Persistent Fever and Neutropenia Yesterday Today and what about

Persistent Fever and Neutropenia: Yesterday, Today and what about Tomorrow? ADMINISTRATION OF ANTIMICROBIALS IN RELATION TO THE COURSE OF GRANULOCYTOPENIA 100% 75% 50% GRANULOCYTES antibacterials >1000 1000 500 0 10 20 30 days <100 FEVER IN A GRANULOCYTOPENIC PATIENT °C 39 38 37 36 man 25 yrs AML central venous line empirical antibiotics mucositis granulocytes 0 3 6 9 12 15 18 21 24 27 30 33 36 39 AFTER 3-5 DAYS °C 39 38 37 36 man 25 yrs AML FEVER PERSISTS!! empirical antibiotics ACTION REQUIRED? mucositis central venous line granulocytes 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 MANUALS FOR DUMMY’S? ALGORITHMS…. . What is happening when an infective agent strikes? INFECTION CONSIDERATIONS mediators (cytokines) + exotoxins FEVER vasoactive molecules perfusion problems organ dysfunction SICK organ damage TREATMENT CONSIDERATIONS mediators (cytokines) + exotoxins FEVER vasoactive molecules perfusion problems organ dysfunction SICK organ damage TREATMENT CONSIDERATIONS TREATMENT CONSIDERATIONS FEVER SICK Can the patient’s condition serve as a parameter to judge therapy? INFECTION ADEQUATELY TREATED? HOW SICK IS ‘SICK’? FEVER SICK? Subjectivity! PHYSICIAN’S REACTION EMPIRICAL ANTIBACTERIAL THERAPY NO RESPONSE FOR 72 HOURS FEVER OBJECTIVE PARAMETER FEVER FEVER OBJECTIVE PARAMETER? FEVER FEVER OBJECTIVE PARAMETER? INFLUENCED BY ANTIPYRETICS NOT INFECTION-SPECIFIC NOT LIKELY TO SUBSIDE RAPIDLY FEVER FEVER OBJECTIVE PARAMETER? INFLUENCED BY ANTIPYRETICS NOT INFECTION-SPECIFIC NOT LIKELY TO SUBSIDE RAPIDLY FEVER FEVER OBJECTIVE PARAMETER? INFLUENCED BY ANTIPYRETICS NOT INFECTION-SPECIFIC NOT LIKELY TO SUBSIDE RAPIDLY FEVER NON-INFECTIOUS CAUSES OF FEVER DURING NEUTROPENIA *Pyrogenic substances cytokines (auto)immune reactions bloodproduct-antigens toxins drugs tissue(tumor)products FEVER OBJECTIVE PARAMETER? INFLUENCED BY ANTIPYRETICS NOT INFECTION-SPECIFIC NOT LIKELY TO SUBSIDE RAPIDLY? FEVER 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 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 36% 11% EORTC - ANTIMICROB AG CHEMOTHER ‘95 CEFTAZIDIME + AMIKACIN PIPERACILLIN-TAZOBACTAM + AMIKACIN CEFTAZIDIME + AMIKACIN MEROPENEM ALONE CEFTAZIDIME ALONE 60% 55% 65% 60% 55% EORTC - ANTIMICROB AG CHEMOTHER ‘96 ICSG - ANN INTERN MED ‘94 COURSE OF TEMPERATURE AFTER START OF ANTIBIOTICS IN NEUTROPENIC PATIENTS 100 DE PAUW et al. Ann Int Med 1994;120:834 RAMPHAL et al Antimicrob.Ag. Chem. 1992 80 %patients 60 40 20 0 0 3 5 7 Days after start 14 21 FEVER PERSISTS….. •Resistent or slowly responding bacteria •Abscess •Foreign body •Non-bacterial infection •Fungus •Viruses *Post-Transplant Lymphoproliferative Disease •Parasites AFTER 3-5 DAYS °C 39 38 37 36 man 25 yrs AML MODIFY!? FEVER PERSISTS!! empirical antibiotics mucositis central venous line ACTION REQUIRED? HOW? 30 33 36 39 42 granulocytes 0 3 6 9 12 15 18 21 24 27 INFECTION CONSIDERATIONS RESPONSE? FEVER? SICK?? GRANULOCYTOPENIA AND FEVER 874 CASES EMPIRICAL ANTIBACTERIAL THERAPY FOR 72 HOURS IMPROVING 60% STABLE 20% DETERIORATION 20% J. Int. Med. 1997; 242: 69-77 Propensity to act dominates B-52 STRATEGY B52 ANTIFUNGALS MACROLIDES ACYCLOVIR AMINOGLYCOSIDE PENICILLIN GLYCOPEPTIDE GROWTH FACTOR RESCUE KIT BROAD SPECTRUM BETALACTAM CLINICAL RESPONSE AT THE END OF THERAPY CEFTAZIDIME VERSUS MEROPENEM (UNIVERSITY MEDICAL CENTER NIJMEGEN) CEFTAZIDIME success 1995 J Antimicrob Chem 1995; 36:185 CLINICAL RESPONSE AT THE END OF THERAPY CEFTAZIDIME VERSUS MEROPENEM (UNIVERSITY MEDICAL CENTER NIJMEGEN) CEFTAZIDIME failure •Persistent pos culture •Clinical deterioration •new focus •vital signs •Death 1995 J Antimicrob Chem 1995; 36:185 CLINICAL RESPONSE AT THE END OF THERAPY CEFTAZIDIME VERSUS MEROPENEM (UNIVERSITY MEDICAL CENTER NIJMEGEN) CEFTAZIDIME modified 1995 J Antimicrob Chem 1995; 36:185 CLINICAL RESPONSE AT THE END OF THERAPY CEFTAZIDIME VERSUS MEROPENEM (UNIVERSITY MEDICAL CENTER NIJMEGEN) CEFTAZIDIME MEROPENEM modified modified 1995 J Antimicrob Chem 1995; 36:185 CEFEPIME VERSUS PIPERACILLIN-TAZOBACTAM AT THE END OF THERAPY Bow et al. Clin Infect Dis 2006; 43:447-459 CEFEPIME n=263 PIPERACILLINTAZOBACTAM n=265 2006 DRUGS USED FOR MODIFICATIONS GLYCOPEPTIDES AMINOGLYCOSIDES SYSTEMIC ANTIFUNGALS 33% 8% 23% J Antimicrob Chem 1995; 36:185 GLYCOPEPTIDE AS RESCUE n = 177 RESPONSE OVERALL 45% 33% 78% -PERSISTING FEVER ONLY -SKIN-SOFT TISSUE INFECTIONS -PERSISTENT GRAM-POSITIVES Brit J Haematol 1990; 76:1-5 94% IMPACT OF MODIFICATIONS BEFORE NEUTROPHIL RECOVERY (UNIVERSITY MEDICAL CENTER NIJMEGEN) EMPIRIC MODIFICATIONS < 20% DEFERVESCENCE J. Int. Med. 1997; 242: 69-77 How can we keep ourselves under control? Guidelines?? 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 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 REASONS FOR MODIFICATION OF ANTIBIOTICS DURING AND OUTSIDE OFFICE HOURS De Pauw et al. J. Int. Med. 1997; 242: 69-77 NUMBER OF MODIFICATIONS 200 100 OBJECTIVE CRITERIA SUBJECTIVE CRITERIA WORKING HOURS OUT OF HOURS 0 Ann Hematol 1996; 72: 273-9 ADMINISTRATION OF ANTIMICROBIALS IN RELATION TO THE COURSE OF GRANULOCYTOPENIA 100% 75% 50% GRANULOCYTES antibacterials >1000 1000 500 0 10 antifungals 20 30 days <100 PERCEIVED NEED FOR PARENTERAL AMPHOTERICIN-B AFTER PROPHYLAXIS IN NEUTROPENIC PATIENTS Europe incidence of invasive fungal disease USA perceived need for empirical amphotericin B 5 10 20 30 40 50 60% Propensity to act dominates!! …….in spite of guidelines RECOMMENDATIONS IDSA 2002 Hughes et al. Clin Infect Dis 2002; 34:730-751 UNEXPLAINED FEVER AND NEUTROPENIA antibiotics for 3-5 days DEFERVESCENCE ANTIFUNGAL unless •neutrophils are returning and •no colonization is present and •no signs of infection found NO DEFERVESCENCE THE DUEL DIAGNOSTIC TESTS specificity culture histology antibody antigen blood cultures PCR 1-3-ß-D-glucan imaging / radiology C-Reactive Protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6) KEY FACTORS FOR SELECTION OF FURTHER THERAPY ELAPSED TIME NEUTROPENIA CULTURE RESULTS PERSISTING FEVER CLINICAL SYMPTOMS KEY FACTORS FOR SELECTION OF FURTHER THERAPY ELAPSED TIME NEUTROPENIA CULTURE RESULTS PERSISTING FEVER CLINICAL SYMPTOMS EVOLUTION OF CAUSES OF FEVER Gram-negative bacteria Gram-positive bacteria Pyrogenic substances *drugs *cytokines parasites *bloodproduct-antigens *toxins *(auto)immune reactions *tissue(tumor)products viruses Fungi: yeasts  moulds time KEY FACTORS FOR SELECTION OF FURTHER THERAPY ELAPSED TIME NEUTROPENIA CULTURE RESULTS PERSISTING FEVER CLINICAL SYMPTOMS EXPLANATION OF FEVER IN NEUTROPENIC PATIENTS ABDOMEN SKIN SOFT TISSUE URINE URTI LUNG BACTEREMIA UNEXPLAINED FEVER AT ONSET OF FEVER Infection 1998; 26: 349-354 AFTER 72 HOURS KEY FACTORS FOR SELECTION OF FURTHER THERAPY ELAPSED TIME NEUTROPENIA CULTURE RESULTS PERSISTING FEVER CLINICAL SYMPTOMS POTENTIAL INFECTION SITES •Peridontium •Pharynx •Esophagus •Lungs •Skin and nails •Perineum •Typhlitis AVERAGE DURATION OF FEVER IN VARIOUS CATEGORIES OF INFECTION DURING NEUTROPENIA d≥10 a y 8 s w 6 i t 4 h f e v e r 2 0 unexplained bacteremia fever Leuk Lymph 1993; 10:461 lower upper skin and respiratory respiratory soft tissue tract tract SITES OF INFECTION AND CAUSATIVE ORGANISMS UPPER RESPIRATORY TRACT: LOWER RESPIRATORY TRACT DIFFUSE: STREPTOCOCCI / ANAEROBES HERPES SIMPLEX YEASTS GRAM-NEG RODS STREPTOCOCCI MOULDS TUBERCULOSIS STREPTOCOCCUS MITIS (CYTOMEGALO)VIRUS PNEUMOCYSTIS SKIN AND SOFT TISSUE: ABDOMINAL: STAPHYLOCOCCI STREPTOCOCCI / CORYNEFORMS ANAEROBES GRAM-NEG RODS Knowledge and experience can help to determine an effective strategy CLINICALLY IMPROVING AFTER 72 HOURS CONTINUED OBSERVATION WITHOUT SPECIFIC INVESTIGATIONS AN ANTIBIOTIC STRATEGY IMPLIES MORE THAN ADMINISTRATION OF APPROPRIATE DRUGS REPEAT DIAGNOSTICS -physical examination -blood cultures -serology -imaging PERSISTING FEVER YIELD OF DIAGNOSTIC PROCEDURES time evolution of the infection yield of diagnostic interventions CLINICALLY IMPROVING AFTER 72 HOURS CONTINUED OBSERVATION WITHOUT SPECIFIC INVESTIGATIONS NO ISOLATE CONTINUE OR SWITCH TO ORAL COMPOUND GRAM NEG ISOLATE CONTINUE FULL DOSE OTHERS ADD SPECIFIC AGENT CLINICALLY STABLE AFTER 72 HOURS CONTINUED OBSERVATION WITH SPECIFIC INVESTIGATIONS UNEXPLAINED FEVER (60%) GRAM NEG ISOLATE OTHERS CLINICAL SITE OF INFECTION CONTINUE FULL DOSE CONTINUE FULL DOSE ADD SPECIFIC AGENT MAINTAIN GRAM-NEG COVER AND ADD AGENT ON BASIS OF SITE CLINICALLY DETERIORATING AFTER 72 HOURS CONTINUED OBSERVATION WITH SPECIFIC INVESTIGATIONS UNEXPLAINED FEVER 25% DOCUMENTED INFECTION 75% CLINICALLY BACTERIOLOGICALLY MODIFY ON THE BASIS OF SITE OF INFECTION FILL THEORETICAL GAPS IN ANTIBIOTIC COVER ADJUST ACCORDING TO RESULTS OF THE CULTURES AFTER 3-5 DAYS (END EMPIRICAL EPISODE) FEBRILE NEUTROPENIC POPULATION RECEIVING EMPIRICAL THERAPY 100% IMPROVING 60% MAINTAIN REGIMEN OR DE-ESCALATE ADJUST ON THE BASIS OF CLINICAL OR MICROBIOLOGICAL FINDINGS EMPIRIC EXTENSION OF COVER STABLE 20% WORSE 20% 12% 8%5% 15% IMPACT OF MODIFICATIONS BEFORE NEUTROPHIL RECOVERY EMPIRIC MODIFICATIONS < 20% DEFERVESCENCE SPECIFIC MODIFICATIONS > 50% DEFERVESCENCE J. Int. Med. 1997; 242: 69-77 EMPIRICAL ANTIMICROBIAL THERAPY IMPROVING STABLE MORTALITY DETERIORATION FUO DOCUMENTED INFECTION FUO DOCUMENTED INFECTION CLINICAL MICROBIOLOGICAL MODIFICATIONS <1% <1% <5% <5% <15% <10% VOLTAIRE’S IDEAL PHYSICIAN The ideal doctor entertains his patient while nature does its work 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 Persistent Fever and Neutropenia: Yesterday, Today and what about Tomorrow? Persistent Fever and Neutropenia: What we did Yesterday, are we still doing Today and I wonder if it will be different Tomorrow? ACKNOWLEDGEMENTS What I have accomplished was only possible with the support of: Peter Donnelly Jack Edwards Jack Bennett Elie Anaissie Gail Triggs, and many other friends My patients and their relatives My wife, and sons: Michiel and Luc FAREWELL AND, OF COURSE, MANY, MANY THANKS TO YOU, MY LOYAL AUDIENCE! I WISH YOU MANY MORE INSTRUCTIVE ICAAC’S