Nocardiosis after Solid Organ Transplantation

Authors: S.M. Hosseini-Moghaddam, M.D. and Shahid Husain, M.D., MS

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Introduction

Nocardia spp. are gram-positive, non-motile aerobic actinomycetes that can be isolated from soil, organic matter, and water. Infection usually arises from inoculation of soft tissues or by inhalation. These microorganisms are ubiquitous environmental saprophytes, and can cause a variety of granulomatous infections that range from localized mycetomas to disseminated diseases (44). Of the 50 known species of Nocardia, the majority of infections in solid organ transplant recipients are caused by Nocardia asteroids sensu strictu, Nocardia farcinica, Nocardia nova, Nocardia brasiliensis, Nocardia otitidiscaviarum and Nocardia transvalensis (9). In tropical regions, where nocardiosis is usually seen as mycetoma caused by N. brasiliensis in a global context, Nocardia causes respiratory or disseminated infections due Nocardia asteroides complex (26).

Clinical Presentation

Nocardiosis may be a life-threatening infection in solid-organ transplant patients. Although all organs can be affected, respiratory, central nervous system and cutaneous systems are the most commonly affected (52). Due to a variety of clinical presentations nocardiosis has been named as the “great imitator” in solid organ transplants (25, 43). Pulmonary nocardiosis has also been reported to occur with invasive aspergillosis (20).

The clinical presentations of pulmonary disease are non specific and the patient may present with symptoms of pneumonia or remain asymptomatic. Radiologically pulmonary nocardiosis may present as a non specific pulmonary infiltrate (33, 34), nodules (38), cavitary parenchymal lesions (43), or as a mass lesion (21).

Isolated cutaneous nocardiosis are rare in immunocompromised hosts. Other presentations in solid organ transplants include soft tissue infection (43), subcutaneous abscesses (37), sepsis (24), and disseminated disease (36). Involvement of central nervous system (CNS) signifies disseminated disease. Nocardiosis of the central nervous system may present as a brain abscess (12), or meningitis (7). Brain lesions may be asymptomatic (3). In one study 40% of the cases of N. farcinica were associated with CNS involvement (23). Hence, clinical as well as radiologic evaluation of the central nervous system should be performed for all transplant patients with cutaneous or pulmonary nocardiosis.

Epidemiology

Lung Transplants

Although pulmonary involvement is a common presentation of nocardiosis in all solid organ transplants, anatomical factors as well as local immunologic defects in lung transplants make them more susceptible to pulmonary opportunistic infections including nocardiosis (6). Isolated extra-pulmonary diseases seem to be uncommon in post-lung transplant patients (45).

In a retrospective cohort study on 473 lungs transplant recipients, Nocardia infection had been reported with a frequency of 2.1% and a median time of onset of 34.1 months after transplantation (23). In another review of 540 recipients of heart, lung, or heart-lung transplants nocardiosis was reported in 1.85% (45).

Mortality as high as 40% had been reported in one study (23, 45). Lung transplant recipients with N. farcinica infection were reported to have the worst outcome (23).

Kidney Transplantation

In a study on 513 renal transplants, the frequency of nocardiosis had been reported as 1.2% (14). Although the majority of clinical presentations included deep-seated skin abscesses, other presentations included pneumonia, cerebral abscess and meningitis (34).

Among renal transplants, pneumonia has been reported as the most frequent clinical presentation, while 20% of patients had disseminated diseases (42). In a series of 513 renal transplants, N. asteroides has been reported as the major pathogen, while N. otitidiscaviarum and N. farcinica were infrequently isolated (34). Another study of renal transplant subjects showed N. nova was the most common species followed by N. farcinica, N. asteroides, and N. brasiliensis (42). In a recent report, N. niigatensis had been isolated from lesions of a renal transplant patient with multiple chronic cutaneous abscesses (39).

Liver Transplantation

Liver transplant recipients were noted to have a higher rate of disseminated disease in a study of 191 liver transplant patients. The incidence of nocardiosis was 3-7% over a period of 3-5 years. N. asteroides was the most frequently isolated species. Although the mortality rate was 43 % in this report, nocardiosis was confirmed to be a direct contributor to death in 28% (16, 41).

Even though the members of the Nocardia asteroides complex cause the majority of pulmonary and disseminated infections, other less frequent Nocardia spp. have also been implicated. Newly described N. veterana has been reported in liver transplants (44).

Pathogenesis and Risk Factors

Immune deficiency, specifically cellular mediated immunity, seems to play a pivotal role in the development of nocardiosis. In a case-control study, 25 cases of actinomycetoma caused by N. brasiliensis were compared with 25 healthy controls. This study showed that cases had normal antigen recognition, but lower IFN-gamma production. Cases were also noted to have higher concentrations of IL-4; IL-10 and TNF-alpha in peripheral blood mononuclear cell cultures. This showed that individuals with nocardiosis had a Th2 type of immune response, but they lacked appropriate Th1 type response (28).

Only a few number of well-designed case-control studies had been conducted to assess the risk factors for nocardiosis. In a case control study involving 35 cases and 70 controls, the risk factors identified for Nocardia infection included usage of steroids (OR= 27; CI 95%: 3.2–235), cytomegalovirus disease (OR= 6.9; CI 95%: 1.02–46 ) within 0- 6 months before the diagnosis, a high median calcineurin inhibitor in the preceding 30 days (OR= 5.8; CI 95%: 1.5–22) and anti-fungal prophylaxis (OR=3.0, CI 95%:1.01- 8.9) (42). Other studies had implicated COPD, alcoholism, diabetes mellitus, viral hepatitis and neutropenia as risk factors in solid organ transplants (27, 34). Administration of tumor necrosis factor inhibitors including infliximab, etanercept and alefacept have been reported to increase the risk of nocardiosis (1). Of these infliximab appeared to have the highest risk (15, 48, 49).

Diagnosis

The diagnosis of infection with Nocardia spp. requires well-trained medical microbiologists. Delays can occur in diagnosis due to negative microscopy (16). A high index of suspicion is the key to diagnosis. Bronchoscopy and biopsy materials should be submitted to the microbiology lab with request for a modified acid-fast (Kinyoun) stain (26). They appear as gram-positive branching and beading rods surrounded by a pyogenic inflammatory reaction (47). The use of selective growth media such as media Thayer-Martin agar with antibiotics may increase the diagnostic yield (31). The N. brasiliensis, N. farcinica and N. pseudobrasiliensis, can be reliably identified by biochemical methods (4). Other species may require molecular methods for the diagnosis (4, 10, 11).

Polymerase chain reaction (PCR) has been successfully utilized for a more rapid diagnosis of nocardial infections. Nocardia isolates could be identified using sequencing and 5’ end 16S rRNA gene PCR (31). DNA sequencing through blood culture has been reported to be helpful for diagnosis of culture-negative infections (40).

Susceptibility Testing

All positive cultures should be submitted for susceptibility testing. Susceptibility tests usually provide good data for appropriate clinical management. However, in vitro susceptibility of the microorganism to Trimethoprim-Sulfamethoxazole (TMP-SMX) may be variable and may not strictly reflect the efficacy of treatment (16). Clinical response has been reported to be achieved with TMP-SMX despite reduced in vitro susceptibility (16).

Antibiotic Susceptibility Data

Some antibiotics such as amikacin, imipenem, minocycline, and TMP-SMX seem to be very effective in vitro against Nocardia spp. (2, 23, 45, 31). All Nocardia species are susceptible to linezolid (35). The common Nocardia species have the following antibiotic susceptibility patterns: N. asteroides seems to remain susceptible to TMP-SMX (26, 46). Although some studies reported N. asteroids resistant to third-generation cephalosporins (cefotaxime and ceftriaxone), it has been demonstrated that these isolates may be the controversial species N. farcinica (53).
Isolates of N. farcinica may be resistant to TMP-SMX (19), but still uniformly remains susceptible to amikacin. Interestingly, N. farcinica is resistant to other aminoglycosides and third generation cephalosporins (54). Up to 36% of N. farcinica can be resistant to imipenem (26).
The majority of N. nova isolates are susceptible to TMP-SMX, third-generation cephalosporins, imipenem, and amikacin (26).
N. brasiliensis is typically susceptible to TMP-SMX and majority of aminoglycosides including gentamicin, amikacin, and tobramycin. On the other hand, only 10 percent of isolates were reported to be susceptible to imipenem (18).
N. transvalensis is typically resistant to aminoglycosides including amikacin and other aminoglycosides (29). While the majority of isolates are susceptible to TMP-SMX, dissemination may occur when a patient receives this drug. Imipenem appears to be a better option for treatment (29).
N. otitidiscaviarum is typically resistant to TMP-SMX, but is generally susceptible to amikacin (35, 50).

Treatment

There are no universally accepted treatment regimens for Nocardia infection in immunocompromised hosts, including combination antimicrobial regimens. The higher prevalence of N. farcinica in lung transplant is worrisome since N. farcinica is not only a more virulent subspecies of Nocardia, but it also exhibits resistance to third generation cephalosporins, tobramycin, and sulfonamides (13, 51, 54). Recently tigecycline, moxifloxacin and ertapenem have also been noted to have excellent in vitro activity against Nocardia species (5). The following management points can be made in the treatment of nocardiosis in solid organ transplant recipients:

Isolates are usually susceptible to TMP-SMX, minocycline, imipenem, linezolid, and amikacin (27). Treatment of nocardiosis should include at least two antibiotics mentioned above. TMP-SMX should be included in the treatment regimen, unless when N. otitidiscaviarum or N. farcinica have been isolated or evidences of allergies or drug side effects exist (Table 1).
Empirical treatment of nocardiosis involving the central nervous system should utilize drugs with good blood-brain barrier penetration including TMP-SMX, third generation cephalosporins (ceftriaxone/cefotaxime), linezolid and imipenem. Intravenous treatment can be switched to oral antibiotic therapy typically after 6 weeks and clinical evidence that show a response to treatment. Oral treatment with drug of choice should be continued for at least 6 months to year based on the response to therapy and extent of involvement. Amikacin should be considered in the initial antibiotic regimen in patients with nocardiosis who have multi-organ involvement. The regimen should be modified according to susceptibility testing results when available.
Although prolonged antibiotic therapy and diminution of immunosuppressive regimen is usually helpful for the management of nocardiosis, surgical drainage of abscesses might be also required (26).
Newer antibiotics (tigecycline, moxifloxacin and ertapenem) should be used after the failure of first line treatment.

Monitoring the Treatment

Significant improvement is usually seen 2-3 weeks after administration of appropriate antibiotic therapy. If the patient remains febrile after a couple of weeks, “treatment failure” could be considered. The main reason for treatment failure is poor penetration of antibiotics into the abscesses. Therefore, surgical drainage may increase the success rate in these situations. Other factors may include the presence of resistant strains or concomitant infections with other organisms such as Aspergillus. The susceptibility results are usually available after 2-3 weeks of therapy. The treatment can be modified based on the results of susceptibility testing. Patients should be regularly monitored in clinic for the side effects of administered drug and an improvement in status. Lesions can be monitored clinically and radiologically. One approach would be to repeat radiological studies after two weeks of the initiation of treatment, at 6 weeks, 3months and 6 months to assess the response to therapy.

Isolated Cutaneous Nocardiosis

Nocardial cutaneous lesions in solid organ transplant patients usually present as systemic disease. Pulmonary and brain lesions should be excluded before making the diagnosis of “isolated cutaneous nocardiosis". Although no report demonstrated the optimal duration of treatment in patients with isolated cutaneous abscesses, there was one anecdotal report that showed sufficient treatment after 6 months of antibiotic therapy, with one year treatment being optimal (55).

Indications of Surgery and Adjuvant Therapy

Long-term antibiotic therapy may be successful in treating transplant patients with disseminated nocardiosis including subcutaneous, pulmonary, and cerebral lesions (24). However, nocardiosis may not respond to prolonged treatment using antibiotic therapy alone and switching to a combined treatment that includes both medical and surgical approaches may be necessary.

Antibiotic therapy in patients with involvement of respiratory and central nervous systems may result in a reduction of pulmonary, but not cerebral lesions. Cerebral lesions may exist even after receiving prolonged antibiotic therapy including TMP-SMX, meropenem or sultamicillin (17). Regardless of the immune status, control of cerebral nocardial lesions may not be achieved with antibiotic treatment alone. Occasionally treatment of large Nocardia brain abscesses requires surgical intervention even in immunocompetent hosts (34).

The treatment of isolated cutaneous nocardial abscesses usually requires surgical drainage. Since cutaneous infection does not involve a vital organ and changes in size and inflammatory characteristics are easily visible, surgical drainage can be postponed after reviewing the improvement of skin lesions following administration of effective antibiotic therapy. There are several reports in the literature that show an improvement of cutaneous abscess using antibiotic therapy alone. While adjuvant intravenous immunoglobulin has been suggested to control nocardiosis in patients with other immune deficiencies (22), their utility in solid organ transplant recipients are as yet undetermined.

Prophylaxis

There have been several reports of breakthrough nocardial infections among patients receiving prophylaxis with TMP-SMX. The Nocardia isolates were susceptible to TMP-SMX in patients who received daily or 2 – 3 times weekly prophylaxis (23, 42, 43, 30). Currently, we do not recommend routine prophylaxis for Nocardia in solid organ transplant recipients.

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Table 1: Dosages of Commonly Used Drugs for the Management of Nocardiosis in Solid-Organ Transplant Recipients.

Name of Antibiotics	Doses	Route of Administration
TMP-SMX	15 mg/kg of the trimethoprim component per day in divided doses*	IV/PO
Amikacin	7.5 mg/kg IV every 12 hours	IV
Minocycline	(100 mg q 12 hours)	PO
Amoxicillin-Clavulanic acid	875 mg twice daily	PO
Ceftriaxone	2 gram q 12 hours	IV
Cefotaxime	2 grams Q 8 hours	IV
Imipenem	500 mg Q 6 hours	IV
Linezolid	600 mg Q 12 hours	PO/IV