Assessment and Management of Fever in the Neutropenic Patient 2003 .


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Definition and Risk of Infection as Absolute Neutrophil Count Declines. Characterized as:A single oral temp > 38.3oC (101oF) ORRepeated oral temps > 38.0oC (100.4oF) for one hourANDANC < 500/mm3 or < 1000/mm3 and < 500/mm3 anticipated. Ann Int Med,1966;64:329. Clin Inf Dis, 2002; 34:730-51. Starting Evaluation in Fever/Neutropenia.
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Assessment and Management of Fever in the Neutropenic Patient 2003 Kevin P. High, M.D., M.Sc. Relate Professor of Medicine Sections on Infectious Diseases and Hematology/Oncology

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Definition and Risk of Infection as Absolute Neutrophil Count Declines Defined as: A solitary oral temp > 38.3 o C (101 o F) OR Repeated oral temps > 38.0 o C (100.4 o F) for one hour AND ANC < 500/mm 3 or < 1000/mm 3 and < 500/mm 3 expected Ann Int Med,1966;64:329 Clin Inf Dis, 2002; 34:730-51

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Initial Evaluation in Fever/Neutropenia Hx/PEx concentrate on lungs, perirectal locale ( no rectal exam), catheter destinations, oropharynx, sinuses, skin (& nail beds) CBC, SMAC (w/LFT\'s) U/A?, Urine Cx 2 blood societies (1 fringe, 1 focal favored; if not, no less than two halfway; volume is the key ~10mL) CXR if SSx\'s or OP Rx mulled over; High Res CT (+) in half w/NL CXR (J Clin Onc1999;17:796-805) injury societies when fitting Clin Inf Dis, 2002; 34:730-51

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Algorithm for Fever/Neutropenia Hemodynamically flimsy &/or new organ brokenness? *Note, there are numerous different regimens; AZM/Clinda, Cipro/Clinda or Vanc/AZM for serious PCN hypersensitivity **If other nephrotoxic meds, consider meropenem or cefepime montherapy No Yes Catheter-related erythema/induration, or chills with CVC flushing? Pip-tazo + cipro + vanco Yes No ANC > 100 & clinically steady? Cefepime* + vanco Pip-tazo* + cipro No Yes Quinolone prophylaxis? Pip-tazo* + gent** Cefepime* monotherapy

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Justification for Empiric Antimicrobial Therapy in Fever/Neutropenia Never been (and most likely never will be) a randomized/controlled trial Retrospective Data (NEJM,1971;284:1061) showed that ~50% of Pseudomonas bacteremias result in death w/in 72 hrs when ANC < 1000 Early trials went for Pseudomonas diminished mortality to 33% (Carb/Gent; JID,1978;147:14) Peak serumcidal levels of > 1:16 corresponded with achievement, ? Blends w/cooperative energy ought to be more intense (Am J Med,1984;76:429)

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Empiric Combinations Anti-Pseudomonal PCN or Cephalosporin + aminoglycoside (NEJM,1993;326:1323) reaction rates all around 70%, no preferred standpoint of one b - lactam over another, ? Tobra versus Gent Advantages; cooperative energy versus some GNRs, ?  resistance Disadvantage; nephrotoxicity Double b - lactam( Ann Int Med,1991;115:849 ) ; CTZ/CPZ + Pip measure up to adequacy, less nephrotoxic, high cost

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Monotherapy: Pro Ceftazidime (NEJM,1986;315:552) equal by and large "achievement" rate to blend treatment; passage criteria = fever + ANC < 500 option of Vancomycin or aminoglycoside just required in 15% in general when contamination characterized, 60% of patients altered (more often than not vanc included) Imipenem (Ann Int Med,1991;115:849) general viability of monotherapy (85%) ? Expanded danger of contagious infxn. Unequivocal hazard consider for S. maltophilia contamination

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Cefipime contrasted with Ceftazidime or Pip/Gent (~ 100 patients for every gathering) dosed 2 gms q 8 hrs Vanc required in 40-45% & antifungals in 35% in both gatherings. viability, survival not diverse % helpless GP GN Cefipime 82 93 Ceftazidime 74 91 Piperacillin 61 93 Gentamicin 76 100 bacterial annihilation in 97% for cefipime, 100% for comparator Cefipime in Treatment of Fever/Neutropenia* *Ramphal, AM J Med,1996.

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Meropenem (58%) versus Imipenem (60%) (Infection,1996;24:480-4) Meropenem (56%) versus CTZ/Amikacin (52%) (AAC,1996;40:1108-15) Cefepime (74%) versus CTZ OR Pip/Gent (76%) (Am J Med,1996;100:83S-89S) Meropenem versus CTZ/Amikacin (80%) versus (77%) (Haematologica,1997;82:668-75) Cefepime ( 79%) versus Imipenem (72%) (J Antim Chemo,1998;42:511-8) Cefepime (57%) versus CTZ (60%) (Ann Pharmacother, 2000;34:989-95) Meropenem (54%) versus CTZ (44%) (J Clin Oncol,2000; 18:3690-8) Meropenem (48%) versus CTZ (38%) (Ann Hematol,2000; 79:152-7) Clinafloxacin (32/95%) versus Imipenem (33/92%) (Clin Inf Dis,2001;32:381-90) Some Published Monotherapy Trials in Febrile Neutropenic Patients

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Monotherapy: Con Ceftazidime + 3d of Amikacin versus CTZ + 9d of Amikacin (NEJM,1986;315:552) section criteria; fever + ANC < 100 adjustment of introductory regimen considered "disappointment" "achievement" rate in 3d gather = 48% versus 81% in 9d bunch in patients with archived bacteremia Death rate 17% versus 8%

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Meta-investigation of Monotherapy versus Blend Therapy* 47 trials, 7807 patients Monotherapy RR All cause mortality 0.85 (0.72,1.02) Same b - lactam no distinction, diverse b - lactams, contrast got to be distinctly noteworthy 0.87 (0.80,0.93) Superinfection 0.97 (0.82,1.14) Treatment Failure 0.92 (0.85,0.99) Any Adverse Event 0.85 (0.72,1.02) Nephrotoxicity 0.42 (0.32, 0.56) *Paul M, Soures-Weiser K, Leibovici L. Br Med J, 2003;326:111-1119

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PRO change in most basic confines in F/N ? Less febrile days in general, and maybe less ampho B utilize viridans streptococci might be lethal and PCN I or R; specific issue with quinolone prophylaxis and regimens that instigate serious mucositis CON general mortality from reported gm(+) bacteremia just 5% dominant part of patients with gm(+) survive and react to expansion of Vanco (AIM,1988;106:30 & NEJM,1988;319:1053) VRE Vancomycin Up Front?

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Changing Etiology of Infection in Cancer Patients* % of Isolates Summarized from Jones, Clin Inf Dis,1999;29:495 Year of Study

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Changing Etiology of Infection in Cancer Patients* % of Isolates Summarized from Jones, Clin Inf Dis,1999;29:495 Year of Study

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Resistance (%) in viridans Streptococci Summarized in Clin Inf Dis, 2002; 34:1524-9

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Response Rates in Trials of Vanco versus No Vanco Up Front* % Response Note: no mortality contrast in any review !!!!!!!! Abridged from Feld, Clin Inf Dis,1999;29:503 Type of Standard Therapy

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Criteria for Adding Vancomycin Up Front* Clinically evident catheter disease CRx w/serious mucositis (high measurement Ara-C) quinolone prophylaxis (?? furthermore, PCN unfavorably susceptible) known colonization of MRSA (+) blood culture for Gm (+) hypotension or other confirmation of hemodynamic insecurity/sepsis *Clin Inf Dis,2002;34:730-51. Recs are An II

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Susceptibility Data for Pseudomonas aeruginosa at WFUBMC (2002)

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Susceptibility Data for Staphylococcus aureus at WFUBMC (20 02 )

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Susceptibility Data for Enterococcus spp. at WFUBMC ( 2002 )

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Algorithm for Fever/Neutropenia Hemodynamically insecure &/or new organ brokenness? *Note, there are numerous different regimens; AZM/Clinda, Cipro/Clinda or Vanc/AZM for extreme PCN hypersensitivity **If other nephrotoxic meds, consider meropenem or cefepime montherapy No Yes Catheter-related erythema/induration, or chills with CVC flushing? Pip-tazo + cipro + vanco Yes No ANC > 100 & clinically steady? Cefepime* + vanco Pip-tazo* + cipro No Yes Quinolone prophylaxis? Pip-tazo* + gent** Cefepime* monotherapy

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Why do we utilize Pip-tazo + Cipro for our blend treatment standard? Biggest enlisting focus in a review as of late distributed (Ann Int Med, 2002;137:77-86) Q 4 h pip + either cipro OR tobra q 8 h No diff in adequacy Less renal disappointment with cipro if on no other nephrotoxic meds % febrile p=0.0052 Days

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Persistent Fever After Initial Therapy* Febrile 3-5 days in the wake of beginning Abxs? ANC < 500 ANC > 500 ? Change Abxs ? Include Vancomycin ? Include Ampho B Stop Abxs after ANC > 500 for 4-5 days; Re-assess *Clin Inf Dis, 2002;34:730-51

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Causes of Persistent Fever in Neutropenic Patients* *Editorial by Corey and Boeckh, NEJM,2002;346:222-4.

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Adding Amphotericin B In F/N patients still febrile 7d after Abx\'s; option of Amphotericin B seems to enhance result ( Am J Med,1982;72:101 ) EORTC trial distributed in 1989 ( Am J Med,1989;86:668 ) the biggest randomized controlled trial of empiric antifungal treatment versus fake treatment in neutropenic patients with proceeded or intermittent fever following 4 days of antibacterial treatment

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EORTC Trial of Empiric Ampho B (Am J Med,1989;86:668-73) 132 Pts, ANC < 500/mm 3 and on Abx\'s for > 4 d 6 recorded contagious diseases (4 extreme) in fake treatment assemble versus one in Rx amass (p= 0.1) 4 parasitic passings versus none (p= 0.05) BUT no general survival contrast * % Responded

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Other Considerations When Adding Antifungal Therapy Image sinuses, trunk (w/CT in proceeded with fever) Specific criteria for liposomal Ampho B Intitial Creat > 2.0 and not on dialysis (long haul) Creat  > 2.0 (x 2 measures no less than 24 hrs separated) & no change after 24 h of IVFs & need to proceeded with nephrotoxic operators (CsA, AGs) headstrong sickness after 500 mg ordinary Ampho B

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Other Alternatives to Ampho B?* 687 patients with ANC < 500 and industrious fever following 5 days of antibacterials Ambisome 3 mg/kg/d versus Ampho B 0.6 mg/kg/d IV Much higher lethality with Ampho B (chills and nephrotoxicity) Proven achievement contagious infxn less in Ambisome bunch 3.2% vs.7.8% % * *Walsh, et al. NEJM,1999:340:764.

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Itraconazole for Empiric Coverage in Fever/Neutropenia 384 patients selected and contrasted with Ampho B "Achievement" = alive, settled fever/neutropenia w/in 28 days, no rising contagious infxn, no cessation because of danger "Unevaluable" = Rx < 3 d * Boogaerts, et al. Ann Int Med, 2001;135:412-22

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Itraconazole for Empiric Therapy in Febrile Neutropenia Important contemplations in this review Ampho B measurements was 0.7-1.0 mg/kg/d oral itraconazole could be substituted for IV as ahead of schedule as 7 days, yet regularly on d 15 (levels OK) Rx proceeded until defervescence AND ANC > 500 x 2d Effective level 250 mg/mL Boogaerts, et al. Ann Int Med, 2001;135:412-22

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Glucan Synthase Inhbitors Activity Against Common and Uncommon Fungi Active Mod Activity Poor Activity Candida spp. H. capsulatum

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