Management of neutropenic fever in

cancer patients

Dr. Hamdy M. ZawamProfessor of Clinical OncologyNEMROCK Cairo University

Risk of Infection in Cancer PatientInfection is a major health

problem in cancer patients :1. Mortality : 40,000 adult cancer patients

treated in large US hospitals : MR 9.5% MR: 21.4% in patients with more than

one comorbidity2. Morbidity3. Cost 4. Treatment results

(Kuderer, et al., Cancer 2006,106:2258)

Factors predisposing to infection in cancer patients:

A) Tumor related factors:1) ↓ Immunity with hematological

tumor:BM infiltration e.g. leukemia, lymphomaHypogammaglobinemia e.g. MM, CLLImpaired cellular immunity e.g. HL, HCL

2) Solid tumorsOvergrowing blood supply → necrosis &

infectionCompression

Post-obstructive pneumoniaGUT or hepatobiliary obstruction by abdominal tumors

B) Therapy-related:1) BM exhaustion (Multiple lines of ttt).2) Post-op complication for solid tumor surgery.3) Disruption of mucosal barriers by CTX or RTH.4) Functional asplenia → splenectomy, RT, GVHD.5) High dose steroids → ↓ neutrophils.6) Lymphocyte depleting agents:

Fludarabine → viral & opportunistic infection Alemtuzumab → CMV Rituximab → PML, HBV reactivation Bortezomib → HZV reactivation

Neutropenia

Neutropenia Major risk factor for serious infections.The lower limit of neutrophils =

2000/mm3

Neutropenia criteria:

Profound neutropenia : ANC >100 cells/mm3

Facilitates bacterial and fungal infections.Blunts inflammatory response allowing

infection to progress much faster

Grade I II III IVCount

per mm3

1500-2000

1000-1500

500-1000

<500

Neutropenia Grade + Duration + Associated comorbiditiesDuration : the risk of fungal

infection increases with the duration of neutropenia

Other factors : why?

( Kruderer, et al., 2006)

Risk of Infection Category In Cancer Patient

Category Low Intermediate High

Expected period of neutropenia

< 7 days 7-10 days > 10 days

Disease/ Therapy

Standard CTX for solid tumors

o Autologous SCT

o Lymphomao Multiple

myelomao CLLo Purine

monotherapy

o Allogenic SCTo Acute Leukemia:

• Induction• Consolidatio

no Purine

combinationo Alemtuzumab

Prophylaxis Against Infection

The most important issue is: How to prevent infection?

1)ANTIBACTERIAL PROPHYLAXIS:

a) Fluoroquinolones ( FQL): The most commonly used in adult patients . In a meta-analysis that evaluated 18 trials

(N=1408): FQL (ciprofloxacin) significantly reduced the

incidence of Gram-negative infection (RR=21%;95% CI, 0.12-0.37)

FQL prophylaxis did not affect : Infection related mortality Rate of Gram +ve and fungal infections Viridans group streptococcal bacteremia breakthrough have been associated with ciprofloxacin prophylaxis.

(Bucaneve et al )

b) Levofloxacin Used in patients with intermediate

to high risk for neutropenia .Levo recepients had lower rate of

microbiologically documented infections, bacteremias, and single-agent Gram -ve bacteremias than placebo group .

(Bucaneve et al )

c) Prophylaxis for Pneumocystis jirovecii (carenii)

ALL (1) Alemtuzumab (1)Recipients of purine analog therapy

(2B)Recipients of prolonged

corticosteroids or temozolomide + RT (2B)

NCCN for Antibacterial Guidelines :FQL prophylaxis (Levo is

preferred) for patients with expected duration of neutropenia ( ANC <1000) for more than 7 days .

TMP/SMX for patients at risk for P.Jirovecii

(When selecting antimicrobial agent for prophylaxis, consideration should be given to the local susceptibility and resistance patterns of pathogens)

2) Antifungal prophylaxisIndications for antifungal prophylaxis:

i. ALL → Fluconazol.ii. MDS → Posaconazol, or Fluconazol.iii. AML → Posaconazol, or Floconazol.iv. Autologus SCT with mucositis until

resolution of neutropenia.v. Secondary prophylaxis in patients

with prior fungal infection.

Should not be used routinely in all patients with neutropenia

Prophylaxis with posaconazol, Itraconazol and voriconazol should be avoided in patients receiving vinca alkaloid–based regimens:Inhibition of P450 3A4 isoenzyme

reduce the clearance of vinca alkaloids and can produce severe neurotoxicity.

3) Antiviral ProphylaxisHepatitis B Virus

Reactivation of latent HBV may occur in the setting of significant immunosuppression.

HBV carries with lymphoid malignancies, especially those treated with anthracyclin–based regimens, have a high risk of HBV reactivation.

Anti CD 20 monoclonal antibodies may have increased risk of HBV reactivation and rare instances of fulminant hepatitis or death.

Routine surveillance for HBV DNA and antiviral prophylaxis with lamivudine (or preemptive therapy upon detection of high levels of HBV s Ag or positive HBV DNA load): recommended in HBsAg-positive or

HBcAb-positive patients wit hematologic malignancies

Prophylaxis With Hematopoietic Growth FactorsHGFs should only be used for primary

prophylaxis of chemotherapy-induced neutropenia in the following situations:1. Risk of FN ≥20%2. Patients with reduced marrow reserve due

to radiotherapy of >20% of marrow.3. HIV+ve.4. Patients aged ≥65years treated with

curative regimens.5. When a reduction in the dose of

chemotherapy is deemed detrimental to outcome.

Caution with HGF:Primary prophylaxis with G-CSF is not

indicated during chemoradiation of the chest due increased of BM suppression associated with increased risk of complications and death.

HGFs should not be given immediately before or with chemotherapy.

Should not be used in patients with infection not related to neutropenia.

Secondary prophylaxis HGF can be used for secondary prophylaxis of FN in the following situations:

1. When it is anticipated that further infections during the next cycles could be life threatening.

2. When the reduction in chemotherapy dose required to avoid neutropenia is below the efficacy threshold.

3. Lack of protocol adherence that compromises cure rate, OS ,or DFS.

Environmental precautionsHand hygiene is the most effective

means of preventing transmission of infection

Standard barrier precautions should be followed for all patients

Plants and dried or fresh flowers should not be allowed in the rooms of hospitalized neutropenic patients

Special precautions for transplant recipients .

Neutropenic Fever

Definition of Neutropenic Fever An absolute neutrophil count <500 or <1000 with a predicted rapid

decline to 500 within 48 hrs+

A single oral temperature >38.3̊ C or 38̊ C persistent for >1 hr

Risk StratificationThe Multinational Association for Supportive Care (MASCC) index

Score >21→ low risk of complication Score <21→ high risk of complication Maximum theoretical score of 26 One of the major drawbacks of MASCC is “Burden of illness“

Characteristic Score

Burden of illness: no or mild symptoms 5Burden of illness: moderate symptoms 3

Burden of illness: severe symptoms 0No hypotension (systolic BP >90 mmHg) 5

No chronic obstructive pulmonary disease 4Solid tumor/lymphoma with no previous fungal

infection4

No dehydration 3Outpatient status (at onset of fever) 3

Age <60 years 2

Other Risk Factors For Febrile Neutropenia

This risk model was based on 1246 patients with NHL: Age > 65 Albumin < 3.5 Baseline ANC < 1500 Hepatic disease Relative dose intensity

(e-eso.net/home.do.Sue Mayor)

APACHE 2 score and MR in 48 patients with febrile neutropenia (NEMROCK)

Score Patients Mortality N %

0-4 1 0 05-9 4 0 0

10-14 5 0 015-19 21 1 420-24 11 5 4525-29 6 5 83

NCCN Guidelines for risk assessment in febrile neutropenia HIGH RISK : (any factor listed below)

Inpatient status at time development of feverSignificant medical comorbidity or clinically

unstableAnticipated prolonged sever neutropenia (< 100 cell /mcL and >7 d )Hepatic insufficiency (5 times ULN of ALT/AST)Renal insufficiency (Cr. Clearance < 30 ml;m)Uncontrolled /progressive cancer.Pneumonia or other complex infection Alemtuzumab therapyMucositis grade 3-4 MASCC Risk Index less than 21

Do we need more criteria ?

Infectious Diseases Society of America (IDSA): Mucositis grade 3-4:

Oral or GIT mucositis that interfere with swallowing or cause sever diarrhea

Neurological or mental-status: Changes of new onset.

Intravascular catheter infection: especially tunnel infection.

(Clinic. Infect. Diseases 2011:52 , Freifeld, et al. )

WORKUP

A) History:Type of malignancy (hematological or

not).Symptoms of infection focus : (GIT/GUT/respiratory/skin /CNS)Previous CTX (time & type) or RTH (time & site)Previous antimicrobial ttt.Previous splenectomy.Previous neutropenia.

B) Examination:Vital signs.Local exam: Oral cavity/ perianal region/ skin &

catheter site. PR: Contraindicated as it may lead to spread of infection ± bleeding)

C) Laboratory:

Routine: CBC/ KFT/ LFT/ electrolytes/ blood glucose/ bleeding profile

Urine & stool analysis (if indicated)

D) Cultures:

i. Blood: 2 sets, preferably 1 peripheral & 1 central to

distinguish catheter-related infection from 2ry sources

ii.Sputum: If patient has productive cough, BAL for infiltrate with uncertain etiology, Nasal wash or BAL for RV.

D) Cultures (cont.)iii. Urine if:

Symptomatic Urine catheterization Abnormal urine analysis

iv. Stool: In patients with diarrhea, stool specimen

is evaluated for Clostridium difficile toxin assay.

v.Skin & mucous membrane: Bacterial: aspiration or bx from skin lesion, or swab

exit site drainage. Viral: from vesicular or ulcerative lesion.

E) Imaging:

Chest X-ray

CT Chest

CT Paranasal SinusesIf invasive Aspergillosis is suspected (sinus tenderness, periorbital cellulitis, nasal obstruction, history of fungal chest infection)

CT Abdomen/Pelvis:If abdominal pain ( to exclude necrotizing enterocolitis)

CT/MRI Brain:If CNS symptoms (+ CSF exam if possible)

Management of Neutropenic fever

Definitive TreatmentFactors influencing initial ttt: MASCC score. Hemodynamic stability. Vancomycin indication. Site of infection. Local antibiotic susceptibility

pattern. Organ dysfunction & drug

allergies.

Management of low risk patients A. Criteria

MASCC score >21 PS ≤1 No co-morbidities Anticipated neutropenia <7 days Creatinine ≤2mg/dL & LFT ≤3x

normal Must be able to tolerate oral ttt Not on prior quinolone prophylaxis

B. Drugs: ◦ ciprofloxacin 750mg q12hrs + amoxicillin-

clavulanate 1gm q12hsC. Consider inpatient ttt for the 1st 2-24

hrs. to confirm low risk status & observe 1st administration & any reaction.

D. Follow-up pt. every 2 days by phone & weekly at outpatient clinic unless:◦ New symptoms/signs◦ Persistent/ recurrent fever◦ +ve culture◦ Drug intolerance

Management of High Risk groupIf the patient is hemodynamically stableA. Start empiric therapy with a single agent broad spectrum IV

antibiotic (according to local antibiogram) such as:1) Ceftazidime (Fortum):

Many centers have found that ceftazidime is no longer a reliable agent for empirical monotherapy of febrile neutropenia.

Decreasing potency against gram-negative organisms and its poor activity against many gram-positive pathogens.

2) Cefepime (Maxipime)

Effective in CNS infection Avoid if Gm-ve infection is suspected

3) Imipenem/cilastatin (Tienam) Adjust dose in renal impairment & CNS disease.

4) Meropenem (Meronem) Effective in nosocomial pneumonia & intra-

abdominal infection.5) Pipracillin-tazobactam (Tazocin)

May result in false +ve galactomann test Limited effect if P. aeroginosa or Extended

Spectrum B-Lactamase infection is suspected (Carbapenems are preferred) Preferred in cases associated with

thrombocytopenia

B. Indications for addition of antibiotics active against gram-positive organisms:

1) Colonization with +ve for MRSA, VRE, or penicillin-resistant strptococcus pneumonia.

2) Blood culture positive for Gm +ve bacteria.

3) Hemodynamic instability or other evidence of sever sepsis.

4) Catheter or soft tissue infection, sever mucositis, FQL prophylaxis.

Modifications to initial empiric therapy

MRSA (methicillin resistant staph. aureus):◦Early addition of vancomycin, linezolid, or

daptomycin VRE (vancomicyn-resistant enterococcus):

◦ linezolid, or daptomycinESBLs (extended spectrum B-lactamase):

◦Consider early use of carbapenems.KPCs (K lebsilla pneumoniae

carbapenemase): ◦Consider early use of polymyxin-colistin or

tigecycline.

C. Modify initial empiric ttt in the following clinical situation

1) If oral vesicular or ulcerative lesion → add antiviral ttt: Acyclovir.2) If oral thrush → add fluconazole (voriconazole in resistant cases)3) If odynophagia & retrosternal burning → consider Candida or HSV4) If infected central venous catheter:

Exit site cellulitis → add Vancomycin Tunnel infection→ Vancomycin lock for 24 hrs. + remove catheter if persistent infection Catheter-associated bacteremia → add appropriate antibiotic + remove catheter

5. If periorbital cellulitis → add Vancomycin (± Amphotericin B if suspicious CT finding of aspergillosis)

6.If lung infiltrates are present → add a fluoroquinolone to cover atypical bacteria

7.If Clostridium difficile is suspected → add metronidazole8. If encephalitis is suspected → add high dose acyclovir with adequate hydration & renal function monitoring

Treatment modification for non-respondersA. Persistent fever after ANC recovery:

Consider disseminated candidiasis → for Fluconazole or Itraconazole

B. Persistent fever with neutropenia:1.Modify antibiotic regimen:

If ceftazidime was used initially shift to carbapenem & add aminoglycosides

If carbapenem was initially used switch to pipracillin-tazobactam & add aminoglycoside & co-trimixazole

Modify according to results of culture & sensitivity while maintaining Gm-ve coverage

2) Persistent spiking fever for 4-7 days → add antifungal

A. Amphotericin B: Renal & electrolyte toxicity maybe

reduced by fluid infusion & electrolyte replacement (esp. K+)

Allergic reaction maybe treated by antipyretics & antihistaminics

Caution : Amphotericin B + aminoglycoside = potential nephrotoxic combination, so either:i. Hydrate the patient appropriately &

monitor serum creatinine dailyii. Add quinolone instead of aminoglycoside

B. Voriconazole : 6mg/ kg q12hrs for 2 doses then 4mg/ kg

q12hrs or switch to 200mg q12hrs PO Weak action against zygomycosis IV form used in caution with renal

insufficiency In patients with moderate or severe renal

impairment (creatinine clearance < 50 mL/min) Oral Voriconazole is preferred

3) Signs of breakthrough sepsis (↓↓ BP, ↓↓urine output, rigors) → ttt as septic shock.

If the patient is hemodynamically unstable1) Fluid resuscitation.2) Vasopressors & oxygen.3) Prompt administration of broad spectrum

I.V. antimicrobials:a. Vancomycin +b. Carbapenem (imipenem or meropenem) + c. Aminoglycoside + d. Antifungal ( Amphotericin B or voriconazole)

4) Stress dose steroids:a. Hydrocortisone → 50mg q6hrs IV +b. Fludrocortisone →50 µg OD PO

Timing of ttt discontinuation for responders with known site of infection:

A. Bacterial Skin/ soft tissue: 7-14 days Pneumonia/ sinusitis: 10-21 days Blood

Gm-ve: 10-14 days Gm+ve: 7-14days ( for S.aureus → at least 2 wks after

1st –ve blood culture)B. Fungal

Candida: at least 2 wks after 1st –ve blood culture Molds (e.g. aspergillus): at least 12 days

C. Viral HSV/ VZV: 7-10 days Influenza: 5 days ( 10 days for high risk patients)

Drug Interaction

1. Amphotericin B + vancomycinpotential nephrotoxic & neurotoxic combinationrenal, auditory and vestibular function, and

serum drug concentrations should be monitored

2. Aminoglycosides + vancomycin additive nephrotoxic or neurotoxic effects. renal function and serum drug concentrations

should be monitored. switching aminoglycosides to quinolones is an

option

Drug Interaction (continued)

3. Amphotericin B + corticosteroidsIncreased risk of hypokalemia (esp. with

fludrocortisone)Potassium supplementation may be

necessary. Patients should be advised to notify their

physician if they experience signs of electrolyte disturbances such as weakness, lethargy, muscle pains or cramps

Thank You