Agranulocytosis Associated With Use of Sulfamethoxazole/Trimethoprim in a Healthy Adult

Abstract

Purpose: A case of sulfamethoxazole/trimethoprim-induced agranulocytosis is reported. Summary: A 53-year-old healthy male presented to the emergency room with a fever of 102.7°F and was found to have a white blood cell (WBC) count of 0.6 × 10³ cells/μL with an absolute neutrophil count (ANC) of 0.0 x 10³ cells/μL. He had recently completed a 10-day course of sulfamethoxazole/trimethoprim for left lower extremity cellulitis. During admission, a bone marrow biopsy was performed which was not concerning for malignancy and no cause for the agranulocytosis other than the sulfamethoxazole/trimethoprim was identified. The agranulocytosis resolved after 6 days of hospitalization with a WBC count of 8.9 × 10³ cells/μL and an ANC of 4.1 x 10³cells/μL on the day of discharge. Conclusion: A 53-year-old male developed agranulocytosis after 10 days of sulfamethoxazole/trimethoprim therapy for the treatment of a skin and soft tissue infection. His neutropenia resolved after sulfamethoxazole/trimethoprim discontinuation.

Introduction

Sulfamethoxazole/trimethoprim is commonly used to treat a variety of gram-negative and gram-positive infections. Use of this agent has been associated with several potential adverse reactions, many of which would be considered mild to moderate severity. Agranulocytosis is a rare but serious side effect of sulfamethoxazole/trimethoprim for which there is a paucity of evidence and risk factors are not well described. Agranulocytosis is defined as an absolute neutrophil count (ANC) below 0.5x10³ cells/μL and as many as 70-90% of cases are attributable to medications, also called idiosyncratic drug-induced agranulocytosis (IDIA). The frequency of IDIA ranges from 1.6 to 15.4 cases per million population per year with a reported mortality rate of about 5%. ¹ While sulfamethoxazole/trimethoprim is known to be associated with IDIA, it has frequently been linked in other cases to complex comorbidities or concomitant medications. Agranulocytosis may also be caused by autoimmune diseases, such as systemic lupus erythematosus, Sjögren’s syndrome, and rheumatoid arthritis, by myelosuppressive antibodies, or T lymphocytes that suppress granulopoiesis. ² Here we report a case of a healthy individual experiencing likely IDIA related to sulfamethoxazole/trimethoprim.

Case Report

A 53-year-old Caucasian male (177.8 cm; 84.5 kg) with a recent history of cellulitis presented to the emergency department with concerns for weakness, fever, chills, sore throat, and myalgias. His physical exam was unrevealing except for oropharyngeal erythema, subtle swelling and erythema of left lower extremity. He reported no abdominal pain, nausea, vomiting, diarrhea, shortness of breath, cough, weight loss and no recent travel or known exposure to infectious illness. The patient had no other significant past medical history, was not currently taking any medications, and illicit drug screening was not conducted due to the absence of drug abuse history. His only reported medication allergy included naproxen which he noted had caused facial swelling in the past.

The patient was recently diagnosed with cellulitis related to a laceration on his left thigh approximately 19 days prior to this admission. At that time, he was given one dose of intramuscular ceftriaxone and was prescribed a 10-day course of sulfamethoxazole/trimethoprim 800/160 mg by mouth twice daily which he completed 6 days prior to this hospitalization.

Upon admission to the emergency department, laboratory tests revealed a white blood cell (WBC) count of 0.6 × 10³ cells/μL (normal range 4.0-11.0 × 10³ cells/μL) with 97% lymphocytes and an absolute neutrophil count (ANC) of 0.0 x 10³ cells/μL, a platelet count of 386 × 10⁹/L, and a hemoglobin of 12.6 g/dL. The patient was admitted for new-onset severe neutropenic fever and was started on empiric piperacillin/tazobactam and vancomycin.

Further workup was guided by the patient’s initial presentation and included a chest x-ray, blood and urine cultures, and testing for viral pathogens including COVID-19, human immunodeficiency virus (HIV), Epstein-Barr Virus (EBV), cytomegalovirus (CMV), Hepatitis B and C virus. All tests were negative for acute infectious etiology, however the patient did have evidence of past/distant exposure to both EBV and CMV. The patient did not have risk factors for tuberculosis (TB) therefore testing was not done for this pathogen and his infectious symptoms resolved without TB treatment indicating that this was not likely to be the cause of his symptoms. A CT scan was not done since the patient had an absence of signs and symptoms suggestive of intrathoracic or intra-abdominal pathology. An infectious etiology was not identified on this comprehensive workup and the patient was continued on empiric therapy for neutropenic fever for a total of 7 days (piperacillin/tazobactam for 2 days followed by cefepime and vancomycin for 5 days). A bone marrow biopsy was performed on hospital day 5 and showed normocellular marrow with left-shifted granulocytic hyperplasia (consistent with granulocyte maturation arrest) and no morphologic evidence of dysplasia, lymphoma, or high-grade myeloid neoplasm. The pathology report suggested that drug-induced agranulocytosis was within the differential given his history of treatment with sulfamethoxazole/trimethoprim. The patient’s WBC nadir was 0.4 × 10³ cells/μL on hospital day 2 with a subsequent rise to 8.9 × 10³ cells/μL on hospital day 7. His ANC remained at 0.0 cells/μL from hospital day 1 through 3, followed by an increase to 3.0 × 10³ cells/μL on hospital day 7 (Figure 1). His absolute lymphocyte count also gradually increased from 0.6 × 10³ cells/μL on the day of admission up to 4.1 × 10³ cells/μL on hospital day 7.

Figure 1.

WBC and ANC Trend through hospital stay.

In the absence of other causes and given the temporal relationship between onset of agranulocytosis after completion of the sulfamethoxazole/trimethoprim course, a diagnosis of IDIA secondary to sulfamethoxazole/trimethoprim was made. A Naranjo Scale assessment was performed with a score of 7 indicating a probable adverse drug reaction to sulfamethoxazole/trimethoprim (Table 1). ³ Sulfamethoxazole/trimethoprim was added to the patient’s allergy list and he was discharged with an outpatient follow-up visit scheduled at one week post-discharge for a repeat CBC with differential.

Table 1.

Estimation of Naranjo Adverse Drug Reaction Probability.

1. Are there previous conclusive reports on this reaction?	Yes (+1)
2. Did the adverse event appear after the suspected drug was administered?	Yes (+2)
3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?	Yes (+1)
4. Did the adverse event reappear when the drug was readministered?	Not done (0)
5. Are there alternative causes (other than the drug) that could, on their own, have caused the reaction?	No (+2)
6. Did the reaction reappear when a placebo was given?	Not done (0)
7. Was the drug detected in blood (or other fluids) in concentrations known to be toxic?	Not done (0)
8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	Not done (0)
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	No (0)
10. Was the adverse event confirmed by any objective evidence?	Yes (+1)
Total score	7
Interpretation of total score: doubtful = 0; possible 1-4; probable 5-8; definite ≥9

Interestingly, the patient reported 2 prior occurrences of sulfamethoxazole/trimethoprim use. Four years prior to this presentation, the patient was given a course of this antibiotic which caused him to “feel unwell” so it was stopped. A year prior to the presentation discussed in this case report, the patient had a similar case of cellulitis from a puncture wound that was first treated with a dose of ceftriaxone and a course of cephalexin. After the cellulitis did not resolve with these antibiotics, he was prescribed a 7-day course of sulfamethoxazole/trimethoprim which resolved his symptoms. His CBC was not obtained after completion of sulfamethoxazole/trimethoprim in either previous course, however the patient reported resolution of both infections with no other noted complications.

Discussion

While hematologic side effects associated with sulfamethoxazole/trimethoprim are rare, this agent is one of the more common offending agents for incident neutropenia. The proposed mechanism for drug induced agranulocytosis is not fully understood, however likely involves an immune-mediated component. This is supported by the fact that in cases of repeat exposure after experiencing IDIA, the onset is often rapid due to the immune system’s memory. ⁴ Rawson and colleagues ⁵ conducted a retrospective evaluation of a national health database in Saskatchewan noting an incidence of agranulocytosis of 3.0 per million between 1982 and 1990 and found significant associations between antecedent use of sulfamethoxazole/trimethoprim, beta-lactam antibiotics, erythromycin, propranolol, antithyroid medications, and sulfasalazine. While additional population based and case-control studies have demonstrated an association between sulfamethoxazole/trimethoprim use and agranulocytosis, specific patient level details are not available to determine whether other contributing factors are present.^6-8

Despite this known association, our case adds value to the literature since our patient was otherwise healthy, had prior use of sulfamethoxazole/trimethoprim, was exposed to a short course of sulfamethoxazole/trimethoprim leading to agranulocytosis, and his agranulocytosis resolved spontaneously without administration of filgrastim. It is possible that the patient’s prior exposure to sulfamethoxazole/trimethoprim led to sensitization and a subsequent IgE mediated drug-toxicity. ⁹ We conducted a review of published cases (Table 2) and noted that the majority of identified cases of agranulocytosis with sulfamethoxazole/trimethoprim reported in the literature were associated with medically complex patients, concomitant medications that may contribute to agranulocytosis, or extended courses of sulfamethoxazole/trimethoprim therapy.^10-18 From the review of the literature, it can also be noted that many cases were missing key patient level details such as concomitant medications/comorbidities which limit the ability to interpret likelihood without that key clinical context.

Table 2.

Published cases of suspected sulfamethoxazole/trimethoprim associated agranulocytosis.

Patient	Age/sex	SMX/TMP Dose	SMX/TMP Duration	Potential concomitant drug causes	Potential concomitant non-drug causes	ANC Nadir (cells/uL)	Time to onset	Time to recovery	G-CSF Treatment (duration)	Bone Marrow Evidence of IDIA
1	64/M	400/80mg daily	27 days	Lansoprazole	Radiation Cancer	40	1 day	6 days	Yes (5 days)	N/A
2	67/M	800/160mg BID	3 days	Chlorpromazine	Not specified	30	4 days	19 days	No	N/A
3	64/F	Not specified	7 days	Ampicillin	Not specified	Not specified	1 day	7 days	Not specified	N/A
4	67/F	Not specified	5 days	Not specified	Not specified	Not specified	8 days	3 days	Not specified	N/A
5	21/F	400/80mg TID	36 days	Prochlorperazine, Promethazine	Not specified	25	5 days	5 days	No	Yes
6	40/M	400/80 mg BID	5 days	Not discussed	Not specified	0	5 days	Fatal on day 16	Yes	Yes
7	74/M	800/160 mg BID	14 days	None	Not specified	14	Not specified	4 days	Yes (3 days)	Yes
8	19/F	800/160 mg BID	9 days	None	None	40	9 days	5 days	No	N/A
9	M**	Not specified	5 days	Not specified	Not specified	100	Not specified	Not specified	Yes (14 days)	Yes
10	77/M	Not specified	6 days	Tetracycline	None	0	3 days	6 days	Not specified	Yes
11	89/F	2 tabs TID x 3d then 1 tab TID	22 days	NSAID		0	22 days	Fatal on day 23	No	N/A
				Furosemide	Cancer
				Digoxin	B12 deficiency

Abbreviations: SMX/TMP, sulfamethoxazole trimethoprim; ANC, absolute neutrophil count; G-CSF, granulocyte colony stimulating factor; N/A, not available; BID, twice daily; TID, three times daily; NSAID, non-steroidal anti-inflammatory drug.

**Age of this case was not specified.

We acknowledge that the patient did receive one dose of ceftriaxone at the start of his sulfamethoxazole/trimethoprim course and this drug has been associated with agranulocytosis. However, since only one dose was given approximately 19 days before presenting with agranulocytosis, it would be highly unlikely that this contributed given the existing literature that ceftriaxone-induced agranulocytosis occurs after prolonged courses with high cumulative doses.^19,20 Also, this patient had a bone marrow biopsy and hematologist evaluation which helped to confirm a diagnosis of drug-induced agranulocytosis strengthening this case as a probable representation of sulfamethoxazole/trimethoprim IDIA.

Conclusion

We present a case of agranulocytosis after 10 days of sulfamethoxazole/trimethoprim therapy which resolved after drug discontinuation. After thorough review of published literature, our case shows consistency with available evidence as it relates to time to onset, and adds value for practitioners in that it represents a medically straightforward patient in contrast to many cases where multiple factors may have contributed to agranulocytosis. This case should caution providers to remain aware of the possibility of hematologic toxicity from sulfamethoxazole/trimethoprim, even in otherwise healthy, previously exposed individuals.