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Saima Abbas M.D Infectious Diseases Fellow-PGY5. Why is this an Oncologic emergency ??

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Text of Saima Abbas M.D Infectious Diseases Fellow-PGY5. Why is this an Oncologic emergency ??

  • Saima Abbas M.DInfectious DiseasesFellow-PGY5

  • Why is this an Oncologic emergency ??

  • Infection + ABX + Immune system = cureNormal Gross AnatomySkin IntegrityIntact mucous membranesIntact ciliary functionAbsence of Foreign Bodies

    Innate Immunity ( PMN,Macrophages, NK cells, Mast cells and basophils) ComplementAdaptive immunityT cells CD 4 and CD 8B cells

  • Case 1July 10th 2009 - NF 1You are paged at 5:00am by the nurse taking care of Mr. Thomas on 4 AB

    He spiked a fever of 38 C (100.4F) one hour ago.

    -There is no order for Tylenol.

  • ~You check your Hem Oncology List .Per sign out:The patient was recently diagnosed with AML is S/P chemotherapy and is stable.You can Order Tylenol and take the next page.


  • OR

    If you are alert, you thinkAm I missing febrile Neutropenia???

  • What are the facts you need to know?Does 38 C define febrile neutropenia?

    Whats his Absolute Neutrophil Count?

    Any transfusion in the last 6 hours?

  • Definition of Fever in FN

    A single oral temp 38.3 C (101 F)or

    A temperature of 38 C (100.4 F) on two occasions separated by 1 hour

  • You request her to repeat the temperature and she reports 38. 2 C (100.8 F)

  • Dont be trickedIf temperature 37 38 C , repeat temperature in 1 hour to see if the above criteria for treatment are met

    Clinical signs of septicemia

    Good history of fever detected by patient before admission and afebrile when you evaluate the patient.

  • Definition of Neutropenia

    ANC 500/mm3 or

    1000/mm3 and predicted

    decline to 500/mm

    ~ Clin Inf Dis, 2002;34:730-51

  • ANC : Mr. ThomasWBC 0.7

    Segs = 38%

    Bands = 2%

  • Absolute Neutrophil Count

    (Total # of WBC) x (% of Neutrophils) = ANCTake the percent of neutrophils (may also be polys or segs) + percent bandsConvert percent to a decimal by dividing by 100 (Example 40% = 40/100 = 0.40) (*move the decimal 2 points to the left)Multiply this number by the total White Blood Cells (WBC)

  • Calculation

  • NeutropeniaNormal ANC 1500 to 8000 cells/mmNeutropenia: ANC < 1500 cells / mm3Mild Neutropenia: 1000-1500 cells / mm3Moderate Neutropenia: 500-999 cells / mm3Severe Neutropenia: < 500 cells / mm3Profound Neutropenia:
  • When Does Neutropenia Occur?Most chemotherapy agents/protocols cause neutropenia nadir at 10-14 daysBut can see anytime from a few days after chemotherapy to up to 4-6 weeks later depending on the agents used

  • Risk of Infection as Absolute Neutrophil Count Declines

  • Epidemiology Up to 60% febrile neutropenia episodes = infection (microbiological or clinical)

    ~20% patients with ANC

  • Epidemiology --NEJM, 1971;284:1061

    Retrospective data have shown that~ 50 % of Pseudomonas Aeruginosa Bacteremia result in death within 72 hours when ANC is < 1000

    Early trials aimed at Pseudomonas showed that Carbapenicillin /Gentamicin decreased Mortality by 33 % ~Journal of Infectious diseases, 1978;147:14

  • Epidemiology Changing etiology of bacteremiaIATG-EORTC 1973-2000 trials of febrile neutropenia

    Gram positive dominant since mid 1980s1) More intensive chemoTxMucositis2) In-dwelling catheters Cutaneous-IV portal3) Selective antiBx pressureFluoroquinolones Co-trimoxazole4) AntacidsPromote oro-oesophageal colonisation with GPC

    Viscoli et al, Clin Inf Dis;40:S240-5Gram negative resurgence

  • Duration of Neutropenia< 7 days LOW risk

    7 to 14 days INTERMEDIATE RISK

    > 14 days HIGH RISK

  • Duration Of Neutropenia 1988,Rubin and colleagues

    < 7 days of neutropenia ~ response rates to initial antimicrobial therapy was 95%, compared to only 32% in patients with more than 14 days of neutropenia (

  • Common MicrobesGram-positive cocci and bacilliStaph. aureus Staphylococcus epidermidisEnterococcus faecalis/faeciumCorynebacterium speciesGram-negativebacilli and cocciEscherichia coliKlebsiella speciesPseudomonas aeruginosaFUNGICandida- Non albicans emergingAspergillus >> in HSCT

  • Initial evaluationEnsure Hemodynamic Stability and No NEW ORGAN DYSFUNCTION HistoryUnderlying disease, remission and transplant status- spleen +/-ChemotherapyDrug history (steroids, any previous antibiotics)Allergies Focused Review of systemsTransfusionsCan cause feversLines or in-dwelling hardware

  • SplenectomyTHINK Strep. PneumoniaeNeisseria meningitidisHemophilus Influenzae

  • Exam (be prepared to find no signs of inflammation)HEENT Look in the mouth any oral sores periodontium, the pharynxLungs Abdomen for tenderness- RLQ (signs of Typhilitis)Perineum including the anus -No rectal exam !

  • Skin Exam- Ask the patient for any area of tenderness?Skin Bone marrow aspirations sites,

    vascular catheter access sites

    and tissue around the nails

    Rashes (Drug eruptions/herpes zoster reactivation / Petechial rashes all are common in these patients)

  • Febrile neutropeniaInvestigationComplete Blood Count (with Differential)-White cells, haemoglobin, plateletsBiochemistry-Electrolytes, urea, creatinine, Liver functionMicrobiology-Blood cultures (peripheral and all central line lumens)-Oral ulcers or sores send swabs ( Viral Cx and fungal Cx ) -Exit site swabs-Wound swabs-Urine Cultures (SSx/Foley Catheter) [- pyuria ?? UA]-Stool Cultures and CDiff Toxin/PCRRadiology-Chest Xray +/- CT abdomen/pelvis

  • Lumbar puncture- Examination of CSF specimens is not recommended as a routine procedure but should be considered if a CNSinfection is suspected and thrombocytopenia is absent or manageable.

  • Skin lesions Aspiration or biopsy of skin lesions suspected of being infected should beperformed for cytologic testing, Gram staining, and culture

  • IMAGING in FNCXR if Symptomatic or if out pt Rx consideredHigh resolution CT Chest Indicated ONLY if persistent fevers with pulmonary symptoms after initiation of empiric AbxCTA if suspect PECT abdomen for Necrotizing Enterocolitis or Typhilitis CT brain R/o ICH / MRI of the spine or brain - more for evaluation of metastatic disease than FN

  • Stratify risk of complications1. Neutropenia with severity of neutropenia (< 50/mm3) with duration of neutropenia (>7 days)2.BacteremiaGram negative > gram positive 3.Underlying malignancy and statusAcute LeukemiaRelapsed diseaseSolid malignancies: Local effects eg obstruction, invasion4.Co-morbidities, age >60

  • Prolonged Neutropenia (>14 days) Haematological malignancy/ Allogenic HSCT Myelosuppresive chemotherapy Concurrent chemotherapy and radiotherapy Age >60 Co-morbidities eg. Diabetes, poor nutritional status. Bone marrow involvement of cancer Delayed surgical healing or open wounds Significant mucositis Unstable (eg hypotensive, oliguric) On steroid dose >20mg prednisone daily Recent hospitalization for infection

    HIGH risk Patients

  • a Concomitant condition of significance (e.g.,shock, hypoxia, pneumonia,or other deep organ infection, vomiting, or diarrhea).

  • Risk modelModel 2(Klatersky et al MASCC 2000 J Clin Onc)

    No or Mild symptoms 5Moderate symptoms 3No Hypotension 5No COPD 4Solid tumour / 4 Haem malignancy (no fungal infection) Outpatient 3No dehydration 3Age 20

  • ORAL vs IVFor patients who are low risk for developing infection-related complications during the course of neutropenia, ~ Oral ciprofloxacin plus amoxicillin/clavulanate

    ~ Oral ciprofloxacin plus clindamycin for PCN allergy

  • If inpatient and high risk

    EMPIRIC ANTIMICROBIAL THERAPY after Blood Cultures. Must be initiated within 1 hour

  • THREE approaches for IV EMPIRIC therapyIV MONO THERAPY



  • Monotherapy IV

    Extended spectrum Antipseudomonal CephalosporinsCefepimeCeftazidimeCarbapenem Imipenem CilastatinMeropenemAnti Pseudomonal PCN Piperacillin- Tazobactam Ticarcillin- Clavulanic acid

  • DUAL therapy aminoglycoside plus an antipseudomonal penicillin (with or without a beta-lactamase inhibitor) or an extended-spectrum antipseudomonal cephalosporin,

  • Dual therapy (2) ciprofloxacin plus anantipseudomonal penicillin.

    IndicationsUnstable patientH/O P. aeruginosa colonization or Invasive disease

  • 5 Indications for Vancomycin1.clinically suspected serious catheter-related infections

    2.known colonization with penicillin- andcephalosporin-resistant pneumococci or MRSA,

    3.positive results of blood culture for gram-positive

    hypotension or other evidence of cardiovascular impairment

    5.H/O ciprofloxacin or trimethoprim-sulfamethoxazole

  • vancomycin resistant enterococcusLinezolid

    Daptomycin (avoid for pneumonia)

    Quinopristin- Dalfopristin

  • PCN allergyNON ANAPHYLACTIC If not allergic to cephalosporins~ Cefepime ANAPHYLACTIC and allergic to cephalosporins-~Aztreonam +/- Aminoglycoside or a FQ

    +/- Vancomycin if indicated


  • Antibiotic stopping guideIDSA, Clin Infect Disease, 2002Minimum 1 week of therapy ifAfebrile by day 3Neutrophils >500/mm3 (2 consecutive days)Cultures negativeLow risk patient, uncomplicated course

    > 1 week of therapy based ifTemps slow to settle (>3 days)Continue for 4-5 days after neutrophil recovery (>500/mm3 )

    Minimum 2 weeksBacteraemia, deep tissue infection After 2 weeks if remains neutropenic (< 500/mm3), BUT afebrile, no disease focus, mucous membranes, skin intact, no catheter site infection, no invasive procedures or ablative therapy plannedcease antibiotics and observe

  • When temperatures do not go away

    Non-bacterial infection (eg fungal, viral)Bacterial resistance to first line therapy (MRSA, VRE)Slow response to drug in useSuperinfectionInadequate doseDrug feverCell wall deficient bacteria (eg Mycoplasma, Chlamydia)Infection at an avascular site (abscess or catheter) Disease-related fever

  • Antifungals Easy to Initiate/ Difficult to stopAggressive search for Fungal InfectionsPulmonary Aspergillosis/Sinusitis / Hepatic CandidiasisCT Chest and AbdomenCT SinusesCultures of suspicious skin lesions

  • ANTI FUNGALSAMPHO B IV drug of choice for high risk patients Alternative optionsFLUCONAZOLE ITRACONAZOLEECHINOCANDINSVoriconazole is NOT FDA approved for empiric therapy for persistent fevers in FN

  • Fluconazole ~ candida Fluconazole acceptable if NOMoulds and Resistant Candida ( C. Krusei and C. glabrata )Uncommon. Low risk patients DO NOT Use Fluconazole if Evidence of Sinusitis orRadiographic evidence of Evidence of Pulmonary diseaseIf patient has received Fluconazole prophylaxis before.

  • ItraconazoleIn a recent controlled study of 384 neutropenic patients with cancer, itraconazole and amphotericin B were equivalent in efficacy as empirical antifungal therapy.FOR BOARDS use AmphoB OR Itraconazole- hopefully should not ask you to choose between Itraconazole and Ampho B

  • Antibiotic Prophylaxis for Afebrile Neutropenic Patients

    Use of antibiotic prophylaxis is not routine because of emerging antibiotic resistance **, except for Trimethoprim-sulfamethoxazole to prevent Pneumocystis carinii pneumonitis.Antifungal prophylaxis with fluconazoleAntiviral prophylaxis with acyclovir or ganciclovir are warranted for patients undergoing allogenic hematopoietic stem cell transplantation. ** CID 40:1087&1094,2005 NEJM 353:977,988&1052,2005

  • Use of Antiviral Drugs

    Antiviral drugs are not recommended for routine use unless clinical or laboratory evidence of viral infection is evident.

  • Granulocyte Transfusions Granulocyte transfusions are not recommended for routine use.

    Use of Colony-Stimulating Factors Use of colony-stimulating factors is not routine but should be considered in certain cases with predicted worsening of course.

  • Role of G-CSFStudies of G-CSF used in febrile neutropenia show: Length of neutropenia but generally not hospitalizationNo mortality advantageGenerally not recommendedException may be those in high risk group esp. if unstable

  • Updates not for BOARDS but for clinical practiceJAC 57:176,2006A meta analysis of 33 RCTs until Feb 2005 on Antipseudomonal B lactams as MONOtherapies showed that ~CEFEPIME increases 30 day all cause mortality ~ Carbapenems were associated with increased Pseudomembranous colitis.

  • Special Situations

  • Neutropenic Enterocolitis or TyphilitisInflammatory process involving colon and/or small bowelischemia, necrosis, bacteremia( translocation from gut) hemorrhage, and perforation.Fever and abdominal pain ( typically RLQ).Bowel wall thickening on ultrasonography or CT imaging.

  • Treatment ( 50-70% mortality)Initial conservative management bowel rest, intravenous fluids, TPN, broad-spectrum antibiotics and normalization of neutrophil counts. Surgical intervention obstruction, perforation, persistent gastrointestinal bleeding despite correction of thrombocytopenia and coagulopathy, and clinical deterioration.

  • Consider Pseudomonal and Clostridial coverage in Empiric therapyClostridium Septicum Clostridium Sordelli Cover with PEN G ,AMP, Clindamycin* Broad Spectrum Abx ( carbapenem ) include Metronidazole if unsure of Cdiff * resistance of Clostridia to clindamycin reported.

  • H/O leukemia and prolonged antibiotic therapy

  • Angioinvasive AspergillosisConfirm with Biopsy Aggressive Antifungal TherapyVoriconazole (Drug of Choice)Caspofungin FDA approved for Ampho and Voriconazole refractory Aspergillus.

  • Case 1- Mr. ThomasJune 20th 2009 diagnosed AML June 21st 2009 R subclavianHickman placed and Chemotherapy initiatedRemission Induction S/P 7+ 3 regimen Cytarabine (Ara C) and Daunorubicin June 28th 2009 - last dose of chemotherapy.July 10th 2009 - Febrile Neutropenia ANC 280 ANC < 500 last 2 days

  • Experiences chills with CVC flushing and erythema and tenderness is noted over the hickman exit site.Allergies NKDA Labs Pancytopenic LFTS ok Creatinine 1.0

  • What is the best next step?1- Cefepime or Zosyn IV stat2- Vancomycin IV stat 3- CXR4- Blood cultures-central and peripheral5- Fluconazole IV stat

  • Cefepime and Vancomycin are initiatedBlood cultures are + for MRSE 2/2.Pt becomes afebrile day 4 of ABX.Surveillance Blood cultures are Negative. Patient is stable. ANC = 300 by DAY 4

    What will you do next?A Stop CefepimeB Add G- CSFC Continue Cepepime until ANC > 500 or a minimum of 7 days.D Continue Vancomycin for a total of 7 days.

  • Remember for boardsDo not order CT scan in a neutropenic patient with a normal CXR.In clinical practice if patient remains febrile for 3 to 5 days then the next step is HRCT. ( 50 % of patients with + imaging have a normal CXR)

  • ConclusionsFebrile Neutropenia is a serious complication of chemotherapyBe vigilant for febrile neutropenia in chemotherapy patientsBe vigilant for infection even when no feverInitiate EMPIRIC antibiotics immediately.Several treatment options depending on risk stratification.