63 - 179 Nocardiosis

179 Nocardiosis

TABLE 178-1  Effective Antibiotics for the Treatment of Donovanosis ANTIBIOTIC ORAL DOSE Azithromycin 1 g on day 1, then 500 mg daily for 7 days

or 1 g weekly for 4 weeks Trimethoprim-sulfamethoxazole 960 mg bid for 14 days Doxycycline 100 mg bid for 14 days Erythromycin 500 mg qid for 14 days (in pregnant women) Tetracycline 500 mg qid for 14 days condition is important, as are the administration of antibiotics and the monitoring of patients for an adequate interval (see below). Epidemiologic treatment of sexual partners and advice about how to improve genital hygiene are recommended. The recommended drug regimens for donovanosis are shown in Table 178-1. Gentamicin can be added if the response is slow. Ceftriaxone, chloramphenicol, and norfloxacin also are effective. Patients treated for 14 days should be monitored until lesions have healed completely. Those treated with azithromycin probably do not need such rigorous follow-up. Surgery may be indicated for very advanced lesions. ■ ■CONTROL AND PREVENTION Donovanosis is probably the cause of genital ulceration that is most readily recognizable clinically. Donovanosis is now limited to a few specific locations, and its global eradication is a distinct possibility. ■ ■FURTHER READING Muller EE, Kularatne R: The changing epidemiology of genital PART 5 Infectious Diseases ulcer disease in South Africa: Has donovanosis been eliminated? Sex Transm Infect 96:596, 2020. O’Farrell N: Donovanosis, in Sexually Transmitted Diseases, 4th ed. KK Holmes et al (eds). McGraw-Hill, 2008, pp 701–708. Rajam RV, Rangiah PN: Donovanosis (granuloma inguinale, granuloma venereum). Monogr Ser World Health Organ 24:1, 1954. Sehgal VN, Prasad AL: Donovanosis. Current concepts. Int J Dermatol 5:8, 1986. Section 7 Miscellaneous Bacterial Infections Michael S. Abers, Gregory A. Filice

Nocardiosis ■ ■INTRODUCTION Bacteria of the genus Nocardia are saprophytic filamentous aerobes ubiquitous in soil and water worldwide. In the past, the majority of isolates associated with pneumonia and systemic disease were iden­ tified biochemically as Nocardia asteroides, but the development of genome sequencing has demonstrated that at least 53 of the more than 100 species of Nocardia are associated with human disease. Most cases of systemic nocardiosis are caused by N. farcinica, N. cyriacigeorgica,

N. nova, N. abscessus, N. otitidiscaviarum, N. transvalensis, N. brasilien­ sis, N. pseudobrasiliensis, N. paucivorans, or N. brevicatena (Fig. 179-1). N. brasiliensis is usually associated with disease limited to the skin. Nocardiosis is usually an opportunistic infection, occurring primarily in individuals with impairments in host defenses. Infections follow­ ing local inoculation and pulmonary or systemic disease have distinct pathogenesis, microbiology, and management.

■ ■MICROBIOLOGY Nocardiae are Gram-positive, weakly acid-fast, and catalase positive. Like other members of the Mycobacteriales order, the cell walls of nocardiae contain mycolic acids (45–65 carbon atoms) and trehalose. Nocardia tend to clump together when grown in liquid media. On solid agar, Nocardia species typically form chalky, wrinkled colonies with a whitish-yellow or orange-brown hue. Growth is optimal at 37°C but can occur at temperatures up to 45°C. ■ ■EPIDEMIOLOGY AND RISK FACTORS Nocardiae are ubiquitous environmental saprophytes found in soil, water, and decaying organic matter worldwide. Humans are frequently exposed via inhalation or direct inoculation of the skin or an eye. Most immunocompetent individuals readily clear nocardiae without devel­ oping clinical disease. Certain impairments in host defenses predispose to invasive infection after inhalation. Primary cutaneous infection usually remains local. Nearly all cases are sporadic, but outbreaks have been reported in nosocomial settings among immunocompromised patients and in immunocompetent individuals related to surgical pro­ cedures or intravenous drug use. Person-to-person spread is not well documented. There is no known seasonality. The incidence of nocardiosis in the general population, estimated on three continents (North America, Europe, and Australia), is approxi­ mately ~0.375 cases per 100,000 persons per year. Nocardia infections are more common among adults than among children and more common among males than females. In contrast to the other forms of nocardiosis that occur worldwide, cases of actinomycetoma have been reported mostly in tropical and subtropical regions, especially in Mexico, Sudan, and India. The most important risk factors are lower socioeconomic status and frequent contact with soil or vegetable matter. Many cases are in laborers. Most cases of systemic nocardiosis occur in patients with host defense defects, including cell-mediated immunity and specific phago­ cyte defects. Those with nocardiosis typically possess one or more of the following risk factors: solid organ transplantation, hematopoietic stem cell transplantation, systemic corticosteroid use or Cushing syndrome, immunosuppressive therapy, or HIV infection. Among transplant recipients, risk factors for nocardiosis include corticoste­ roid dose, recent augmentation of immunosuppression for rejection or graft-versus-host disease, elevated calcineurin inhibitor levels, and patient age. Rare but well-described syndromes associated with nocar­ diosis include pulmonary alveolar proteinosis (PAP), neutralizing autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF), chronic granulomatous disease (CGD), and interleukin 12 (IL-12) or IL-12R deficiency. In the absence of any major risk factor for Nocardia infection, children and adults with nocardiosis should be tested for CGD. ■ ■PATHOGENESIS Pulmonary and systemic nocardiosis both occur following inhalation of fragmented bacterial mycelia. In healthy individuals, a variety of host defense mechanisms, including both innate and adaptive immune responses, help control and eliminate nocardiae from the respiratory tract without causing clinical disease. The importance of neutrophils and macrophages in antinocardial host defense is suggested by the fre­ quency of nocardiosis in patients with CGD. Nocardiae have evolved a number of properties that enable survival within phagocytes, including neutralization of oxidants, prevention of phagosome–lysosome fusion, and prevention of phagosome acidification. Neutrophils phagocytose nocardiae and limit their growth but do not kill them efficiently. Neutralizing autoantibodies against GM-CSF have been found in the majority of patients with autoimmune PAP and appear to be central to the pathogenesis of this disease. Nocardiae stimulate the production of GM-CSF in phagocytes in vitro, and extrapulmonary nocardiosis has been observed in several patients with autoantibodies to GM-CSF, most of whom had not had pulmonary alveolar proteinosis. The rela­ tionships between pulmonary alveolar proteinosis, nocardiosis, and antibodies to GM-CSF remain incompletely defined.

Amox-clav TMP-SMX Linezolid N. farcinica N. cyriacigeorgica N. nova complexa N. abscessus complexb N. beijingensis N. brasiliensis N. brevicatena/paucivorans N. otitidiscaviarum N. transvalensis complexc N. pseudobrasiliensis aIncludes N. nova, N. veterana, N. africana, N. elegans, N. aobensis, N. kruczakiae bIncludes N. abscessus, N. arthitidis, N. asiatica, N. pneumoniae. Note: N. beijingensis is a member of N. abscessus complex, but is listed separately cIncludes N. transvelensis, N. wallacei, N. blacklockiae FIGURE 179-1.  Nocardia species most commonly associated with human disease and their in vitro susceptibility patterns. TMP-SMX: trimethoprim-sulfamethoxazole. (Adapted from multiple sources.) Primary cutaneous nocardiosis typically follows penetrating injury of the skin by an object contaminated with soil or vegetable matter. Thorn-associated injuries, such as those associated with gardening, are a particularly common source of infection. Nocardiae may spread to draining lymph nodes, but dissemination to anatomically distant sites is uncommon. The ocular epithelium serves as a barrier that excludes nocardiae from the deeper tissues. Traumatic injury of the corneal epithelium provides a portal of entry for nocardiae to enter the ocular tissues, resulting in keratitis. The infectious process is limited to the superficial tissues. ■ ■PATHOLOGY The characteristic histologic feature of nocardiosis is an abscess with extensive infiltration of neutrophils and prominent necrosis. Granula­ tion tissue may surround the lesion, but extensive fibrosis and encap­ sulation are uncommon. Pyogranulomatous inflammation occurs in a minority of cases. In contrast, actinomycetoma is characterized by granulomatous inflammation and the formation of sinus tracts. ■ ■CLINICAL MANIFESTATIONS Pleuropulmonary Disease  The onset of pulmonary nocardiosis is typically subacute, with symptoms evolving over days to weeks prior to presentation. Among severely immunocompromised patients, the onset may be more acute. Cough is prominent and produces small amounts of thick, purulent sputum that is not malodorous. Fever, anorexia, and malaise are common; weight loss, dyspnea, pleuritic chest pain, and hemoptysis are uncommon. Without definitive treat­ ment, patients frequently experience remissions and exacerbations over a period of weeks to months. Typical radiographic patterns include infiltrates, nodules, and masses in one or more lobes (Figs. 179-2 and 179-3). Nodules fre­ quently cavitate (Fig. 179-3). Pleural effusion or empyema occurs in about one-third of cases. In some cases, empyema may occur in the absence of lung involvement. Extrapulmonary Disease  Dissemination to anatomically distant sites occurs in up to one-third of patients with pneumonia. While blood cultures are frequently negative, nocardiae likely reach meta­ static sites of infection via hematogenous spread. Virtually any organ can be involved, but the central nervous system (CNS) and skin and subcutaneous tissues are the most common sites.

Clarithromycin Ciprofloxacin Moxifloxacin Doxycycline Minocycline Tobramycin Ceftriaxone Imipenem Amikacin

90% of isolates are susceptible 50–90% of isolates are susceptible 15–50% of isolates are susceptible <15% of isolates are susceptible CHAPTER 179 The CNS is involved in up to two-thirds of cases of disseminated nocardiosis. The vast majority of patients present with one or more brain abscesses. One-third of patients have no symptoms of CNS involvement, and one-fourth of patients do not have apparent pulmo­ nary disease at presentation. Brain imaging demonstrates one or more ring-enhancing lesions that characteristically have a multilobulated appearance (Fig. 179-4). Multiple abscesses are seen in two-thirds of patients. Many abscesses can be detected with contrast-enhanced computed tomography (CT), but magnetic resonance imaging (MRI) with intravenous gadolinium is more sensitive. N. farcinica appears to have a special predilection for CNS involvement. Meningitis is uncommon and is usually due to spread from a nearby brain abscess. Nocardiosis FIGURE 179-2.  Nocardia pneumonia. A dense infiltrate with a possible cavity and several nodules are apparent in the right lung.

FIGURE 179-3.  Pulmonary nocardiosis. A computed tomography scan shows solid nodules (yellow arrows) and a cavitated nodule (yellow arrowhead) in the right lung as well as a right-sided pleural effusion and an abscess of the right chest wall (red asterisk). Bronchiectasis, which was unrelated to nocardiosis, is present in the left lung. A neutrophilic pleocytosis is typically seen in the cerebrospinal fluid, but cultures are rarely positive. Involvement of the skin and subcutaneous tissues occurs in onefifth of patients with disseminated disease. Typical manifestations include subcutaneous abscesses, papules, nodules, and ulcers. Skin abscesses involve adjacent muscle in a minority of cases. Abscesses involving virtually every organ have been described with the most common sites being kidney, adrenal gland, muscle, bone, joint, eye, lymph node, and thyroid gland. Endocarditis has been reported and can affect native or prosthetic valves. Central venous catheter infec­ tions have been reported. Peritonitis has been reported in patients undergoing peritoneal dialysis. PART 5 Infectious Diseases Primary Cutaneous Nocardiosis  Primary cutaneous nocardio­ sis follows transcutaneous nocardial inoculation and takes one of three forms: cellulitis, lymphocutaneous syndrome, or actinomycetoma. Cellulitis begins 1–3 weeks after a recognized breach of the skin, often with soil contamination. Pain, swelling, erythema, and warmth develop over days to weeks. The lesions are usually firm and not fluc­ tuant. Depending on the nature of the inoculation injury, disease may spread to nearby muscles, tendons, bones, and joints. Dissemination is rare. Lymphocutaneous disease usually begins as a pyodermatous nodule at the site of inoculation, followed by central ulceration and purulent or honey-colored drainage. Subcutaneous nodules often appear along lymphatics that drain the primary lesion. Most cases follow inoculation of a limb, but cases involving the face have been reported, especially in children. Most cases of nocardial lymphocutaneous syndrome FIGURE 179-4.  Multiloculated Nocardia brain abscess in the left cerebellum.

are associated with N. brasiliensis. Similar disease occurs with other pathogens, most notably Sporothrix schenckii (Chap. 225) and Myco­ bacterium marinum (Chap. 185). Mycetoma is an indolent, slowly progressive infection of the skin and subcutaneous tissues with nodular swellings and draining sinuses. Actinomycetoma refers to cases of mycetoma caused by filamentous bacteria. Nearly all cases of Nocardia-associated actinomycetoma are caused by N. brasiliensis. Clinical manifestations usually begin with a nodular swelling, sometimes at a site of local trauma. Lesions (Fig. 179-5) typically develop on the feet or lower legs but may involve the hands, the posterior part of the neck, the upper back, the head, and other sites. The nodule eventually breaks down, and a fistula appears, typically followed by others. The fistulae tend to come and go, with new ones forming as old ones disappear. The discharge is serous or purulent, may be bloody, and often contains 0.1­ to 2-mm white granules consist­ ing of masses of mycelia (Fig. 179-5). The lesions spread slowly along fascial planes to involve adjacent areas of skin, subcutaneous tissue, and bone. Over months or years, there may be extensive deformation of the affected part. Lesions involving soft tissues are only mildly pain­ ful; those affecting bones or joints are more so (Fig. 179-5). Systemic symptoms are absent or minimal, but mycetoma cases are often associ­ ated with prolonged, severe disability. Infection rarely disseminates from actinomycetoma, but lesions on the head, neck, and trunk can invade locally to involve deep organs. The World Health Organization has designated mycetoma a neglected tropical disease. Primary Ocular Disease  Primary ocular nocardiosis includes keratitis, scleritis, and exogenous endophthalmitis. These infections typically occur in otherwise healthy individuals. Patients may report recent exposure to soil. Ocular trauma, surgery, and the use of contact lenses are common risk factors. The onset of disease is typically sub­ acute. Signs and symptoms alone cannot distinguish nocardiosis from other ocular diseases. Spread beyond the eye does not occur. ■ ■DIAGNOSIS The first step in diagnosis is examination of sputum or pus for branch­ ing, beaded, Gram-positive filaments 1 μm wide and up to 50 μm long (Fig. 179-6). These filaments tend to fragment; this may produce apparent cocci and coccobacilli forms. Most nocardiae are acid-fast in direct smears if a weak acid is used for decolorization (e.g., in the mod­ ified Kinyoun, Ziehl-Neelsen, and Fite-Faraco methods). The organ­ isms often take up silver stains. Recovery from specimens containing mixed flora can be improved with selective media (colistin–nalidixic acid agar, modified Thayer-Martin agar, or buffered charcoal–yeast extract agar). Nocardiae grow well on most fungal and mycobacterial media, but procedures used for decontamination of specimens for mycobacterial culture can kill nocardiae and should not be used when nocardiosis is on the differential diagnosis. Nocardiae grow relatively slowly; colonies may take up to 2 weeks to appear and may not develop their characteristic appearance—white, yellow, or orange, with aerial hyphae—for up to 4 weeks. When the diagnosis of nocardiosis is being considered, clinicians should inform the microbiology laboratory so that cultures can be incubated for pro­ longed periods of time. Sputum smears are frequently negative in patients with pulmonary nocardiosis. In such cases, bronchoalveolar lavage fluid or a lung biopsy specimen should be obtained. Isolation of Nocardia from a respiratory specimen does not always indicate pulmonary infection. Nocardia may colonize the respiratory tract of patients with underly­ ing bronchiectasis or other structural lung diseases. In such cases, isolation of Nocardia from a respiratory sample must be considered in the greater clinical context. When nocardiae are present in respira­ tory specimens from patients with intact host defenses, pulmonary nocardiosis should be diagnosed only when clinical and radiographic features are supportive. Nocardiosis is less likely if Gram-stained specimens are negative and cultures are not consistently positive. In contrast, a positive culture in an immunosuppressed patient usually reflects clinical disease, and empirical antimicrobial therapy should be started.

A B C D FIGURE 179-5.  Nocardia brasiliensis mycetoma. A. Draining sinuses and giant white grains with a seropurulent discharge. B. Radiography of the foot showing marked soft tissue enlargement and bony lytic lesions. C. Direct microscopy of grains stained with Lugol’s iodine (×40). D. Periodic acid–Schiff stain of skin biopsy (×40). (Images provided by Roberto Arenas and Mahreen Ameen, St. John’s Institute of Dermatology, Guy’s & St Thomas’ NHS Trust, London, UK. Reprinted from R Arenas, M Ameen: Lancet Infect Dis 10:66, 2010, with permission from Elsevier.) Occasionally, Nocardia isolated from blood cultures may represent contamination in individuals without risk factors for nocardiosis, par­ ticularly those who lack clinical manifestations suggestive of nocardial disease. Actinomycetoma, eumycetoma (cases involving fungi; Chap. 225), and botryomycosis (cases involving cocci or bacilli, often Staphylo­ coccus aureus) are difficult to distinguish clinically but are readily distinguished with microbiologic testing or biopsy. Granules should be sought in any discharge. Suspect particles should be washed in saline, examined microscopically, and cultured. Granules in actinomycetoma are usually white, pale yellow, pink, or red. They consist of tight masses of fine filaments (0.5–1 μm wide) radiating outward from a central core (Fig. 179-5). Granules in eumycetoma cases are white, yellow, FIGURE 179-6.  Gram-stained brain biopsy specimen from a patient with CNS nocardiosis. (Reproduced with permission from N Hauser et al: An immunocompromised woman with a brain lesion. Am J Med 133:e516-e517.)

CHAPTER 179 Nocardiosis brown, black, or green; under the microscope, they appear as masses of broader filaments (2–5 μm wide) encased in a matrix. Granules of botryomycosis consist of loose masses of cocci or bacilli. Organisms can also be seen in wound discharge or histologic specimens. Culture is the most reliable method for determining the causative organism in cases of mycetoma. When possible, isolates should be speciated at least to a complex level, by either matrix-assisted laser desorption/ionization–time of flight mass spectrometry (commonly referred to as MALDI-TOF) or genomic sequencing (typically 16S rRNA, secA1, hsp65, or gyrB). When possible, antimicrobial susceptibility testing should be performed, ideally with a Clinical Laboratory Standards Institute–approved broth dilution test. E-tests are less definitive. Nocardiae grow more slowly than most clinically important bacteria, and they tend to clump in sus­ pension so that susceptibility test endpoints are difficult to interpret. Thus, experience is required for interpretation of susceptibility testing results. ■ ■EVALUATION OF PATIENTS WITH ESTABLISHED NOCARDIOSIS Timely identification of metastatic sites of infection is a critical com­ ponent of managing patients with nocardiosis. Disseminated nocar­ diosis is exceedingly uncommon in patients with primary cutaneous or ocular disease that develops following traumatic injury. Patients with other forms of nocardiosis, regardless of symptoms, should undergo contrast-enhanced imaging of the CNS to identify undiagnosed brain abscesses. MRI is the preferred imaging modality, with CT reserved for scenarios when MRI cannot be performed. The presence of a previously undiagnosed immunologic defect should be considered in patients with disseminated nocardiosis who lack typical risk factors for infection. Such patients should undergo testing for HIV infection. Further testing for underlying immuno­ logic disorders should be guided by a careful history and physical examination.

TABLE 179-1  Treatment Duration for Nocardiosis DISEASE DURATION Pulmonary or systemic     Intact host defenses 6–12 months   Deficient host defenses 12 monthsa   CNS disease 12 monthsb Primary cutaneous disease (cellulitis, lymphocutaneous disease) 2 months Osteomyelitis, arthritis, laryngitis, sinusitis 4 months Actinomycetoma 6–12 months after clinical cure Keratitis Topical: until clinical cure   Systemic: until 2–4 months after clinical cure aIn some patients with AIDS and CD4+ T lymphocyte counts of <200/μL or with chronic granulomatous disease, therapy for pulmonary or systemic disease may be continued indefinitely. bIf all apparent central nervous system (CNS) disease has been excised, the duration of therapy may be reduced to 6 months. TREATMENT Nocardiosis Trimethoprim-sulfamethoxazole (TMP-SMX) is the drug of choice for most cases of nocardiosis (Fig. 179-1 and Table 179-1). At the outset, 10–20 mg/kg of TMP and 50–100 mg/kg of SMX are given each day in two divided doses. Later, daily doses can be reduced to as little as 5 mg/kg and 25 mg/kg, respectively. In persons with sulfonamide allergies, desensitization usually allows continuation of therapy with these effective and inexpensive drugs. PART 5 Infectious Diseases Linezolid is highly bioavailable and uniformly active against all Nocardia species. Treatment-limiting toxicity frequently develops after 2–3 weeks of standard-dose therapy. Tedizolid is associated with less toxicity, but clinical experience is limited. Amikacin is active against nearly all Nocardia species with the notable exceptions of N. transvalensis and some N. pseudobrasiliensis isolates. Doses of 5–7.5 mg/kg every 12 h or 15 mg/kg every 24 h are typically used. Serum drug levels should be monitored during prolonged therapy, especially in patients with diminished renal function and in the elderly. Among the β-lactams, ceftriaxone and imipenem have activ­ ity against many Nocardia species and are frequently used when combination therapy is indicated. Ceftriaxone is not active against N. farcinica, which is among the most common species isolated in nocardiosis. In patients with CNS involvement, meropenem is preferred to imipenem as the latter is associated with a higher risk of seizures. Amoxicillin (875 mg) combined with clavulanate (125 mg), given twice a day, has been effective in treating N. brasiliensis and some cases of N. farcinica. Among the quinolones, moxifloxacin appears to be most active. Minocycline (100–200 mg twice daily) is often effective; other tetra­ cyclines are usually less effective. Tigecycline appears to be active in vitro against some species, but clinical experience is limited. Empirical treatment of patients with severe disease should con­ sist of combination therapy with two or three of the following agents: TMP-SMX, linezolid, amikacin, and imipenem (or merope­ nem if the CNS is involved). Clinical improvement is usually noticeable after 1–2 weeks of therapy but may take longer. After definite clinical improvement, therapy can be continued with a single oral drug, usually TMP-SMX. Some experts use two or more drugs for the entire course of therapy, but whether multiple drugs are better than a single agent is not known, and additional drugs increase the risk of toxicity. Surgical management of nocardial disease is similar to that of other bacterial diseases. Brain abscesses should be aspirated, drained, or excised if the diagnosis is unclear, if an abscess is large,

or if an abscess fails to respond to antimicrobial therapy. Surgi­ cal options include needle aspiration and open drainage/excision. Needle aspiration is less invasive, but patients frequently require multiple aspirations. Small or inaccessible brain abscesses can be treated medically. Brain imaging should be repeated to document the resolution of lesions, although radiographic improvement typi­ cally lags behind clinical improvement. With appropriate treatment, the mortality rate for localized pulmonary nocardiosis is <10%. Disseminated nocardiosis car­ ries a higher mortality rate, especially among patients with CNS involvement. Primary cutaneous and ocular nocardiosis often respond to anti­ microbial therapy. Occasionally, surgical management is required for patients with actinomycetoma or scleritis that fails to response to antimicrobial therapy. The mortality rate for actinomycetoma is exceedingly low, but patients suffer often from substantial mor­ bidity, disfigurement, disability, and/or stigmatization. Patients with nocardial keratitis should not receive adjunctive topical corticosteroids. ■ ■PREVENTION Use of TMP-SMX in high-risk populations to prevent Pneumocystis disease may reduce but does not eliminate the risk of nocardiosis. The incidence of nocardiosis is low enough that prophylaxis solely to prevent a first episode of Nocardia infection (i.e., primary pro­ phylaxis) is not recommended. The role of secondary prophylaxis to prevent recurrent nocardiosis has not been adequately studied. Some experts recommend secondary prophylaxis for patients who remain at high risk for Nocardia infection after the completion of antimicro­ bial therapy. ■ ■FURTHER READING Averbuch D et al: Nocardia infections in hematopoietic cell transplant recipients: A multicenter international retrospective study of the Infectious Diseases Working Party of the European Society for Blood and Marrow Transplantation. Clin Infect Dis 75:88, 2022. Corsini Campioli C et al: Clinical presentation, management, and outcomes of patients with brain abscess due to Nocardia species. Open Forum Infect Dis 8:ofab067, 2021. Hamdi AM et al: Retrospective analysis of antimicrobial susceptibility profiles of Nocardia species from a tertiary hospital and reference lab­ oratory, 2011 to 2017. Antimicrob Agents Chemother 64(3):e01868, 2020. Lebeaux D et al: Outcome and treatment of nocardiosis after solid organ transplantation: New insights from a European study. Clin Infect Dis 64:1396, 2017. Margalit I et al: How do I manage nocardiosis? Clin Microbiol Infect 27:550, 2021. Passerini M et al: Trimethoprim-sulfamethoxazole significantly reduces the risk of nocardiosis in solid organ transplant recipients: Systematic review and individual patient data meta-analysis. Clin Microbiol Infect 30:170, 2024. Restrepo A et al: Nocardia infections in solid organ transplantation: Guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation. Clin Transplant 33:e13509, 2019. Rosen LB et al: Nocardia-induced granulocyte macrophage colonystimulating factor is neutralized by autoantibodies in disseminated/ extrapulmonary nocardiosis. Clin Infect Dis 60:1017, 2015. Traxler RM et al: Updated review on Nocardia species: 2006–2021. Clin Microbiol Rev 35:e0002721, 2022. Wang H et al: Epidemiology and antimicrobial resistance profiles of the Nocardia species in China, 2009 to 2021. Microbiol Spectr 10:2,

Yetmar ZA et al: Mortality after nocardiosis: Risk factors and evalu­ ation of disseminated infection. Open Forum Infect Dis 10:ofad409, 2023.