Approach

As nocardiosis is a rare disease, the choice of drug, its administration, and duration of treatment have not been well established in clinical trials.[43]​ Most of the recommendations are based on the results of basic research, animal models, and clinical expert opinions.

Although treatment should be guided by Nocardia speciation and susceptibility testing, clinicians usually start treatment empirically, when the results are still not available. Sulfonamides (e.g., trimethoprim/sulfamethoxazole) have been the agents of choice for the treatment of nocardiosis for more than 60 years. Depending on the clinical presentation, the evolution of the disease, and the involved body site, adjuvant surgical treatment may also be necessary.

Initial medical treatment for patients with severe disease

Severe disease is considered to be disseminated disease, central nervous system (CNS) involvement, or pulmonary disease with signs of extensive infection. Although sulfonamides have classically been the drug of choice, patients with severe disease are typically treated with a combination of two or three drugs. Combination therapy is used both to ensure adequate antimicrobial coverage and because of possible synergy between antibiotics.[62] 

For the treatment of severe disease, some experts recommend a triple regimen consisting of trimethoprim/sulfamethoxazole, amikacin, and carbapenem (e.g., imipenem/cilastatin). Alternatively, a two-drug regimen may be advised for severe disease not involving the CNS, such as trimethoprim/sulfamethoxazole plus amikacin or imipenem/cilastatin, or imipenem/cilastatin plus amikacin. Linezolid is another option to include in an initial regimen for severe disease.[43]

Sulfonamides

  • Sulfonamides are considered a drug of choice for nocardiosis. Trimethoprim/sulfamethoxazole achieves good penetration into the CNS, and has good bioavailability when given orally.

  • However, these drugs are associated with a high incidence of adverse events such as allergic reactions, acute kidney injury, hyperkalemia, hematologic toxicity, and severe nausea.[63]​ Monitoring for renal toxicity, electrolyte disturbances, and hematologic toxicity is recommended during treatment.

  • Resistance to sulfonamides is possible with some Nocardia species. For example, Nocardia farcinica is commonly resistant to trimethoprim/sulfamethoxazole.

Linezolid

  • Linezolid, an oxazolidinone antibiotic, has shown strong in-vitro activity against most of the Nocardia species and strains tested.[64] Additionally, linezolid has high oral bioavailability and can penetrate the CNS.[65][66]​ There is growing evidence to support the use of a linezolid-containing regimen in the treatment of nocardiosis, including among patients with CNS involvement, although some clinicians have raised concerns that the range of serious adverse effects might limit its widespread use.[62][67][68][69]

  • One 2019 retrospective study of 20 patients with moderate-to-severe nocardiosis found that initial empirical treatment with a linezolid-containing regimen was at least as safe and effective as other first-line agents. In this study, the most common adverse effects were thrombocytopenia and anemia; however, adverse effects necessitating discontinuation of treatment were more common in patients treated with trimethoprim/sulfamethoxazole than linezolid.[70] Another small study reported that 45% of patients developed myelosuppression and 18% developed neuropathy as an adverse effect of linezolid treatment for nocardiosis.[68] Other linezolid-associated adverse effects, reported in small series of patients receiving treatment for nocardiosis, include optic neuritis and lactic acidosis.[65][67]​​ The duration of treatment and the presence of preexisting factors (e.g., underlying neurologic disease, treatment with chemotherapy, diabetes, alcohol use disorder) appear to increase the risk of developing neurologic complications.[71] The risk of thrombocytopenia has also been reported to increase when linezolid is used for more than 10 days.[72]

  • The risk of hematologic and neurologic complications might limit the use of linezolid to monitored hospital settings and for initial, empirical treatment. Careful monitoring for these complications is recommended with treatment.

Amikacin

  • Amikacin, an aminoglycoside antibiotic, is often included in initial empiric treatment regimens due to high susceptibility rates across Nocardia species. However, its use is associated with potential nephrotoxicity and ototoxicity, including vestibular dysfunction and irreversible hearing loss.

  • Careful monitoring of serum amikacin levels and for signs of nephrotoxicity and ototoxicity, are recommended when treating with amikacin, especially if the treatment duration is prolonged.

  • Amikacin achieves poor CNS penetration, therefore a two-drug regimen containing this drug may be insufficient for the treatment of CNS disease.

Initial medical treatment for patients with nonsevere pulmonary disease

Nonsevere pulmonary disease may be treated with trimethoprim/sulfamethoxazole monotherapy, or with a two-drug regimen consisting of trimethoprim/sulfamethoxazole plus another agent such as ceftriaxone, ciprofloxacin, moxifloxacin, linezolid, or minocycline.[21][43]​ Choice of antibiotic therapy is guided by the treating clinician and depends on whether the infection is mild or moderate.

Initial medical treatment for patients with cutaneous disease

Cutaneous nocardiosis may be treated with trimethoprim/sulfamethoxazole monotherapy or combination therapy with trimethoprim/sulfamethoxazole plus another agent (e.g., moxifloxacin, ciprofloxacin, imipenem/cilastatin, linezolid) is recommended for mycetoma or if there is deep tissue involvement or extension to the bone.[12][43][73][74]​​​ Imipenem/cilastatin has shown to be effective for actinomycetomas due to Nocardia refractory to sulfonamides.[75]

Follow-up treatment

After empiric therapy is initiated, treatment should be guided by the results of Nocardia speciation and susceptibility testing.[43]​ When the results of typing and sensitivity tests are available, treatment should be targeted toward that isolate. After the patient has clinically improved, oral agents can be considered for follow-up therapy. Potentially useful drugs, according to the species involved, are cephalosporins (e.g., ceftriaxone), other beta-lactams (e.g., amoxicillin/clavulanate), trimethoprim/sulfamethoxazole, minocycline, fluoroquinolones (e.g., ciprofloxacin, moxifloxacin), linezolid, and carbapenems (e.g., meropenem, imipenem/cilastatin, ertapenem). Most Nocardia farcinica isolates are resistant to the cephalosporins, but cephalosporins are highly active against N asteroides type VI, N nova, and N abscessus. The latter species is more frequently resistant to imipenem/cilastatin. N cyriacigeorgica has also been reported to be resistant to imipenem/cilastatin.[46][76]​​​ Since susceptibility to different carbapenems changes for different Nocardia species, there may be utility in testing Nocardia for imipenem/cilastatin, meropenem, and ertapenem sensitivity.[77] Fluoroquinolones are active against most N farcinica and N brasiliensis strains. N brasiliensis is also frequently susceptible to amoxicillin/clavulanate.[8] However, because resistance patterns within the same species may differ, treatment will be individual to each patient and cannot be standardized.

Duration of treatment and secondary prophylaxis

Duration of therapy is variable and depends on the location of the lesions and the immune status of the patient. Primary cutaneous nocardiosis can be treated for 3-6 months. However, mycetoma requires more prolonged therapy. Pulmonary and disseminated nocardiosis without CNS involvement should be treated for at least 6 months.[20] For patients with CNS involvement, treatment duration depends on clinical and imaging responses, but treatment should be continued for 1 year or longer. In HIV-infected patients with low CD4 T-cell count and patients who have received transplants, secondary prophylaxis with an active oral agent needs to be maintained until the immune status improves.[30]

Surgical treatment

Some locations of nocardiosis may require adjunctive surgical treatment, particularly for patients with brain abscesses. However, the optimal treatment approach has not been established, and Nocardia brain abscesses have been managed either conservatively, with aspirations, or with open craniotomy and enucleation.[54][78][79]​ Thus, every case needs a careful multidisciplinary evaluation by the primary physician, the infectious diseases specialist, and the surgeon. Surgery or bronchoscopy can also be considered for draining pulmonary abscesses or empyemas.[7]

Cutaneous lesions and mycetoma may sometimes require surgical treatment, as well as some ocular infections and rare cases with other body site involvement.[80][81][82][83][84][85]

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