The case report describes a woman who has an acute psychosis episode during the second course of trimethoprim/sulfamethoxazole therapy, after having an allogeneic hematopoietic stem cell transplant that favored a dose-related effect of this adverse effect.

Key words : Trimethoprim/sulfamethoxazole, Psychosis, Stem cell transplant

Introduction

Trimethoprim/sulfamethoxazole (TMP/SMX), a coformulation in a ratio of 1 to 5, that is the drug of choice for prophylaxis and treating Pneumocystis jiroveci(i) pneumonia in immunocompromised patients and allogeneic hematopoietic stem cell transplant (HSCT) recipients.¹ The adverse effect of TMP/SMX therapy is uncommon and consists mainly of skin rash, while acute psychosis has been noted as a rare complication of the drug in case reports.^2-7

We describe a woman having an acute psychosis episode after undergoing an HSCT during her second course of TMP/SMX therapy at a higher dosage. The patient received a third, reduced-dosage TMP/SMX therapy, without psychosis 6 months later, which might favor a dose-related effect of this rare complication.

A 42-year-old woman was diagnosed with acute myeloid leukemia with t(8;21)(q22;q22)/RUNX1-RUNX1T1 in February 2011. Complete remission was achieved after the initial chemotherapies, but the disease returned 1 year later. She was scheduled for an allogeneic HSCT after salvage treatment. A survey before her HSCT showed normal heart, lung, renal, and liver functions, with no known allergies. A psychiatric survey also showed good status for an HSCT without a history of psychiatric problems. Prophylactic antibiotics, consisting of levofloxacin (1 tablet daily by mouth) and TMP/SMX (2 tablets 2 times a day by mouth) were prescribed for 2 weeks before the transplant without any adverse effects. And unrelated allogeneic HSCT was performed, and engraftment of the stem cells was confirmed 11 days later by a bold marrow examination, with recovery of white cell counts and platelet counts gradually later.

Unfortunately, dyspnea and desaturation occurred 13 days after the transplant. Imaging studies revealed bilateral pulmonary infiltrates with effusions. Considering that she had acute respiratory distress syndrome, and possibly a Pneumocystis jiroveci(i) pneumonia infection, the intravenous form of TMP/SMX was prescribed 320 mg every 8 hours (15 mg/kg of TMP daily). The infection was controlled 3 days later, but the patient had restless, hand tremors, and sleep disturbances 5 days after the TMP/SMX was prescribed.

Biochemistry showed no special abnormalities. Results of a brain computed tomography scan and cerebrospinal fluid after a lumbar puncture were unremarkable. After withdrawal of any other medications and with supportive care, these symptoms progressed to visual hallucinations, psychotic behavior, and acute confusion 8 days after the beginning of the TMP/SMX treatment. Because we considered that she had a substance-induced psychotic disorder, the TMP/SMX was withdrawn, and the patient returned to a normal mental status 48 hours after we discontinued the drugs. The patient was discharged from the hospital without further sequelae.

Six months later, she was again admitted because of a relapse of the disease and infection. Trimethoprim/sulfamethoxazole was prescribed again in a reduced oral dosage, and she had no psychoses.

Trimethoprim/sulfamethoxazole is a well-tolerated antibiotic, widely used to treat many common infections, such as cystitis or bronchitis. Undesired side effects of the central nervous system rarely have been identified, and only few case reports have been noted (Table 1).^2-7 Because the psychosis did not improve after discontinuation of the other medications, and it recovered only after we withdrew the TMP/SMX, we suggest that the TMP/SMX induced this complication. The pathomechanisms of TMP/SMX-related psychosis remain unclear,^7,8 and the characteristics of these cases vary in age, disease status, medication route, dosage, and time of onset. We question whether this is an individual’s difference, or whether there is a dose-related effect to the psychosis.

In a retrospective study, Lee and associates⁸ demonstrated that the incidence of psychosis increased from 0% to 23.5% when the trimethoprim dosage was increased from < 12 mg/kg/day to > 18 mg/kg/day. Our case agrees with the hypothesis that the psychotic reaction happened only with the second course, and with a higher dosage, and no adverse effects were found in other courses of treatment. However, the psychosis could occur in patients with a standard dosage of TMP/SMX,⁴ or even a reduced dosage,⁷ which raises the question that it is the individual that leads to this adverse effect. Therefore, drug and/or metabolite level monitoring should be performed to clarify things. Withdrawal of the drug reverses this adverse effect and fortunately, most symptoms resolve completely after discontinuation of the drug (Table 1).

In conclusion, this case suggests that TMP/SMX-related acute psychosis could happen after an HSCT, and this may be dose-dependent with the patient. Neither risk factors nor biomarkers can predict this complication; therefore, we should remain alert the possibility of TMP/SMX-related psychosis in patients under treatment. Further studies about the drug level are required to draw a clearer conclusion about dosage and side effects.

References:

1. De Castro N, Neuville S, Sarfati C, et al. Occurrence of Pneumocystis jiroveci pneumonia after allogeneic stem cell transplantation: a 6-year retrospective study. Bone Marrow Transplant. 2005;36(10):879-883.
   CrossRef - PubMed
2. Mermel LA, Doro JM, Kabadi UM. Acute psychosis in a patient receiving trimethoprim-sulfamethoxazole intravenously. J Clin Psychiatry. 1986;47(5):269-270.
   PubMed
3. McCue JD, Zandt JR. Acute psychoses associated with the use of ciprofloxacin and trimethoprim-sulfamethoxazole. Am J Med. 1991;90(4):528-529.
   CrossRef - PubMed
4. Gregor JC, Zilli CA, Gotlib IH. Acute psychosis associated with oral trimethoprim-sulfamethoxazole therapy. Can J Psychiatry. 1993;38(1):56-58.
   PubMed
5. Saidinejad M, Ewald MB, Shannon MW. Transient psychosis in an immune-competent patient after oral trimethoprim-sulfamethoxazole administration. Pediatrics. 2005;115(6):e739-e741.
   CrossRef - PubMed
6. Weis S, Karagülle D, Kornhuber J, Bayerlein K. Cotrimoxazole-induced psychosis: a case report and review of literature. Pharmacopsychiatry. 2006;39(6):236-237.
   CrossRef - PubMed
7. Walker LE, Thomas S, McBride C, et al. 'Septrin psychosis' among renal transplant patients with Pneumocystis jirovecii pneumonia. J Antimicrob Chemother. 2011;66(5):1117-1119.
   CrossRef - PubMed
8. Lee KY, Huang CH, Tang HJ, et al. Acute psychosis related to use of trimethoprim/sulfamethoxazole in the treatment of HIV-infected patients with Pneumocystis jirovecii pneumonia: a multicentre, retrospective study. J Antimicrob Chemother. 2012;67(11):2749-2754.
   CrossRef - PubMed