eMedicine Specialties > Hematology > Immune System and Disorders

Granulocytopenia: Treatment & Medication

Author: Kush Sachdeva, MD, Southern Oncology and Hematology Associates, South Jersey Healthcare, Fox Chase Cancer Center Partner
Contributor Information and Disclosures

Updated: Apr 8, 2009

Treatment

Medical Care

  • Discontinue drugs if they are suspected as the causative agents of neutropenia.
  • Corticosteroid therapy could be effective in immune-mediated neutropenia.
  • Correct nutritional deficiency (cobalamin or folic acid deficiency) if detected.
  • Treat the fever as an infection, as follows9,10,11,12,13,14,15,16,17 :
    • Third-generation cephalosporins (eg, ceftazidime, cefepime) or imipenem-cilastatin and meropenem can be used as a single agent.
    • Gentamicin or another aminoglycoside should be added if the neutropenic patient's condition is unstable or the individual appears septic.
    • Beta-lactam antibiotics (eg, ticarcillin, piperacillin) are usually used in combination with a third-generation cephalosporin or an aminoglycoside.
    • Vancomycin should be added if methicillin-resistant Staphylococcus aureus or Corynebacterium species is suspected.
    • If the neutropenic patient's fever does not respond within 4-5 days or if the fever recurs with the administration of broad-spectrum antibiotics after an initial afebrile interval, consider adding empiric antifungal coverage with amphotericin B (preferably lipid formulation), a broad-spectrum azole (eg, voriconazole), or an echinocandin (eg, caspofungin).
  • Fever in patients with low-risk neutropenia can be treated on an outpatient basis with oral antibiotics. In some studies, low-risk patients have been defined as patients whose cause of neutropenia is known; who are hemodynamically stable; who have an expected duration of neutropenia of less than 7 days, whose tumor is under control; and who are without any comorbid conditions, nausea, vomiting, or mucositis. Fluoroquinolones (eg, ciprofloxacin, ofloxacin) are oral antibiotics that are used frequently, either alone or in combination with amoxicillin-clavulanate or clindamycin.
  • Myeloid growth factors, granulocyte colony-stimulating factors (GCSFs), and granulocyte-macrophage colony-stimulating factor (GM-CSFs) can be used in an attempt to shorten the duration of neutropenia in patients who have received chemotherapy. GCSFs are lineage-specific for the production of functionally active neutrophils, and they can also be used for patients with severe, chronic neutropenia. GM-CSFs simulate the production of neutrophils, monocytes, and eosinophils. Filgrastim and pegfilgrastim are examples of GCSFS; sargramostim is an example of a GM-CSF. Usually, these agents are administered no sooner than 24 hours after chemotherapy completion.
  • Neutrophil (granulocyte) transfusion, although disappearing from clinical practice, has some clinical usefulness in treating neonatal sepsis. Its use in adults with neutropenia, in whom adequate increments of WBC counts are difficult to achieve, has not been demonstrated in randomized clinical trials.31 Granulocyte transfusion could be considered in cases of gram-negative sepsis with no improvement in 24-48 hours.
  • Cyclic neutropenia patients have recurrent mouth infections, usually present in childhood; GCSF has been effective treatment.
  • Congenital neutropenia patients could have recurrent severe infections and could be treated successfully with growth factors.  
  • Important supportive measures
    • Careful handwashing before and after direct contact with patients with neutropenia
    • Meticulous care of indwelling venous catheters and avoidance of urinary catheters and other invasive maneuvers that violate natural infection barriers

Surgical Care

  • In individuals with neutropenia and Felty syndrome who have recurrent life-threatening bacterial infections, splenectomy is the treatment of choice.
  • Indwelling central venous catheters should be removed in febrile neutropenic patients if septic thromboembolism is suspected. Other indications for catheter removal include the following:
    • Corynebacterium jeikeium infection
    • Infection with Candida species
    • Polymicrobial infection
    • Persistent fevers
    • Pocket-space abscess
    • Tunnel infections
  • In general, surgery should be avoided in a patient with neutropenia; however, surgical drainage of abscesses that have pus or watery exudate under pressure may occasionally be lifesaving. Perirectal abscesses and cholecystitis with cholangitis are examples of infections that, if left undrained, lead to polymicrobial sepsis, despite antibiotic therapy.

Consultations

  • Hematology consultation
  • Infectious disease consultation

Diet

  • Neutropenic patients should follow the following dietary restrictions:
    • Avoid raw and undercooked meat or well water.
    • Commercial fruit juices, beer, milk, and milk products should be pasteurized.
    • Aged cheese and cheese-based dressings should not be used.
    • Avoid unwashed raw fruits and vegetables.
    • Outdated products and all moldy products should not be consumed.

Medication

In cases of neutropenia, third-generation cephalosporins (eg, ceftazidime, cefepime) with or without gentamicin are used as first-line therapy. Imipenem-cilastatin and meropenem can be substituted for cephalosporins. Vancomycin should be used initially if a vascular access device – related infection is suspected. Other antibiotic and antifungal agents are added as appropriate.

Antibiotics

Antibiotic therapy should cover all likely pathogens in the context of the clinical setting in a patient with neutropenia.


Ceftazidime (Fortaz, Ceptaz)

Third-generation cephalosporin with broad-spectrum, gram-negative activity. Lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. Inhibits bacterial cell wall synthesis by binding to 1 or more of the penicillin-binding proteins, which, in turn, inhibit the final transpeptidation step of peptidoglycan synthesis in bacterial cell wall synthesis, thus inhibiting cell wall biosynthesis.

Adult

1-2 g IV/IM q8-12h

Pediatric

Neonates: 30 mg/kg IV q12h

Infants and children: 30-50 mg/kg per dose IV q8h; not to exceed 6 g/d

Adolescents: Administer as in adults.

Nephrotoxicity may increase with aminoglycosides, furosemide, and ethacrynic acid; probenecid may increase ceftazidime levels

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adjust the dose in the presence of renal impairment, CrCl 30-50 mL/min: q12h, CrCl 10-30 mL/min: q24h, CrCl <10 mL/min: q48-72h


Cefepime (Maxipime)

Fourth-generation cephalosporin with good gram-negative coverage. Similar to third-generation cephalosporins but has better gram-positive coverage.

Adult

1-2 g IV q12h

Pediatric

Not established, but 50 mg/kg IV q8h is used; not to exceed 2 g

Probenecid may increase the effects of cefepime; aminoglycosides increase the nephrotoxic potential of cefepime.

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Adjust the dose in the presence of renal insufficiency, CrCl 10-30 mL/min: 500 mg q12h, CrCl <10 mL/min: 250 mg q24h; prolonged use of cefepime may predispose patients to superinfection.


Imipenem-cilastatin (Primaxin)

For treatment of multiple organism infections in which other agents do not have wide-spectrum coverage or are contraindicated because of the potential for toxicity. Beta-lactam drugs, which are structurally different from penicillin and cephalosporins with broad-spectrum antibacterial activity.

Adult

500 mg IV q6-8h infused over 20-30 min

Alternatively, 500-750 mg IM q12h or intra-abdominally

Pediatric

<12 years: Not established; 15-25 mg/kg/dose IV q6h suggested for >3 mo

Infection with fully susceptible organisms: Not to exceed 2 g/d

Infection with moderately susceptible organisms: Not to exceed 4 g/d

Coadministration with cyclosporine may increase CNS adverse effects of both agents; coadministration with ganciclovir may result in generalized seizures.

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Avoid use in children <12 y; adjust the dose in the presence of renal insufficiency, CrCl 10-50 mL/min: 250 mg q6-12h, CrCl <10 mL/min: 125-250 mg q12h


Ciprofloxacin (Cipro)

Fluoroquinolone with activity against pseudomonads, streptococci, MRSA, S epidermidis, and most gram-negative organisms but no activity against anaerobes. Inhibits bacterial DNA synthesis and, consequently, growth. Trovafloxacin (Trovan) overcomes many of these limitations. Continue treatment for at least 2 d (7-14 d typical duration of treatment) after signs and symptoms have disappeared.

Adult

500 mg PO bid

Pediatric

<18 years: Not recommended

>18 years: Administer as in adults.

Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with the metabolism of fluoroquinolones; ciprofloxacin reduces the therapeutic effects of phenytoin; probenecid may increase ciprofloxacin serum concentrations; may increase the toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase the effects of anticoagulants (monitor PT)

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust the dose in the presence of renal function impairment, CrCl 10-50 mL/min: 50-75% of dose, CrCl <10 mL/min: 50% of dose; superinfections may occur with prolonged or repeated antibiotic therapy.


Amphotericin B (Amphocin, Fungizone)

Empirically indicated in persistent neutropenic fever after a minimum of 4 d of broad-spectrum antibiotics (eg, imipenem or ceftazidime). For empiric therapy for fungal infections or for documented fungal infections. Produced by a strain of Streptomyces nodosus. Can be fungistatic or fungicidal. Binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak, with subsequent fungal cell death.

Adult

Empiric therapy: 3 mg/kg/d IV

Systemic fungal infections: 3-5 mg/kg/d IV

Pediatric

Administer as in adults.

Antineoplastic agents may enhance the potential for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; the risk of renal toxicity is increased with cyclosporine; increases flucytosine and skeletal muscle toxicity

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Monitor renal function, serum electrolytes (eg, magnesium, potassium), liver function, CBC, and hemoglobin concentrations; resume therapy at the lowest level (eg, 0.25 mg/kg) when therapy is interrupted for more than 7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in patients with neutropenia who receive leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion)


Liposomal amphotericin B (AmBisome)

Liposomal preparation of amphotericin B. A large, multicenter, randomized, double-blind trial found liposomal amphotericin B to be as effective as standard amphotericin B for empiric treatment of neutropenic fever and showed less breakthrough fungal infections and toxicity.

Adult

Empiric therapy: 3 mg/kg/d IV

Systemic fungal infections: 3-5 mg/kg/d IV

Pediatric

Administer as in adults.

Antineoplastic agents may enhance the potential for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; the risk of renal toxicity is increased with cyclosporine; increases flucytosine and skeletal muscle toxicity

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Monitor renal function, serum electrolytes (eg, magnesium, potassium), liver function, CBC, and hemoglobin concentrations; resume therapy at the lowest level (eg, 0.25 mg/kg) when therapy is interrupted for more than 7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in patients with neutropenia who receive leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion)


Vancomycin (Vancocin)

Potent antibiotic directed against gram-positive organisms and active against Enterococcus species. Useful in the treatment of septicemia and skin structure infections. Indicated for patients who cannot receive or whose condition has failed to respond to penicillins and cephalosporins or for patients who have infections with resistant staphylococci. For abdominal penetrating injuries, this drug is combined with an agent active against enteric flora and/or anaerobes.

To avoid toxicity, the current recommendation is to assay vancomycin trough levels after third dose drawn 0.5 h before next dosing. Use creatinine clearance to adjust dose in patients diagnosed with renal impairment.

Used in conjunction with gentamicin for prophylaxis in penicillin-allergic patients undergoing gastrointestinal or genitourinary procedures.

Adult

Should be administered IV, and dose is adjusted to weight and creatinine clearance:
<60 kg: 750 mg
60-100 kg: 1 g
100-120 kg: 1.25 g
>120 kg: 1.5 g

Dosing interval is adjusted to creatinine clearance:
>90 mL/min: q12h
40-90 mL/min: q24h
30-40 mL/min: q48h
20-30 mL/min: q72h
10-20 mL/min: q96h

Pediatric

40 mg/kg/d IV divided qid; dosing interval adjusted to creatinine clearance

Erythema, histaminelike flushing, and anaphylactic reactions may occur when administered with anesthetic agents; when taken concurrently with aminoglycosides, risk of nephrotoxicity may increase above that with aminoglycoside monotherapy; effects in neuromuscular blockade may be enhanced when coadministered with nondepolarizing muscle relaxants

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Use with caution in patients with renal impairment or those receiving other nephrotoxic/ototoxic drugs; dosing interval is adjusted to creatinine clearance, 40-90 mL/min: q24h, 30-40 mL/min: q48h, 20-30 mL/min: q72h, 10-20 mL/min: q96h


Gentamicin (Garamycin)

Bactericidal drug that blocks functioning of initiation complex and causes misreading of mRNA. Gentamicin or another aminoglycoside should be added to other broad-spectrum antibiotics if the neutropenic patient's condition is unstable or the individual appears septic. Aminoglycoside antibiotic for gram-negative coverage. Used in combination with both an agent against gram-positive organisms and one that covers anaerobes.

Not the DOC. Consider if penicillins or other less toxic drugs are contraindicated, when clinically indicated, and in mixed infections caused by susceptible staphylococci and gram-negative organisms.

Adult

1-2.5 mg/kg IV/IM (depends on indication) and dosing interval is adjusted to creatinine clearance:
>60 mL/min: q8h
40-60 mL/min: q12h
20-40 mL/min: q24h
10-20 mL/min: q48h
<10 mL/min: q72h

Follow each regimen by at least a trough level drawn on the third or fourth dose (0.5 h before dosing); may draw a peak level 0.5 h after 30-min infusion

Pediatric

<5 years: 2.5 mg/kg IV/IM q8h

> 5 years: 1.5-2.5 mg/kg IV/IM q8h or 6-7.5 mg/kg/d divided q8h; not to exceed 300 mg/d; monitor as in adults

Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; aminoglycosides enhance the effects of neuromuscular blocking agents; thus, prolonged respiratory depression may occur; coadministration with loop diuretics may increase the auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor regularly)

Documented hypersensitivity; non-dialysis-dependent renal insufficiency

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Preexisting renal insufficiency; vestibular or cochlear impairment; myasthenia gravis; hypocalcemia


Piperacillin and tazobactam sodium (Zosyn)

Fourth-generation penicillin that has broad-spectrum coverage with activity against Pseudomonas aeruginosa. Piperacillin interferes with bacterial cell wall synthesis during active multiplication. Tazobactam prevents degradation of piperacillin by binding to the active site on beta lactamase.

Adult

2-4 g IV q6-8h

Pediatric

<12 years: Not established

>12 years: 2-4 g IV q6-8h

Tetracyclines may decrease the effects of ticarcillin; high concentrations of ticarcillin may physically inactivate aminoglycosides if administered in same IV line; when administered concurrently with aminoglycosides, the effects are synergistic; probenecid may increase penicillin levels.

Documented hypersensitivity; do not treat severe pneumonia, bacteremia, pericarditis, emphysema, meningitis, and purulent or septic arthritis with an oral penicillin during the acute stage

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Perform CBCs before the initiation of therapy and at least weekly during therapy; monitor for liver function abnormalities by measuring AST and ALT during therapy; exercise caution in patients diagnosed with hepatic insufficiencies; perform urinalysis, BUN, and creatinine determinations during therapy, and adjust the dose if values become elevated; monitor blood levels to avoid possible neurotoxic reactions.


Amoxicillin/clavulanate (Augmentin)

Beta-lactam antibiotic and beta-lactamase inhibitor, clavulanic acid, is the combination used to treat bacteria resistant to beta-lactam antibiotics. Two prospective randomized clinical trials showed PO antibiotics were safely substituted for IV antibiotics in low-risk patients with neutropenic fever. Until validated in large randomized trials, routine outpatient treatment for these patients is not recommended.

Adult

500 mg PO q12h

Pediatric

<40 kg (<12 wk): 30 mg/kg/d PO q12h

<40 kg (>12 wk): 45 mg/kg/d PO q12h; alternatively, 40 mg/kg/d PO q8h

>40 kg: Administer as in adults.

Dosing based on amoxicillin component

Coadministration with warfarin or heparin increases the risk of bleeding.

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in the presence of renal impairment; modify the dose and/or frequency

Colony-stimulating factors (CSFs)

Colony-stimulating factor agents stimulate key steps in neutrophil function.


Filgrastim (Neupogen, GCSF)

Activates and stimulates production, maturation, migration, and cytotoxicity of neutrophils. Can be used in an attempt to shorten the duration of neutropenia.

Adult

5 mcg/kg/d IV/SC, based on actual body weight

Pediatric

Administer as in adults.

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not use 12-24 h before or within 24 h after administering cytotoxic chemotherapy, because this may increase the sensitivity of rapidly dividing normal myeloid cells to cytotoxic chemotherapy; can potentially act as growth factor for any tumor types, particularly myeloid malignancy


Sargramostim (Leukine, GM-CSF)

Recombinant DNA product similar to an endogenous cytokine known as GM-CSF. Stimulates production of neutrophils, monocytes, and eosinophils by binding directly to high-affinity receptors on the surface of hematopoietic cells.

Adult

250 mcg/m2/d infuse IV over 2 h or SC

Pediatric

Administer as in adults.

Increased toxicity; lithium and corticosteroids may potentiate myeloproliferative effect

Documented hypersensitivity; excess myeloid blasts (>10%) in the bone marrow or blood

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Concomitant use of chemotherapy or radiotherapy; preexisting cardiac condition; hypoxia; CHF; fluid retention; renal or hepatic impairment; if ANC >20,000/mm3 and platelet >500,000/mm3, discontinue or decrease the dose by 50%; can act as growth factor for any tumor types, particularly myeloid malignancy


Pegfilgrastim (Neulasta)

A long-acting filgrastim created by covalent conjugate of recombinant granulocyte CSF (ie, filgrastim) and monomethoxypolyethylene glycol. As with filgrastim, it acts on hematopoietic cells by binding to specific cell surface receptors, thereby activates and stimulates production, maturation, migration, and cytotoxicity of neutrophils.

Adult

6 mg SC once/chemotherapy-cycle

Pediatric

<45 kg: Not established

>45 kg: Administer as in adults.

Do not administer in the period between 14 d before and 24 h after the administration of cytotoxic chemotherapy or radiation, because it increases the sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy; lithium may potentiate the release of neutrophils.

Documented hypersensitivity to E coli -derived proteins, PEG, or filgrastim

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Splenic rupture has been reported rarely; ARDS secondary to an influx of neutrophils to sites of inflammation in the lungs may occur; may precipitate sickle cell crisis; may cause bone pain; risk of developing myelodysplastic syndrome or acute myeloid leukemia in certain patients; leukocytosis; possible tumor growth

More on Granulocytopenia

Overview: Granulocytopenia
Differential Diagnoses & Workup: Granulocytopenia
Treatment & Medication: Granulocytopenia
Follow-up: Granulocytopenia
Multimedia: Granulocytopenia
References
Further Reading
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Keywords

granulocytopenia, neutropenia, agranulocytosis, granulopenia, leukopenia, hypogranulocytosis, neutrophils, eosinophils, basophils, granulocytes, granulocyte colony-stimulating factor, GCSF, granulocyte-macrophage colony-stimulating factor, GM-CSF

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Contributor Information and Disclosures

Author

Kush Sachdeva, MD, Southern Oncology and Hematology Associates, South Jersey Healthcare, Fox Chase Cancer Center Partner
Disclosure: Nothing to disclose.

Medical Editor

Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, and American Society of Hematology
Disclosure: Novartis Honoraria Speaking and teaching; Schering Honoraria Speaking and teaching; Cephalon Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Troy H Guthrie, Jr, MD, Director of Cancer Institute, Baptist Medical Center
Troy H Guthrie, Jr, MD is a member of the following medical societies: American Federation for Medical Research, American Medical Association, American Society of Hematology, Florida Medical Association, Medical Association of Georgia, and Southern Medical Association
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
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