AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Granulocytopenia 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.

Pathophysiology

Neutropenia 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.

Race

Race and genetic background can influence the neutrophil count. African Americans and Yemenite Jews have lower mean ANCs.

Age

Age can influence the neutrophil count.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Fever and recurrent infection, primarily of the oropharynx and skin, are hallmarks of significant neutropenia. Obtaining a careful drug history is important.

• Common presenting symptoms of neutropenia
• • Low-grade fever
  • Sore mouth
  • Odynophagia
  • Gingival pain and swelling
  • Skin abscesses
  • Recurrent sinusitis and otitis
  • Symptoms of pneumonia (eg, cough, dyspnea)
  • Perirectal pain and irritation
• Congenital neutropenia - Suggested by a personal history of lifelong infections, family history of recurrent infections, and limited survival
• Chronic, benign familial neutropenia - Suggested by a history of long-standing neutropenia without infection

Physical

• Fever
• Stomatitis
• Periodontal infection
• Cervical lymphadenopathy
• Skin infection
• Splenomegaly
• Associated petechial bleeding
• Perirectal infection
• Growth retardation in children

Causes

The causes of neutropenia can be classified as either acquired (most common) or congenital.

• Acquired neutropenia (disorder of production)
• • Intrinsic bone marrow diseases
    • Aplastic anemia
    • Hematologic malignancy (eg, leukemia, lymphoma, myelodysplasia, myeloma)
    • Ionizing radiation
    • Tumor infiltration
    • Granulomatous infection
    • Myelofibrosis
  • Drugs, including, but not limited to, the following:
    • Acetaminophen
    • Antithyroid drugs
    • Cytotoxic chemotherapeutic agents
    • Gold salts
    • Chloramphenicol
    • Indomethacin
    • Phenylbutazone
    • Phenothiazines
    • Semisynthetic penicillins
    • Cephalosporins
    • Antituberculosis drugs
    • Trimethoprim/sulfamethoxazole
    • Anticonvulsants
    • Cimetidine
    • Ranitidine
    • Ibuprofen
    • Hydralazine
    • Captopril
    • Tocainide
    • Chlorpropamide
    • Benzodiazepines
    • Ticlopidine
    • Zidovudine
  • Infection, including, but not limited to, the following:
    • Bacterial sepsis
    • Viral infections (eg, influenza, measles, Epstein Barr virus, cytomegalovirus, viral hepatitis, HIV-1)
    • Toxoplasmosis
    • Brucellosis
    • Typhoid
    • Tuberculosis
    • Malaria
    • Dengue fever
    • Rickettsial infection
    • Babesiosis
• Idiopathic
• Nutritional deficiency (eg, vitamin B-12, folate, copper)
• Acquired neutropenia (peripheral destruction of neutrophils usually is immune mediated)
• • Alloimmune neutropenia in the neonate usually reflects a transplacental transfer of maternal alloantibodies to neutrophil antigens present on the neutrophils of the fetus.
  • Drug immune-mediated neutropenia
    • Aminopyrine
    • Quinidine
    • Cephalosporins
    • Penicillins
    • Sulfonamides
    • Phenothiazines
    • Phenylbutazone
    • Hydralazine
    • Other medications - Have been implicated
  • Autoimmune neutropenia may be associated with the following:
    • Crohn disease
    • Rheumatoid arthritis (with or without Felty syndrome)
    • Sjögren syndrome
    • Chronic autoimmune hepatitis
    • Hodgkin lymphoma
    • Systemic lupus erythematosus
    • Thymoma
    • Goodpasture disease
    • Wegener granulomatosis
  • Large granular lymphocyte proliferation or leukemia
• Acquired neutropenia (shifts of neutrophils from the circulating to the marginated pool of neutrophils)
  • Bacterial infection
  • Cardiopulmonary bypass
  • Hemodialysis
  • Splenic sequestration
  • Sepsis
• Congenital neutropenia
• • Cyclic neutropenia
  • Cartilage-hair hypoplasia syndrome
  • Chediak-Higashi syndrome
  • Dyskeratosis congenita
  • Infantile genetic agranulocytosis (Kostmann syndrome)
  • Lazy leucocyte syndrome
  • Myelokathexis
  • Schwachman-Diamond syndrome
  • Reticular dysgenesis
• Eosinopenia may be associated with the following:
  • Acute bacterial infection
  • Glucocorticoid administration
  • Hypogammaglobulinemia
  • Physical stress
  • Thymoma
• Decreased circulating basophils may be associated with the following:
  • Anaphylaxis
  • Acute infection
  • Drug-induced hypersensitivity
  • Congenital absence of basophils
  • Hemorrhage
  • Hyperthyroidism
  • Ionizing radiation
  • Neoplasia
  • Ovulation
  • Urticaria
  • Drugs (eg, corticosteroid, adrenocorticotropic hormone [ACTH] therapy, chemotherapeutic agents, thyroid hormones)

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Autoimmune diseases
Cyclic neutropenia
Congenital neutropenia
Drug-induced neutropenia
Large granular lymphocytic leukemia
Pseudoneutropenia
Chronic myelomonocytic leukemia

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Prior to a major workup, rule out infectious and drug-induced causes; then, obtain the following studies:
• • Complete blood count
  • Differential white count
  • Platelet count
  • Wright-stained peripheral smear: Associated anemia and/or thrombocytopenia and the presence of immature leukocyte precursors on peripheral smear suggest a hematologic malignancy.
• The following studies are applicable in some patients:
• • Antinuclear antibody
  • Rheumatoid factor
  • Serum immunoglobulin studies
  • Liver function tests

Imaging Studies

• Perform long-bone radiographs if a form of congenital neutropenia is suspected.
• Obtain liver-spleen radionuclide scans if the presence of splenomegaly and splenic sequestration are suspected. This study also allows evaluation of hepatocellular function and colloid shift, which occurs when hypersplenism is caused by cirrhosis with portal hypertension.

Other Tests

• Obtain vitamin B-12 and folate levels to evaluate for nutritional deficiency and pernicious anemia.
• If a patient with neutropenia presents with fever, perform an infection workup, including blood cultures for anaerobic and aerobic organisms. Obtain 2 sets of blood cultures, 10-15 minutes apart, from the peripheral veins and each port of catheter if the patient has central venous access. Other lab studies used for a complete fever workup include the following:
• • Urinalysis
  • Urine culture and sensitivity
  • Culture of wound or catheter discharge
  • Stool for Clostridium difficile
  • Skin biopsy, if new erythematous and tender skin lesions are present
  • Broad-spectrum antibiotics should be started within 1 hour of cultures

Procedures

• Concurrent anemia, thrombocytopenia, and/or an abnormal result on peripheral blood smear suggest an underlying hematologic disorder. In this setting, perform a bone marrow aspiration and obtain a biopsy from the posterior iliac crest. Cytogenetic analysis and cell-flow analysis of aspirate may be indicated. Bone marrow biopsy helps to exclude metastatic carcinoma, lymphoma, granulomatous infection, and myelofibrosis. If mycobacterial or fungal infection is suspected, the aspirate can be cultured.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Discontinue drugs if they are suspected as the causative agents of neutropenia.
• Correct nutritional deficiency (cobalamin or folic acid deficiency) if detected.
• Treat the fever as an infection, as follows:
• • 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 patient is unstable or appears septic.
  • Beta-lactam antibiotics (eg, ticarcillin, piperacillin) usually are 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 fever does not respond within 4-5 days or if the fever recurs with 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, with the tumor under control; and who are without any comorbid conditions, nausea, vomiting, or mucositis. Fluoroquinolone (eg, ciprofloxacin, ofloxacin) is an oral antibiotic that is 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. Filgrastim and pegfilgrastim are examples of GCSF; sargramostim is an example of GM-CSF. Usually, these agents are administered no sooner than 24 hours after chemotherapy completion. GCSF is lineage-specific for the production of functionally active neutrophils and also can be used for patients with severe, chronic neutropenia. GM-CSF simulates the production of neutrophils, monocytes, and eosinophils.
• Neutrophil 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.
• 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 Felty syndrome who have recurrent life-threatening bacterial infections, splenectomy is the treatment of choice.
• Indwelling central venous catheters should be removed in febrile patients if septic thromboembolism is suspected. Other indications 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 occasionally may be lifesaving. Perirectal abscess 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

• 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 fruit and vegetables.
  • Outdated products and all moldy products should not be consumed.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 appropriately.

Drug Category: Antibiotics

Therapy should cover all likely pathogens in the context of the clinical setting.

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

Drug Category: Colony-stimulating factors (CSFs)

These agents stimulate key steps in neutrophil function.

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

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Deterrence/Prevention:

• Patients should avoid exposure to people with respiratory tract infections.
• Patients should avoid overcrowded areas.
• Patients should wear a facemask in public places if the ANC is below 1000/mm³.

Prognosis:

• Prognosis depends on the underlying cause. Improved broad-spectrum antibiotic agents, combined with improved supportive care, have improved the prognosis for most patients with severe neutropenia. Ultimately, patient survival depends on recovery of adequate neutrophil numbers.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to treat neutropenic fevers on an outpatient basis with extreme caution
• Patient failure to be reliable and have strong support at home by family and friends
• Patient failure to fit the criteria for low-risk neutropenia (see Medical Care)
• Failure to properly inform the patient about the seriousness and complications of neutropenic infections
• Failure to acknowledge a fever and to offer appropriate on-time care, thereby allowing the condition to become life threatening

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Alanis A, Rehm S, Weinstein AJ. Comparative efficacy and toxicity of moxalactam and the combination of nafcillin and tobramycin in febrile granulocytopenic patients. Cleve Clin Q. 1983;50(4):385-95. [Medline].
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Article Last Updated: Jun 30, 2006