# Fever and Neutropenia: March 6, 2008

# 

# Neutropenia

ANC Less than 500 neutrophils and/or band forms /mm3 or an absolute
neutrophil count between 500 -1000/mm3 which is anticipated to fall to
\< 500/mm3 within 24 hours.

# 

# Non neutropenic fever:

# 

Non-neutropenic (with line or hardware)

Single fever \> 38.5C (101.3F)

or x 2 \>=38C (100.4F) 4 hr apart

With line no source Ceftriaxone rotate lines

I.V Ceftriaxone: 50-75mg/kg qd (or can be divided BID)

If limb prosthesis add Vancomycin

Pneumonia: Broncoscopy if immunosuppressed and Ceftriaxone and
Azithromycin.

**[Fever without Neutropenia early engraftment (31-100
days)]{.underline}**

Consult with ID:

First line Ceftazadime +/- Vancomycin (catheter related infection)

# Fever with neutropenia 

Two oral temperatures above ≥ 38C (100.4F) 1hr apart, or any temperature
≥ 38.3C (101F). Or if clinically indicated and no fever.

Other Indications: Pain, severe mucositis without fever.

Pneumonia: Broncoscopy if immunosuppressed and Ceftriaxone and
Azithromycin.

**[1^st^ Line Treatment]{.underline}**

IV ceftazidime and modifications as clinically indicated.

If limb prosthesis add Vancomycin

Known allergy to β-lactams , treat with IV aztreonam and vancomycin.

# Rescue Regimens

**Indications:** hypotension, positive follow-up cultures at 48h, or
abdominal pain

Currently CC recommendations: Meropenem 20mg/kg IV every 8hrs Max 2g
every 8 hrs

**and** Tobramycin: 6 mg/kg/d q8h in 3 divided doses **and** Vancomycin:
1gm q 12h in patients ≥ 50 kg 40mg/kg q6h in patients \< 50 kg

When aminoglycoside renal toxicity is a significant concern,
levofloxacin (preferred to cipro according to CC Microbiology
susceptibility testing) may be substituted for tobramycin.

**Alternatively:**

Imipenem: 50 mg/kg/d q6h in all patients

**and** Tobramycin 6 mg/kg/d q8h: DOSE see below

NOTE: Any patient who is allergic to β-lactams and/or presents with
neurological signs/symptoms or sensitivity to imipenem will be placed on
an alternate rescue regimen of aztreonam, vancomycin and Tobramycin.

# Alternate Rescue Regimen Dosages for Imipenem intolerant patients

Aztreonam: 200 mg/kg/d q6h in 4 divided doses in all patients

Vancomycin: 1gm q 12h in patients ≥ 50 kg 40mg/kg q6h in patients \< 50
kg

Tobramycin 6 mg/kg/d q8h

**[Febrile on or after day 4-7:]{.underline}**

Patients who have persistent or recrudescent fever on or any time after
day 4-5 will be empirically started on Ambisone (avoid with
cyclosporine) or Caspofungin (has not been studied as initial therapy
for invasive aspergillosis) or Voriconazole.

Note: Caspofungin can be used in patients with liver impairment caution
with cyclosporine. I.V Voriconazole avoided if creatinine clearance
\<50ml/min due to carrier toxicity. Voriconazole and rapamycin
(sirolimus) potential interactions due to same metabolic pathway

Voriconazole effective against all fungal infections

**Specific Modifications of Therapy**

1.  Clinical instability and/or hypotension ≥ 20 mm Hg below baseline.
    Switch to Rescue Regimen of imipenem (or meropenem) and Tobramycin
    or other combination broad spectrum regimen as deemed appropriate by
    the responsible physician in consultation with the PI or protocol
    chairperson.

2.  Persistent or Recrudescent Fever

    a.  Days 1-4: No therapy modification unless there is evidence of
        progression of, or new infection.

    b.  Day 5+ or beyond: Institute empiric antifungal for any fever
        present on day 7 or occurring at any time there after.

3.  Documented Infection with resolution of counts prior to completing
    defined course of study drug

Patients with documented infections who have recovered their neutrophil
count, are afebrile, and showing improvement in their documented
infection ( i.e. repeated cultures are negative, other clinical signs of
improvement) may be discharged on outpatient.

# Indwelling Line Infections

1.  **Line-related Bacteremias.**

There is no expert consensus regarding the definition of line related
infection. Bacteremia in the presence of an indwelling venous catheter
or port is, however, sufficient cause to imply that a catheter related
source cannot be ruled out. The following characteristics of the
infection may help to more clearly incriminate the catheter or port.

• A positive line or port culture but a negative peripheral culture, or
a delay in becoming positive compared to line culture.

• A positive culture from only one port of a multi-lumen line.

In order to most effectively evaluate these infections emphasis must be
placed on blood culture information. Both peripheral and line blood
cultures most be obtained at 48 hours post initiation of primary therapy
or therapy modifications regardless of the patients fever status. If the
cultures are positive, the line or device should be removed as long as
the following information has been validated:

a.  Antimicrobials are being administered on a therapeutic schedule to
    all ports of a multi-lumen line.

b.  The antimicrobial agent being used has therapeutic activity against
    the isolate in question.

c.  The patient is receiving therapeutic levels of the current agent.

**Antimicrobial management:** Line-related bacteremias require
intravenous antibiotic therapy through all lumens of the line, in a
rotating fashion. Appropriate therapy will be as follows:

a.  Gram negative line related infections - Ceftazidime + aminoglycoside

b.  Gram positive line related infections - Add vancomycin

> NOTE1: Follow-up blood cultures taken at 48 hours post initiation of
> therapy are required for all line infections. If positive, line is
> pulled. Also, Bacillus species positive blood cultures may result in
> line removal.
>
> NOTE2: Antibiotic lock (c.f hep lock) are being used for proven line
> infections.

2.  **Yeast Positive Blood Cultures**

Yeast positive blood cultures, even a single colony, is considered a
serious indication for line removal. Staph aureus line infection strong
indication for removal, discuss with ID and PI.

**Tunnel infections**

**Definition:** Erythema and or pain along a tunneled VAD of \>2cm in
size.

**Antibiotic Management:** Present at onset of fever and neutropenia -
ceftazidime and vancomycin.

Guidelines for Line Removal in tunnel infections:

• Mild symptoms - (Mild tenderness and/or erythema over tunnel) Observe
for 24-48 hours to assess therapy response, if inadequate response,
remove line.

• Severe symptoms - (Moderate to severe tenderness and/or erythema over
tunnel) Remove line in conjunction with above recommended antibiotic
therapy.

NOTE: The use of vancomycin as additional empiric antibiotic support is
based upon statistics showing that approximately 75% of these line
related infections are caused by staph species. Caution must be taken to
review all associated culture results and to modify therapy as indicated
by sensitivity patterns.

3.  **Exit Site Infections: (\<2cm)**

Symptoms of erythema, tenderness and/or discharge around a line
insertion site.

• If there is no local response within 24 hrs of therapy initiation and
no positive cultures from the site, add vancomycin empirically.

• If there is no local response within 24 hours of ceftazadime therapy
initiation but, positive cultures from the site have been identified,
review sensitivity patterns and modify therapy appropriately.

# Bacteremia

1\. Pre-antibiotic cultures positive

If the patient is stable, positive pre-antibiotic blood cultures are not
indicative of line-related infection, and isolates are susceptible to
Ceftazidime. Clinical deterioration at any point (as judged by the
protocol chairperson or PI) will be treated with rescue regimen of
Meropenem, Vancomycin and Tobramycin (see above)..

If pre-antibiotic isolates are not susceptible antibiotic therapy if
indicated by organism sensitivity patterns.

2\. Persistent or new bacteremia occurring in patients already receiving
antibiotics

Evaluate current therapy dosage and administration history and organism
sensitivity patterns, make therapy modifications in conjunction with ID.

# Abdominal Focus of Infection

1.  **Abdominal pain/peritoneal signs/abscess**

Switch to intravenous rescue regimen of combinational broad-spectrum
therapy of Imipenem (or meropenem) and Tobramycin.

2.  **Peri-rectal disease**

Mild to moderate signs of peri -rectal disease at the onset of fever and
neutropenia -- Consider antibiotics.

Severe peri-rectal disease at the outset of fever and neutropenia or if,
after 24 to 48 hours, there is no improvement on study drugs - Modify
study drug therapy regimen by adding Metronidazole .

Peri-rectal infections are qualified as follows:

• Mild: tenderness alone

• Moderate: tenderness with erythema

• Severe: induration and/or fluctuance

NOTE: CT scan often performed with severe symptoms to rule out
perirectal abscess.

3.  **Diarrhea**

Diarrhea will be routinely evaluated for the presence of pathogens and
for Clostridium difficile toxin. Patients with stools positive for C.
difficile will begin oral metronidazole (iv metronidazole can be given,
efficacy not proven). If other stool pathogens are isolated, they will
be treated accordingly.

4.  **Pulmonary infiltrates**

Pulmonary infiltrates at onset of fever and neutropenia - Treat with
ceftazidime and additional therapy as indicated based upon cultures
obtained from sputum and/or bronchoalveolar lavage.

Treat diffuse infiltrates or infiltrates suspicious for an \"atypical
pneumonia\" with the addition of trimethoprim-sulfamethoxazole with or
without erythromycin until a definitive diagnosis is made by
bronchoscopy.

5.  **Intra-oral lesions**

Mucositis is a common side effect of many chemotherapy regimens.
Mucositis can be complicated by reactivation of Herpes simplex or by
superinfection with Candida albicans. Cultures for these agents should
be performed in all patients presenting with mucositis, and in all
patients with discrete intra-oral lesions (white plaques may represent
either H. simplex or C. albicans - only culture will distinguish.)

Severity of mucositis will be based on CTEP and drugs will be modified
as follows:

• grade 1-2: culture directed addition of oral or intravenous acyclovir,
or clotrimazole troches

• grade 3-4: addition of IV metronidazole or clindamycin

\` Necrotizing gingivitis, caused by oral anaerobes, is a specific
entity characterized by a discrete line of erythema at the gumline. The
development of this problem will require the institution of intravenous
metronidazole.

NOTE1: Meropenem is an alternative initial therapy for F&N and evidence
of musositis.

6.  **Esophagitis**

Symptoms of dysphagia progressing to odynophagia (pain when swallowing)
may represent progressive mucositis due to chemo or radiation therapy,
or may be of an infectious etiology. Since Herpes simplex and Candida
albicans are the most common infectious etiologies of esophagitis in the
neutropenic patient, empiric coverage for one or both of these may
become necessary if symptoms of esophagitis develop. Cytomegalovirus and
Staphylococcus aureus are less common causes of esphogitis in this
setting. Esophagoscopy and biopsy is discouraged in the neutropenic
patient due to the potential for serious complications from this
invasive procedure. The decision to place a patient on antimicrobial
therapy for esophagitis is a clinical judgment based upon culture data
as well as knowledge of the common side effects of prior chemotherapy.
(Some regimens commonly produce mucositis).

7.  **Herpesvirus infections**

Herpes simplex : Mucocutaneous herpes simplex infections should be
documented by culture, if possible (esophagitis may be the exception)
and treated with either oral acyclovir at 400 mg 5 times daily or
intravenous acyclovir at 250 mg/m2 every 8 hours.

Herpes zoster : Chickenpox or zoster, due to herpes zoster virus, should
be treated with intravenous acyclovir at 500 mg/m2 every 8 hours in
neutropenic patients.

# Cellulitis

If cellulitis is unresponsive to empiric antibiotic therapy within 24
hours, patient will be switched to Imipenem (or meropenem) and
Tobramycin.

**[Bacterial infections requiring specific antibiotic
modifications.]{.underline}**

1.  Coagulase negative staphylococci - bacteremia due to Coagulase
    negative staphylococci are defined as 2 blood cultures from any
    sites positive in the setting of fever and neutropenia, or one
    positive blood culture from a line. The majority of Coagulase
    negative staphylococci isolates in the Clinical Center are resistant
    to β-lactam antibiotics and, thus, intravenous Vancomycin should be
    instituted.

2.  Methicillin-resistant staphylococcus aureus - infections due to
    methicillin-resistant S. aureus require intravenous Vancomycin and
    isolation of the patient.

3.  Corynebacterium JK - most commonly associated with line infections,
    this organism must be treated with intravenous Vancomycin (1 gram q
    12 hr).

4.  Acinetobacter, Enterobacter, Citrobacter, Serratia, Pseudomonas
    aeruginosa - Bloodstream infections due to these organisms will
    require treatment with intravenous Ceftazidime or Imipenem (or
    meropenem) , plus an aminoglycoside to reduce the incidence of
    resistance.

5.  Non-aeruginosa pseudomonads - Stenotrophomonas (Pseudomonas)
    maltophilia and P. cepacia are typically resistant to the
    anti-pseudomonal (aeruginosa) drugs employed, but are generally
    sensitive to trimethoprim-sulfamethoxazole (or newer quniolones e.g.
    levofloxacin or moxifloxacin). Suspected or confirmed infections due
    to the non-aeruginosa pseudomonads should be treated with
    trimethoprim-sulfamethoxazole until sensitivities are available.

    i.  Clostridium difficile diarrhea - should be treated initially
        with oral metronidazole.

**[Fungal infections (blood, visceral)]{.underline}**

**[Antifungals]{.underline}**

Patients who have persistent or recrudescent fever on or any time after
day 4-5 will be empirically started on Ambisone (avoid with
cyclosporine) or Caspofungin (has not been studied as initial therapy
for invasive aspergillosis) or Voriconazole.

Note: Caspofungin can be used in patients with liver impairment caution
with cyclosporine. I.V Voriconazole avoided if creatinine clearance
\<50ml/min due to carrier toxicity.

Coadministration of voriconazole and sirolimus (Rapamycin) is
contraindicated. **Probable Mechanism:** inhibition by voriconazole of
cytochrome P450 3A4-mediated sirolimus metabolism. Increased level of
Sirolimus causes HUS, stroke

Voriconazole effective against all fungal infections

1.  Oral or esophageal Candida may be initially treated with
    fluconazole, but may require Ambisome OR Caspofungin OR Voriconazole
    for refractory disease.

2.  Bloodstream infections due to Candida species require removal of any
    indwelling catheters and Caspofungin OR Ambisome OR Voriconazole

3.  Hepatosplenic candidiasis is treated with Ambisome OR Caspofungin OR
    Voriconazole for a prolonged course and for a total of at least 2
    grams, until radiographic and/or biopsy evidence of infection are
    completely resolved.

4.  5-FC (5-fluorocytosine) is added to Amphotericin B for treatment of
    cryptococcal meningitis and for bloodstream infections due to C.
    tropicalis.

5.  Aspergillus infections should be confirmed by biopsy and treated
    with Ambisome OR Voriconazole (Caspofungin has not been studied for
    initial therapy, but can be used in patients who are refractory or
    intolerant to other antifungals).