Drug-Induced Neutropenia

Neutropenia, also referred to as agranulocytosis, granulocytopenia, and granulopenia, is a decrease in circulating neutrophils, also known as granulocytes (a type of white blood cell), in the peripheral blood. Neutropenia can be caused by a failure of the bone marrow to make enough neutrophils, or when white blood cells are destroyed faster than they can be made. This results in the lowering of the immunologic barrier to fungal and bacterial infection.

Neutropenia occurs more frequently in females and the elderly. On average, approximately one in a million people are diagnosed with drug-induced neutropenia worldwide each year. The mortality rate is 6-10 percent. For cancer patients with meutropenic fever it is 4-30 percent.

Neutropenia is often diagnosed after a patient has contracted an infection. If the patient presents with anemic symptoms, such as fatigue, weakness, or labored breathing after exertion, or with symptoms of thrombocytopenia, other conditions, including those that may be present concurrently, such as pancytopenia and bone marrow failure, should be considered.

A careful review of the patient’s drug history may uncover the offending drug and prevent the need for an extensive diagnostic workup. For a more definitive diagnosis, however, a blood differential test may be performed. Besides neutrophils, a blood differential also reveals the relative proportion of lymphocytes, monocytes, eosinophils, and basophils in the blood.

In addition to chemicals and cytotoxic chemotherapy, the following drugs are among those that have been known to cause neutropenia.

Highest risk categories: macrolides, procainamides, and antithyroid medications such as thiouracil, propylthiouracil, carbimazole, methimazole (aka. Tapazole), thiocyanate, and potassium perchlorate
Antimicrobials: acyclovir, cephalosporins, chloramphenicol (numerous trade names), chloroquine, ciprofloxacin (Cipro), clindamycin (Cleocin), dapsone, doxycycline, ethambutol, flucytosine (Ancobon), fludarabine (Fludara), gentamicin, griseofulvin (aka. Grisovin), hydroxychloroquine (Plaquenil), imipenem/cilastatin (Primaxin, Tienam, Cilanim), isoniazid (Rimifon), levamisole (aka. Ergamisole), lincomycin, mebendazole (Ovex, Vermox, Antiox, Pripsen), metronidazole (Flagyl), minocycline (Minocin), nitrofurantoin (Furadantin, Macrobid, Macrodantin), novobiocin, penicillin, pyrimethamine (Daraprim), quinacrine (Atabrine), rifampin (Rifadin, Rifater, Rimactane), ristocetin, streptomycin, sulfonamides, terbinafine (Lamisil, Terbisil), thiacetazone, trimethoprim (Proloprim, Monotrim, Triprim), vancomycin, zidovudine (AZT)
Anti-inflammatory agents and analgesics: acetylsalicylic acid (Aspirin), aminopyrine, barbiturates, benoxaprofen (Oraflex), diflunisal (Dolobid), dipyrone, ibuprofen (several including Advil, Motrin, Nuprin), indomethacin (Indocin, Indocid, Indochron among others), mesalazine (aka. Mesalamine), phenylbutazone (Clofezone in combination), quinine, sulindac (Clinoril), tolmetin (Tolectin)
Antidepressants, antipsychotics, and neuropharmacologic agents: amoxapine (Asendin, Asendis, Defanyl, Demolox, Moxadil), chlordiazepoxide (Librium, among others), clozapine (Clozaril, Leponex, Fazaclo, Froidir), desipramine (Norpramin, Pertofrane), diazepam (Valium), imipramine (Antideprin, Deprenil, Deprimin, Deprinol, Depsonil, Dynaprin, Eupramin, Imipramil, Irmin, Janimine, Melipramin, Surplix, Tofranil), meprobamate (Miltown, Equanil, Meprospan), risperidone (Risperdal) and phenothiazines (chlorpromazine, mepazine, methylpromazine, prochlorperazine, promazine, thioridazine, trifluoperazine, trimeprazine)
Anticonvulsants: carbamazepine (Tegretol, Biston, Calepsin, Carbatrol, Epitol, Equetro, Finlepsin, Sirtal, Stazepine, Telesmin,Teril, Timonil, Trimonil, Epimaz), ethosuximide (Zarontin, Emeside), Mesantoin, phenytoin (Phenytek, Dilantin), trimethadione and valproic acid (Valproate)
Cardiovascular drugs: aprindine, captopril (Capoten, Inhibace), diazoxide, hydralazine, methyldopa (Aldomet, Apo-Methyldopa, Dopamet, Novomedopa), nifedipine (Adalat, Nifedical, Procardia), procainamide (Pronestyl, Procan, Procanbid), propafenone (Rythmol, Rytmonorm), propranolol (Inderal, Avlocardyl, Dociton, Inderalici, InnoPran, Sumial), quinidine, ticlopidine, and vesnarinone
Antihistamines: brompheniramine (Bromfed, Dimetapp, Bromfenex, Dimetane), cimetidine (Tagamet), methaphenilene, mianserin, ranitidine (Zantac, Zinetac), thenalidine, and tripelennamine (Pyribenzamine)
Additional drugs: acetazolamide (Diamox), allopurinol (Zyloprim), aminoglutethimide (Cytadren), bezafibrate (Bezalip), chlorpropamide, cinchophen (Atophan, Quinophan, Phenaquin), colchicine, ethacrynic acid (Edecrin), famotidine (Pepcid, Pepcidine), flutamide (Eulexin, Flutamin), intravenous immunoglobulin (IVIG), levodopa, methazolamide (Neptazane), metoclopramide (Maxolon, Reglan, Degan, Maxeran, Primperan, Pylomid), penicillamine (Cuprimine, Depen), phenindione, pyrithyldione, rauwolfia, retinoic acid (Tretinoin), spironolactone (Aldactone, Spiractin, Spirotone, Novo-Spiroton, Verospiron, Berlactone), tamoxifen (Nolvadex, Istubal, Valodex), thiazides, tolbutamide (Orinase)

Care depends on the cause, duration, and severity of the neutropenia, and may include:

Removal of any offending agents or drugs
Meticulous oral hygiene to prevent infections of the teeth and mucosa
Avoidance of rectal exams and temperature measurements
Avoidance of fresh fruits, flowers, vegetables to eliminate potential sources of infection
Good skin care for wounds and abrasions

Delays in administering the first dose of antibiotics are associated with higher mortality rates. The Infectious Diseases Society of America (IDSA) recommends that empiric broad-spectrum antibiotics be started immediately. The Centers for Disease Control and Prevention (CDC) suggests adding vancomycin if Staphylococcus aureus infections are suspected. Antibiotics often used in preventing infections in those with neutropenia include: