Nocardia spp. Pneumonia in a Solid Organ Recipient: Role of Linezolid

We describe a rare infection with Nocardia spp. (N. pseudobrasiliensis species identification based on high-performance liquid chromatography analysis) in a 68-year-old renal transplant recipient. He presented with pneumonia complicated by hypoxic respiratory failure. He was allergic to sulphonamides. He was initially successfully treated with linezolid. However, he suffered severe sensory neuropathy after 4 months of therapy, necessitating linezolid cessation and completion of treatment with azithromycin. He had clinical and radiological resolution of his pneumonia and was disease free at subsequent follow-up 4 years later. This case highlights the need for alternative therapies for nocardiosis for patients that cannot be treated with sulphonamides due to allergies or/and infection with multidrug-resistant pathogens. It also illustrates the treatment limiting side effects of long-term therapy with linezolid.


Introduction
Nocardiosis is a potentially lethal opportunistic infection in transplant recipients on immunosuppressive therapy [1][2][3][4]. Nocardia pseudobrasiliensis is an uncommon human pathogen that is frequently multidrug resistant [5,6]. For decades, the sulphonamide class of antibiotics has been the mainstay of therapy in nocardiosis; however, resistance to this class of drugs, allergies, or intolerances have necessitated the use of alternative antibiotics [1-4, 7, 8]. Linezolid has been shown to have promise in the treatment of nocardiosis even as monotherapy [7,8]. Herein, we describe a case of Nocardia pseudobrasiliensis pneumonia treated with linezolid.

Case Presentation
e patient is a 68-year-old Caucasian male who received an allogeneic renal transplant 3 years before. He had end-stage renal disease from hypertensive nephropathy. Other comorbidities included sick sinus syndrome status post permanent pacemaker, gastroesophageal re ux disease, osteoarthritis, and depression. His medication regimen was tacrolimus, mycophenolate, prednisone, amlodipine, clonidine, metoprolol, simvastatin, aspirin, clopidogrel, calcium carbonate, magnesium oxide, and omeprazole. He is allergic to sulpha-containing drugs, furosemide and levooxacin. He is a former smoker with no prior recreational drug use or alcohol abuse. He denies any recent travel or unusual exposures. He was admitted for a 2-to 3-week history of progressive shortness of breath, nonproductive cough, fevers, night sweats, and a 7 kg weight loss. On admission, he was pyrexial with a temperature of 39.4°C, respiratory rate of 34/min, blood pressure of 105/60 mmHg, and pulse rate of 94/min. Auscultation of the chest disclosed reduced breath sounds and crackles on the right base. A complete blood count showed neutrophilic leukocytosis of 13000/μL and a total white cell count of 14100/μL. Serum chemistry was signi cant for a high BUN-to-creatinine ratio and a hypoxic respiratory failure on arterial blood gas testing (pH 7.47, pO 2 40.6, and pCO 2 31.4 mmHg). A chest X-ray and CT chest demonstrated a right middle lobe consolidation. A CT head with contrast was negative for any cerebral mass lesion(s). e tacrolimus level was supratherapeutic at 56 ng/mL (therapeutic range 5-20). He was intubated for hypoxic respiratory failure on day 2. He underwent bronchoscopy the same day. Microbiology tests were negative for viral (adenovirus, in uenza A and B, parain uenza 1, 2, and 3, RSV, metapneumovirus, HSV, EBV, CMV, BKV), fungal (Histoplasma, Cryptococcus, and Aspergillus antigens), and bacterial pathogens. Bronchial washings showed an acid-fast bacillus on staining. Cultures grew variable branching lamentous bacteria after 3 days of incubation, later identi ed as Nocardia pseudobrasiliensis using high-performance liquid chromatography (HPLC method done in Quest Diagnostics Infectious Diseases, a reference laboratory in California). Susceptibility testing was done by the microbroth dilution panel using Trek RGM panel and showed multidrug resistance with susceptibility to amikacin, cipro oxacin, clarithromycin, linezolid, and moxi oxacin (Table 1). Azithromycin susceptibility was inferred from clarithromycin susceptibility.
e patient responded to the empiric therapy with intravenous azithromycin 500 mg daily, meropenem 1000 mg 8 hourly, and linezolid 600 mg twice daily. He was extubated on day 7. Antibiotics were adjusted to oral linezolid 600 mg twice daily monotherapy on the eighth day. Tacrolimus was temporarily discontinued, and dose was adjusted to a target trough level of 5-7 ng/mL on resumption of therapy. After 4 months of linezolid treatment, the patient developed severe sensory polyneuropathy, necessitating a change to oral azithromycin 500 mg daily therapy. He completed 1 year of treatment with radiological resolution of the initial pulmonary in ltrate as early as 4 months into therapy. His neuropathy signi cantly improved but did not fully resolve. At 4 years of follow-up, he has no symptoms or signs of relapse.

Discussion
Among the ubiquitous saprophytic lamentous Gram-positive bacteria in the aerobic Actinomyces group is the species Nocardia, rst isolated on Guadeloupe Island by Edmond Nocard in 1888 from farcy-(lymphadenitis-) a icted cattle [9,10]. At least 50 nocardial species have been identi ed as human pathogens though 113 species have been elucidated to date (see http://www.bacterio.net/nocardia.html).
Nocardia pseudobrasiliensis is an uncommon pathogen phenotypically similar to N. brasiliensis species but biochemically distinguished by its adenine metabolism and nitrate reductase activity [6,7]. Di erentiating the two pathogens is of paramount importance as N. pseudobrasiliensis is typically a multidrug-resistant species capable of causing invasive and disseminated diseases [6,7]. Moreover, N. pseudobrasiliensis can also cause disease in immunocompetent subjects [7].
ere is paucity of data on the evaluation of risk factors for nocardial infection despite the widespread practice of transplant medicine in the current era. Peleg et al. did a matched case-control analysis of 35 nocardial infections that occurred among 5126 transplant recipients over a tenyear period ending in 2005 [3]. Independent risk factors for nocardial infection in their study were the use of high-dose steroids, prior CMV infection, and high calcineurin inhibitor levels in the blood as was the case in our patient. In addition, they discovered that lung transplant recipients were the most susceptible hosts among solid organ recipients. A recent multicentre European study con rmed the ndings by Peleg et al. [3]. e incubation period of nocardiosis is unknown; however, in transplant recipients, one study showed that the median time from transplantation to the development of nocardiosis was 34.1 months as was the case in our subject [1].
Due to a low prevalence of nocardiosis, there are no de nitive clinical studies on the most e ective antibiotics. Clinical expert opinions and conclusions from basic research or animal models are the cornerstone of recommendations, with sulphonamides being the drug of choice for at least the last six decades [1][2][3][4]11]. Newer data show a change in the antibiotic susceptibility of Nocardia species. Schlaberg and coworkers analyzed susceptibility patterns of 1299 nocardial isolates comprising 39 di erent species, 11 of which were newly described [11]. ey showed that all species were linezolid susceptible with resistance to sulphonamides 2%. e resistance to sulphonamides was even higher in N. transvalensis complex (19%) and N. pseudobrasiliensis (31%), as was the isolate in our subject [11]. Almost all species of Nocardia are susceptible to amikacin; however, its use in  [7]. Subsequently, several reports con rmed the e cacy of linezolid in nocardiosis [1,8]. Linezolid is a very attractive antibiotic with excellent oral bioavailability of 100%, which allows early switch of this agent from intravenous to oral formulation [1,7,8]. In addition, it has extensive tissue distribution, achieving therapeutic concentrations in almost every organ in the body including the CNS [8].
However, its cost and toxicity of long-term linezolid therapy have been the main disadvantages in its widespread use [1,8]. Substantial reduction of the cost occurred with the release of generic versions of linezolid at the end of 2015. Rare but serious neurological complications (optic and peripheral sensory neuropathies) have been reported with prolonged linezolid use and are more prevalent in subjects with preexisting neurological conditions, alcoholics, diabetics, or recipients of chemotherapeutic agents as was the case in our subject [12][13][14][15]. Duration but not the indication for linezolid use is the major determinant of neurological side e ects, and studies have shown that optic neuropathies resolve after linezolid cessation, while peripheral neuropathies do not [12]. Other important side e ects include myelosuppression (especially thrombocytopenia and rarely aplastic anemia) and type B lactic acidosis. [15]. ese side e ects appear to be mediated by direct mitochondrial protein synthesis inhibition by linezolid, and they disappear gradually after linezolid withdrawal [15]. e optimal duration of therapy is not clear, and recommendations are guided by the tendency for relapses of nocardiosis [1][2][3][4]. Pulmonary disease should be treated for 6-12 months depending on the resolution of the disease and therapeutic response, although newer studies have demonstrated favorable outcomes with shorter courses (<4 months) [2]. Our patient was treated for a longer duration than recommended due to paucity of data on azithromycin e cacy in the treatment of nocardiosis. Prolonged treatment also minimizes the risks of relapse [16]. In retrospect and based on the new European data, we believe that less than 4 months of linezolid therapy could have been adequate for our patient, and the shorter linezolid course would have prevented the evolution of sensory neuropathy.

Conflicts of Interest
e authors declare that there are no con icts of interest regarding the publication of this paper.