Nocardia Infections in Solid Organ Transplantation

Nocardia species are ubiquitous saprophytic gram-positive bacteria in the 'aerobic actinomycetes' group 1, which also includes Corynebacterium, Rhodococcus, Gordonia, Tsukamurella, Actinomadura and Mycobacterium 2-4. More than 30 of the 80 Nocardia species characterized have been associated with disease 2, 5, 6. The most important causes of infection in transplant recipients are Nocardia asteroides sensu stricto 1, N. farcinica, N. nova, N. brasiliensis, N. otitidiscaviarum and the N. transvalensis complex 4, 6-9. Molecular methods have now identified many new species which cause infection 2, 6, 10, including N. veterana 11, N. abscessus 12, N. paucivorans 13, and N. wallacei and N. blacklockiae of the N. transvalensis complex 9. Nocardia cyriacigeorgica is becoming a commonly identified human pathogen 2, 5, 14-19. From 1995 to 2004, the most common Nocardia species of 765 United States (US) isolates were N. nova (28%), N. brasiliensis (14%), N. farcinica (14%) and N. cyriacigeorgica (13%) 19. Nocardia infections appear to have increased in the last two decades, likely due to better detection and identification procedures as well as to an expanding immunocompromised population 2, 20, since the majority of patients with nocardiosis are immunosuppressed 2, 14. The frequency of nocardial infections in solid organ transplant recipients varies between 0.7% and 3.5%, and historically, infections were mostly reported in heart, kidney and liver transplant recipients and less frequently in lung transplant recipients 21-23. However, several recent reviews have shown greater rates of nocardial infection among lung transplant recipients. A review of 5126 organ transplant recipients demonstrated a 3.5% rate of Nocardia infection among lung transplant recipients, with rates in heart, intestine, kidney or liver recipients of 2.5%, 1.3%, 0.2% and 0.1%, respectively 23. Two other large retrospective studies showed rates of nocardial infection in lung transplant recipients of 1.9% 24 and 1.78% 25, and in the latter study this accounted for 37% of all the transplant-associated Nocardia infections. Regarding species in solid organ transplant recipients, Peleg et al. identified N. nova in 49% of 35 patients, followed by N. farcinica in 28%, N. asteroides in 23%, and N. brasiliensis in 3% 23. Among the nocardial infections reported by Santos, nine (47%) were due to N. asteroides, two each to N. brevicatena and N. brasiliensis and one to N. otitidiscaviarum, but five cases (26%) were not speciated 25. However, the prevalence of nocardial infections in general, and specific Nocardia species appears to vary by geography 19, 26, 27. In the US it has been observed that nocardial infections are more frequent in the dry, windy climates of the southwest, possibly because such conditions facilitate aerosolization and dispersal of the organisms 27. Furthermore, there may be species and strain differences in virulence due to cell wall composition, inhibition of immune responses and a variety of other virulence factors 1, 2, 28. N. farcinica, for example, has been demonstrated to be more virulent than other Nocardia species in a mouse model 29. The protective immune response to Nocardia is primarily a T-cell-mediated one 30. Therefore, the organism is most commonly seen in solid organ transplant recipients, persons with human immunodeficiency virus (HIV) infection (CD4 counts < 100 cells/mm3), those with lymphoreticular malignancy and individuals treated with chronic corticosteroid therapy, with more than 60% of reported cases associated with one of these conditions 31. Although nocardial infection in transplant recipients often develops within the first year posttransplant, infection rarely occurs within the first month 14, 18, 23, 32. Nocardiosis has also occurred late posttransplant in some series, with a median time to infection from transplant of 34–38 months 25, 33. The diagnosis should be considered at any time posttransplant if intensified immunosuppression (including antilymphocyte globulin or high-dose steroids) has recently been used 23, 34. Studies have demonstrated that up to 63% of solid organ transplant recipients with nocardiosis develop infection in the first year after transplant, and receipt of high-dose steroids, cytomegalovirus disease in the preceding 6 months and intensified immunosuppression, including a high median calcineurin inhibitor level in the preceding 30 days, were independently associated with subsequent Nocardia infection 14, 18, 20, 23, 33. Newer immunosuppressive therapies may also be risk factors for nocardiosis. Despite the fact that animal studies have demonstrated little contribution from B lymphocytes in preventing Nocardia infection 35, rituximab, a monoclonal antibody used to prevent and treat antibody-mediated rejection, was recently described as a potential risk factor for the development of cerebral nocardiosis 36, 37. In addition, profound hypogammaglobulinemia in combination with transplant immunosuppression has been implicated as a factor in the development of nocardial infections 38. It is therefore possible that deficits in B-cell function may affect cell-mediated immune responses against Nocardia. Tumor necrosis factor (TNF) has also been shown to be important in clearing Nocardia in animal models 39, and there have been recent reports of Nocardia infections complicating immunomodulatory treatment of rheumatologic diseases with TNF blockers 40, 41. Finally, alemtuzumab, a humanized monoclonal antibody against the CD52 antigen found on mononuclear cells, is increasingly being used for the prevention or treatment of organ rejection and it has been associated with a number of opportunistic infections including nocardiosis 42, 43. The main route of Nocardia infection is via the respiratory tract, and subsequent spread to other tissues, particularly the brain, may occur. Nocardial infection predominantly causes pneumonia in transplant recipients 14, 23, 25, 44 and disease is typically subacute with symptoms often present for weeks 6. Nocardiosis should be considered a diagnostic possibility in any transplant recipient patient with an indolent pulmonary process. The host response to infection may range from a granulomatous to purulent reaction 1, 45. Radiological examination usually demonstrates irregular nodular lesions 18, 23, 33 that may cavitate, and may be accompanied by a 'halo sign' 46. However, the infection may also appear as diffuse pneumonic infiltrates or consolidative with pleural effusions 14, 23, 25, 44, 46, 47. Local spread to contiguous structures including the chest wall has been observed 46, and hematogenous dissemination is not uncommon. In fact, because extrapulmonary disease complicates up to 50% of cases of pulmonary nocardiosis, the diagnosis of Nocardia pulmonary infection should prompt a search for disseminated disease, and further investigation should include magnetic resonance imaging (MRI) of the brain to exclude cerebral abscess, as up to one-third of cases have central nervous system (CNS) involvement 1, 6, 33, 44, 48, 49. Nocardiosis should always be considered a diagnostic possibility in patients with nodular lesions of the lungs and brain. Nocardia can also infect the skin and subcutaneous tissues, either via direct inoculation or hematogenous spread. Primary cutaneous infection has occurred in immunocompromised and immunocompetent persons after penetrating injuries, especially with outdoor activities 14, 25, 50. Subcutaneous nodules and a sporotrichoid type of infection can develop, as well as mycetoma, pyomyositis and bone abscess 1, 33. While much less common, other typical locations for Nocardia dissemination include the eyes, kidneys and bone or joints 1, 33, 51, 52. Unusual manifestations of systemic disease in transplant recipients include epididymo-orchitis 53 and pericarditis 54. Despite its propensity to disseminate hematogenously, Nocardia is isolated from blood cultures only rarely 25, and this is often associated with central venous catheters, particularly in cancer patients 55, 56. The definitive diagnosis of nocardial disease requires demonstration of the organism on culture from a suspected site, particularly given the broad differential diagnosis of pulmonary, brain and soft tissue infections in transplant recipients. It is important to obtain lung or skin biopsies, where possible, to confirm the diagnosis. Biopsy of brain abscesses, while preferred, may not always be feasible, but the finding of brain lesions in the setting of confirmed pulmonary or soft tissue Nocardia infection is a strong indication of CNS nocardiosis, as is radiographic improvement of brain abscesses during treatment for nocardiosis. Contamination of clinical specimens may occur, as can colonization of the respiratory tract, but the latter is typically in patients with underlying lung disease who are not on immunosuppressive therapy 1, 2, 6, 14. Isolation of Nocardia from a transplant recipient should always be carefully investigated 1, 31. Nocardia is a branching bacterium 57 and will usually stain with a modified acid-fast (Kinyoun) stain 1. Organisms appear in tissue sections as gram-positive branching and beaded rods surrounded by a pyogenic inflammatory reaction 2, 57. Nocardia grow in nonselective media and can form aerial hyphae, but the laboratory should be informed of the possibility of Nocardia, because growth can be obscured in a mixed specimen such as sputum, and cultures may need to be incubated for a longer time period 1. Growth is generally inhibited at 50°C 9 and the yield of a culture for Nocardia can be increased by use of selective media such as Thayer–Martin agar with antibiotics 58. Nocardia may take 2 days to several weeks to grow in culture but growth is often seen in 3–5 days, and colonies appear chalky white if producing aerial hyphae 1, 3. Determination of the species of Nocardia can help guide therapy (see below), and accurate identification generally requires molecular methodology 10. Only a few species, such as N. brasiliensis, N. farcinica and N. pseudobrasiliensis, can be reliably identified by biochemical methods 6, 59. The mainstay of treatment of nocardial infections in transplant recipients is antibiotic therapy. Because there are no controlled clinical trials comparing treatment regimens for nocardiosis, initial selection of antibiotic therapy should take into account the site and severity of disease, the potential for drug interactions and the species of Nocardia 2. Antimicrobial susceptibility testing is strongly recommended [III] (Table 1) 60, 61. In 2003, the Clinical and Laboratory Standards Institute (CLSI) published the first approved methods for susceptibility testing of aerobic actinomycetes 6, 62, and this standard was updated in 2011 60. The primary antimicrobials recommended for susceptibility testing include amikacin, amoxicillin-clavulanate, ceftriaxone, ciprofloxacin, clarithromycin, imipenem, linezolid, minocycline, sulfamethoxazole or trimethoprim-sulfamethoxazole (TMP-SMX) and tobramycin. Secondary agents include cefepime, cefotaxime, doxycycline, gentamicin, gatifloxacin and moxifloxacin 6, 60, 62. However, few laboratories routinely do this testing and data correlating susceptibility results with clinical outcomes are sparse 2, 6, 14. Still, testing is recommended particularly when there is disseminated infection, treatment failure or relapse, or when newly identified or relatively resistant species of Nocardia (e.g. N. farcinica, N. abscessus) are isolated [III] 2. The possibility of antimicrobial resistance among certain species of Nocardia, the demonstration of synergy with certain combinations of antibiotics in animal models 63, and the high mortality that may be associated with nocardiosis 14 have all led to the recommendation that a combination of agents be used as initial therapy in persons who are seriously ill, those who have disseminated or CNS disease and those who are immunocompromised [III] (Table 2) 1, 6, 18, 44, 54, 64, 65. High-dose sulfonamides such as sulfadiazine (1.5 g qid) and sulfisoxazole (2 g qid) were used successfully for many years in the treatment of nocardial infections [II-3] 2, 6, 80, although these agents can be associated with renal toxicity 1. Obtaining sulfonamide serum drug levels can ensure adequate drug absorption and provide dosing guidance when there is concern for drug toxicity 1. Target serum levels should be 10–15 mg/dL 1. Although antimicrobial regimens for nocardiosis have not been compared by controlled clinical trials, TMP-SMX is now generally the preferred agent in treating most nocardial infections (Table 2) [II-2]. The synergy observed in vitro between TMP and SMX against various Nocardia isolates may confer an advantage over older sulfonamide agents, and TMP-SMX has demonstrated clinical efficacy and achieves high tissue concentrations in lung, brain, skin and bone 15, 80, 81. Recommended initial treatment dosing with TMP-SMX is 15 mg/kg/day orally or intravenously in two to four divided doses, particularly if there is disseminated or CNS disease, although there appears to be a range of effective doses, depending on the site and severity of infection 2, 80. The main side effects are nausea/vomiting, rash, including erythema multiforme, myelosuppression, hyperkalemia and crystalluria 1. Organ transplant recipients may be at higher risk for myelosuppression and nephrotoxicity as their immunosuppressive medications (e.g. mycophenolate mofetil, azathioprine and calcineurin inhibitors) often have overlapping side effects. Some species of Nocardia, such as N. farcinica, N. nova and N. otitidiscaviarum, may have high-grade resistance to sulfonamides, so species identification and susceptibility testing are especially recommended 2, 6, 14, 16, 19, 61, 82, 83. A 10-year retrospective evaluation of US Nocardia isolates performed by the Centers for Disease Control and Prevention noted a very high rate of TMP-SMX resistance (42% overall) 19. However, clinical correlation of TMP-SMX susceptibility test results with outcomes were not provided, and other recent studies have not corroborated extensive resistance to TMP-SMX among Nocardia isolates 5, 15, 61. There may be regional and strain differences to account for the discrepant results 5, but another possibility is interlaboratory variability in susceptibility testing methodology and interpretation of in vitro MICs 15, 61. Proficiency testing for labs performing Nocardia susceptibility testing is advocated, as is the use of control strains of Nocardia with known susceptibility patterns 15, 61. Alternative treatment regimens have been less well studied but there is enough evidence to suggest there are options for patients with allergy or intolerance to sulfonamides or for Nocardia species that are less susceptible to sulfonamides. Amikacin is very active against all species of Nocardia, although it may have variable activity against N. transvalensis 2, 19, and imipenem displays good activity in vitro except against N. brasiliensis, N. abscessus and N. otitidiscaviarum 6 (Table 1). Imipenem coadministered with amikacin alone or in a three-drug regimen with TMP-SMX has been increasingly accepted as initial therapy for cerebral disease and for very ill patients with nocardiosis [III] 1, 6, 44, 45, particularly while susceptibility testing is pending. The combination of imipenem and amikacin has demonstrated additive or synergistic effects in vitro 95, 96 and has been effective in human cases 18, 24, 97. Both imipenem and amikacin appear to display synergy against Nocardia when combined with sulfa medications as well 84. Tripodi et al. also showed that amikacin combined with imipenem, moxifloxacin or TMP-SMX displayed rapid in vitro bactericidal activity against multiple Nocardia isolates 18. Imipenem and amikacin dosing must be adjusted for creatinine clearance. Also, caution is required in using amikacin in transplant recipients taking cyclosporine or tacrolimus as aminoglycoside nephrotoxicity may be enhanced. In critically ill patients with significant renal dysfunction where it may be desirable to avoid TMP-SMX and aminoglycosides, treatment with linezolid is an option until susceptibility test results are available (Tables 1, 2 and discussion below) [III]. There are increasing reports of successful outcomes with the use of meropenem in the treatment of Nocardia, generally in combination with other agents and especially for treatment of brain abscesses 14, 64, 85, 98-100. Susceptibility studies suggest meropenem is less active against the more common N. asteroides complex organisms than imipenem; however it is more active against N. brasiliensis and N. otitidiscaviarum 93. With its less frequent dosing, good penetration of the blood brain barrier and reported lower incidence of seizures 101, meropenem is an additional option for therapy. However, until there are further data, including studies associating outcomes with Nocardia susceptibility testing, its use should be on an individual patient basis [III]. Of note, ertapenem has significantly less activity in vitro against Nocardia species than imipenem and meropenem 102. Third-generation cephalosporins such as ceftriaxone and cefotaxime are additional options for intracranial nocardial infections [III]; these agents obtain excellent CNS penetration and there are case reports of successful therapy with their use, typically in combination with other active agents 65, 103, 104. However, some Nocardia species such as N. farcinica, N. transvalensis and N. otitidiscaviarum are relatively resistant to cephalosporins 5, 6, 19, 54, 74, 105. Minocycline has been a popular alternative to TMP-SMX in the treatment of Nocardia [III] 54, 86, 106. Given 200 mg twice daily either orally or intravenously, it achieves adequate intracerebral levels 106 but CNS dissemination has occurred in patients on lower dose minocycline 107. Minocycline has activity against the majority of Nocardia species, but many strains are resistant or not fully susceptible 11, 77, 102, and therefore the use of minocycline should be guided by susceptibility testing. Toxicities include photosensitivity, headache, nausea, disequilibrium, esophageal ulceration and skin discoloration with prolonged use. It cannot be given to pregnant patients or children, due to bone and dental toxicity 86. At present, the data supporting the use of ampicillin, macrolides, or the fluoroquinolones for treatment of nocardial infection are not as robust as for the antimicrobials discussed above, and their in vitro activities appear more variable (Table 1). Case reports of both treatment success and failure with amoxicillin alone or in combination with clavulanate regimens have been published 44, 50, 90, 108, 109. The use of amoxicillin-clavulanate should be guided by in vitro sensitivity testing given its variable activity against Nocardia spp. (Table 1 and Ref. 18). Tigecycline and fluoroquinolones have demonstrated in vitro activity against many species of Nocardia 16, 18, 102, 110. Gatifloxacin and moxifloxacin appear to have better activity against Nocardia spp. compared to ciprofloxacin 76, although ciprofloxacin has been used successfully as combination therapy 18, 85. Moxifloxacin treatment has demonstrated mixed results. It was successful in two cases of N. farcinica CNS infection 111, 112 and as continuation therapy after parenteral antibiotics in two heart transplant recipients 18. However, there is a report of recurrent N. farcinica CNS infection in a patient receiving moxifloxacin despite in vitro susceptibility and high levels of the drug in the abscess material 113. Moxifloxacin appears to be more active in vitro against N. farcinica than against other common Nocardia species 6, 16, 76 and has shown bactericidal effect against Nocardia isolates when combined with either imipenem or TMP-SMX 18. Nemonoxacin, a novel oral appears to have the MICs for Nocardia compared to ciprofloxacin and is an antibiotic which is more as a primary therapy for nocardial infections [III] Antimicrobial sensitivity testing has shown that it has excellent activity against all species of Nocardia, including N. farcinica 16, 18, 19, 26, 61, A recent review of the patients with nocardiosis treated with linezolid as or in combination with other agents reported a high success rate with and (including cerebral and disseminated although and myelosuppression were common In vitro studies have shown an effect against Nocardia isolates for combinations of linezolid with amikacin and imipenem but linezolid is bactericidal when used in combination with moxifloxacin 18. is given mg twice a either intravenously or with few significant drug interactions include and in the setting of inhibitor use in as well as the may its use for nocardiosis 23, 33, may be required in the treatment of nocardial infection, especially for cerebral nocardiosis not to antibiotic therapy, and for other large soft tissue therapy should be performed in with antibiotic treatment 1, 64, 85, A of immunosuppression may be a 18, particularly in or disease, such as cerebral or disseminated infection 2 [III]. However, several have that this is not finding good treatment outcomes despite immunosuppressive agents 44, of immunosuppression should be considered on a The of therapy for nocardiosis is but are guided by the of Nocardia to and reports of after of therapy 2. In addition, the type and level of the immunosuppression is an important patients will a clinical improvement within 1 of therapy 18. the patient is very ill at parenteral therapy should be for weeks and clinical improvement should be seen to an oral regimen [III] 2, While extrapulmonary abscesses have been with of parenteral antibiotics 2, and there is a recent report successful treatment of pulmonary nocardiosis with months of therapy in a of heart transplant recipients using an initial weeks of combination parenteral therapy 18, the standard recommended treatment for nocardiosis is generally much nocardiosis should be treated at for months [III] 1, 2, 4, 80 and improvement of lesions to therapy. and soft tissue infections should be treated for months depending on the response to therapy and of disease [III] 1, 2, 48, 80. infection with Nocardia should be treated with and several months of antibiotics of immunosuppression for rejection during nocardial therapy may an of the of of therapy, patients should be for of with cerebral nocardiosis should or magnetic resonance imaging of the brain. Some for Nocardia therapy is as described [II-3] 49. The response of nocardial infections to therapy is on the underlying disease and the and site of and soft tissue infections are often treated cerebral infection has been described to mortality rates of 30 to Among published each of which at cases of nocardiosis, the mortality rate was 14. Among organ transplant recipients there is a range of rates et al. noted a mortality rate 25, but several other have reported rates of or more among organ transplant recipients 14, 18, 23, in diagnosis and of therapy have been associated with outcomes There have been few reported cases of nocardial infection in transplant recipients, it to therapy In fact, nocardiosis appears to be a infection in and in one of patients with Nocardia isolated from 1995 to at a large were 14. There are only with Nocardia asteroides reported in the from to with only two of these noted to be transplant recipients reported in these cases are to those used in including linezolid, amikacin, amoxicillin-clavulanate and with therapy generally given for months to more than 1 to the possibility of discoloration and potential for effects on should not be used in than and fluoroquinolones are also generally in due to potential used daily for the prevention of pneumonia in the first 6 months (see prevention TMP-SMX the rate of nocardial infection among solid organ transplant recipients [III] 44, to has been observed among persons with infection TMP-SMX is a very as its to the prevention of and many common and However, there are increasing reports of infections by Nocardia isolates in patients taking TMP-SMX 14, 54, some the of this agent for prevention of nocardiosis 14. and found that in their were on TMP-SMX at the diagnosis of nocardiosis, of which were susceptible to the drug 14. in their of Nocardia and noted that most TMP-SMX for 25. In many of these dosing of TMP-SMX is not Because the dosing of TMP-SMX at some for of in organ transplant recipients is two to than blood levels due to dosing although nocardiosis has also been reported despite daily TMP-SMX 54. factors may be sulfa posttransplant immunosuppression and possibly other that affect a immune response 23, 24, Given the the efficacy of lower dose TMP-SMX for primary prevention of nocardiosis, it is to definitive on the dose and for after initial Nocardia infection has been reported in the setting of solid organ but typically after therapy 24, noted in the above, some to TMP-SMX for against Nocardia to prevent although few published reports provide dosing TMP-SMX daily 24 and a have been used 24, [III]. of Nocardia from is likely to be the main route of although penetrating cutaneous is another potential route of inoculation 1, 45, 50. has not been reported 2. While most patients develop of infection have including among transplant recipients, with possible being or However, these studies have often strain testing with molecular methods to confirm the between infections 6. In some cases have demonstrated common and in by using and methods Although there are no that prevent TMP-SMX in as noted above, may the incidence of the disease 31. However, the efficacy of may on the dose of TMP-SMX antimicrobial resistance to TMP-SMX and the of the In the rapid diagnostic testing may available to in Nocardia to the species level using methods such as reaction on clinical specimens and also be used to provide rapid diagnosis and in of therapy studies will also for a selection of antibiotics to be used in the treatment of the especially if the fluoroquinolones and as will provide oral to the regimens use, with less was modified from a by and published in the of and by the of and the of The of this have no of to as described by the of