A 56-Year-Old Woman With Systemic Lupus Erythematosus on Trimethoprim-Sulfamethoxazole Prophylaxis Presenting With Breakthrough Nocardiosis

Introduction

Immunocompromised individuals are at increased risk for a variety of health complications [1], among which opportunistic infections are a leading cause of morbidity [2,3]. This population includes organ transplant recipients, individuals receiving long-term immunosuppressive therapy, and those with HIV infection or hematologic malignancies [3,4]. Current guidelines, including those of the Infectious Diseases Society of America recommendations for adults and adolescents with HIV [5,6] and the American Society of Transplantation Infectious Diseases Community of Practice guidelines [7], recommend trimethoprim-sulfamethoxazole (TMP-SMX) as the preferred prophylactic agent for Pneumocystis jirovecii pneumonia in these high-risk groups [3]. TMP-SMX also provides prophylactic coverage against Toxoplasma gondii and Nocardia species in the setting of opportunistic infection prevention [8,9].

Nocardiosis, caused by aerobic actinomycetes of the genus Nocardia, is a rare but potentially severe opportunistic infection [10]. Nocardia species are filamentous, weakly acid-fast, gram-positive bacteria commonly found in soil, dust, and decaying organic matter [11]. Human infection typically occurs via inhalation, direct inoculation, or hematogenous dissemination [12,13]. Although exposure in the environment is widespread, disease predominantly affects immunocompromised hosts, particularly those with autoimmune conditions receiving corticosteroids, cytotoxic drugs, or long-term immunosuppressive therapy [10]. Pulmonary involvement is the most frequent manifestation; however, dissemination to the central nervous system (CNS), skin, or other organs is not uncommon and is associated with considerable morbidity and mortality [14].

Pulmonary nocardiosis often presents with nonspecific clinical and radiographic features that can mimic tuberculosis, malignancy, or fungal infection, complicating early diagnosis [15]. CNS involvement, in particular, carries a poor prognosis even with appropriate antimicrobial therapy [16]. TMP-SMX has long been regarded as the cornerstone for both the prophylaxis and treatment of nocardiosis [17]. Nevertheless, breakthrough infections have increasingly been reported in patients receiving low-dose prophylaxis [18,19]. Contributing factors may include subtherapeutic serum drug concentrations, species-specific differences in virulence and antimicrobial susceptibility, and impaired host immunity [18,19].

Here, we report a case of a 56-year-old woman with systemic lupus erythematosus (SLE) who developed disseminated Nocardia africana/nova infection despite long-term TMP-SMX prophylaxis, highlighting the challenges of correlating in vitro susceptibility with in vivo therapeutic response.

Case Report

A 56-year-old Chinese woman received a diagnosis of SLE in 2021, based on malar rash, arthralgia, positive anti–double-stranded DNA antibodies, and decreased complement levels. Since diagnosis, she had been maintained on long-term infection prophylaxis with oral TMP-SMX (1 tablet daily), along with prednisone (15 mg daily), hydroxychloroquine (200 mg twice daily), and esomeprazole (40 mg daily). During routine follow-up, chest computed tomography (CT) revealed incidental pulmonary opacities, although the patient remained asymptomatic. A calcified nodule was also noted in the right thyroid gland. In July 2023, she underwent extended radical thyroidectomy and partial right lung lobectomy, which confirmed right-sided thyroid carcinoma. Histopathology of the resected lung tissue revealed a cryptococcal granuloma, and she subsequently completed a 3-month course of fluconazole (400 mg daily).

In November 2024, follow-up CT demonstrated a newly developed dense consolidation in the right upper lobe (Figure 1). Empirical intravenous ceftazidime (2 g twice daily) was initiated, and fluconazole (400 mg daily) was continued. Bronchoscopy with bronchoalveolar lavage was performed, and next-generation sequencing of the lavage fluid identified Aspergillus terreus, Aspergillus flavus, and Talaromyces marneffei. Antifungal therapy was switched to oral voriconazole (200 mg every 12 hours), achieving a trough plasma concentration of 1.85 μg/mL. After 1 month of voriconazole therapy, repeat chest CT on December 4, 2024, showed progression of the right upper lobe consolidation (Figure 2). To clarify the etiology, a CT-guided percutaneous lung biopsy was performed on December 6, 2024 (Figure 3). Histopathology revealed suppurative inflammation with focal granulomatous changes, without evidence of fungal elements or acid-fast bacilli. Microbiological culture of the biopsy specimen yielded N. africana/nova complex, weakly acid-fast positive (Figure 4), confirming pulmonary nocardiosis. Antimicrobial susceptibility testing demonstrated susceptibility to TMP-SMX (minimal inhibitory concentration [MIC], 1 μg/mL), linezolid (MIC, 1 μg/mL), amikacin (MIC, ≤1 μg/mL), imipenem (MIC, ≤2 μg/mL), and clarithromycin (MIC, ≤0.06 μg/mL), intermediate susceptibility to ceftriaxone (MIC, 16 μg/mL), cefepime (MIC, 16 μg/mL), and minocycline (MIC, 4 μg/mL), and resistance to amoxicillin/clavulanate (MIC, >64 μg/mL), ciprofloxacin (MIC, >4 μg/mL), doxycycline (MIC, 8 μg/mL), tobramycin (MIC, 16 μg/mL), and moxifloxacin (MIC, 4 μg/mL) (Table 1).

Considering her history of long-term low-dose TMP-SMX prophylaxis and the TMP-SMX susceptibility of the isolate, a breakthrough Nocardia infection was diagnosed. On December 12, 2024, therapy was escalated to high-dose TMP-SMX (3 tablets orally 3 times daily) combined with linezolid (600 mg orally twice daily) (Figure 5). Follow-up CT on December 21, 2024, demonstrated reduction of pulmonary lesions, and the patient was discharged on the same regimen (Figure 6). After 1 month, chest CT on January 5, 2025, showed marked improvement of the right upper lobe consolidation (Figure 7). Due to limited access to oral linezolid in her rural residence and favorable clinical response with confirmed TMP-SMX susceptibility, linezolid was discontinued, and high-dose TMP-SMX monotherapy was maintained.

In March 2025, the patient was readmitted with acute confusion and altered mental status. Chest CT revealed relapse of pulmonary infection with cavitary lesions and pleural effusion (Figure 8). Brain magnetic resonance imaging demonstrated multiple ring-enhancing cerebral abscesses, consistent with disseminated nocardiosis (Figure 9). Admission to the intensive care unit was recommended; however, the patient’s family declined further aggressive interventions due to financial constraints, and she was discharged home for palliative care.

Discussion

This case highlights the diagnostic and therapeutic challenges of nocardiosis in immunocompromised hosts and underscores that breakthrough Nocardia infections can occur despite long-term TMP-SMX prophylaxis and documented in vitro susceptibility. Our patient, a 56-year-old woman with SLE receiving chronic corticosteroid therapy, developed progressive pulmonary nocardiosis with subsequent CNS dissemination, ultimately resulting in a fatal outcome.

Nocardiosis is an uncommon but serious opportunistic infection, predominantly affecting individuals with impaired cell-mediated immunity [13,17]. Established risk factors include long-term corticosteroid exposure, autoimmune disease, and solid organ or hematologic malignancy [12,20]. In patients with SLE, both the underlying immune dysregulation and prolonged immunosuppressive therapy contribute to increased Nocardia bloodstream infection [21]. Pulmonary involvement is most common; however, dissemination, particularly to the CNS, occurs in up to 40% of cases and is associated with substantially increased mortality [16,21,22]. CNS nocardiosis can present with minimal or nonspecific neurological symptoms, delaying diagnosis, as observed in our patient, until advanced disease developed [16,23].

TMP-SMX has long been considered the cornerstone of both the prophylaxis and treatment for nocardiosis [17,24]. Among hematopoietic stem cell transplant recipients, multiple studies have consistently suggested that TMP-SMX prophylaxis is associated with a lower incidence of nocardiosis [25–28]. However, emerging evidence indicates that low-dose TMP-SMX prophylaxis does not reliably prevent nocardiosis [29]. In solid organ transplant recipients, 18% to 40% of nocardiosis cases have been reported despite TMP-SMX prophylaxis, suggesting that prophylaxis reduces but does not eliminate risk [29]. Similar observations have been reported in patients with autoimmune diseases and hematologic malignancies [30]. However, a recent meta-analysis reported that TMP-SMX prophylaxis was associated with a 70% reduction in the odds of nocardiosis among solid organ transplant recipients [18]. However, while TMP-SMX may reduce the risk, it does not completely eliminate it. Patients presenting with a compatible clinical syndrome should be evaluated for nocardiosis regardless of prophylaxis [31].

A case series of immunocompromised hosts by Palombo et al illustrates the variability of presentation and outcomes [19]. Patients 1 and 3, who lacked TMP-SMX prophylaxis, developed rapidly progressive pulmonary nocardiosis with poor outcomes despite broad-spectrum antibiotics, both succumbing within 30 days. In contrast, patient 2, who received TMP-SMX prophylaxis, achieved favorable outcomes with early targeted therapy and prolonged follow-up. Similarly, patients 4, 5, and 6 demonstrated variable courses: some resolved with prolonged targeted therapy, while others developed disseminated infection or CNS involvement, particularly under intensive immunosuppression or delayed diagnosis [19].

Our patient developed breakthrough pulmonary nocardiosis despite ongoing low-dose TMP-SMX prophylaxis, an uncommon event that underscores prophylaxis limitations in high-risk, immunosuppressed patients [30]. Her initial presentation was indolent and asymptomatic, with pulmonary nodules discovered incidentally, highlighting the potential for subclinical disease in patients on prophylaxis. Despite confirmed TMP-SMX susceptibility, the infection eventually disseminated to the CNS, emphasizing the interplay between host immunity, pathogen virulence, and pharmacologic factors in disease progression. This contrasts with Palombo et al’s patients 2 and 5, in whom early recognition, targeted therapy, and combination regimens prevented dissemination [19]. Previous studies and case series have similarly reported relapse or treatment failure despite apparent susceptibility, particularly in patients with ongoing immunosuppression and CNS involvement [14,19,22].

The present case also emphasizes important therapeutic considerations. Current expert recommendations favor combination therapy for disseminated nocardiosis or CNS involvement, typically using TMP-SMX with agents such as linezolid, imipenem, or amikacin, followed by prolonged maintenance therapy [30,31]. Socioeconomic factors [32], as in this patient, may further complicate adherence to optimal treatment regimens and contribute to adverse outcomes [33,34].

In summary, this case reinforces that nocardiosis remains a life-threatening opportunistic infection in immunocompromised patients and that breakthrough infection can occur despite appropriate TMP-SMX prophylaxis and in vitro susceptibility.

Conclusions

This case demonstrates that breakthrough nocardiosis can develop in immunocompromised patients despite long-term TMP-SMX prophylaxis and apparent in vitro susceptibility. Clinicians should maintain a high index of suspicion for nocardiosis in patients receiving corticosteroids or other immunosuppressive therapies and recognize that in vitro susceptibility does not always predict in vivo therapeutic success. This report highlights that breakthrough Nocardia infections can occur with appropriate low-dose TMP-SMX prophylaxis.