Saima Abbas M.DInfectious 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 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…..

OR

If you are alert, you think…

Am I missing febrile Neutropenia???

What are the facts you need to know?

Does 38 C define febrile neutropenia?

What’s 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)

Don’t 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/mm³ 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/ mm³

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)

~20% patients with ANC <100 cells/mm³ with febrile neutropenia episodes have bacteremias.

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 chemoTx

•Mucositis2) In-dwelling catheters

• Cutaneous-IV portal3) Selective antiBx pressure

•Fluoroquinolones• Co-trimoxazole

4) Antacids•Promote oro-oesophageal colonisation with GPC

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

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 evaluationEnsure Hemodynamic Stability and No NEW

ORGAN DYSFUNCTION History

Underlying disease, remission and transplant status- spleen +/-

ChemotherapyDrug history (steroids, any previous antibiotics)Allergies

Focused Review of systems Transfusions

Can cause fevers Lines or in-dwelling hardware

Splenectomy

THINK Strep. Pneumoniae

Neisseria meningitidisHemophilus Influenzae

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 neutropeniaInvestigation 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 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 model

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

•No or Mild symptoms 5•Moderate symptoms 3•No Hypotension 5•No COPD 4•Solid tumour / 4 Haem malignancy (no fungal infection) •Outpatient 3•No dehydration 3•Age <60 yrs 2 LOW RISK=score>20

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

2. Carbapenem • Imipenem –Cilastatin• Meropenem

3. Anti –Pseudomonal PCN • Piperacillin- Tazobactam• Ticarcillin- Clavulanic acid

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 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

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 guideIDSA, 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 planned…cease 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 TransfusionsGranulocyte transfusions are not recommended for routine use.

Use of Colony-Stimulating FactorsUse of colony-stimulating factors is not routine but should beconsidered 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

hospitalizationNo mortality advantage

Generally not recommendedException 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 SepticumClostridium SordelliCover 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 stat2- Vancomycin IV stat 3- CXR4- Blood cultures-central and peripheral5- 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

What will you do next?

A Stop Cefepime

B Add G- CSF

C Continue Cepepime until ANC > 500 or a minimum of 7 days.

D 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.