GUIDELINES FOR MANAGEMENT OF NEUTROPENIC FEVER

A) DEFINITION

• Fever is defined as a temperature over 38 C on 2 readings within one hour or a single temperature determination of 38.5 C or greater.
• Neutropenia is defined as an absolute neutrophil count (ANC) < 1.5. In many outpatient situations it is not possible to determine whether the neutrophil count is dropping or increasing so using an ANC of < 1.0 to determine intervention is more practical.

B) BACKGROUND

• Most patients receiving chemotherapy experience reduction of platelet count, white blood cell count and hemoglobin as a result of depression of bone marrow function. The drop in blood counts tends to be maximal 12-16 days after chemotherapy and to recover within 21 days but can occur earlier and recovery can be delayed longer. In view of this, fever or other symptoms of infection occurring at any time in a patient on chemotherapy should prompt clinical evaluation and a blood count.
 
• Untreated febrile neutropenia carries a mortality of up to 20% whereas prompt evaluation and appropriate intravenous antibiotic therapy can reduce mortality to less than 2%. For this reason all patients receiving myelosuppressive chemotherapy need to be instructed carefully and repeatedly about the signs and symptoms of infection and the need to report for assessment promptly if they occur.

C) INITIAL ASSESSMENT OF THE PATIENT WITH FEVER AND A HISTORY OF RECENT CHEMOTHERAPY

1. Physical examination with evaluation of vital signs and examination of mouth, chest, skin and skin folds, sites of implanted venous access devices and perianal area (no digital rectal exams).
2. CBC, Electrolytes, Serum Creatinine, Liver Function studies.
3. Two blood cultures (1 Aerobic and 1 Anaerobic) taken twice, ½ hour apart. If a venous access line or port is present one of the blood cultures should be done through this device and so marked.
4. Urinalysis and midstream urine culture.
5. Swabs for C&S from clinically suspicious sites.
6. Sputum for C&S if obtained.
7. Chest X-Ray

Nb. ANTIBIOTIC TREATMENT MUST BE INSTITUTED QUICKLY AND NOT DELAYED TO OBTAIN CHEST X-RAY OR URINE SPECIMEN.

D) INITIAL TREATMENT OF NEUTROPENIC FEVER

1. Admission to hospital is indicated in most cases. (see G below). A private room is preferred, if available. There is no need for reverse isolation, dietary restriction or avoidance of plants or flowers in these patients. Strict hand washing by staff before touching patients is important however.
2. PROMPT (within 30 minutes) institution of intravenous antibiotic treatment;
• Ceftazidime 2 grams q8h IV is the most commonly recommended initial treatment.
• Penicillin allergy; in most cases, use of a cephalosporin antibiotic as advised will be safe. In the rare case where there is a major clinical concern about a severe reaction to a cephalosporin an appropriate alternate would be to give Imipenem 500mg q6h IV.
• Vancomycin 1gm q12h IV (adjusted for renal dysfunction if necessary) is added in certain situations;
• Severe sepsis.
• Presence of an indwelling intravenous line or port.
• Recent course of oral fluoroquinolone.
• Evidence of cellulitis or other infection suggestive of gram positive infection or a preliminary blood culture showing gram positive organisms.
• Severe orophayngeal mucositis.
• Documented carriage of Methicillin Resistant Staph. Aureus (MRSA)
3. Antipyretics should be used with caution as the fever pattern is an important part of monitoring of the course of these patients. If an antipyretic is indicated for patient comfort, an interval of at least 6 hours between doses should be observed.
4. Consultation with Internal Medicine if needed.
5. Inform Cancer Clinic of admission within 24 hours, earlier if any concerns.

E) CONTINUING MANAGEMENT OF PATIENTS WITH NEUTROPENIC FEVER

1. Intravenous antibiotics should be continued until the patient has been afebrile at least 48 hours and ANC is above 1.0 (or >500 and rising).
2. Blood cultures are positive in about 25% of cases. If organisms resistant to the initial antibiotic treatment chosen are detected, alteration of antibiotic may be indicated, especially if the patient is still febrile and ANC remains low. In patients with positive blood cultures, continued antibiotic treatment for 10 days is recommended; in a clinically stable patient this course can be completed using oral antibiotics as an outpatient.
3. Patients who do not show reduction of fever after 72 hours of treatment or who are clinically unstable require reevaluation. In most cases specialist consultation should be sought.
4. The use of granulocyte colony stimulating factors (GCSF, eg Neupogen) has been shown to be effective in reducing duration of neutropenia but not to change outcome. The use of GCSF is not recommended for routine use in febrile neutropenia.

F) DISCHARGE FROM HOSPITAL

1. A patient who is clinically stable, has been afebrile for 48 hours and who has an ANC >1.0 (or >500 and rising) can be discharged home. In some cases (e.g. frail elderly, concomitant illness, distant residence) observation of the patient for 24 hours in hospital after discontinuing antibiotics might be indicated.
2. Continued use of oral antibiotics at home is not indicated, with the exception of the situation described in E2 above.
3. It is important that the patient have a follow up appointment arranged, usually with the Cancer Clinic.

G) OUTPATIENT ORAL ANTIBIOTIC TREATMENT

Outpatient oral antibiotic treatment of febrile neutropenia can be considered in cases where the following criteria are met;

• A.N.C. is over 0.5 and the chemotherapy was for treatment of a solid tumor (ie not a hematologic malignancy, a lymphoma or part of a transplantation regimen).
• The patient is clinically stable and does not show hemodynamic compromise.
• The patient is evaluated to be reliable and able to comply with treatment, to follow up as requested and to return to the hospital if the medical condition deteriorates.

Oral Ciprofloxacin 500 mg q12h + amoxicillin/Clavulanate 500mg q8h is an appropriate regimen. In cases of penicillin allergy, Clindamycin 450 mg q8h is substituted for Amoxicillin/Clavulanate.

In all cases when a patient with neutropenic fever is sent home on oral antibiotics a follow up evaluation should be done 24 hours later by a nurse or physician at the emergency Department or the Cancer Clinic.

Criteria for continuation/discontinuation of oral antibiotic treatment in neutropenic fever are the same as those for inpatient intravenous antibiotic treatment programs.

H) PREVENTION OF NEUTROPENIC SEPSIS

• The great majority of infectious agents responsible for febrile neutropenia come from the patients own body (oropharynx, bowel, bladder, skin) and only rarely is acquisition of a pathogen from outside the problem. Thus, patients on chemotherapy are not required to practice extreme isolation measures such as avoidance of crowds and social gatherings, avoidance of contact with children, dietary changes, etc. Obviously, caution in contact with clinically infected persons should be encouraged. Usual hygienic practices such as regular hand washing are important.
• The use of prophylactic antibiotics has not been found to be particularly useful and is not recommended routinely. Prompt treatment of infections such as bacterial cystitis is important.
• Dental work should be avoided during periods of neutropenia. Dental work which cannot be deferred requires antibiotic prophylaxis.
• The use of a granulocyte colony stimulating factor (eg. Neupogen) to avert prolonged or severe neutropenia is considered in certain cases to allow full dose intensity of curative chemotherapy or to prevent neutropenic fever in patients in whom there is a great risk of such an event. In the majority of cases use of these agents is not recommended however.

- Dr. John Jensen

Thanks to Dr. Mark Doreen, Medical Oncologist at the QE 2 Health Sciences Centre in Halifax, Nova Scotia for reviewing the draft copy of this article.

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