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Epidemiology

  1. Top of page
  2. Epidemiology
  3. Transmission
  4. Diagnosis
  5. Treatment
  6. Future studies
  7. References

Nocardia species are ubiquitous environmental saprophytes, living in soil, organic matter and water (1). They are part of the genus of aerobic actinomycetes and related organisms within this group, which can cause human infection, include Corynebacterium, Rhodococcus, Gordona, Tsukamurella and Actinomadura (2). There are at least 12 species within the genus of Nocardia, with the following strains being the most important cause of infection in transplant recipients: Nocardia asteroides complex (N. asteroides sensu strictu, N. farcinica, and N. nova), Nocardia brasiliensis, Nocardia otitidiscaviarum and Nocardia transvalensis (2–4).

The frequency of nocardial infections in solid organ transplant recipients varies between 0.7% and 3% and has mostly been reported in heart, kidney and liver transplant recipients, and less frequently in lung transplantation (5). The main route of infection is pulmonary, with subsequent dissemination to other tissues, in particular to the brain where it causes abscesses. Other areas that may be involved include the bones, eye and skin, where subcutaneous nodules can develop (6). Primary cutaneous infection may occur after penetrating injuries, especially with outdoor activities (7). It is uncertain why some centers see higher rates of disease but clusters have been associated with nearby construction and the inhalation of contaminated dust (8).

Immunosuppression is the major risk factor for nocardial infections, and the organism is most commonly seen in solid organ transplant recipients, HIV infected patients (CD4 counts <100), and patients with lymphoreticular malignancy or treated with chronic corticosteroid therapy. It is uncommon for nocardial infection to occur within the first month of organ transplantation, although the diagnosis should be considered if aggressive immunosuppression (such as OKT3) has recently been used (9). Importantly, cytomegalovirus (CMV) disease, which also appears to result in decreased systemic immunity, is an important cofactor in the development of nocardial infection (9,10). Profound hypogammaglobulinemia after transplantation has been implicated as a factor in the development of nocardial and other bacterial infections (11). Trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis in the first 6 months post-transplantation for prevention of Pneumocystis jiroveci pneumonia (See Pneumocystis prevention guidelines) reduces the rate of nocardial infections, (AIII) (12) and the same observation has been suggested in the setting of HIV infection, particularly when TMP-SMX is given daily (13). TMP-SMX prophylaxis is a very cost-effective intervention, as its benefits extend to the prevention of Toxoplasmosis gondii and Listeria monocytogenes also (13). However, there are reports of breakthrough nocardial infections while on TMP-SMX prophylaxis, despite all isolates being sensitive to TMP-SMX (5, 13, 14)., Nocardial infection predominantly causes pneumonia in transplant patients, with 90% caused by N. asteroides complex (12). Pulmonary nocardiosis can have many responses ranging from granulomatous to purulent reactions (1, 15). Radiological examination usually demonstrates irregular nodular lesions, which may progress to cavitation. However, they may also appear as diffuse pneumonic infiltrates or consolidative with pleural effusions (16, 17). Upon diagnosis of pulmonary nocardiosis, it should be assumed the patient has disseminated disease and further investigation should include magnetic resonance imaging (MRI) of the brain to exclude cerebral abscess (18, 19). The differential diagnosis of a syndrome with both pulmonary and brain nodular lesions should include Nocardia as well as Aspergillus spp., Mycobacteria, Rhodococcus equi and Cryptococcus neoformans as well as post-transplant lymphoproliferative disorder (PTLD). Nocardial infections may present with subcutaneous nodules, incipient pyomyositis such as an iliopsoas abscess or bone abscess. Other rare events of dissemination include endophthalmitis and septic arthritis (1, 6). The organism on rare occasions is isolated from blood cultures, and this often associated with central venous catheters (20).

Transmission

  1. Top of page
  2. Epidemiology
  3. Transmission
  4. Diagnosis
  5. Treatment
  6. Future studies
  7. References

Inhalation of the organism appears to be the main route of transmission. Penetrating cutaneous injury is another route of inoculation (1,7,14,15). Although there have been descriptions of clusters of outbreaks around construction sites, most patients develop sporadic infections and it is unknown whether they were colonized prior to transplantation (8,14). There has been no effective measure to prevent inhalation, however, TMP-SMX prophylaxis may actually reduce the incidence of the disease (14).

Diagnosis

  1. Top of page
  2. Epidemiology
  3. Transmission
  4. Diagnosis
  5. Treatment
  6. Future studies
  7. References

The definitive diagnosis of nocardial disease requires demonstration of the organism on culture from a suspected site. Nocardia is a Gram-positive, aerobic, branching bacteria (21). Nocardia will usually stain with a modified acid-fast (Kinyoun) stain (1). They appear in tissue sections as Gram-positive branching and beading rods (21). Nocardia grow in nonselective media, however, the laboratory should be informed of the possibility of Nocardia, because a mixed specimen such as sputum can obscure the growth of the organism and the yield can be increased by use of selective media such as Thayer-Martin agar with antibiotics (22). Growth of Nocardia may take 2–5 days (but sometimes weeks) and colonies appear chalky white if producing aerial hyphae (1).

Treatment

  1. Top of page
  2. Epidemiology
  3. Transmission
  4. Diagnosis
  5. Treatment
  6. Future studies
  7. References

The mainstay of treatment of nocardial infections in transplant patients is antibiotic therapy. Initial selection of antibiotic therapy should take into account the site and severity of disease, the potential drug interactions and the species of Nocardia. Antimicrobial susceptibility testing is strongly recommended, (AIII) (Table 1) however, few laboratories can routinely do this testing. At present, there is not any internationally validated reference method and there are few studies correlating laboratory data with clinical outcome. Because of the possibility of a resistant species of Nocardia, (e.g. N. farcinica), in a transplant recipient who is very ill, it is preferred to use a combination of agents until sensitivities have returned (23).

Table 1. Antimicrobial susceptibility of Nocardia spp. (% isolates susceptible)
Antibiotic N. asteroides complex N. farcinica N. nova N. brasiliensis
  1. X – not enough data for accurate results

  2. Composite date from following references: (3, 41–50)

  3. Interpretation of data based on National Committee for Clinical Laboratory Standards (NCCLS) breakpoints for bacteria that grow aerobically. [41]

TMP-SMX91–10089–10089–100100
Imipenem70–10065–8510025
Amikacin85–100100100100
Minocycline95–100X90–10075–90
Ceftriaxone75–100590–10090–100
Ciprofloxacin25–5070–90010–30
Amoxicillin/clavulanate40–7040–70565–95

Recommended therapeutic regimens for the treatment of Nocardia infections are shown in Table 2. TMP-SMX is the preferred agent in treating nocardial infections (AII). It achieves high tissue concentrations in lung, brain, skin and bone (24). Recommended treatment dosing with TMP-SMX is 15 mg/kg/day in two to four divided doses for organ transplant recipients, and can be given intravenously or orally, although the latter is associated with nausea (25). The main side-effects are rash, nausea and vomiting, however, more serious side-effects are erythema multiforme, bone marrow suppression, hyperkalemia and crystalluria (1). Sulfonamides alone are equally effective in the treatment of nocardial infections when used in high doses. These include sulfadiazine (1.5 g qid) and sulfisoxazole (2 g qid), however, gastro-intestinal tolerability sometimes limits this option (1, 12, 15, 18, 24, 25)(AII). Strains of Nocardia such as N. farcinica, N. nova, and N. otitidiscaviarum may have high-grade resistance to sulfa containing regimens. Therefore, it is important to identify which Nocardia species is present and get susceptibility testing (26).

Table 2. Suggested therapy for Nocardia infections in transplant patients
DiseasePrimary therapyAlternative
  1. *Based on animal studies and numerous case reports. (1,5,6,23–50).

  2. †Adjust therapeutic agents based on patient's renal function.

  3. ‡Meropenem (1 g q8 h) may be an alternative agent depending on species (CII).

  4. This table is a guide and depends on antimicrobial susceptibility, severity of condition and immunosuppression of the patient and their associated allergies. Alternate agents such as amoxicillin-clavulanate, ceftriaxone, ciprofloxacin and macrolides may be effective; (CIII) however, there is insufficient information to support their use as initial therapy and these agents should be considered only if standard therapy is ineffective.

  5. Note: Sulfonamides may be substituted for TMP-SMX.

Pulmonary – stableTMP-SMX†– 15 mg/kg in 3–4 divided doses, either IV or PO (AII)Imipenem + amikacin (AIII) or minocycline (BIII) or linezolid (BIII)
Pulmonary – criticalImipenem† (500 mg q6 h) + amikacin† 10–15 mg/kg/d) (AIII) or TMP-SMX (AII)Linezolid 600 mg q12 h (BIII)
Cerebral*Imipenem‡+ amikacin (AIII) or TMP-SMX (AII)Linezolid 600 mg (BIII) q12 h or ceftriaxone (BIII) 2 g q12 h or cefotaxime† (BIII) 2 g q8 h or minocycline (BIII) 200 mg q12 h
Disseminated*Imipenem + amikacin (AIII) or TMP-SMX (AII)Ceftriaxone, cefotaxime, linezolid or minocycline (BIII) after initial therapy

Alternative regimens have been less studied, however, there is enough evidence to suggest they could be used in patients with allergy or intolerance to sulfa. Imipenem coadministered with amikacin has been increasingly accepted as initial therapy for pulmonary, cerebral and very ill patients with nocardiosis (27, 28)(AIII). This combination has been effective in animal models (26) and reported human cases, and in some centers is used as primary therapy until TMP-SMX susceptibility has been confirmed (28, 29). Both imipenem and amikacin have to be adjusted for creatinine clearance and the toxicities are rash and seizures for imipenem and renal failure and deafness with amikacin. Also, caution is required in using amikacin in transplantation patients taking cyclosporine or tacrolimus as aminoglycoside nephrotoxicity may be enhanced. Of note, both imipenem and amikacin appear to have a synergistic effect on Nocardia with sulfa (30).

There are increasing reports of successful outcomes with the use of meropenem in the treatment of Nocardia, especially with brain abscesses (23). Sensitivity 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 (29). Its ease of use, less frequent dosing (especially in renal failure) and good penetration of the blood-brain barrier make meropenem a desirable therapy. However until there is further associated clinical data with sensitivity testing, decisions regarding its use should be made on an individual patient basis (BIII).

Third generation cephalosporins are a safe alternative for intracranial nocardial infections, with agents such as ceftriaxone and cefotaxime all obtaining excellent CNS penetration and case-reports of successful therapy (31)(BIII). However, some Nocardia species such as N. farcinica, N. transvalensis and N. otitidiscaviarum are resistant to cephalosporins (1,32).

Minocycline has become a popular alternative to TMP-SMX in the treatment of Nocardia. Given 200 mg twice daily either orally or intravenously, it has similar efficacy and also achieves adequate intracerebral levels (33)(BIII). Toxicity is usually photosensitivity, headache, nausea, dysequilibrium and esophageal ulceration. It cannot be given to pregnant patients or children due to bone and dental toxicity (33). At present there are little data supporting the use of ampicillin, macrolides or the quinolone class of drugs, although there are case reports of both treatment success and failure with amoxicillin alone and in combination with clavulanate regimens (34–37)(CIII).

Linezolid is an oxazolidinone antibiotic, which is gaining more attention as potentially a primary therapy against nocardial infections. Antimicrobial sensitivity testing has shown that it has activity against all species of Nocardia, including N. farcinica (38). A recent report demonstrated the successful treatment of 6 patients with disseminated nocardiosis, including central nervous system infection with linezolid (of which four of the patients received linezolid monotherapy) (39). Linezolid is given 600 mg twice a day and can be given either intravenously or orally. It does not need renal or hepatic adjustment, and does not have any significant drug interactions (39). Main reported toxicities include nausea, vomiting and rash. More serious toxicities include thrombocytopenia and aplastic anemia (38). With its excellent bio-availability, lack of significant drug interactions with immunosuppressive agents, central nervous system penetration and activity against all Nocardia species, linezolid could be used in the future as a first or second line agent in the treatment of these infections (39) (BIII). Frequent monitoring of blood counts is required in patients receiving linezolid.

Surgical drainage may be required in the treatment of Nocardia, especially in cerebral nocardiosis which does not respond to antibiotic therapy, and in other large soft tissue collections. Surgical therapy should be performed in conjunction with antibiotic coverage and reduction of immunosuppression (1,23,37).

The length of therapy in the treatment of nocardial infections in the transplant patient will depend ultimately on their immunosuppression. Most patients will show a clinical improvement once therapy is started within a week. If the patient is very ill at presentation, then parenteral therapy should be continued for 3 to 4 weeks before changing to an oral regimen. Cerebral nocardiosis should be treated at least for 9–12 months (1,2,25)(AIII). Pulmonary and soft tissue infections should be treated between 6 and 12 months depending on response to therapy and resolution of disease (1,18,25)(AIII). Immunosuppression should be reduced, if possible, to the lowest tolerable level. Following discontinuation of therapy, patients should be monitored for relapse of disease with follow up CT scans of the area involved or MRI scans of the brain. Some centers will continue prophylaxis against Nocardia once therapy is complete (19)(BII).

Future studies

  1. Top of page
  2. Epidemiology
  3. Transmission
  4. Diagnosis
  5. Treatment
  6. Future studies
  7. References

In the future, rapid diagnostic testing will assist in the rapid determination of Nocardia spp. Gene probes, ribotyping, restriction endonuclease analysis could provide rapid diagnosis and assist in early institution of therapy (40). Also, further studies will allow for a broader selection of antibiotics to be used in the treatment of the condition, especially if the newer quinolones, macrolides and ketolides prove effective as they will provide potent oral alternatives to the regimens we presently use with less toxicity.

References

  1. Top of page
  2. Epidemiology
  3. Transmission
  4. Diagnosis
  5. Treatment
  6. Future studies
  7. References
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