You are in: eMedicine Specialties > Hematology > Immune System and Disorders GranulocytopeniaArticle Last Updated: Jun 30, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 10
  Author: Kush Sachdeva, MD, Private Practice, Southern Oncology and Hematology Associates, South Jersey Hospital System, Fox Chase Cancer Center Kush Sachdeva is a member of the following medical societies: American Society of Clinical Oncology Coauthor(s): James O Ballard, MD, Acting Chair of Medical Humanities, Kienle Chair for Humane Medicine, Professor, Departments of Medicine and Pathology, Division of Hematology/Oncology, Milton S Hershey Medical Center, Pennsylvania State University Editors: Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Troy H Guthrie, Jr, MD, Director of Cancer Institute, Baptist Medical Center; Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems; Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University Author and Editor Disclosure Synonyms and related keywords: granulopenia, hypogranulocytosis, neutropenia, neutrophils, eosinophils, basophils, granulocytes, agranulocytosis, granulocytopenia INTRODUCTIONSection 2 of 10
  BackgroundGranulocytopenia is defined as a reduced number of blood granulocytes, namely neutrophils, eosinophils, and basophils. The term granulocytopenia often is used synonymously with neutropenia. Agranulocytosis refers to a complete absence of neutrophils in peripheral blood. Neutropenia is the primary focus of this article. Neutropenia is defined specifically as a decrease in the number of circulating neutrophils in the nonmarginal pool, which constitutes 4-5% of total body neutrophil stores. Most of the neutrophils are contained in the bone marrow, either as mitotically active (one third) or postmitotic mature cells (two thirds). Age, race, genetic background, environment, and other factors can influence the neutrophil count. The lower limit of the absolute neutrophil count (ANC) in adults is 1800/mm3, but for practical purposes, a value of less than 1500/mm3 is used to define neutropenia. Neutropenia is classified as mild, moderate, or severe, based on the ANC. The ANC is calculated by multiplying the total white blood cell (WBC) count by the percentage of neutrophils plus the band forms of neutrophils in the differential. Mild neutropenia is present when the ANC is 1000-1500/mm3, moderate neutropenia is present with an ANC of 500-1000/mm3, and severe neutropenia refers to an ANC of less than 500/mm3. PathophysiologyNeutropenia can be caused by insufficient or injured bone marrow stem cells, shifts in neutrophils from the circulating pool to the marginal blood or tissue pools, increased destruction in the circulation, or a combination of these mechanisms. Intravascular stimulation of neutrophils by plasma-activated complement 5 (C5a) and endotoxin may cause increased margination along the vascular endothelium, decreasing the number of circulating neutrophils. The term pseudoneutropenia refers to neutropenia caused by increased margination. Disorders of the pluripotent myeloid stem cell and committed myeloid progenitor cell, which cause decreased neutrophil production, include some congenital forms of neutropenia, aplastic anemia, acute leukemia, and myelodysplastic syndrome. Other examples include bone marrow tumor infiltration, radiation, infection (especially viral), and bone marrow fibrosis. Cancer chemotherapy, other drugs, and toxins may damage hematopoietic precursors by directly affecting bone marrow. Peripheral loss of neutrophils can occur during infection and by immunological destruction triggered by autoimmune diseases (eg, Felty syndrome) and by drugs acting as haptens. The risk of serious infection increases as the ANC falls to the severely neutropenic range ( <500/mm3). The duration of severe neutropenia directly correlates with the total incidence of all infections and those infections that are life threatening. Bacterial organisms most often cause fever and infection in neutropenic patients. Historically, gram-negative aerobic bacteria (eg, Escherichia coli, Klebsiella species, Pseudomonas aeruginosa) have been most common in these patients. However, gram-positive cocci, especially Staphylococcus species and Streptococcus viridans, have emerged as the most common pathogens because of the increasing use of indwelling right atrial catheters. After treating neutropenic patients with broad-spectrum antibiotics for several days, superinfection with fungi is common. Candida species are the most frequently encountered organisms in this setting. RaceRace and genetic background can influence the neutrophil count. African Americans and Yemenite Jews have lower mean ANCs. AgeAge can influence the neutrophil count. CLINICALSection 3 of 10
HistoryFever and recurrent infection, primarily of the oropharynx and skin, are hallmarks of significant neutropenia. Obtaining a careful drug history is important.
Physical
CausesThe causes of neutropenia can be classified as either acquired (most common) or congenital.
DIFFERENTIALSSection 4 of 10
Acute Lymphoblastic Leukemia Acute Myelogenous Leukemia Agranulocytosis Aplastic Anemia Bone Marrow Failure Brucellosis Cytomegalovirus Ehrlichiosis Felty Syndrome Folic Acid Deficiency Hairy Cell Leukemia Hepatitis, Viral Infectious Mononucleosis Influenza Myelodysplastic Syndrome Myelophthisic Anemia Neutropenia Paroxysmal Nocturnal Hemoglobinuria Pernicious Anemia Sepsis, Bacterial Splenomegaly Systemic Lupus Erythematosus Toxoplasmosis Tuberculosis Wegener Granulomatosis
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| Drug Name | Ceftazidime (Fortaz, Ceptaz) |
|---|---|
| Description | 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 Dose | 1-2 g IV/IM q8-12h |
| Pediatric Dose | 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 |
| Contraindications | Documented hypersensitivity |
| Interactions | Nephrotoxicity may increase with aminoglycosides, furosemide, and ethacrynic acid; probenecid may increase ceftazidime levels |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Adjust dose in renal impairment, CrCl 30-50 mL/min: q12h, CrCl 10-30 mL/min: q24h, CrCl <10 mL/min: q48-72h |
| Drug Name | Cefepime (Maxipime) |
|---|---|
| Description | Fourth-generation cephalosporin with good gram-negative coverage. Similar to third-generation cephalosporins but has better gram-positive coverage. |
| Adult Dose | 1-2 g IV q12h |
| Pediatric Dose | Not established but 50 mg/kg IV q8h is used; not to exceed 2 g |
| Contraindications | Documented hypersensitivity |
| Interactions | Probenecid may increase effects of cefepime; aminoglycosides increase the nephrotoxic potential of cefepime |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Adjust dose in 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 |
| Drug Name | Imipenem-cilastatin (Primaxin) |
|---|---|
| Description | 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 Dose | 500 mg IV q6-8h infused over 20-30 min Alternatively, 500-750 mg IM q12h or intra-abdominally |
| Pediatric Dose | <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 |
| Contraindications | Documented hypersensitivity |
| Interactions | Coadministration with cyclosporine may increase CNS adverse effects of both agents; coadministration with ganciclovir may result in generalized seizures |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Avoid use in children <12 y; adjust dose in renal insufficiency, CrCl 10-50 mL/min: 250 mg q6-12h, CrCl <10 mL/min: 125-250 mg q12h |
| Drug Name | Ciprofloxacin (Cipro) |
|---|---|
| Description | 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 Dose | 500 mg PO bid |
| Pediatric Dose | <18 years: Not recommended >18 years: Administer as in adults |
| Contraindications | Documented hypersensitivity |
| Interactions | Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; ciprofloxacin reduces therapeutic effects of phenytoin; probenecid may increase ciprofloxacin serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT) |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in 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 |
| Drug Name | Amphotericin B (Amphocin, Fungizone) |
|---|---|
| Description | Empirically indicated in persistent neutropenic fever after a minimum of 4 d of broad-spectrum antibiotics (eg, imipenem or ceftazidime). For empirical 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 Dose | Empirical therapy: 3 mg/kg/d IV Systemic fungal infections: 3-5 mg/kg/d IV |
| Pediatric Dose | Administer as in adults |
| Contraindications | Documented hypersensitivity |
| Interactions | Antineoplastic agents may enhance the potential for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; risk of renal toxicity is increased with cyclosporine; increases flucytosine and skeletal muscle toxicity |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| 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) |
| Drug Name | Liposomal amphotericin B (AmBisome) |
|---|---|
| Description | Liposomal preparation of amphotericin B. 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 Dose | Empiric therapy: 3 mg/kg/d IV Systemic fungal infections: 3-5 mg/kg/d IV |
| Pediatric Dose | Administer as in adults |
| Contraindications | Documented hypersensitivity |
| Interactions | Antineoplastic agents may enhance the potential for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; risk of renal toxicity is increased with cyclosporine; increases flucytosine and skeletal muscle toxicity |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| 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) |
| Drug Name | Vancomycin (Vancocin) |
|---|---|
| Description | 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 have 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, current recommendation is to assay vancomycin trough levels after third dose drawn 0.5 h prior to 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 Dose | 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 Dose | 40 mg/kg/d IV divided qid; dosing interval adjusted to creatinine clearance |
| Contraindications | Documented hypersensitivity |
| Interactions | 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 - Safety for use during pregnancy has not been established. |
| 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 |
| Drug Name | Gentamicin (Garamycin) |
|---|---|
| Description | 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 is unstable or septic-appearing. 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 Dose | 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 Dose | <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 |
| Contraindications | Documented hypersensitivity; non-dialysis-dependent renal insufficiency |
| Interactions | Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; aminoglycosides enhance effects of neuromuscular blocking agents; thus, prolonged respiratory depression may occur; coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor regularly) |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Preexisting renal insufficiency; vestibular or cochlear impairment; myasthenia gravis; hypocalcemia |
| Drug Name | Piperacillin and tazobactam sodium (Zosyn) |
|---|---|
| Description | 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 Dose | 2-4 g IV q6-8h |
| Pediatric Dose | <12 years: Not established >12 years: 2-4 g IV q6-8h |
| Contraindications | Documented hypersensitivity; do not treat severe pneumonia, bacteremia, pericarditis, emphysema, meningitis, and purulent or septic arthritis with an oral penicillin during the acute stage |
| Interactions | Tetracyclines may decrease effects of ticarcillin; high concentrations of ticarcillin may physically inactivate aminoglycosides if administered in same IV line; effects when administered concurrently with aminoglycosides are synergistic; probenecid may increase penicillin levels |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Perform CBCs prior to 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 dose if values become elevated; monitor blood levels to avoid possible neurotoxic reactions |
| Drug Name | Amoxicillin/clavulanate (Augmentin) |
|---|---|
| Description | 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 Dose | 500 mg PO q12h |
| Pediatric Dose | <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 |
| Contraindications | Documented hypersensitivity |
| Interactions | Coadministration with warfarin or heparin increases risk of bleeding |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Caution in renal impairment, modify dose and/or frequency |
These agents stimulate key steps in neutrophil function.
| Drug Name | Filgrastim (Neupogen, GCSF) |
|---|---|
| Description | Activates and stimulates production, maturation, migration, and cytotoxicity of neutrophils. Can be used in an attempt to shorten the duration of neutropenia. |
| Adult Dose | 5 mcg/kg/d IV/SC, based on actual body weight |
| Pediatric Dose | Administer as in adults |
| Contraindications | Documented hypersensitivity |
| Interactions | None reported |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Do not use 12-24 h before or within 24 h after administering cytotoxic chemotherapy because this may increase sensitivity of rapidly dividing normal myeloid cells to cytotoxic chemotherapy; can potentially act as growth factor for any tumor types, particularly myeloid malignancy |
| Drug Name | Sargramostim (Leukine, GM-CSF) |
|---|---|
| Description | 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 Dose | 250 mcg/m2/d infuse IV over 2 h or SC |
| Pediatric Dose | Administer as in adults |
| Contraindications | Documented hypersensitivity; excess myeloid blasts (>10%) in the bone marrow or blood |
| Interactions | Increased toxicity; lithium and corticosteroids may potentiate myeloproliferative effect |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Concomitant use of chemotherapy or radiotherapy; preexisting cardiac problem; hypoxia; CHF; fluid retention; renal or hepatic impairment; if ANC >20,000/mm3 and platelet >500,000/mm3, discontinue or decrease dose by 50%; can act as growth factor for any tumor types, particularly myeloid malignancy |
| Drug Name | Pegfilgrastim (Neulasta) |
|---|---|
| Description | 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 Dose | 6 mg SC once/chemotherapy-cycle |
| Pediatric Dose | <45 kg: Not established >45 kg: Administer as in adults |
| Contraindications | Documented hypersensitivity to E coli?derived proteins, PEG, or filgrastim |
| Interactions | Do not administer in the period between 14 d before and 24 h after administration of cytotoxic chemotherapy or radiation, since it increases sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy; lithium may potentiate the release of neutrophils |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| 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 |
Deterrence/Prevention:
Prognosis:
Article Last Updated: Jun 30, 2006
