 동종조혈모세포이 식

문제 2

침습성 진균 감염 예방을 위해 posaconazole이 가장 필

요한 환자는?

(69)

24세 여자

ALL로 관해유도 항암치료 중 호중구감소열 발생 (ANC 10/mm

3

)

1병일 째 통증을 동반한 피부병변(사진 1) 3병일 째 같은 부위 피부병변 변화(사진 2)

문제 3

(70)

사진 1 사진 2

(71)

가장 적절한 경험적 치료 선택은?

1) Cefazolin 2) Ceftriaxone 3) Gentamicin 4) Cefepime 5) Vancomycin

문제 3

(72)

1) Amphotericin B deoxycholate 2) Caspofungin

3) Fluconazole

4) Liposomal amphotericin B 5) Voriconazole

문제 4

AML로 형제간 동종 조혈모세포이식 중 호중구감소성 발

열로 cefepime 사용했으나 발열이 지속되어 경험적 항

진균제를 고려 중이다. 예방으로 micafungin사용 중이었

고 폐렴은 확인되지 않았다. 가장 가장 적절한 것은?

(73)

54세 여자 골수이형성증후군으로 동종 조혈모세포이식 중

Hickman catheter 통증 호소하고 있다. 경구 fluconazole 200 mg/일로 예방 중이었고, 혈액배양에서 Yeast 동정 중 이라는 연락 받았다.

문제 5

ANC 250/mm

3

, PLT 28,000/mm

3

Catheter 주위 피부(사진 1)

(74)

사진 1

(75)

가장 적절한 조치는?

1) Caspofungin으로 변경

2) Fluconazole 주사제로 변경

3) Fluconazole 경구 유지 + Flucytosine 추가 4) Liposomal amphotericin B로 변경

5) Voriconazole 주사제로 변경

문제 5

(76)

감 사 합 니 다

참조

관련 문서

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