Persistent Fever and Neutropenia: Yesterday, Today and what about Tomorrow

1
Persistent Fever and Neutropenia Yesterday,
Today and what about Tomorrow?
2
ADMINISTRATION OF ANTIMICROBIALS IN RELATION TO
THE COURSE OF GRANULOCYTOPENIA
100 75 50
gt1000
1000
GRANULOCYTES
500
lt100
0 10
20
30 days
3
FEVER IN A GRANULOCYTOPENIC PATIENT
C
man 25 yrs AML
39
38
37
36
granulocytes
4
AFTER 3-5 DAYS
C
FEVER PERSISTS!! ACTION REQUIRED?
man 25 yrs AML
39
38
37
36
granulocytes
5
MANUALS FOR DUMMYS?
ALGORITHMS..
6
What is happening when an infective agent strikes?
7
CONSIDERATIONS
INFECTION
mediators (cytokines) exotoxins
SICK
organ damage
8
CONSIDERATIONS
TREATMENT
mediators (cytokines) exotoxins
SICK
organ damage
9
CONSIDERATIONS
TREATMENT
10
CONSIDERATIONS
TREATMENT
FEVER
SICK
11
Can the patients condition serve as a parameter
to judge therapy?
12
HOW SICK IS SICK?
INFECTION ADEQUATELY TREATED?
FEVER
SICK?
13
Subjectivity!
14
PHYSICIANS REACTION
EMPIRICAL ANTIBACTERIAL THERAPY NO RESPONSE FOR
72 HOURS
15
FEVER OBJECTIVE PARAMETER
16
FEVER OBJECTIVE PARAMETER?
17
FEVER OBJECTIVE PARAMETER?
INFLUENCED BY ANTIPYRETICS NOT
INFECTION-SPECIFIC NOT LIKELY TO SUBSIDE RAPIDLY
18
FEVER OBJECTIVE PARAMETER?
INFLUENCED BY ANTIPYRETICS NOT
INFECTION-SPECIFIC NOT LIKELY TO SUBSIDE RAPIDLY
19
FEVER OBJECTIVE PARAMETER?
INFLUENCED BY ANTIPYRETICS NOT
INFECTION-SPECIFIC NOT LIKELY TO SUBSIDE RAPIDLY
20
NON-INFECTIOUS CAUSES OF FEVER DURING NEUTROPENIA

• Pyrogenic substances
• cytokines
• (auto)immune reactions
• bloodproduct-antigens
• toxins
• drugs
• tissue(tumor)products

21
FEVER OBJECTIVE PARAMETER?
INFLUENCED BY ANTIPYRETICS NOT
INFECTION-SPECIFIC NOT LIKELY TO SUBSIDE RAPIDLY?
22
QUESTION 2

• HOW MANY OF YOUR FEBRILE NEUTROPENIC PATIENTS MAY
  BE EXPECTED TO BE FREE OF FEVER AFTER 72 HOURS OF
  ADEQUATE BROAD-SPECTRUM ANTIMICROBIAL THERAPY?
• ALL
• MORE THAN HALF
• LESS THAN HALF
• NONE

23
COURSE OF FEVER AFTER 3 DAYS
PERSISTANCE OF FEVER ON DAY 3
EORTC - NEW ENGL J MED 87 CEFTAZIDIME
AMIKACIN SHORT CEFTAZIDIME AMIKACIN FULL
COURSE EORTC - ANTIMICROB AG CHEMOTHER 95
CEFTAZIDIME AMIKACIN PIPERACILLIN-TAZOBACTAM
AMIKACIN EORTC - ANTIMICROB AG CHEMOTHER 96
CEFTAZIDIME AMIKACIN MEROPENEM
ALONE ICSG - ANN INTERN MED 94 CEFTAZIDIME
ALONE
36 11 60 55 65 60 55
24
COURSE OF TEMPERATURE AFTER START OFANTIBIOTICS
IN NEUTROPENIC PATIENTS
DE PAUW et al. Ann Int Med 1994120834 RAMPHAL
et al Antimicrob.Ag. Chem. 1992
patients
3
5
Days after start
25
FEVER PERSISTS..

• Resistent or slowly responding bacteria
• Abscess
• Foreign body
• Non-bacterial infection
• Fungus
• Viruses
• Post-Transplant Lymphoproliferative Disease
• Parasites

26
AFTER 3-5 DAYS
C
MODIFY!? HOW?
FEVER PERSISTS!! ACTION REQUIRED?
man 25 yrs AML
39
38
37
36
granulocytes
27
CONSIDERATIONS
INFECTION
RESPONSE?
FEVER?
SICK??
28
GRANULOCYTOPENIA AND FEVER874 CASES
IMPROVING 60
DETERIORATION 20
STABLE 20
J. Int. Med. 1997 242 69-77
29
Propensity to act dominates
30
B-52 STRATEGY
31
CLINICAL RESPONSE AT THE END OF
THERAPYCEFTAZIDIME VERSUS MEROPENEM(UNIVERSITY
MEDICAL CENTER NIJMEGEN)
CEFTAZIDIME
J Antimicrob Chem 1995 36185
32
CLINICAL RESPONSE AT THE END OF
THERAPYCEFTAZIDIME VERSUS MEROPENEM(UNIVERSITY
MEDICAL CENTER NIJMEGEN)

• Persistent pos culture
• Clinical deterioration
• new focus
• vital signs
• Death

CEFTAZIDIME
J Antimicrob Chem 1995 36185
33
CLINICAL RESPONSE AT THE END OF
THERAPYCEFTAZIDIME VERSUS MEROPENEM(UNIVERSITY
MEDICAL CENTER NIJMEGEN)
CEFTAZIDIME
1995
J Antimicrob Chem 1995 36185
34
CLINICAL RESPONSE AT THE END OF
THERAPYCEFTAZIDIME VERSUS MEROPENEM(UNIVERSITY
MEDICAL CENTER NIJMEGEN)
CEFTAZIDIME
MEROPENEM
1995
J Antimicrob Chem 1995 36185
35
CEFEPIME VERSUS PIPERACILLIN-TAZOBACTAMAT THE
END OF THERAPYBow et al. Clin Infect Dis 2006
43447-459
PIPERACILLIN- TAZOBACTAM n265
CEFEPIME n263
2006
36
DRUGS USED FOR MODIFICATIONS
GLYCOPEPTIDES AMINOGLYCOSIDES SYSTEMIC
ANTIFUNGALS
33 8 23
J Antimicrob Chem 1995 36185
37
GLYCOPEPTIDE AS RESCUE
n 177
RESPONSE OVERALL -PERSISTING FEVER ONLY
-SKIN-SOFT TISSUE INFECTIONS
-PERSISTENT GRAM-POSITIVES
45 33 78 94
Brit J Haematol 1990 761-5
38
IMPACT OF MODIFICATIONS BEFORE NEUTROPHIL
RECOVERY(UNIVERSITY MEDICAL CENTER NIJMEGEN)
EMPIRIC MODIFICATIONS lt 20 DEFERVESCENCE
J. Int. Med. 1997 242 69-77
39
How can we keep ourselves under
control?Guidelines??
40
REASONS TO MODIFY ANTIBIOTIC THERAPY(UNIVERSITY
MEDICAL CENTER NIJMEGEN)
DETERIORATION OF VITAL SIGNS ANTIBIOTIC-RELATED
ADVERSE EVENT PERSISTENCE OF A TRUE
PATHOGEN RESISTANT PATHOGEN WITHOUT
CLINICAL IMPROVEMENT NEW
FEVER, NEW PATHOGEN OR
PROGRESSING FOCUS
Ann Hematol 1996 72 273-9
41
QUESTION 3

• IF GUIDELINES TO ADJUST AN ANTIBIOTIC REGIMEN IN
  A NEUTROPENIC PATIENT WITH PERSISTING FEVER ARE
  INTRODUCED, A REDUCTION IN THE NUMBER OF
  MODIFICATIONS MAY BE ANTICIPATED
• YES
• ONLY DURING DAYTIME
• NO

42
REASONS FOR MODIFICATION OF ANTIBIOTICSDURING
AND OUTSIDE OFFICE HOURSDe Pauw et al. J. Int.
Med. 1997 242 69-77
NUMBER OF MODIFICATIONS
OBJECTIVE CRITERIA
SUBJECTIVE CRITERIA
Ann Hematol 1996 72 273-9
43
ADMINISTRATION OF ANTIMICROBIALS IN RELATION TO
THE COURSE OF GRANULOCYTOPENIA
100 75 50
gt1000
1000
GRANULOCYTES
500
lt100
0 10
20
30 days
44
PERCEIVED NEED FOR PARENTERAL AMPHOTERICIN-B
AFTER PROPHYLAXIS IN NEUTROPENIC PATIENTS
FEAR FACTOR
Europe
incidence of invasive fungal disease
perceived need for empirical amphotericin B
USA
5 10 20 30 4
0 50 60
45
Propensity to act dominates!! .in spite of
guidelines
46
RECOMMENDATIONS IDSA 2002Hughes et al. Clin
Infect Dis 2002 34730-751
UNEXPLAINED FEVER AND NEUTROPENIA
47
THE DUEL
48
DIAGNOSTIC TESTS
culture histology
antibody antigen blood cultures
PCR 1-3-ß-D-glucan imaging / radiology
C-Reactive Protein (CRP), procalcitonin
(PCT), interleukin-6 (IL-6)
49
KEY FACTORS FOR SELECTION OF FURTHER THERAPY
ELAPSED TIME NEUTROPENIA CULTURE
RESULTS CLINICAL SYMPTOMS
50
KEY FACTORS FOR SELECTION OF FURTHER THERAPY
ELAPSED TIME NEUTROPENIA CULTURE
RESULTS CLINICAL SYMPTOMS
51
EVOLUTION OF CAUSES OF FEVER
Gram-negative bacteria
time
52
KEY FACTORS FOR SELECTION OF FURTHER THERAPY
ELAPSED TIME NEUTROPENIA CULTURE
RESULTS CLINICAL SYMPTOMS
53
EXPLANATION OF FEVER IN NEUTROPENIC PATIENTS
ABDOMEN
SKIN SOFT TISSUE
URINE
URTI
LUNG
UNEXPLAINED FEVER
BACTEREMIA
AT ONSET OF FEVER
AFTER 72 HOURS
Infection 1998 26 349-354
54
KEY FACTORS FOR SELECTION OF FURTHER THERAPY
ELAPSED TIME NEUTROPENIA CULTURE
RESULTS CLINICAL SYMPTOMS
55
POTENTIAL INFECTION SITES

• Peridontium
• Pharynx
• Esophagus
• Lungs
• Skin and nails
• Perineum
• Typhlitis

56
AVERAGE DURATION OF FEVER IN VARIOUS CATEGORIES
OF INFECTION DURING NEUTROPENIA
10 8 6 4 2 0
d a y s w i t h f e v e r
unexplained fever
skin and soft tissue
lower respiratory tract
upper respiratory tract
bacteremia
Leuk Lymph 1993 10461
57
SITES OF INFECTION AND CAUSATIVE ORGANISMS
UPPER RESPIRATORY TRACT STREPTOCOCCI /
ANAEROBES HERPES SIMPLEX YEASTS
LOWER RESPIRATORY TRACT
GRAM-NEG RODS STREPTOCOCCI MOULDS TUBERCULOSIS DI
FFUSE STREPTOCOCCUS
MITIS (CYTOMEGALO)VIRUS PNEUMOCYSTIS
SKIN AND SOFT TISSUE
STAPHYLOCOCCI STREPTOCOCCI / CORYNEFORMS
ABDOMINAL
ANAEROBES GRAM-NEG
RODS
58
Knowledge and experience can help to determine an
effective strategy
59
CLINICALLY IMPROVING AFTER 72 HOURS
CONTINUED OBSERVATION WITHOUT SPECIFIC
INVESTIGATIONS
60
AN ANTIBIOTIC STRATEGY IMPLIES MORE THAN
ADMINISTRATION OF APPROPRIATE DRUGS
REPEAT DIAGNOSTICS -physical examination -blood
cultures -serology -imaging
61
YIELD OF DIAGNOSTIC PROCEDURES
time
evolution of the infection
yield of diagnostic interventions
62
CLINICALLY IMPROVING AFTER 72 HOURS
CONTINUED OBSERVATION WITHOUT SPECIFIC
INVESTIGATIONS
63
CLINICALLY STABLE AFTER 72 HOURS
CONTINUED OBSERVATION WITH SPECIFIC INVESTIGATIONS
64
CLINICALLY DETERIORATING AFTER 72 HOURS
CONTINUED OBSERVATION WITH SPECIFIC INVESTIGATIONS
65
AFTER 3-5 DAYS (END EMPIRICAL EPISODE)
66
IMPACT OF MODIFICATIONS BEFORE NEUTROPHIL
RECOVERY
EMPIRIC MODIFICATIONS lt 20 DEFERVESCENCE SPE
CIFIC MODIFICATIONS gt 50 DEFERVESCENCE
J. Int. Med. 1997 242 69-77
67
EMPIRICAL ANTIMICROBIAL THERAPY
MORTALITY
MODIFICATIONS
68
VOLTAIRES IDEAL PHYSICIAN
The ideal doctor entertains his patient while
nature does its work
69
QUESTION 4

• A DOCTOR MUST BE VERY SURE ABOUT WHAT HE IS GOING
  TO DO AND VERY SUSPICIOUS OF WHAT HE IS DOING
• I AGREE
• THINKING IS A WASTE OF TIME

70
Persistent Fever and Neutropenia Yesterday,
Today and what about Tomorrow?
71
Persistent Fever and Neutropenia What we did
Yesterday, are we still doing Today and I
wonder if it will be different Tomorrow?
72
ACKNOWLEDGEMENTS
My patients and their relatives
My wife, and sons Michiel and Luc
73
FAREWELL
AND, OF COURSE, MANY, MANY THANKS TO YOU, MY
LOYAL AUDIENCE! I WISH YOU MANY MORE INSTRUCTIVE
ICAACS