Saima Abbas M.

D Infectious Diseases Fellow-PGY5

Why is this an Oncologic emergency ??

Infection + ABX + Immune system = cure

Normal Gross Anatomy Skin Integrity Intact mucous membranes Intact ciliary function Absence of Foreign Bodies

Innate Immunity ( PMN, Macrophages, NK cells, Mast cells and basophils) Complement Adaptive immunity T cells CD 4 and CD 8 B cells

Case 1 July 10th 2009 - NF 1

You 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..

OR
Am I missing febrile Neutropenia???

If you are alert, you think

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 tricked

If 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. Thomas

WBC 0.7 Segs = 38% Bands = 2%

Absolute Neutrophil Count

(Total # of WBC) x (% of Neutrophils) = ANC Take the percent of neutrophils (may also be polys or segs) + percent bands Convert 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

Neutropenia
Normal ANC 1500 to 8000 cells/mm Neutropenia: ANC < 1500 cells / mm3 Mild Neutropenia: 1000-1500 cells / mm3 Moderate Neutropenia: 500-999 cells / mm3 Severe Neutropenia: < 500 cells / mm3 Profound Neutropenia: <100 cells/ mm

When Does Neutropenia Occur?

Most chemotherapy agents/protocols cause neutropenia nadir at 10-14 days But 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) patients with ANC <100 cells/mm with febrile neutropenia episodes have bacteremias.

~20%

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

Changing etiology of bacteremia

IATG-EORTC 1973-2000 trials of febrile neutropenia Gram positive dominant since mid 1980s
1) More intensive chemoTx Mucositis 2) In-dwelling catheters Cutaneous-IV portal 3) Selective antiBx pressure Fluoroquinolones Co-trimoxazole 4) Antacids Promote orooesophageal colonisation with GPC

Gram 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 ( <.001) ~ patients with intermediate durations of neutropenia between 7 and 14 days had response rates of 79%

Common Microbes
Gram-positive cocci and bacilli Staph. aureus Staphylococcus epidermidis Enterococcus faecalis/faecium Corynebacterium species Gram-negative bacilli and cocci Escherichia coli Klebsiella species Pseudomonas aeruginosa FUNGI Candida- Non albicans emerging Aspergillus >> in HSCT

Initial evaluation
Ensure Hemodynamic Stability and No NEW ORGAN DYSFUNCTION History
Underlying disease, remission and transplant

status- spleen +/ Chemotherapy Drug history (steroids, any previous antibiotics) Allergies

Focused Review of systems Transfusions

Can cause fevers

Lines or in-dwelling hardware

THINK Strep. Pneumoniae Neisseria meningitidis Hemophilus Influenzae

Splenectomy

Exam (be prepared to find no signs of inflammation)

HEENT Look in the mouth any oral sores periodontium, the pharynx Lungs 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 neutropenia
Investigation

Complete Blood Count (with Differential)

-White cells, haemoglobin, platelets

Biochemistry
-Electrolytes, urea, creatinine, Liver function

Microbiology
-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/PCR

Radiology
-Chest Xray +/- CT abdomen/pelvis

Lumbar puncture

Examination of CSF specimens is not recommended as a routine procedure but should be considered if a CNS infection is suspected and thrombocytopenia is absent or manageable.

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

IMAGING in FN

CXR if Symptomatic or if out pt Rx considered High resolution CT Chest Indicated ONLY if persistent fevers with pulmonary symptoms after initiation of empiric Abx CTA if suspect PE CT 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 complications

1. Neutropenia
2.Bacteremia
Gram negative > gram positive

with severity of neutropenia (< 50/mm3) with duration of neutropenia (>7 days)

3.Underlying malignancy and status

Acute Leukemia Relapsed disease Solid malignancies: Local effects eg obstruction,

invasion

4.Co-morbidities, age >60

HIGH risk Patients

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

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

Risk model
Model 2
(Klatersky et al MASCC 2000 J Clin Onc)

No or Mild symptoms Moderate symptoms No Hypotension No COPD Solid tumour / Haem malignancy (no fungal infection) Outpatient No dehydration Age <60 yrs LOW RISK=score>20

5 3 5 4 4

3 3 2

ORAL vs IV

For 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 therapy

IV MONO THERAPY

IV DUAL THERAPY

COMBINATION THERAPY Mono or dual therapy + VANCOMYCIN

Monotherapy IV
1.

Extended spectrum Antipseudomonal Cephalosporins

Cefepime Ceftazidime Imipenem Cilastatin Meropenem Piperacillin- Tazobactam Ticarcillin- Clavulanic acid

2.

Carbapenem

3.

Anti Pseudomonal PCN

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

Dual therapy
(2) ciprofloxacin plus an antipseudomonal penicillin.

Indications Unstable patient H/O P. aeruginosa colonization or Invasive disease

5 Indications for Vancomycin

1. clinically suspected serious catheter-related infections 2. known colonization with penicillin- and cephalosporin-resistant pneumococci or MRSA, 3. positive results of blood culture for gram-positive
4.

hypotension or other evidence of cardiovascular impairment

5. H/O ciprofloxacin or trimethoprim-sulfamethoxazole

vancomycin resistant enterococcus

Linezolid

Daptomycin (avoid for pneumonia)

Quinopristin- Dalfopristin

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

+/- Vancomycin if indicated

MAINTAIN BROAD SPECTRUM ACTIVITY FOR A MINIMUM OF 7 DAYS OR UNTIL ANC >500

Antibiotic stopping guide

IDSA, Clin Infect Disease, 2002

Minimum 1 week of therapy if

Afebrile by day 3 Neutrophils >500/mm3 (2 consecutive days) Cultures negative Low risk patient, uncomplicated course

> 1 week of therapy based if

Temps slow to settle (>3 days) Continue for 4-5 days after neutrophil recovery (>500/mm3 )

Minimum 2 weeks
Bacteraemia, 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 use Superinfection Inadequate dose Drug fever Cell wall deficient bacteria (eg Mycoplasma, Chlamydia) Infection at an avascular site (abscess or catheter) Disease-related fever

Antifungals
Easy to Initiate/ Difficult to stop Aggressive search for Fungal Infections Pulmonary Aspergillosis/Sinusitis / Hepatic Candidiasis CT Chest and Abdomen CT Sinuses Cultures of suspicious skin lesions

ANTI FUNGALS
AMPHO B IV drug of choice for high risk patients Alternative options FLUCONAZOLE ITRACONAZOLE ECHINOCANDINS Voriconazole is NOT FDA approved for empiric therapy for persistent fevers in FN

Fluconazole ~ candida
Fluconazole acceptable if NO Moulds and Resistant Candida ( C. Krusei and C. glabrata ) Uncommon.

Low risk patients

DO NOT Use Fluconazole if Evidence of Sinusitis or Radiographic evidence of Evidence of Pulmonary disease If patient has received Fluconazole prophylaxis before.

Itraconazole
In 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 fluconazole Antiviral 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-CSF

Studies of G-CSF used in febrile neutropenia show:

Length of neutropenia but generally not

hospitalization No mortality advantage

Generally not recommended

Exception may be those in high risk

group esp. if unstable

Updates not for BOARDS but for clinical practice

JAC 57:176,2006 A 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 Typhilitis

Inflammatory process involving colon and/or small bowel ischemia, 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 therapy

Clostridium

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 Aspergillosis
Confirm with Biopsy Aggressive Antifungal Therapy

Voriconazole (Drug of Choice) Caspofungin FDA approved for Ampho and

Voriconazole refractory Aspergillus.

Case 1- Mr. Thomas

June 20th 2009 diagnosed AML June 21st 2009 R subclavian Hickman placed and Chemotherapy initiated Remission 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 stat

2- Vancomycin IV stat
3- CXR 4- Blood cultures-central and peripheral

5- Fluconazole IV stat

Cefepime and Vancomycin are initiated

Blood 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

A B C

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

Remember for boards

Do 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)

Conclusions
Febrile Neutropenia is a serious complication of chemotherapy Be vigilant for febrile neutropenia in chemotherapy patients Be vigilant for infection even when no fever Initiate EMPIRIC antibiotics immediately. Several treatment options depending on risk stratification.