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.