Current Guideline for Neutropenic Fever
Dong-Gun Lee
Div. of Infectious Diseases,
Dept. of Internal Medicine,
The Catholic Univ. of Korea
CONTENTS
Prophylaxis
• Bacteria
• Fungi including Pneumocystis jirovecii
• Virus
Empirical Anti-Bacterial Tx
Persistent Neutropenic Fever & Empirical Anti-Fungal Tx
Update on Invasive Candidiasis/Aspergillosis
Korean J Intern Med 2011;26:220-52 Infect Chemother 2011;43:285-321
NA09-013
Prophylaxis:
Bacteria
Fungi with PcP
Virus
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).
Ann Hematol 2013;92:433-42
NCCN Guidelines, Vesion2.2017. Feb 21, 2017
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm513183.htm
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)
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).
Br J Haematol 2011;153:681-97
Clin Microbiol Infect 2012;18 (Suppl 2):1-15
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
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
Fungus-free survival & overall survival
Posaconazole Fluconazole
P = 0.584 P = 0.004
Cho SY, Lee DG, et al. Mycoses 2015;58:565
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).
Swiss Med Wkly 2016;146:w14281 Ann Hematol 2013;92:433-42
J Antimicrob Chemother 2016;71:2397-404
ECIL-5 Guideline for PcP Prophylaxis
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)
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).
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.
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.
Neutropenic Fever:
Focus on Bacteria
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?
Ecthyma gangrenosum = Pseudomonas aeruginosa bacteremia?
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?
Use of Glycopeptide (2)
31. The use of glycopeptides as empirical antimicrobial therapy is recommended,
•
if the patient’s blood cultures are positive for Grampositive bacteria,
•
a catheter-related infection is suspected,•
there is colonization with MRSA or a Hx of MRSAinfection,
•
the patients has severe sepsis or shock pending the results of cultures,•
or the patient has a skin or soft tissue infection (A-II).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
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
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
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
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)
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)
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
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
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.
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.
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.
BMC Infect Dis 2013;45:406-14
VSE vs. VRE BSI in NF
BMC Infect Dis 2013;45:406-14
Factors associated with Mortality
(Enterococcus BSI)
ECIL-4, Haematologica 2013;98:1826-35
Empirical Antibacterial Therapy
in the era of Growing Resistance
ECIL-4, Haematologica 2013;98:1826-35
Empirical Antibacterial Therapy
in the era of Growing Resistance
Empirical Anti-Fungal
Therapy
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 feverReasons of Persistent Fever 3-5 days
after Initiating Antibiotic Therapy
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
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
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
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
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
CANDIDIASIS
Clin Infect Dis 2016;62 (4):e1-50
Major change since 2009 guideline
1. An echinocandin is recommended as initial therapy for candidemia.
• 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
ESCMID guideline for Candida, 2012
Clin Microbiol Infect 2012;18 (Suppl 7):19-37
Clin Microbiol Infect 2012;18 (Suppl 7):53-67
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
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)
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
st24 hrs
Minimun of 14 days after negative blood culture
- if no evidence of tissue or invasive candidiasis
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
ASPERGILLOSIS
Fauci AS at el. Harrison 17th Ed, p1258 Infect Dis Clin N Am 2016;30:125-42
Conditions at risk of IA
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
최재기 등. 2014년 대한감염학회 추계학술대회
Period 1; n = 193 Period 2; n = 81 1st/Apr/2013
Survival Improvement in Catholic BMT Center
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