Nocardial endocarditis in native aortic valve with nocardial sepsis in a case of breast cancer

Abstract

Central venous catheter-associated bacteraemia caused by Nocardia species is very rare; the diagnosis of nocardiosis in patients with cancer is challenging because its clinical presentation is varied, sometimes mimicking metastases, and the high index of clinical suspicion is required for prompt institution of therapy. Herein, we report a case of nocardial sepsis with native aortic valve endocarditis in a patient with breast cancer in whom multidisciplinary team involvement and prompt initiation of therapy have led to successful outcome.

Background

Patients with indwelling venous catheters are prone to a variety of infections. Nocardiosis is a rare opportunistic infection caused by several species of the genus Nocardia, family Actinomycetaceae, which predominantly affects patients with defective cell-mediated immunity. Nocardia is transmitted to humans either by respiratory or, rarely, by percutaneous routes. Central venous catheter (CVC)-related bacteraemia caused by Nocardia species is very rare, with only few cases reported in literature. Establishment of diagnosis of nocardiosis in patients with cancer is challenging because its clinical presentation is varied, sometimes mimicking metastases, in keeping with its description as ‘the great imitator’. Herein, we report a case of nocardial sepsis with native aortic valve endocarditis associated with an indwelling CVC in a patient with breast cancer, with review of literature regarding its management.

Case presentation

A 53-year-old woman, with no comorbidities, presented with a 5 cm lump in her left breast and swelling in left axilla in December 2014. After clinical and radiological evaluation, she was diagnosed to have stage IIIA breast cancer, which was histopathologically confirmed as infiltrating ductal carcinoma grade III, oestrogen/progesterone receptor negative and HER2 receptor positive. She received four cycles of neoadjuvant chemotherapy with epirubicin and cyclophosphamide followed by a breast-conserving surgery. She also underwent CVC with a 9.6 Fr Bard port, during the surgical procedure. She completed postoperative adjuvant chemotherapy with 12 cycles of weekly paclitaxel followed by whole breast radiation. She completed 1 year of adjuvant trastuzumab in April 2016. Three months after the completion of treatment, she presented to another institution with increasing fatigue, headache and cough without expectoration. She was evaluated with CT scan of thorax, which showed the presence of multiple nodules in the lung parenchyma, which were suspected to be pulmonary metastases. A positron emission tomography (PET) scan was done to complete the metastatic workup. It revealed fluorodeoxyglucose (FDG) avid multiple bilateral lung parenchymal nodules suggestive of metastases, without any other site of recurrence. Patient was referred back to us for further treatment in November 2016. On examination, she was febrile, normotensive with heart rate of 100 beats/min. Examinations of bilateral breast, axilla and supraclavicular fossa were unremarkable. Fine crepitation was noticed in bilateral infrascapular regions.

Investigations

At the time of presentation, patient had already undergone CT scan of thorax and a PET scan. CT scan showed the presence of multiple nodules in the lung parenchyma with ground glass haziness (figure 1) and PET scan revealed FDG avid multiple bilateral lung parenchymal nodules and no other site of uptake. In view of history of fever and the presence of long-standing CVC, an echocardiogram (ECHO) was done to look for infective endocarditis (IE), which showed sessile 5×6 mm vegetation in the right coronary cusp of aortic valve. Transoesophageal echocardiography was also done to confirm transthoracic ECHO findings which revealed a sessile vegetation measuring 9×10 mm on the right cusp of aortic valve leaflet, associated with moderate aortic regurgitation (figure 2). Three sets of blood cultures, including one from Port-a-cath (PORT), were obtained. Blood culture report showed Nocardia species from all three sites. MRI of the brain showed no evidence of central nervous system (CNS) involvement; it was done to rule out CNS disease as CNS involvement determines the duration of antibiotic treatment in nocardial infection.

Figure 1.

CT scan thorax showing multiple lung parenchymal nodules with pleural-based air space opacity in right lower lobe of lung.

Figure 2.

Transoesophageal two-dimensional echocardiography showing 10 mm vegetation in the right cusp of aortic valve.

Differential diagnosis

Differential diagnosis considered were lung infection or lung metastasis (relapse of breast cancer). In view of history of fever, cough, presence of long-standing CVC and radiological evaluation showing B/L small nodules with ground glass haziness, a provisional diagnosis of invasive fungal infection in the lung was our first differential and she was started on intravenous caspofungin. Moreover, the ECHO showed sessile 5×6 mm vegetation in the right coronary cusp of aortic valve, which substantiated the diagnosis of infection rather than metastatic disease. Finally, the blood culture grew Nocardia that confirmed the diagnosis of nocardial sepsis with aortic valve endocarditis. Metastatic disease was not considered as working diagnosis as no abnormality was detected on local examination; furthermore, PET scan showed only FDG avid multiple bilateral lung parenchymal nodules and no other site of uptake.

Treatment

In view of history of fever, cough, presence of long-standing CVC and radiological evaluation showing B/L small nodules with ground glass haziness, a provisional diagnosis of invasive fungal infection in the lung was made and she was started on intravenous caspofungin. The patient continued to have fever and cough while receiving antifungal drugs. Blood culture report, obtained 6 days later, showed Nocardia species. In view of the diagnosis of disseminated nocardiosis (nocardial sepsis and native aortic valve endocarditis), she was started on intravenous meropenem (1000 mg every 8 hours) and intravenous amikacin (1000 mg every 24 hours) while antifungal drugs were stopped.

Within 2 weeks of the above antibiotic treatment, she reported significant improvement in fatigue and became afebrile. CT scan of the thorax showed near complete resolution of lung parenchymal nodules (figure 3). Her repeat blood culture, obtained 14 days after starting antibiotics, did not show any nocardial growth. She was planned to be given 6 weeks of intravenous antibiotics followed by 24 weeks of oral antibiotic treatment.

Figure 3.

CT scan thorax showing near complete resolution of pulmonary infiltration following 2 weeks of antimicrobial therapy.

After 41 days of intravenous antibiotics, she was noticed to have increasing intensity of diastolic murmur and widening of pulse pressure. An ECHO showed worsening of aortic regurgitation. In view of clinical deterioration, patient was taken up for aortic valve replacement. The operative findings included 13×12 mm vegetation on right coronary cusp extending to left coronary cusp, both leaflets flail and severe aortic regurgitation. A prosthetic aortic valve was placed. The excised aortic valve was subjected to histopathological and microbiological examination and it was negative for both malignancy and Nocardia. She was started on anticoagulation with oral warfarin 2 mg/day, antiplatelet drugs (oral aspirin 75 mg/day and oral clopidogrel 75 mg/day) and was continued on intravenous meropenem and amikacin in the same doses for two more weeks in the postoperative period. She was started on oral trimethoprim–sulfamethoxazole (TMP-SMZ) (80/400 mg, two times per day 1 tab), which was planned to be given for 6 months. However, she showed intolerance to this drug with nausea, vomiting and rising serum creatinine, despite dose interruptions and de-escalation. Therefore, TMP-SMZ was stopped and she was started on oral linezolid at a dose of 600 mg two times per day. Treatment with linezolid was planned for 6 months but it was stopped after 4.5 months because of grade IV anaemia with this drug. She received antibiotics for a total duration of 8 months from the diagnosis of nocardial infection.

Outcome and follow-up

Clinical evaluation, ECHO and CT scan, 6 months after the completion of antibiotics did not show any evidence of relapse of nocardial infection. The patient continues to be in good health at the time of last follow-up in January 2019.

Discussion

Nocardiosis is an aerobic, typically filamentous, branched, gram positive and weak acid-fast bacillus that causes a rare but potentially life-threatening infection.¹ On gram stain, Nocardia can resemble Actinomyces species; however, Actinomyces is not acid fast and grows under anaerobic conditions. It is predominantly an opportunistic infection, but can also occasionally affect immunocompetent individuals.² Predisposing factors include immunosuppressive therapy, especially steroids, chemotherapy drugs, solid organ and bone marrow transplantation, chronic bronchopulmonary diseases and AIDS.³

The characteristic feature of Nocardia is its ability to disseminate to virtually any organ, including the CNS, and its tendency to relapse or progress despite appropriate therapy.⁴ Nocardiosis should be suspected in any patient with cancer who presents with brain, soft tissue, or cutaneous lesions and a concurrent or recent pulmonary infection. Pulmonary involvement is the most common clinical presentation (seen in more than two-thirds of the cases) as inhalation is the primary route of exposure to Nocardia.⁵ Patients present with fever, cough, shortness of breath, chest pain, haemoptysis, weight loss and accelerating fatigue. The chest radiograph and CT scan show nodular infiltrates, cavitary lesions or may show consolidation. Clinically and radiologically, it is difficult to differentiate Nocardia from fungal (aspergillosis, mucormycosis) or mycobacterial infection.⁶ We made an initial provisional diagnosis of invasive pulmonary fungal infection before the final diagnosis of nocardial sepsis was made. Moreover, in patients with cancer, it is easy to mistake pulmonary findings for metastases, as was also the case in this patient before she presented to us.

Extrapulmonary nocardiosis is common in infected patients and usually presents as abscess formation resembling pyogenic infection. CNS is the most common extrapulmonary site for nocardial infection, seen in 20%–44% of patients.⁷ Patients can present with headache, nausea, vomiting, seizures or altered sensorium. Other rare sites of involvement are skin, cardiac valves and blood stream. Infective endocarditis (IE) caused by Nocardia is extremely rare with only a few previous reports, usually involving prosthetic valves but rarely in native valves.^{8 9}

Our patient had nocardial bacteraemia and IE. The same organism Nocardia was isolated from peripheral blood as well as from the PORT. There was no apparent source of blood stream infection other than the PORT in this patient. The quantitative culture of blood samples is not done in our microbiology labs and we do not have information about the differential time to growth in blood from PORT versus peripheral blood. In view of the above facts, our patient is best considered to have catheter-associated blood stream infection.¹⁰ Akhrass et al have reported the clinical characteristics and outcome of 17 patients with cancer with nocardia bacteraemia who had CVC. Ten patients grew Nocardia from CVC while seven did not (respiratory tract was the source of infection in these cases).¹¹ It is well known that Nocardia can be easily missed by Gram staining and has very slow growth in liquid or solid media.⁴ Isolation of bacteria in culture is often unsuccessful. If available, antimicrobial drug susceptibility tests should be performed on Nocardia isolates to guide therapy. Drug susceptibility of Nocardia varies among species.¹² In our patient, species typing and antibiotic sensitivity pattern could not be done because of lack of this facility.

Treatment of nocardiosis is challenging because Nocardia species are variably resistant to antibiotics and long duration of required treatment. TMP-SMZ is the most commonly used antibiotic. Various studies have reported sensitivity to TMP-SMZ in 84%–98% of isolates.¹³ Other active agents include amikacin, carbapenems, third-generation cephalosporins, linezolid, dapsone and tigecycline.^{14 15} Empirical treatment with the combination of agents is recommended in disseminated nocardiosis, based on the possibility of antimicrobial resistance among various species of Nocardia, synergistic activity of combination therapy as demonstrated in animal models¹⁶ and the high mortality linked with disseminated nocardiosis.¹⁷ In general, for CNS positive cases, three-drug combination of carbapenem, amikacin and TMP-SMZ is recommended¹⁸ since it covers all clinical isolates and resistance against this combination has not been reported so far. For CNS-negative disease, the combination of carbapenem and amikacin remains the first-line therapy.¹⁹ Patients with nocardiosis require prolonged antibiotic therapy to prevent relapse. Recommended durations of treatment are 3–6 months for cutaneous infections, 6–12 months for pulmonary infection and minimum of 1 year in patients with CNS involvement.²⁰ Patients can be switched to oral therapy after 6 weeks of intravenous antibiotics in cases of documented response with close monitoring of continued clinical response. Our patient did not have CNS involvement; we initially treated her with the combination of meropenem and amikacin. She had significant response within 14 days of this treatment in the form of near complete resolution of pulmonary lesions and improved effort tolerance.

Most patients have clinical improvement within 2 weeks of initiation of antibiotics. Lack of response is due to poor penetration of drug into the infected tissue compartment, the presence of an abscess requiring surgical drainage or primary drug resistance. Surgical intervention may be a useful adjunct in these situations. Lung nodules and infiltrates resolved in our patients with antibiotic therapy but aortic valve vegetation did not respond. She underwent aortic valve replacement, which led to a successful outcome.

Conclusion

The diagnosis of nocardial infection is challenging, because signs, symptoms and radiological findings are not specific and a high index of clinical suspicion is necessary. The diagnosis should be kept among differentials in patients with cancer with long duration indwelling CVCs who present with the symptoms of infection and pulmonary infiltrates. IE should be carefully looked for in such patients. Prompt institution of appropriate antibiotics, which need to be given for prolonged durations, along with surgical debridement if required, is important to achieve successful outcome.

Learning points.

• Patients with long-standing indwelling central venous catheter can present with rare and unusual infections.

• It is difficult to differentiate infections from metastatic disease especially in patients with cancer.

• A strong clinical suspicion and prompt institution of therapy is required for successful outcome.

• Multidisciplinary team is essential for diagnosis and treatment of rare infections like nocardiosis.

• In cancer, patient’s central venous catheter should be removed as soon as the adjuvant chemotherapy or targeted therapy is completed to avoid unusual infections.