Trimethoprim-Sulfamethoxazole and Clozapine

To the Editor: Clozapine, an atypical antipsychotic drug, is associated with a .8 percent incidence of agranulocytosis when taken for more than 52 weeks (1). Other classes of drugs, including antithyroid drugs, nonsteroidal anti-inflammatory drugs, antibiotics, sulfonamides, cardiotonics, and anticonvulsants, have been associated with a higher risk of neutropenia and agranulocytosis (2). Trimethoprim-sulfamethoxazole, initially introduced for the treatment of urinary or respiratory tract infections, has been associated with neutropenia and thrombocytopenia. Thrombocytopenia is defined as a platelet count of less than 100 × 10³/μL (3,4).

We present a case of neutropenia and thrombocytopenia that may have been related to a combination of clozapine and trimethoprim-sulfamethoxazole.

Ms. A was a 47-year old woman with a 22-year history of schizoaffective disorder, bipolar type, and panic disorder. She responded well to 375 mg a day of clozapine over five and a half years. Clozapine was well tolerated, and Ms. A's white blood cell count ranged from a low of 6.3 × 10³/μL to a high of 13.1 × 10³/μL. During this period she experienced several episodes of bronchitis and was successfully treated with cephalexin and cephalothin. She had been treated at least twice with trimethoprim-sulfamethoxazole and experienced only mild stomach upset.

In August 1998, after she had been taking clozapine for five years, Ms. A was treated with double-strength trimethoprim-sulfamethoxazole for bronchitis. Four days after she started taking the antibiotic, she complained to her internist about confusion and exhaustion. A blood sample was drawn late in the day, and trimethoprim-sulfamethoxazole was immediately discontinued. The following day, Ms. A visited the internist complaining of confusion, paranoia, disorganization, and exhaustion. Analysis of the previous day's blood sample showed a white blood cell count of 2.3 × 10³/μL, with 65.8 percent polymorphonuclear neutrophils, 30.3 percent lymphocytes, 3.9 percent monocytes, an absolute neutrophil count of 1,513.4/mm³, a platelet count of 102 × 10³/μL, and normal red blood cell indexes.

Ms. A was transported to a general hospital for further evaluation. Repeat tests showed a white blood cell count of 4.8 × 10³/μL and a platelet count of 66 × 10³/μL. The white cell differential included 43 percent polymorphonuclear neutrophils, 9 percent bands, 30 percent lymphocytes, 3 percent atypical lymphocytes, 13 percent monocytes, 1 percent myelocytes, 1 percent metacytes, and an absolute neutrophil count of 2,496/ mm³. Other medical causes of neutropenia and thrombocytopenia were ruled out.

Ms. A's blood cell counts returned to baseline within five days. Two weeks after trimethoprim-sulfamethoxazole was discontinued, a follow-up analysis showed a white blood cell count of 6.6 × 10³/μL, a platelet count of 232 × 10³/μL, an absolute neutrophil count of 2,706/mm³, and a normal differential.

Ms. A's clinical picture was consistent with trimethoprim-sulfamethoxazole-induced neutropenia—an absolute neutrophil count below 1,800/mm³—and thrombocytopenia. Both disorders resolved after trimethoprim-sulfamethoxazole was discontinued.

Clozapine may have enhanced the bone marrow-suppressive effect of trimethoprim-sulfamethoxazole, leading to the development of neutropenia and thrombocytopenia in a patient who previously tolerated both drugs without incident. Although most physicians are aware of the risks of prescribing a combination of carbamazepine and clozapine, few pay close attention to the risks of prescribing antibiotics such as trimethoprim-sulfamethoxazole, which may have a greater relative risk of neutropenia than carbamazepine (2). Patients taking clozapine should be closely monitored when trimethoprim-sulfamethoxazole is prescribed.