Adverse Reactions to Trimethoprim/Sulfamethoxazole in AIDS

Case Report

A 37-year-old, 60-kg, Puerto Rican woman with AIDS was admitted to the hospital with fever, cough, and generalized weakness. HIV infection had been diagnosed in 1996. Her CD4+ lymphocyte count 2 months before admission was 14 cells/mm³, and HIV-1 RNA viral load was >750 000 copies/mm³. She had a history of HIV nephropathy, with a baseline serum creatinine level of 2.5 mg/dL (normal 0.5–1.5). Disseminated histoplasmosis had been diagnosed 8 months prior to this admission and treated with intravenous amphotericin B lipid complex followed by oral itraconazole. The patient had been prescribed antiretroviral therapy with zidovudine/lamivudine, amprenavir, and ritonavir, but had not taken these drugs because of her reluctance to use any medicines for her HIV disease. She did not report any adverse effects from these antiretrovirals. She had also not taken any of her other prescribed medications (itraconazole, TMP/SMX, azithromycin) during the 6-week period prior to hospitalization. She had no history of essential tremor or any other neurologic disease and no prior episodes of pancreatitis.

The patient reported generalized weakness, fever, and 3 weeks of nonproductive cough. Physical examination revealed fever (38.8 °C), RR 18 breaths/min, and normal BP and HR. She had oral candidiasis. Her lungs were clear to auscultation. The abdomen was soft and nondistended with a liver span of 9 cm, a palpable spleen tip, moderate right upper quadrant tenderness, and no rebound tenderness or guarding. She had no rash. Neurologic examination revealed normal sensory and motor function and a normal cranial nerve examination. The patient had no tremor and had normal stance and gait.

Laboratory testing revealed a white blood cell count of 1.1 × 10³/mm³ (4.8–10.8); hemoglobin 6.1 g/dL (12–16); platelet count 46 000/mm³ (180–400); serum aspartate aminotransferase (AST) 752 U/L (5–40), serum alanine aminotransferase (ALT) 223 U/L (5–40), lactate dehydrogenase (LDH) 571 U/L (60–250), alkaline phosphatase 552 U/L (30–115), and albumin 2.2 g/dL (3.5–5.5). Total bilirubin, prothrombin, and partial thromboplastin times were normal. Serum creatinine was 2.9 mg/dL. Chest X-ray showed no infiltrates. Abdominal ultrasound showed marked hepatomegaly, with the right lobe measuring 19 cm in length. The liver was echogenic and heterogeneous, and there was no hepatic mass. Biliary structures appeared normal and her spleen was near the upper limit of normal size. The patient refused bone marrow aspiration.

On hospital day 2, intravenous amphotericin B lipid complex 5 mg/ kg/d was started to treat presumed relapse of disseminated histoplasmosis. Given the patient's 3-week history of nonproductive cough in the setting of her not having taken Pneumocystis carinii pneumonia (PCP) prophylaxis, a sputum sample was sent for direct fluorescent antigen testing, and empiric PCP therapy was initiated with TMP/SMX 15 mg/ kg/d. Ibuprofen and diphenhydramine were administered prior to infusion of amphotericin B lipid complex. Acetaminophen was given when the patient developed a fever. No other medications were administered.

On the morning of day 4, the patient developed a high-frequency tremor that involved both upper extremities, was present at rest, and worsened with activity. Laboratory testing revealed serum creatinine 5.6 mg/dL, with serum potassium 5.4 mEq/L. Serum calcium was 6.7 mg/dL (8.5–10.5) with albumin 1.5 g/dL (3.5–5.5). On day 5, the patient's serum creatinine had increased to 5.9 mg/dL. In view of concern about renal toxicity, TMP/SMX and ibuprofen were discontinued that afternoon. In the absence of any confirmatory clinical or microbiologic evidence of PCP, no alternative therapy was initiated.

The following morning (day 6), the patient developed acute onset of severe epigastric pain, nausea, and vomiting. She appeared acutely ill and was tachycardic (HR 100 beats/min) and tachypneic (RR 22 breaths/ min). Her abdomen was very distended, with marked epigastric tenderness, voluntary guarding, and hypoactive bowel sounds. Lung examination revealed bibasilar rales. She had no rash. She had a severe high-frequency tremor, worse than on previous examination, which involved her head in addition to both upper extremities and made it difficult for her to write or use utensils. She had normal muscle tone and deep tendon reflexes. Cognitive and cranial nerve functions were normal.

Laboratory testing showed white blood cell count of 3.2 × 10³/mm³, hemoglobin 7.7 g/dL, and platelet count 32 000/mm³. Serum creatinine was 5.2 mg/dL and potassium was 5.0 mEq/L. Serum amylase was 542 U/L (16–108) and lipase 2018 U/L (20–190). Transaminases had decreased, with ALT 316 U/L and AST 113 U/L. Alkaline phosphatase was 509 U/L and total bilirubin 0.3 mg/dL. Serum calcium was 6.4 mg/dL (8.5–10.5) with serum albumin 1.5 g/dL. Abdominal computed tomography with oral contrast showed peripancreatic edema and ascites. The diagnosis of acute pancreatitis was made, and the patient was transferred to the medical intensive care unit. Intravenous metronidazole and ceftazidime were started.

Within 72 hours of stopping TMP/SMX, by the morning of day 8, the patient's gastrointestinal symptoms and tremor had resolved. Serum amylase had fallen to 289 U/L and serum lipase to 244 U/L. Serum creatinine decreased to 2.6 mg/dL over the next 5 days. Urinary assay for Histoplasma capsulatum was confirmatory, with a value of 11.0 antigen units (strongly positive). She improved consistently and was discharged home 10 days later after having received 14 days of intravenous amphotericin B lipid complex. Treatment for histoplasmosis was continued with oral fluconazole, and she was given dapsone for PCP prophylaxis. Two months after discharge, the urinary H. capsulatum assay level was 3.2 antigen units. Liver function tests normalized, with AST 26 U/L, ALT 17 U/L, and alkaline phosphatase 75 U/L. Thrombocytopenia and leukopenia improved, with platelet count rising to 129 000/mm³ and white blood cell count to 4.2 × 10³/mm³, but she remained severely anemic (hemoglobin 6.3 g/dL) and required blood transfusions.

Discussion

Widespread use of TMP/SMX for treatment and prophylaxis in the HIV-infected population has been associated with adverse reactions involving a variety of organ systems. Our patient developed severe central nervous system, gastrointestinal, and renal adverse effects shortly after starting therapy with TMP/SMX. Previous reports of TMP/SMX-induced adverse reactions have included individual reports of tremor, pancreatitis, and impaired renal function, but to our knowledge (PubMed, October 2003), this is the first case reported in which all of these manifestations occurred simultaneously.^1–3,5–10

Both trimethoprim and sulfamethoxazole have been implicated as causes of drug toxicity. Trimethoprim, an inhibitor of dihydrofolate reductase, has been proposed as the cause of adverse effects involving the central nervous system. Dihydrofolate reductase reduces 7,8-dihydrobiopterin to tetrahydrobiopterin, an essential cofactor in the production of dopamine, epinephrine, norepinephrine, and serotonin. Decreased production of dopamine can then lead to symptoms of parkinsonism including tremor.

A case was described of parkinsonian symptoms developing after administration of TMP/SMX to a 48-month-old child with a deficiency of dihydropteridine reductase, an enzyme essential in the regeneration of tetrahydrobiopterin. ¹¹ Another report described 4 cases of patients with AIDS who developed tremor within days of starting therapy with TMP/SMX. ⁵ Other neurologic symptoms, including apathy, ankle clonus, and wide-based gait, were also present in some of these cases. All symptoms resolved within 2–3 days of stopping TMP/SMX. Over a minimum of a 12-month follow-up period, only 1 of these patients developed dementia, making it unlikely that their tremor and other neurologic symptoms represented early manifestations of AIDS encephalopathy. Our patient had no preexisting signs or symptoms of encephalopathy and has not manifested any evidence of neurologic disease since her discharge from the hospital.

Sulfamethoxazole is metabolized by 2 pathways. N-acetylation, the predominant metabolic pathway, is mediated by the polymorphic enzyme N-acetyltransferase, with activity inherited as an autosomal recessive trait. ¹⁰ In patients who have genetically determined slow N-acetylation, use of sulfonamides can result in a high level of substrate available for alternate metabolic pathways. The alternate pathway involves cytochrome P450 oxidative enzymes producing toxic hydroxylamine derivatives that bind to macromolecules and cause cell death or elicit an immunologic response. ¹² These derivatives are scavenged by the antioxidant glutathione. In HIV-infected persons, glutathione concentrations are significantly lower than those of normal controls.^13,14 It is postulated that this deficiency of glutathione, needed for the detoxification of hydroxylamine derivatives, may exacerbate the toxic effects of sulfamethoxazole metabolites, and plays a role in the pathogenesis of hypersensitivity reactions to sulfonamides in HIV-infected patients. ¹³

Trimethoprim can inhibit renal tubular secretion of potassium and creatinine, leading to hyperkalemia and increases in serum creatinine concentrations.^15,16 In addition, tubular necrosis and insterstitial nephritis may result from sensitivity to sulfonamides.^17,18 Mechanisms underlying the development of acute pancreatitis associated with use of TMP/SMX are not well understood. HIV infection is associated with an increased risk of acute pancreatitis. ¹⁹ Medications frequently used for treatment and prophylaxis may also cause pancreatitis in this population. In addition to didanosine and pentamidine, which are more commonly implicated, TMP/SMX has been associated with the development of acute pancreatitis.^19,20

Summary

While TMP/SMX remains a very important agent for prophylaxis and treatment of infections in HIV-infected persons, the potential severity of adverse effects requires that clinicians have a low threshold for discontinuing this drug if patients develop symptoms attributable to toxicity of either moiety. Neurologic, gastrointestinal, and severe dermatologic reactions are seen with greater frequency in this population and warrant close attention to the possibility of an adverse drug effect caused by TMP/SMX.