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Treatment of nocardiosis

Treatment of nocardiosis
Literature review current through: Jan 2024.
This topic last updated: Jul 13, 2023.

INTRODUCTION — Nocardiosis is an uncommon gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. Nocardia spp have the ability to cause localized or systemic suppurative disease in humans and animals [1-5]. Nocardiosis is typically regarded as an opportunistic infection, but approximately one-third of infected patients are immunocompetent [5].

Two clinically important characteristics of nocardiosis are its ability to disseminate to virtually any organ, particularly the central nervous system, and its tendency to relapse after initial therapy or progress despite appropriate therapy.

The treatment of nocardiosis will be reviewed here. The microbiology, epidemiology, pathogenesis, clinical manifestations, and diagnosis of nocardiosis are discussed separately. (See "Nocardia infections: Clinical microbiology and pathogenesis" and "Nocardia infections: Epidemiology, clinical manifestations, and diagnosis".)

ANTIBIOTIC SUSCEPTIBILITY — In vitro antimicrobial susceptibility patterns have varied among different studies, countries, and Nocardia species (table 1). In a retrospective review of 765 isolates submitted voluntarily to the United States Centers for Disease Control and Prevention (CDC) between 1995 and 2004, 42 percent were resistant to trimethoprim-sulfamethoxazole (TMP-SMX) and 61 percent were resistant to sulfamethoxazole [6]. This incidence of resistance is significantly higher than in other reports. There are limitations to this study, with the authors concluding that the presented data are probably not representative of all United States cases. As an example, patients who were failing treatment due to resistance may have been more likely to have had their isolates sent to the CDC than patients with susceptible isolates who were responding to treatment.

In contrast, in a study of 552 clinical isolates collected from six major medical referral centers in the United States between 2005 and 2011, which was prompted by the unexpected results of the CDC study, only 2 percent of isolates were resistant to TMP-SMX and/or sulfamethoxazole [7]. Possible reasons for the discrepancy between these results and the results of the CDC study are that there might have been differences in the preparation of samples, methods of susceptibility testing, and/or local laboratory interpretation of results of in vitro susceptibility testing [8].

Other studies have shown results consistent with the study of 552 clinical isolates described above. Among 138 Nocardia isolates collected in Taiwan between 1998 and 2009, only 2 percent were resistant to TMP-SMX [9]. Similarly, a French study reported that only 21 of 730 isolates (3 percent) were resistant to trimethoprim-sulfamethoxazole [10]. However, a smaller study of 28 cases from Switzerland found 16 percent of Nocardia isolates were resistant to TMP-SMX [11], and in an Australian study that evaluated 270 isolates, 9.3 percent were resistant to TMP-SMX [12]. Given that some isolates are resistant to TMP-SMX, formal antimicrobial susceptibility testing is always necessary to ensure optimal antibiotic therapy.

Molecular methods used to identify Nocardia species have resulted in the reclassification and renaming of many isolates. For example, Nocardia isolates that in the past were identified as N. asteroides complex have now been reclassified to other, or new, species and, because of this, N. asteroides is now rarely encountered. Awareness of such changes is important in the interpretation and use of susceptibility results from past reports when non-molecular methods of speciation were used [13-15]. (See "Nocardia infections: Clinical microbiology and pathogenesis".)

As explained above, there is significant variation in susceptibility patterns between published reports; however, common susceptibility patterns for different Nocardia species include:

N. farcinica is uniformly susceptible to amikacin but is resistant to other aminoglycosides, such as tobramycin [14,16]. Many, but not all, isolates have been reported as susceptible to TMP-SMX [14,15]. N. farcinica is generally resistant to third-generation cephalosporins [6,14-17].

In most studies, isolates of N. nova have been susceptible to TMP-SMX, third-generation cephalosporins, and clarithromycin [14,15,18]. However, one review reported 53 percent resistance to both TMP-SMX and third-generation cephalosporins [6]. Most isolates are susceptible to imipenem and amikacin [6,14,15,18].

N. brasiliensis is typically susceptible to TMP-SMX and amikacin [14,15,18]. Susceptibility to third-generation cephalosporins has been variable, with a review reporting susceptibility in 87 percent of isolates [14]. Only 20 to 40 percent of isolates are susceptible to imipenem [14,15,19,20].

N. cyriacigeorgica is usually susceptible to TMP-SMX, imipenem, ceftriaxone, and amikacin but resistant to amoxicillin-clavulanic acid [14,15,18].

N. abscessus is usually susceptible to TMP-SMX, imipenem, ceftriaxone, amikacin, and amoxicillin-clavulanic acid. It is also usually susceptible to minocycline [14,15].

N. otitidiscaviarum is generally susceptible to TMP-SMX and to amikacin but may be resistant to imipenem [14,15].

Many N. transvalensis isolates are susceptible to TMP-SMX, imipenem, and third-generation cephalosporins [14,20]. N. transvalensis is usually resistant to amikacin and other aminoglycosides [14,21-23].

Reported susceptibility to carbapenems is variable between geographical regions, between and within nocardia species, and between individual carbapenems. The majority of experience has been with imipenem with susceptibility ranging from 30 to 90 percent of tested isolates [6,14,15]. One study of the in vitro activity of various antibiotics against 51 Nocardia isolates from more than 10 Nocardia species found that meropenem was fourfold less active than imipenem and that ertapenem was 16-fold less active than imipenem [24].

All of the Nocardia species described above are susceptible to linezolid [6,24-26]. Tedizolid is a second oxazolidinone antimicrobial, as yet not widely available. Susceptibility testing of common nocardia isolates have documented lower MIC50 values compared with MIC50 for linezolid. The authors interpret this as tedizolid being two- to three- fold more active than linezolid for some nocardia isolates [27].

Amoxicillin-clavulanate has activity against some isolates (table 1). There are reports of in vitro susceptibility of clinical isolates to clarithromycin. In one study that included 186 Nocardia isolates, 96 percent of 55 N. nova isolates were susceptible to clarithromycin, but, with many other Nocardia species, the percentage of susceptible isolates was less than 50 percent [28]. In another study, 87 percent of 17 Nocardia isolates, including all 6 N. nova isolates, were susceptible [29].

TREATMENT — No prospective randomized trials have determined the most effective therapy for nocardiosis [30]. In addition, it is unlikely that such trials will ever be performed since a large number of patients with similar clinical manifestations would be required. Two hallmarks of nocardiosis are its relative rarity and the diversity of the clinical presentation in different patients. Thus, the choice of antimicrobials is based upon cumulative retrospective experience [31], severity of the infection, investigations in animal models, and in vitro antimicrobial activity profiles.

Approach to antimicrobial therapy — Clinical isolates of Nocardia spp are variably resistant to antibiotics. As a result, we recommend initial empiric coverage with two or three agents in patients with severe infection [30], as defined below. (See 'Severe infection' below.)

By contrast, patients with mild to moderate pulmonary nocardiosis without involvement of other organs and those with isolated cutaneous infection can be treated with monotherapy. (See 'Mild to moderate pulmonary disease' below and 'Cutaneous infection' below.)

Most authorities recommend trimethoprim-sulfamethoxazole (TMP-SMX) as part of first-line therapy for nocardiosis [30,32]. If the patient is allergic to sulfonamides, desensitization should be performed when possible. If this is not appropriate or if the patient is intolerant of sulfonamides, then alternative agents should be chosen based upon susceptibility studies of the clinical isolate, if available. The approach to patients with sulfonamide allergies is discussed in detail separately. (See "Sulfonamide allergy in HIV-uninfected patients".)

Trimethoprim-sulfamethoxazole — Sulfonamides have been considered the standard of therapy for more than 50 years, despite the lack of controlled comparative data. This consensus is based in part upon the results of a few retrospective reviews in which there was a trend toward increased survival in nocardiosis with the use of sulfonamide-containing regimens [33]. As noted above, if the patient is allergic to sulfonamides, desensitization should be performed when possible. (See 'Approach to antimicrobial therapy' above.)

Although all sulfonamides appear to be equally efficacious, TMP-SMX is considered by most clinicians to be the drug of choice. Dosing recommendations are presented below. (See 'Isolated cutaneous infection' below and 'Mycetoma' below and 'Initial intravenous therapy' below and 'Switch to oral therapy' below.)

Some Nocardia spp are less susceptible or resistant to this regimen by in vitro susceptibility testing. Nevertheless, there have been few reports of patients failing to respond to TMP-SMX [7]. (See 'Antibiotic susceptibility' above.)

In patients who develop Nocardia infection while taking low-dose TMP-SMX for Pneumocystis pneumonia prophylaxis, the majority of their isolates remain susceptible to TMP-SMX [34]. As an example, in a study of 35 solid organ transplant recipients with Nocardia infection, 24 (69 percent) were receiving prophylactic TMP-SMX (most at a dose of 1 single-strength tablet three times a week), and all breakthrough infections except one involved isolates that were susceptible to TMP-SMX [34]. Furthermore, many of the breakthrough infections were treated successfully with combination regimens that included TMP-SMX. In this setting, it is reasonable to use TMP-SMX as part of empiric combination therapy while awaiting susceptibility results. Appropriate combination regimens are discussed in greater detail below and are summarized in the following table (table 2). (See 'Severe infection' below.)

TMP-SMX has demonstrated synergy against Nocardia in several in vitro studies; the optimal ratio of TMP to SMX in vitro ranges from 1 to ≤5 to a ratio of 1 to 10 [35,36]. However, controversy exists over the optimal synergistic ratio in vivo and whether this ratio should be achieved in the serum or tissues.

Commercial preparations contain a ratio of TMP to SMX of 1:5. Following administration, the ratio achieved is usually 1:20 in the serum and cerebrospinal fluid [35] and approximately 1:7 in tissues, pus, and cerebral nocardial abscesses [37,38]. There is evidence that TMP-SMX is synergistic against Nocardia at a wide range of ratios, including the 1:20 ratio achieved in serum [35,37]. It has not been demonstrated that the TMP component adds clinical benefit over a sulfonamide alone [37].

TMP-SMX has the additional benefits of excellent penetration into most tissue compartments, including the central nervous system (CNS), and high serum concentrations after oral administration. TMP-SMX is the only parenteral sulfonamide currently available in the United States.

Other agents — Despite the success of TMP-SMX in the treatment of nocardiosis, combination therapy with other agents is warranted in patients with severe infections. These drugs are also indicated in patients with sulfonamide intolerance or allergy and documented clinical treatment failures. The choice of agent varies with susceptibility testing and with known patterns of response with different Nocardia spp. (See 'Antibiotic susceptibility' above.)

In vitro susceptibilities and animal models of disease have demonstrated activity against Nocardia with a variety of antibiotics, including amikacin, imipenem, meropenem, third-generation cephalosporins (ceftriaxone and cefotaxime), minocycline, extended spectrum fluoroquinolones (eg, moxifloxacin), linezolid, tigecycline, and dapsone [12,24,30,39-41].

Several anecdotal reports indicate that these agents are successful in treating patients with nocardiosis [42-44]. There are a few reports of successful treatment of N. nova infections using clarithromycin either as a single agent [45] or as part of a combination regimen [46].

The majority of nocardia isolates are susceptible to linezolid. However there is as yet limited clinical data for this antimicrobial, and its use is associated with myelosuppression, particularly thrombocytopenia as well as neurotoxicity (eg, peripheral neuropathy, serotonin syndrome) [47,48]. However, linezolid is being considered more often for nocardia therapy. In a retrospective study from Australia of 20 patients treated with linezolid there was no difference in the adverse effects in those patients receiving linezolid compared with those receiving other medications [49]. The median duration of linezolid treatment in this study was 28 days. In this series, therapeutic drug monitoring allowed successful dose reduction. Despite rare case reports of linezolid duration for up to nine months, linezolid seems unlikely to become widely used for long durations [50]. However, because of its oral bioavailability, broad activity against various Nocardia species, and its excellent CNS penetration, it could be considered early in severe infection as a short-term option and as a part of an initial combination with close monitoring for adverse effects.

There are few reports of the use of tedizolid in the treatment of nocardiosis; tedizolid may be associated with a lower incidence of myelosuppression [51,52].

Cutaneous infection — Four patterns of cutaneous disease have been observed: primary cutaneous, lymphocutaneous, cutaneous involvement from a disseminated focus, and mycetoma.

Isolated cutaneous infection — Despite reports of spontaneous resolution of some cutaneous lesions, it is judicious to treat all such patients with systemic antibiotics because of the possibility of more widespread disease. Single-agent oral therapy is usually sufficient for patients with cutaneous disease from an inoculation injury.

Empiric monotherapy regimens for patients with normal renal function include TMP-SMX (5 to 10 mg/kg of the trimethoprim component orally in two divided doses) and, less preferably, minocycline (100 mg orally twice daily) (table 2). Alternative oral agents may be used if the isolate proves susceptible. These include amoxicillin-clavulanate, doxycycline, macrolides, and fluoroquinolones. Linezolid, although active in vitro and in vivo, has significant hematologic toxicity, which requires careful monitoring and may limit its use.

Mycetoma — Management of nocardial mycetoma usually involves antibiotics alone. Surgical excision may be undertaken before diagnosis but is usually not warranted [53]. TMP-SMX (10 mg/kg of the trimethoprim component orally per day in two divided doses) with or without dapsone (100 mg orally once daily) is commonly used for disease of short duration, of limited extent, and with low risk of dissemination (table 2) [54]. For patients with more severe disease (eg, with bone or visceral involvement), with longer duration disease, or disease that is refractory to sulfonamides, consideration should be given to intravenous (IV) imipenem alone or in combination with amikacin [54].

Duration of treatment — The optimal duration of therapy for cutaneous disease, including mycetoma, has not been determined, but most recommend a prolonged course because of the relapsing nature of Nocardia infection. Immunocompetent patients with cutaneous disease should be treated with oral therapy for 3 to 6 months, although patients with mycetomas require 6 to 12 months. Immunocompromised patients with cutaneous disease should generally be treated for a minimum of one year.

Mild to moderate pulmonary disease — For patients with mild to moderate pulmonary nocardiosis without involvement of other organs, we give monotherapy with oral TMP-SMX (table 2). The appropriate dose depends upon the immune status and renal function of the host; these doses are intended for patients with normal renal function:

For immunocompetent patients with mild or moderate pulmonary nocardiosis, we give TMP-SMX 5 to 10 mg/kg orally of the trimethoprim component per day in two divided doses.

For immunocompromised patients with mild or moderate pulmonary nocardiosis, we give TMP-SMX 15 mg/kg orally of the trimethoprim component per day in three or four divided doses.

Dosing must be adjusted in patients with impaired renal function.

Severe infection — Severe nocardiosis includes cases of pulmonary disease with extensive lung involvement or with direct spread from the lung to the pleura, chest wall, or another contiguous organ. Severe infection also includes all cases of disseminated disease (involvement of more than one noncontiguous site) or central nervous system disease.

Initial intravenous therapy — Despite the lack of data to support the superiority of combination therapy over single-drug regimens, most infectious diseases specialists initially treat severe nocardial infection with two intravenous drugs prior to the availability of susceptibility results (table 2) [1,2]. However, in cases of life-threatening infection, we suggest using three intravenous drugs [1]. (See 'Antibiotic susceptibility' above and "Nocardia infections: Epidemiology, clinical manifestations, and diagnosis", section on 'Antimicrobial susceptibility testing'.)

The following doses are intended for patients with normal renal function; dosing must be adjusted in patients with impaired renal function:

We suggest that patients with severe infection that does not involve the CNS be treated initially with TMP-SMX (15 mg/kg IV of the trimethoprim component per day in three or four divided doses) plus amikacin (7.5 mg/kg IV every 12 hours). An alternative approach that some clinicians favor for the initial treatment of severe disease is imipenem (500 mg IV every 6 hours) plus amikacin [2,30,55].

We suggest that patients with CNS disease be given TMP-SMX (15 mg/kg IV of the trimethoprim component per day in three or four divided doses) plus imipenem (500 mg IV every 6 hours). In patients with CNS disease who have multiorgan involvement, we favor using amikacin in addition to the above regimen.

Antimicrobial susceptibilities should be performed on all Nocardia isolates as a guide to therapy. Susceptibility testing is particularly important in patients infected with Nocardia species known to have high frequencies of antimicrobial resistance, such as N. farcinica or other newly identified species [20]. One caveat is that immunocompromised patients may fail therapy even though the organism remains susceptible on repeat testing. Susceptibility testing is also repeated for patients who fail to respond to initial therapy.

Initial treatment (ie, induction therapy) should be administered intravenously for at least three to six weeks and/or until clinical improvement is documented. We favor at least two intravenous agents during this phase of therapy for all patients with severe disease. Patients initially on three intravenous drugs who both improve on initial intravenous combination therapy and are proven to have susceptible isolates may be switched to two intravenous drugs to complete the induction phase of therapy. The results of susceptibility testing should be used to tailor the regimen. As an example, if the isolate is susceptible to the third-generation cephalosporins (ceftriaxone, cefotaxime), imipenem can be switched to one of these agents.

Switch to oral therapy — Selected patients who clinically improve with induction intravenous therapy and do not have CNS disease may be switched to oral monotherapy (usually after three to six weeks) based upon susceptibility results.

In patients with CNS disease and/or multiorgan involvement, particularly if there is also immunocompromise, we suggest switching to combination oral therapy (with two drugs based upon susceptibility studies) after a minimum of six weeks of intravenous therapy and clear evidence of clinical improvement. Patients who are switched to oral therapy should be closely monitored to confirm a continued clinical response.

Recommended antibiotic regimens that can be part of an oral regimen following induction intravenous therapy for patients with normal renal function include the following [20]:

A sulfonamide (eg, TMP-SMX 10 mg/kg of the trimethoprim component per day in two or three divided doses) and/or

Minocycline (100 mg twice daily) and/or

Amoxicillin-clavulanate (875 mg twice daily)

Dosing must be adjusted in patients with impaired renal function.

Sulfonamide resistance or allergy — For patients infected with sulfonamide-resistant organisms, we suggest a two-drug regimen consisting of imipenem (500 mg IV every 6 hours) plus amikacin (7.5 mg/kg IV every 12 hours).

For those who are allergic to TMP-SMX, desensitization should be attempted when possible. If desensitization is not possible, we use imipenem plus amikacin as outlined above. We also use this regimen for patients with severe infection until the target dose of TMP-SMX has been reached during desensitization. The approach to desensitization is discussed in detail separately. (See "Sulfonamide allergy in HIV-uninfected patients".)

Duration of treatment — The optimal duration of antimicrobial treatment for severe disease has not been determined, but most recommend a prolonged course because of the relapsing nature of Nocardia infection. We usually treat for a duration of 3 to 6 months for isolated cutaneous infection in immunocompetent patients but for 6 to 12 months in immunocompromised patients. Serious pulmonary infection is treated for 6 to 12 months or longer [30]. All immunocompromised patients (except those with isolated cutaneous infection) as well as patients with CNS involvement should be treated for at least one year [2], and some suggest indefinite suppressive therapy in immunocompromised patients. Within these ranges, the total duration of therapy (IV followed by oral) is based upon the severity and extent of disease and the clinical and radiographic response to treatment. (See 'Secondary prophylaxis' below.)

The duration of intravenous therapy varies with the patient's immune status. In immunocompromised patients, maximal tolerated doses should be given intravenously for at least six weeks and until clinical improvement has occurred; in contrast, immunocompetent patients may be successfully treated with a shorter duration of intravenous therapy. Following the intravenous induction phase, patients may be stepped down to oral antibiotics based upon susceptibility studies [2,39]. (See 'Switch to oral therapy' above.)

Outcomes — The extent of disease and underlying conditions may significantly influence the outcome of Nocardia therapy. In two retrospective studies that included immunocompromised and nonimmunocompromised patients, all-cause mortality at 12 months ranged from 19 to 22 percent [56,57]. However, mortality is increased in immunocompromised hosts. In a multicenter European study, solid organ transplant recipients with nocardiosis had a 10-fold higher one-year mortality compared with transplant patients who did not have nocardiosis (16.2 versus 1.3 percent) [58].

Poor prognosis is also associated with a delay in diagnosis and/or premature discontinuation of appropriate therapy [59]. As an example, retrospective studies suggest improved outcomes when therapy is given for a prolonged period. In different observational studies, no fatalities occurred among 78 patients treated for more than six months [60], and relapses were rare in 34 patients treated for more than three months [37]. In a small study of HIV-infected patients, relapses were associated with a mean duration of therapy of eight weeks; no relapses were seen in patients treated for a mean of 45 weeks [59].

A poor prognosis is also reported in patients who have Nocardia bacteremia. In a systematic review of 138 cases reported in the literature between 1999 and 2018, the 30-day all-cause mortality rate was 28 percent and the overall all-cause mortality rate was 40 percent (median duration of follow-up 120 days) [61].

Promptly instituted and effective therapy is usually associated with a good outcome even when the disease has disseminated. In a case-control study that included 35 organ transplant recipients with nocardiosis, 31 (89 percent) were cured, including 6 of 7 patients with disseminated disease [34].

Monitoring — Patients with nocardiosis should be monitored for the response to therapy and possible drug toxicity. Following discharge from the hospital, patients should be seen frequently (eg, at least monthly) to monitor for changes in signs and symptoms as well as to detect any adverse drug effects.

In addition, radiographic studies are useful to evaluate clinical improvement in patients with severe infection. It is our practice to obtain follow-up imaging studies (eg, chest radiographs and/or computed tomography [CT] scans for pulmonary disease, and brain CT or magnetic resonance imaging [MRI] scans for CNS disease) after 1, 3, 6, and 12 months of treatment. For patients who have completed therapy and for those receiving prophylaxis to prevent relapse of prior nocardiosis, it is our practice to repeat the radiologic studies at 6 and 12 months after clinical cure.

Colonization — Isolation of Nocardia in a patient with underlying lung disease is most often considered an indication for specific therapy. However, there have been occasional reports in which such an isolate has been considered a non-pathogen (ie, colonizer) and treatment not instituted [62,63]. This may be in the setting of stable but chronic respiratory disease. Such patients should be seen frequently so that treatment can be initiated if evidence of disease emerges.

Treatment failures — Clinical improvement is usually seen within two weeks after initiation of appropriate therapy. Patients who continue to be symptomatic and/or have progression of their primary lesions after two weeks of therapy should be carefully reevaluated. Poor response may represent primary drug resistance, inadequate serum antibiotic concentrations, poor penetration of drug into the infected tissue compartment, or the presence of an abscess requiring surgical drainage. Alternative regimens for treatment of drug-resistant infection are presented above. (See 'Severe infection' above.)

Surgery — Surgical intervention may be necessary in several settings:

Cerebral and large soft tissue abscesses that do not respond to antibiotic therapy [64,65]

Empyemas and mediastinal fluid collections

Pulmonary nocardiosis complicated by pericarditis, which is almost always fatal unless pericardial drainage is performed [66,67]

CNS nocardiosis that fails to respond to medical therapy may require craniotomy or aspiration [64]. However, in a retrospective series of 11 patients with Nocardia brain abscesses treated at a single institution over a 31-year period, repeated aspiration was as effective as craniotomy [65]. (See "Nocardia infections: Epidemiology, clinical manifestations, and diagnosis".)

Patients on immunosuppressive therapy — Immunosuppressive therapy predisposes patients to Nocardia infection. In patients who are on these drugs because they have undergone transplantation, immunosuppression cannot be stopped, but the dose should be decreased as much as possible. In patients receiving immunosuppressive therapy for other reasons, it is ideal to discontinue the immunosuppressive agent if alternatives are available. Among tumor necrosis factor-alpha inhibitors, infliximab has been associated with a greater risk of nocardial infection than etanercept [68]. (See "Nocardia infections: Epidemiology, clinical manifestations, and diagnosis", section on 'Immunocompromising conditions'.)

Secondary prophylaxis — Following initial therapy of nocardiosis in patients whose immunosuppression cannot be reversed (eg, HIV, hematopoietic cell or solid organ transplant recipients, and patients receiving high-dose glucocorticoids or cytotoxic therapy), we suggest indefinite secondary prophylaxis to prevent relapse or recurrence of nocardiosis [33,69]. For secondary prophylaxis, we use TMP-SMX one double-strength tablet daily. Other experts have a similar approach [33,58,69].

A retrospective case-control study of solid organ transplant recipients found that the use of TMP-SMX prophylaxis did not prevent nocardiosis, although it is possible that the TMP-SMX dose used was too low [13]. Nevertheless, the authors recommend secondary prophylaxis with TMP-SMX because it is usually well tolerated and it may prevent other opportunistic infections if used at a higher dose [58]. Other reports have also suggested that TMP-SMX given two or three times a week for Pneumocystis pneumonia prophylaxis did not prevent nocardiosis in patients at high risk of disease [34,70-73].

SUMMARY AND RECOMMENDATIONS

Key clinical features – Nocardiosis is an uncommon gram-positive bacterial infection that usually causes infection in immunocompromised hosts. Two characteristics that distinguish nocardiosis are the ability to disseminate to virtually any organ, particularly the central nervous system, and the tendency to relapse or progress despite appropriate therapy. (See 'Introduction' above and "Nocardia infections: Epidemiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)

Indications for treatment – Patients with systemic disease require antibiotic therapy. We also recommend antibiotic therapy even in patients with limited cutaneous disease (Grade 1C). (See 'Treatment' above.)

Antibiotic selection – Antibiotics that are typically effective against Nocardia spp include trimethoprim-sulfamethoxazole (TMP-SMX), amikacin, imipenem, and third-generation cephalosporins (ceftriaxone and cefotaxime). However, antibiotic susceptibilities vary among isolates. The suggested regimens discussed below are empiric and should be tailored once information on susceptibilities is available. Dosing is presented in the table (table 2). (See 'Approach to antimicrobial therapy' above.)

Cutaneous infection – Patients with isolated cutaneous infection can usually be managed with oral monotherapy. We suggest initial therapy with oral TMP-SMX (Grade 2C). Patients who do not respond require intravenous therapy as discussed below for severe disease. (See 'Isolated cutaneous infection' above.)

Mycetoma – For patients with nonsevere mycetomas, we suggest initial therapy with oral TMP-SMX with or without dapsone (Grade 2C). For patients with severe mycetomas, we suggest initial therapy with imipenem with or without amikacin (Grade 2C). (See 'Mycetoma' above.)

Isolated pulmonary infection – For patients with mild to moderate pulmonary nocardiosis without involvement of other organs, we suggest monotherapy with oral TMP-SMX (Grade 2C). (See 'Mild to moderate pulmonary disease' above.)

Severe or CNS infection – Most experts would treat severe infection with two or three intravenous agents while awaiting results of susceptibility testing. In patients without central nervous system (CNS) disease, we suggest treating with TMP-SMX plus amikacin (Grade 2C). In patients with CNS disease, we suggest TMP-SMX plus imipenem (Grade 2C). In patients with CNS disease who have multiorgan involvement, we also add amikacin. (See 'Severe infection' above.)

In selected patients with severe disease who have improved after receiving three to six weeks of intravenous therapy and do not have CNS disease, treatment can be switched to an oral regimen. In these patients, we suggest a monotherapy oral regimen to complete the treatment course (Grade 2C). The oral agent is selected based on susceptibility testing; we use TMP-SMX if the isolate is susceptible. (See 'Switch to oral therapy' above.)

Duration of therapy – The optimal duration of antimicrobial treatment for severe disease has not been determined, but most recommend a prolonged course because of the relapsing nature of Nocardia infection. We usually treat for a duration of 3 to 6 months for isolated cutaneous infection in immunocompetent patients but for 6 to 12 months in immunocompromised patients with isolated cutaneous infection. For patients with serious pulmonary infection, we treat for 6 to 12 months or longer. All immunocompromised patients (except those with isolated cutaneous infection) as well as patients with CNS involvement should be treated for at least one year. Within these ranges, the duration of therapy is based upon the severity and extent of disease and the clinical and radiographic response to treatment. (See 'Duration of treatment' above.)

Monitoring response – Patients with nocardiosis should be monitored for the response to therapy and possible drug toxicity. (See 'Monitoring' above.)

Secondary prophylaxis – In immunocompromised patients whose immunosuppression cannot be reversed, we suggest indefinite secondary prophylaxis therapy with TMP-SMX (Grade 2C). Since breakthrough Nocardia infections have been seen when less frequent dosing regimens have been used for Pneumocystis pneumonia prophylaxis (eg, twice or three times per week), we use one double-strength tablet daily. (See 'Secondary prophylaxis' above.)

  1. Brown-Elliott BA, Brown JM, Conville PS, Wallace RJ Jr. Clinical and laboratory features of the Nocardia spp. based on current molecular taxonomy. Clin Microbiol Rev 2006; 19:259.
  2. Lerner PI. Nocardiosis. Clin Infect Dis 1996; 22:891.
  3. Lederman ER, Crum NF. A case series and focused review of nocardiosis: clinical and microbiologic aspects. Medicine (Baltimore) 2004; 83:300.
  4. Beaman BL, Burnside J, Edwards B, Causey W. Nocardial infections in the United States, 1972-1974. J Infect Dis 1976; 134:286.
  5. Beaman BL, Beaman L. Nocardia species: host-parasite relationships. Clin Microbiol Rev 1994; 7:213.
  6. Uhde KB, Pathak S, McCullum I Jr, et al. Antimicrobial-resistant nocardia isolates, United States, 1995-2004. Clin Infect Dis 2010; 51:1445.
  7. Brown-Elliott BA, Biehle J, Conville PS, et al. Sulfonamide resistance in isolates of Nocardia spp. from a US multicenter survey. J Clin Microbiol 2012; 50:670.
  8. Conville PS, Brown-Elliott BA, Wallace RJ Jr, et al. Multisite reproducibility of the broth microdilution method for susceptibility testing of Nocardia species. J Clin Microbiol 2012; 50:1270.
  9. Lai CC, Liu WL, Ko WC, et al. Antimicrobial-resistant nocardia isolates, Taiwan, 1998-2009. Clin Infect Dis 2011; 52:833.
  10. Lebeaux D, Bergeron E, Berthet J, et al. Antibiotic susceptibility testing and species identification of Nocardia isolates: a retrospective analysis of data from a French expert laboratory, 2010-2015. Clin Microbiol Infect 2019; 25:489.
  11. Ambrosioni J, Lew D, Garbino J. Nocardiosis: updated clinical review and experience at a tertiary center. Infection 2010; 38:89.
  12. Tan YE, Chen SC, Halliday CL. Antimicrobial susceptibility profiles and species distribution of medically relevant Nocardia species: Results from a large tertiary laboratory in Australia. J Glob Antimicrob Resist 2020; 20:110.
  13. Coussement J, Lebeaux D, van Delden C, et al. Nocardia Infection in Solid Organ Transplant Recipients: A Multicenter European Case-control Study. Clin Infect Dis 2016; 63:338.
  14. Valdezate S, Garrido N, Carrasco G, et al. Epidemiology and susceptibility to antimicrobial agents of the main Nocardia species in Spain. J Antimicrob Chemother 2017; 72:754.
  15. McTaggart LR, Doucet J, Witkowska M, Richardson SE. Antimicrobial susceptibility among clinical Nocardia species identified by multilocus sequence analysis. Antimicrob Agents Chemother 2015; 59:269.
  16. Wallace RJ Jr, Tsukamura M, Brown BA, et al. Cefotaxime-resistant Nocardia asteroides strains are isolates of the controversial species Nocardia farcinica. J Clin Microbiol 1990; 28:2726.
  17. Torres OH, Domingo P, Pericas R, et al. Infection caused by Nocardia farcinica: case report and review. Eur J Clin Microbiol Infect Dis 2000; 19:205.
  18. Wallace RJ Jr, Brown BA, Tsukamura M, et al. Clinical and laboratory features of Nocardia nova. J Clin Microbiol 1991; 29:2407.
  19. Khardori N, Shawar R, Gupta R, et al. In vitro antimicrobial susceptibilities of Nocardia species. Antimicrob Agents Chemother 1993; 37:882.
  20. Sorrell TC, Mitchell DH, Iredell JR. Nocardia species. In: Principles and Practice of Infectious Diseases, 6th ed, Mandell GL, Bennett JE, Dolin R (Eds), Elsevier, Philadelphia 2005. p.2916.
  21. McNeil MM, Brown JM, Georghiou PR, et al. Infections due to Nocardia transvalensis: clinical spectrum and antimicrobial therapy. Clin Infect Dis 1992; 15:453.
  22. Wallace RJ Jr, Steele LC, Sumter G, Smith JM. Antimicrobial susceptibility patterns of Nocardia asteroides. Antimicrob Agents Chemother 1988; 32:1776.
  23. Wilson RW, Steingrube VA, Brown BA, et al. Recognition of a Nocardia transvalensis complex by resistance to aminoglycosides, including amikacin, and PCR-restriction fragment length polymorphism analysis. J Clin Microbiol 1997; 35:2235.
  24. Cercenado E, Marín M, Sánchez-Martínez M, et al. In vitro activities of tigecycline and eight other antimicrobials against different Nocardia species identified by molecular methods. Antimicrob Agents Chemother 2007; 51:1102.
  25. Brown-Elliott BA, Ward SC, Crist CJ, et al. In vitro activities of linezolid against multiple Nocardia species. Antimicrob Agents Chemother 2001; 45:1295.
  26. Yetmar ZA, Challener DW, Seville MT, et al. Outcomes of Nocardiosis and Treatment of Disseminated Infection in Solid Organ Transplant Recipients. Transplantation 2023; 107:782.
  27. Brown-Elliott BA, Wallace RJ Jr. In Vitro Susceptibility Testing of Tedizolid against Isolates of Nocardia. Antimicrob Agents Chemother 2017; 61.
  28. Larruskain J, Idigoras P, Marimón JM, Pérez-Trallero E. Susceptibility of 186 Nocardia sp. isolates to 20 antimicrobial agents. Antimicrob Agents Chemother 2011; 55:2995.
  29. Al Akhrass F, Hachem R, Mohamed JA, et al. Central venous catheter-associated Nocardia bacteremia in cancer patients. Emerg Infect Dis 2011; 17:1651.
  30. Restrepo A, Clark NM, Infectious Diseases Community of Practice of the American Society of Transplantation. Nocardia infections in solid organ transplantation: Guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation. Clin Transplant 2019; 33:e13509.
  31. Anagnostou T, Arvanitis M, Kourkoumpetis TK, et al. Nocardiosis of the central nervous system: experience from a general hospital and review of 84 cases from the literature. Medicine (Baltimore) 2014; 93:19.
  32. Yang J, Ren HT, Wang J, et al. Clinical characteristics, susceptibility profiles, and treatment of nocardiosis: a multicenter retrospective study in 2015-2021. Int J Infect Dis 2023; 130:136.
  33. Wilson JP, Turner HR, Kirchner KA, Chapman SW. Nocardial infections in renal transplant recipients. Medicine (Baltimore) 1989; 68:38.
  34. Peleg AY, Husain S, Qureshi ZA, et al. Risk factors, clinical characteristics, and outcome of Nocardia infection in organ transplant recipients: a matched case-control study. Clin Infect Dis 2007; 44:1307.
  35. Smego RA Jr, Moeller MB, Gallis HA. Trimethoprim-sulfamethoxazole therapy for Nocardia infections. Arch Intern Med 1983; 143:711.
  36. Beaumont RJ. Trimethoprim as a possible therapy for nocardiosis and melioidosis. Med J Aust 1970; 2:1123.
  37. Wallace RJ Jr, Septimus EJ, Williams TW Jr, et al. Use of trimethoprim-sulfamethoxazole for treatment of infections due to Nocardia. Rev Infect Dis 1982; 4:315.
  38. Smith PW, Steinkraus GE, Henricks BW, Madson EC. CNS nocardiosis: response to sulfamethoxazole-trimethoprim. Arch Neurol 1980; 37:729.
  39. Threlkeld SC, Hooper DC. Update on management of patients with Nocardia infection. Curr Clin Top Infect Dis 1997; 17:1.
  40. McNeil MM, Brown JM, Hutwagner LC, Schiff TA . Evaluation of therapy for Nocardia asteroides complex infections. Infect Dis Clin Prac 1995; 4:287.
  41. Vera-Cabrera L, Gonzalez E, Choi SH, Welsh O. In vitro activities of new antimicrobials against Nocardia brasiliensis. Antimicrob Agents Chemother 2004; 48:602.
  42. Beaman BL, Boiron P, Beaman L, et al. Nocardia and nocardiosis. J Med Vet Mycol 1992; 30 Suppl 1:317.
  43. Fihman V, Berçot B, Mateo J, et al. First successful treatment of Nocardia farcinica brain abscess with moxifloxacin. J Infect 2006; 52:e99.
  44. Moylett EH, Pacheco SE, Brown-Elliott BA, et al. Clinical experience with linezolid for the treatment of nocardia infection. Clin Infect Dis 2003; 36:313.
  45. Naik S, Mateo-Bibeau R, Shinnar M, et al. Successful treatment of Nocardia nova bacteremia and multilobar pneumonia with clarithromycin in a heart transplant patient. Transplant Proc 2007; 39:1720.
  46. Nizam I, Kohan L, Kerr D. Nocardia nova septic arthritis following total knee replacement: a case report. J Orthop Surg (Hong Kong) 2007; 15:390.
  47. Attassi K, Hershberger E, Alam R, Zervos MJ. Thrombocytopenia associated with linezolid therapy. Clin Infect Dis 2002; 34:695.
  48. Bishop E, Melvani S, Howden BP, et al. Good clinical outcomes but high rates of adverse reactions during linezolid therapy for serious infections: a proposed protocol for monitoring therapy in complex patients. Antimicrob Agents Chemother 2006; 50:1599.
  49. Davidson N, Grigg MJ, Mcguinness SL, et al. Safety and Outcomes of Linezolid Use for Nocardiosis. Open Forum Infect Dis 2020; 7:ofaa090.
  50. Pea F, Cojutti P, Pagotto A, et al. Successful long-term treatment of cerebral nocardiosis with unexpectedly low doses of linezolid in an immunocompromised patient receiving complex polytherapy. Antimicrob Agents Chemother 2012; 56:3438.
  51. Chomei Y, Nishimura S, Iwata K. Long-term use of tedizolid for pulmonary nocardiosis. J Infect Chemother 2022; 28:1172.
  52. Matin A, Sharma S, Mathur P, Apewokin SK. Myelosuppression-sparing treatment of central nervous system nocardiosis in a multiple myeloma patient utilizing a tedizolid-based regimen: a case report. Int J Antimicrob Agents 2017; 49:488.
  53. Arenas R, Ameen M. Giant grains of nocardia actinomycetoma. Lancet Infect Dis 2010; 10:66.
  54. Ameen M, Arenas R, Vásquez del Mercado E, et al. Efficacy of imipenem therapy for Nocardia actinomycetomas refractory to sulfonamides. J Am Acad Dermatol 2010; 62:239.
  55. Clark NM, Reid GE, AST Infectious Diseases Community of Practice. Nocardia infections in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4:83.
  56. Steinbrink J, Leavens J, Kauffman CA, Miceli MH. Manifestations and outcomes of nocardia infections: Comparison of immunocompromised and nonimmunocompromised adult patients. Medicine (Baltimore) 2018; 97:e12436.
  57. Paige EK, Spelman D. Nocardiosis: 7-year experience at an Australian tertiary hospital. Intern Med J 2019; 49:373.
  58. Lebeaux D, Freund R, van Delden C, et al. Outcome and Treatment of Nocardiosis After Solid Organ Transplantation: New Insights From a European Study. Clin Infect Dis 2017; 64:1396.
  59. Uttamchandani RB, Daikos GL, Reyes RR, et al. Nocardiosis in 30 patients with advanced human immunodeficiency virus infection: clinical features and outcome. Clin Infect Dis 1994; 18:348.
  60. Geiseler PJ, Andersen BR. Results of therapy in systemic nocardiosis. Am J Med Sci 1979; 278:188.
  61. Williams E, Jenney AW, Spelman DW. Nocardia bacteremia: A single-center retrospective review and a systematic review of the literature. Int J Infect Dis 2020; 92:197.
  62. Hardak E, Yigla M, Berger G, et al. Clinical spectrum and outcome of Nocardia infection: experience of 15-year period from a single tertiary medical center. Am J Med Sci 2012; 343:286.
  63. Margalit I, Muhsen K, Ben Ari Y, et al. Nocardia colonization in contrast to nocardiosis: a comparison of patients' clinical characteristics. Eur J Clin Microbiol Infect Dis 2020; 39:759.
  64. Mamelak AN, Obana WG, Flaherty JF, Rosenblum ML. Nocardial brain abscess: treatment strategies and factors influencing outcome. Neurosurgery 1994; 35:622.
  65. Lee GY, Daniel RT, Brophy BP, Reilly PL. Surgical treatment of nocardial brain abscesses. Neurosurgery 2002; 51:668.
  66. Poland GA, Jorgensen CR, Sarosi GA. Nocardia asteroides pericarditis: report of a case and review of the literature. Mayo Clin Proc 1990; 65:819.
  67. Leang B, Lynen L, Lim K, et al. Disseminated nocardiosis presenting with cardiac tamponade in an HIV patient. Int J STD AIDS 2004; 15:839.
  68. Wallis RS, Broder MS, Wong JY, et al. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 2004; 38:1261.
  69. Simpson GL, Stinson EB, Egger MJ, Remington JS. Nocardial infections in the immunocompromised host: A detailed study in a defined population. Rev Infect Dis 1981; 3:492.
  70. King CT, Chapman SW, Butkus DE. Recurrent nocardiosis in a renal transplant recipient. South Med J 1993; 86:225.
  71. van Burik JA, Hackman RC, Nadeem SQ, et al. Nocardiosis after bone marrow transplantation: a retrospective study. Clin Infect Dis 1997; 24:1154.
  72. Chouciño C, Goodman SA, Greer JP, et al. Nocardial infections in bone marrow transplant recipients. Clin Infect Dis 1996; 23:1012.
  73. Walensky, RP, Moore, RD. A case series of 59 patients with nocardiosis. Infect Dis Clin Pract 2001; 10:249.
Topic 5513 Version 30.0

References

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