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DTT 2023; 2(2): 145-155

Published online September 30, 2023 https://doi.org/10.58502/DTT.23.0017

Copyright © The Pharmaceutical Society of Korea.

Efficacy and Safety of Linezolid in the Treatment of Nontuberculous Mycobacterial Pulmonary Disease: A Review

Mi Seon Park1,2 , Eun Joo Choi1

1Department of Pharmacy, College of Pharmacy, Chosun University, Gwangju, Korea
2Department of Pharmacy, Jeonbuk National University Hospital, Jeonju, Korea

Correspondence to:Eun Joo Choi, ejchoi@chosun.ac.kr

Received: April 28, 2023; Revised: June 8, 2023; Accepted: June 11, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ((http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

The incidence of nontuberculous mycobacteria (NTM) pulmonary disease has been increasing worldwide. However, treatment options for NTM pulmonary disease are limited by the multidrug-resistant nature of these organisms and the toxicities of antibiotics. Although linezolid (LZD) has shown its activity against NTM species in vitro studies, long-term use of LZD may be limited by its side effects. Therefore, we aimed to evaluate the efficacy and safety of LZD in the treatment of NTM pulmonary disease through a literature review. A literature search was conducted using search engines such as PubMed, Embase, and Cochrane library up to March 25, 2022. We evaluated the treatment outcomes including improvement of clinical symptoms, culture conversion, and the incidence of side effects. Of the 1,073 articles searched, 3 retrospective studies and 6 case reports met the inclusion criteria. LZD was mostly used in the treatment of Mycobacterium abscessus as a combination therapy of three or more antibiotics. Treatment success was reported in 2 retrospective studies at 67% and 81%, respectively, and in 4 out of 6 case reports. Discontinuation of LZD due to serious side effects such as myelosuppression and neuropathy was reported in 3 retrospective studies in 0%, 22%, and 39%, respectively, and in 2 out of 6 case reports. In the treatment of NTM pulmonary disease, the majority of patients on combination therapies including LZD had positive outcomes. However, many patients experienced side effects leading to discontinuation of the treatment. All NTM patients with LZD treatment should be monitored closely for the presence of serious side effects.

Keywordsnontuberculous mycobacteria (NTM), linezolid, efficacy, safety, treatment

Nontuberculous mycobacteria (NTM) refers to mycobacteria excluding the Mycobacterium tuberculosis complex and Mycobacterium leprae (Jhun and Koh 2019). Currently, there are approximately 200 known species of NTM, and new species are being identified (Daley et al. 2020; Chen et al. 2022). Most NTM is widely distributed in the natural environment, such as water and soil, and although they exhibit low pathogenicity, some species can induce diseases including pulmonary disease, lymphadenitis, skin, and soft tissue osteomyelitis, and disseminated disease (Kang 2021), among which pulmonary disease is the most common type that accounts for ≥ 90% of human diseases caused by NTM (The Korean Academy of Tuberculosis and Respiratory Diseases [KATRD] guideline 2020). Various causal pathogens of NTM pulmonary disease have been reported in numerous countries and regions, but the most frequent ones include the Mycobacterium avium complex (MAC; Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium chimaera), Mycobacterium kansasii, Mycobacterium xenopi, and Mycobacterium abscessus (MAB) (Jeon 2019).

Recently, the incidence of tuberculosis among pulmonary diseases in South Korea has shown a decreasing trend; however, on the contrary, the frequency of NTM isolation from clinical samples has rapidly increased, and the number of patients receiving the diagnosis and treatment of NTM pulmonary disease has increased worldwide, including in South Korea (Yoo et al. 2012; Kwon and Koh 2014; Jhun and Koh 2019; Winthrop et al. 2020). Patients with NTM pulmonary disease vary in symptom and disease progression, and the lack of treatment for pulmonary diseases of the fibrocavitary form or with severe symptoms generally leads to extensive parenchymal destruction and death as the disease progresses (Koh 2011). However, effective treatment for NTM pulmonary disease is yet to be developed, and although the treatment generally necessitates 18-24 months of combined use of antibiotics, the related side effects and drug resistance pose challenges to the current treatment (KATRD 2020).

Linezolid is an oxazolidinone-based antibiotic originally developed for the treatment of Gram-positive bacteria, especially those resistant to conventional antibiotics such as methicillin-resistant Staphylococcus aureus. The drug has subsequently been shown to have an antimicrobial effect against the Mycobacterium tuberculosis complex, and it is thus recommended as the core drug in the treatment of multidrug-resistant tuberculosis (MDR-TB) at present (Tang et al. 2015; Zhang et al. 2015; Agyeman and Ofori-Asenso 2016; World Health Organization [WHO] 2019). NTM species have also shown susceptibility to linezolid in an in vitro test, which prompted clinical treatments using linezolid (Brown-Elliott et al. 2003; Cavusoglu et al. 2007). In South Korea, NTM pulmonary disease has been reported to be most frequently caused by MAC as in overseas countries, where the second-most common causal pathogen is MAB, a relatively rare species (Ko et al. 2018). MAB pulmonary disease, compared to MAC pulmonary disease, shows resistance to several antibiotics, and despite injection therapy over long-term hospitalization, the treatment outcome has been poor (Juhn and Koh 2019). Linezolid is advantageous because it exhibits efficacy against MAB with resistance to other antibiotics and allows oral administration, unlike injected drugs that demand hospitalization (Daley et al. 2020). However, in long-term treatment, linezolid can induce hematological side effects such as anemia and thrombocytopenia, as well as neurological side effects such as peripheral neuritis and optic neuropathy, which can be fatal in the case of NTM pulmonary disease, which requires antibiotic treatment for 18 months or longer (Tang et al. 2015; Zhang et al. 2015; Agyeman and Ofori-Asenso 2016; Daley et al. 2020; KATRD 2020). Despite these side effects, linezolid's health insurance benefits for the use of linezolid in treating NTM pulmonary disease have been expanded in Korea (Health Insurance Review and Assessment Service [HIRA] 2019) due to the lack of other alternative drugs for MAB, which is commonly isolated in Asia (16%) compared to North America (3.2%) and Europe (2.9%) (Zweijpfenning et al. 2018). However, recent guidelines on the use of linezolid published in Korea and overseas (2020 ATS/ERS/ESCMID/IDSA guidelines) vary, and data on ideal drug combinations or administration periods are insufficient (Table 1 and 2) (Ryu et al. 2016; Daley et al. 2020; KATRD 2020, Kims online®; Lexicomp®). Thus, we aimed to contribute to the success of the treatment of NTM pulmonary disease using safe linezolid by conducting a literature review on the efficacy and safety of linezolid based on previously published clinical studies.

Table 1 Recommended treatment regimens for nontuberculous mycobacterial pulmonary disease

SpeciesNo. of drugsPreferred regimen
2020 ATS/ERS/ESCMID/IDSA guideline2020 KATRD Korean guidelines
M. avium complex
Nodular-bronchiectatic3AZM (CLR), RIF (RFB), ETBCLR (AZM), RIF, ETB
Cavitary≥ 3AZM (CLR), RIF (RFB), ETB, AMK IV (SM)CLR (AZM), RIF, ETB
Refractory≥ 4AZM (CLR), RIF (RFB), ETB, inhaled AMK (AMK IV or SM)CLR (AZM), RIF, ETB, AMK IV (SM)
M. kansasii3AZM (CLR), RIF (RFB), ETBINH, RIF, ETB
3INH, RIF (RFB), ETB
M. xenopi≥ 3AZM (CLR) and/or MXF, RIF (RFB), ETB, AMKN/A
M. abscessus
Macrolide susceptibleInitial phase ≥ 3Parenteral (choose 1-2): AMK, IPM (or FOX), TGC
Oral (choose 2): AZM (CLR), CLO, LZD
Parenteral (choose 2): AMK, FOX (or IPM), TGC
Continuation phase ≥ 2Oral/inhaled (choose 1-2): AZM (CLR), CLO, LZD, inhaled AMKOral: CLR (AZM)
Macrolide inducible resistanta)Initial phase ≥ 4Parenteral (choose 2-3): AMK, IPM (or FOX), TGC
Oral (choose 2-3): AZM (CLR), CLO, LZD
Continuation phase ≥ 2Oral/inhaled (choose 2-3): AZM (CLR), CLO, LZD, inhaled AMK
Macrolide mutational resistantInitial phase ≥ 4Parenteral (choose 2-3): AMK, IPM (or FOX), TGC
Oral (choose 2-3): AZM (CLR), CLO, LZD
Continuation phase ≥ 2Oral/inhaled (choose 2-3): AZM (CLR), CLO, LZD, inhaled AMK

AMK, amikacin; AZM, azithromycin; CLR, clarithromycin; CLO, clofazimine; ETB, ethambutol; FOX, cefoxitin; INH, isoniazid; IPM, imipenem; IV, intravenous; LZD, linezolid; MXF, moxifloxacin; N/A, not available; RFB, rifabutin; RIF, rifampicin; SM, streptomycin; TGC, tigecycline.

a)Inducible resistance: The organism develops resistance to the macrolides in vitro after prolonged incubation (susceptible at day 3, but resistant at day 14), or by preincubation in macrolide-containing media (Ryu et al. 2016).

NOTE: This table was modified based on 2020 ATS/ERS/ESCMID/IDSA guideline and 2020 KATRD Korean guidelines (Daley et al. 2020; KATRD 2020).


Table 2 Dosing and metabolism of drugs for nontuberculous mycobacterial pulmonary disease (Daley et al. 2020; Kims online®; Lexicomp®)

DrugDaily dosing (day)3 times weekly dosing (day)Hepatic impairmentRenal impairment CrCl (mL/min)Metabolism/transport effect
Oral
Azithromycin200-500 mg500 mgN/AN/A

Substrate of CYP3A4 (minor)

Inhibits P-glycoprotein/ABCB1

Ciprofloxacin500-750 mg twiceN/AN/ACrCl 30-50: 250-500 mg twice daily

Substrate of OAT1/3, P-glycoprotein/ABCB1 (minor)

Inhibits CYP1A2 (moderate), CYP3A4 (weak)

CrCl < 30: 500 mg once daily
Clarithromycin500 mg twice500 mg twiceN/ACrCl < 30: 500 mg once daily

Substrate of CYP3A4 (major)

Inhibits CYP3A4 (strong), OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/ABCB1

Clofazimine100-200 mgN/AAdministrationwith cautionN/AN/A
Doxycycline100 mg once or twiceN/AN/AN/AN/A
Ethambutol15 mg/kg25 mg/kgN/ACrCl < 30: increase dosing interval

Substrate of OCT1, OCT2

Isoniazid5 mg/kg (max: 300 mg)N/AAdministrationwith cautionN/A

Substrate of CYP2E1 (minor)

Inhibits CYP2E1 (moderate), CYP3A4 (weak)

Induces CYP2E1 (weak)

Linezolid600 mg once or twiceN/AN/AN/A

Inhibits monoamine oxidase

Moxifloxacin400 mgN/AN/AN/AN/A
Trimethoprim-sulfamethoxazole800/160 mg tab twiceN/AAdministrationwith cautionCrCl 15-30: dose reduction to 50%

Substrate of CYP2C9 (minor), CYP3A4 (minor)

Inhibits CYP2C8 (weak), OCT1, OCT2

CrCl < 15: dose reduction to 25-50%, administration with caution
Rifabutin150-300 mg300 mgAdministrationwith cautionCrCl < 30: dose reduction of 50% if toxicity is suspected

Substrate of CYP1A2 (minor), CYP3A4 (major)

Induces CYP2C9 (weak), CYP3A4 (moderate), UGT1A4

Rifampicin10 mg/kg (450-600 mg)600 mgAdministrationwith cautionN/A

Substrate of OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/ABCB1 (minor)

Inhibits OATP1B1/1B3 (SLCO1B1/1B3)

Induces BCRP/ABCG2, CYP1A2 (weak), CYP2B6 (moderate), CYP2C19 (strong), CYP2C8 (moderate), CYP2C9 (moderate), CYP3A4 (strong), OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/ABCB1, UGT1A1, UGT1A9

Parenteral
Amikacin (IV)10-15 mg/kga)15-25 mg/kga)N/AReduce dose or increase dosing intervalN/A
Cefoxitin (IV)2-4 g 2-3 times (max: 12 g/day)N/AN/AReduce dose or increase dosing intervalSubstrate of OAT1/3
Imipenem (IV)500-1,000 mg,
2-3 times
N/AN/AReduce dose or increase dosing intervalN/A
Streptomycin (IV or IM)10-15 mg/kg15-25 mg/kgN/AReduce dose or increase dosing intervalN/A
Tigecycline (IV)25-50 mg
1-2 times
N/A25 mg 1-2 times in severe hepatic impairmentN/AN/A
Inhalation
Amikacin liposome inhalation suspension590 mgN/AN/AN/AN/A
Amikacin, parenteral formulation250-500 mgN/AN/AN/AN/A

CrCl, creatinine clearance; IM, intramuscular; IV, intravenous; N/A, not available.

a)Monitoring of serum concentrations is recommended to ensure efficacy and avoid toxicity.

NOTE: This table was modified and developed based on 2020 ATS/ERS/ESCMID/IDSA guideline (Daley et al. 2020).

Literature search

This study was conducted based on the methodology of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) (Moher et al. 2015). The selected search words were “Linezolid,” “Nontuberculous mycobacteria,” “Mycobacterium avium,” “Mycobacterium intracellulare,” “Mycobacterium abscessus,” “Mycobacterium chelonae,” “Mycobacterium fortuitum,” “Mycobacterium chimaera,” and “Mycobacterium xenopi.” The search was performed by the search formula combining the Boolean operators (Supplementary Table 1). For the literature search, the databases of MEDLINE (source: PubMed), Embase, and Cochrane Library were searched for the period up to March 25, 2022.

Article selection and categorization

After the exclusion of duplicated articles from the search result, two researchers independently performed the selection of articles based on the criteria. According to the inclusion criteria, studies were eligible if they investigated the clinical outcomes of linezolid treatment in patients with NTM pulmonary disease, included the study subjects aged ≥ 18 years, and were published only in English. The title and abstract of each article were reviewed to exclude animal studies, studies on pediatric patients, studies published in languages other than English, studies with only the abstract, and those such as reviews, commentaries, and editorial letters. The full texts of the selected articles were subsequently reviewed to exclude studies that could not evaluate the efficacy and safety of linezolid treatments in patients with NTM pulmonary disease. When the two researchers disagreed during the review of full texts, the inclusion of the respective articles was determined if a mutual agreement could be reached. However, owing to the highly limited number of clinical studies on linezolid treatment regarding NTM pulmonary disease, all clinical studies including case reports were selected for this study.

Data extraction

The data extracted from the retrieved articles included study design, publication year, sample size, demographic characteristics, clinical information associated with linezolid (dosage, treatment duration), and clinical outcomes (culture conversion, clinical cure, and side effects).

With the exclusion of duplicated articles from 1,073 articles presented by the PubMed, Embase, and Cochrane library search engines, 926 studies were selected. Based on the title and abstract, 504 articles that did not meet the inclusion criteria were primarily excluded. After a review of the full text, 20 articles unrelated to NTM, 193 articles unrelated to linezolid, 176 articles regarding the use of linezolid in NTM diseases other than a pulmonary disease, and 24 articles that prevent the determination of independent effects of linezolid owing to various regimen changes, i.e., a total of 413 articles, were excluded. Through the agreement of the two researchers after expert review, 6 case reports and 3 retrospective studies, including 2 articles reporting approximately 78% of pulmonary disease among NTM infections, were selected for this study (Fig. 1).

Figure 1.Flow diagram of study selection. NTM, nontuberculous mycobacteria.

Characteristics of the studies

Table 3 presents the study design and subject characteristics in the final set of nine selected studies. The 9 articles included in this study were clinical studies published between 2004 and 2021, comprising 3 retrospective studies (2 observational studies and 1 cohort study) and 6 case reports, conducted on a total of 133 subjects. For the causal pathogen of NTM pulmonary disease against which linezolid was used, one among three retrospective clinical studies applied linezolid solely for the treatment of MAB, and the other two applied linezolid mainly against MAB but also for the treatment of MAC and M. chelonae. Among the 6 case reports, linezolid was used to treat MAB in 4, M. mucogenicum in 1, and Mycolicibacter kumamotonensis (the M. terrae complex) in 1 (Spellberg et al. 2004; Faulk et al. 2013; Winthrop et al. 2015; Inoue et al. 2017; Li et al. 2019; Singh et al. 2019; Manika et al. 2021; Poon et al. 2021; Wen 2021).

Table 3 Baseline characteristics of included studies

StudyPublication (year)CountryNo. of patients receiving linezolidAge (years)Species Identification
Retrospective study
1Winthrop et al.2015North America102Median: 58 (range: 3-88)M. abscessus (44%), M. avium complex (33%), M. chelonae (14%)
2Li et al.2019China16Median: 39.5 (IQR: 36-43.8)M. abscessus
3Poon et al. (retrospective cohort)2021USA9Median: 66 (IQR: 61-72)M. abscessus complex (56 %)
Case report
1Spellberg et al.2004USA164M. abscessus
2Faulk et al.2013USA156M. abscessus
3Inoue et al.2017Japan151M. abscessus
4Singh et al.2019India156M. abscessus
5Wen et al.2021China132M. mucogenicum
6Manika et al.2021Greece168Mycolicibacter kumamotonensis (M. terrae complex)

Efficacy evaluation for linezolid

The treatment of NTM pulmonary disease commenced with the final diagnosis based on clinical symptoms, microbiological analysis, and radiological test (Table 4). Drug susceptibility tests were subsequently performed in certain studies, and in some cases, linezolid was combined with other antibiotics even when the susceptibility test result indicated intermediate susceptibility or resistance. The initial daily dose deviated across 300, 600, or 1,200 mg, and the dose was either reduced according to drug tolerance or side effects or discontinued and then readministered depending on the patient’s status. In the combined treatment, linezolid was mainly administered with three or more different drugs including macrolides (e.g., clarithromycin and azithromycin), aminoglycosides (e.g., amikacin and tobramycin), quinolones (e.g., levofloxacin and moxifloxacin), and other antibiotic drugs such as cefoxitin. The duration of linezolid treatment varied across studies: 21.4 weeks (median, range: 1-201 weeks) and 13 months (median) in two retrospective observational studies; 29 days (IQR: 19-79 days) in one retrospective cohort study; and 53 days to 12 months in the case reports.

Table 4 Efficacy and safety of linezolid in the treatment of nontuberculous mycobacterial pulmonary disease

StudySusceptibility testSusceptibility resultsInitial daily LZD doseDuration of LZD treatmentOther medications for NTM treatmentClinical outcomeSafety, AEsDiscontinuation of LZD due to AEs
Retrospective study
1Winthropet al.--300 mg (12%), 600 mg (79%), 1,200 mg (5%)Mean: 21.4 wks (range: 1-201 wks)Macrolides (80%), aminoglycosides (45%) and fluoroquinolones (33%)-AEs: 46/102 (45%) attributed to LZD after a median 19.9 wks (range 0.1-107 wks). Peripheral neuropathy (24%), gastro-intestinal intolerance (9%), anemia (8%), thrombocytopenia (6%)39% (40/102)
2Li et al.--600 mgMedian: 13 months (IQR: 13-13 months)FOX (initial 4 wks), AMK (initial 12 wks), AZM, MXF and LZD for last 12 months after the first sputum conversionCulture conversion rate: 81% at 18 monthsAEs: 10/16 (62%)
leukopenia (38%), hepatotoxicity (25%), gastrointestinal symptoms (13%), anemia (6%)
Severe SEs: 1 (6.2%, leukopenia)
0% (0/16)
3Poon et al.Yes-300 mg (11%), 600 mg (33%), 1,200 mg (56%)Median (IQR): 24 days (19-79 days)LZD with other antibiotics67% (2/3) patients were clinically cured (efficacy assessment)Discontinuation due to hematologic AEs (2/9, 22%), non-AEs (2/9, 22%), Loss to follow-up (1/9, 11%)22.2% (2/9)
Case report
1Spellberg et al.YesSusceptible to AMK, CLR, LZD; intermediate to FOX; resistant to CIP, LVX, DOX, TMP/SMX1,200 mg26 wksAMK, CLR, FOX, LZD for 3 wks → CLR, LZD for 26 wks-AEs: Anemia, severe neuropathy leading to discontinuation of LZD100% (1/1)
2Faulk et al.YesSusceptible to AMK, TGC-2 monthsTOB, CLR for 4 month, LVX (initial 3 wks) → IPM, CLR for 4 months → FOX, TGC, LZD for 3 days (discontinued because of severe intolerance) → restarted on AMK, FOX, LZD for 2 monthsStill on treatmentSevere intolerance leading to discontinuation of LZD100% (1/1)
3Inoue et al.Yes-600 mg6 monthsMEM, AMK, CLR add STFX on day 6 and LZD on day 18 (for 35 days) → CLR, LZD, FARO for 6 monthsClinical improvement-N/A
4Singh et al.YesSusceptible to CLR; resistance to AMK, IPM, MXF, LZD300 mg12 monthsAMK 8 wks, CLR, FARO, LZD, ETB for 1 yrsCulture negative conversion and clinical improvement-N/A
5Wen et al.--1,200 mg53 daysCLR, LZD (TGC and CZA for the treatment of Klebsiella pneumoniae)Clinical improvement-N/A
6Manika et al.YesSusceptible to CLR, AMK, DOX, RFB, ETB, TMP/SMX; intermediate susceptible to LZD; resistance to RIF, CIP, MXF600 mg12 monthsAZM, AMK, MXF, LZDClinical improvement-N/A

AEs, adverse events; AMK, amikacin; AZM, azithromycin; CZA, ceftazidime-avibactam; CIP, ciprofloxacin; CLR, clarithromycin; DOX, doxycycline; ETB, ethambutol; FARO, faropenem; FOX, cefoxitin; IPM, imipenem; LVX, levofloxacin; LZD, linezolid; MEM, meropenem; MIN, minocycline; MXF, moxifloxacin; N/A, not available; RFB, rifabutin; RIF, rifmpicin; wks, weeks; STFX, sitafloxacin; TOB, tobramycin; TMP/SMX, trimethoprim-sulfamethoxazole; TGC, tigecycline; yrs, years.


The clinical improvement after linezolid treatment, including culture conversion and improvement in clinical symptoms, was reported as 67% and 81% in two retrospective studies (Li et al. 2019; Poon et al. 2021). In the retrospective study by Winthrop et al. (2015), the efficacy of linezolid treatment could not be verified because the study focused on drug tolerance. Four among six case reports showed clinical improvements, whereas one reported ongoing treatment and one did not indicate clear results.

Safety evaluation for linezolid

The side effects that frequently occurred owing to the administration of linezolid were hematological side effects, such as anemia, thrombocytopenia, and leukopenia; neurological side effects, such as peripheral neuritis and optic neuropathy; gastrointestinal side effects such as nausea and vomiting; and hepatotoxicity. In the retrospective observational study on drug tolerance, conducted by Winthrop et al. (2015), linezolid-related side effects occurred in approximately 45% of patients during the period between 0.1-107 weeks of linezolid administration, which caused treatment discontinuation in 39% of patients. The frequent side effects were peripheral neuritis (24%), side effects in the digestive system (9%), anemia (8%), and thrombocytopenia (6%) (Winthrop et al. 2015). In the other retrospective observational study, drug side effects occurred in approximately 62% of patients, with severe leukopenia in 6.2% of patients, which nevertheless did not lead to discontinuation (Li et al. 2019). In the retrospective cohort study, linezolid treatment was discontinued in two out of nine patients (22%) owing to a hematological side effect (Poon et al. 2021). In two out of six case reports, side effects caused the discontinuation of linezolid treatment in each study were anemia and peripheral neuritis in one and intolerance to antibiotics including linezolid in the other (Table 4).

According to the 2020 ATS/ERS/ESCMID/IDSA guidelines and KATRD guidelines for the treatment of NTM pulmonary disease, both guidelines recommend the combination of macrolides, rifampicin, and ethambutol for MAC treatment. In MAB treatment, oral drugs are recommended in combination with intravenous amikacin, imipenem (or cefoxitin), or tigecycline in the initial phase. However, in selecting oral drugs, ATS/ERS/ESCMID/IDSA recommends in combination with macrolides, clofazimine, linezolid, or inhaled amikacin according to the results of the macrolide resistance, but KATRD did not mention the use of drugs other than macrolide (Tables 1 and 2) (Ryu et al. 2016; Daley et al. 2020; KATRD 2020). For this reason, we conducted a literature review to verify the efficacy and safety of linezolid in the treatment of NTM pulmonary disease. The results showed that linezolid was used in combination with other antibiotics in the treatment of MAB pulmonary disease as well as NTM pulmonary disease with various pathogenic species, including MAC and M. chelonae. A notable positive effect of linezolid was observed in the treatment of MAB. However, the findings of this study also indicated that long-term administration of linezolid caused frequent side effects, especially hematological side effects such as anemia and thrombocytopenia as well as neurological side effects such as peripheral neuritis, which led to discontinuation.

The second-most common causal pathogen of NTM pulmonary disease in South Korea is MAB. However, there is still insufficient evidence for the ideal drug combination in MAB treatment, although the guidelines for MAB treatment in South Korea and overseas have been revised in 2020 (Jhun and Koh 2019; Daley et al. 2020). MAB shows inducible resistance related to the erythromycin resistance methylase (erm) (41) gene against macrolides as the core drugs, in addition to resistance against most antibiotics including moxifloxacin and cefoxitin as the core drugs (Ryu et al. 2016; Cho et al. 2019; Daley et al. 2020). However, MAB exhibited relatively high susceptibility at 74.7% to amikacin and 62.1% to linezolid (Cho et al. 2019). Despite its good outcomes on MAB, amikacin has limitations including side effects such as renal toxicity upon long-term administration and demands hospitalization for intravenous injection (Ballarino et al. 2009; Leber and Marras 2011; Jhun and Koh 2019). Linezolid was found to ensure high clinical and symptomatic improvements at 67% and 81%, respectively, in two retrospective studies that applied the drug primarily for MAB treatment, as reviewed in this study. Four out of six case reports reviewed in this study also revealed the efficacy of linezolid with clinical and symptomatic improvements. Through a review of this literature, including the studies published after the revision of the NTM treatment guideline, positive clinical effects that can support the use of linezolid in MAB treatment, which is common in Korea, were confirmed (Daley et al. 2020). There remains, however, the need to verify the efficacy of linezolid through large-scale prospective studies, as the currently available studies are mostly small-scale observational studies and case reports.

An obstacle in the NTM treatment despite the positive effects of linezolid is the hematological or neurological side effect that occurs upon long-term administration. In a retrospective observational study of tolerability to linezolid by Winthrop et al. (2015), approximately half of the patients experienced side effects. A similar trend of side effects upon the long-term use of linezolid was shown by a relatively larger volume of studies on MDR-TB compared to NTM (Agyeman and Ofori-Asenso 2016; Oehadian et al. 2022; Zhang et al. 2022). A study by Sotgiu G et al. reported that the administration of linezolid (> 600 mg/day) significantly increased the incidence of side effects (Sotgiu et al. 2012), and a study by Oehadian A. et al. reported the risk factors as the dose of linezolid, duration of linezolid treatment, renal function, and reduction of platelet counts before treatment (Oehadian et al. 2022). Recently, new methods have been tested to reduce the side effects, such as low-dose linezolid treatment (≤ 600 mg/day), ≤ 2 mg/L of linezolid blood concentration, and combined treatment with pyridoxine (Spellberg et al. 2004; Soriano et al. 2007; Winthrop et al. 2015; Cheng et al. 2021; Tietjen et al. 2022; Wasserman et al. 2022; Zhang et al. 2022). There is a possibility of applying the methods used to reduce the side effects of linezolid in the treatment of tuberculosis or NTM pulmonary disease that shares the need for long-term linezolid administration; however, as linezolid shows higher minimum inhibitory concentration against most NTM species than against the M. tuberculosis complex, the treatment could fail with the dose used in the treatment of tuberculosis (Wallace et al. 2001; Brown-Elliott et al. 2003). Thus, further studies should find ways to ensure the safety of linezolid and increase its efficacy in the treatment of NTM pulmonary disease.

For the successful outcome of the treatment of NTM pulmonary disease, the prescribed drugs must be regularly and continuously administered for the assigned period in addition to the selection of suitable drugs based on the NTM species and susceptibility test results. However, patients may readily receive drugs irregularly due to various side effects during the long-term administration of multiple drugs such as tuberculosis treatment (Munro et al. 2007). The positive influence of pharmacists in the management of tuberculosis has been verified in overseas studies, such as the improvement of drug compliance through related education provided by pharmacists, the monitoring of drug interactions, and the improvement of lifestyle (Juan et al. 2006; Clark et al. 2007; Mitrzyk 2008). In South Korea, however, there is a general lack of studies regarding the role of pharmacists in tuberculosis and NTM treatments. With the steady increase in the specialization and extension of the role of pharmacists in South Korea, what pharmacists could do regarding the monitoring of drug interactions, therapeutic drug monitoring, and intervention to support appropriate antibiotic prescribing have been emphasized, and positive effects have been shown across numerous studies (Ah et al. 2020; Wang et al. 2021; Park et al. 2022). In the treatment of NTM pulmonary disease, likewise, not only linezolid but most other drugs for NTM treatment also exhibit a high incidence of side effects. Therefore, the appropriate drug monitoring following renal or hepatic function, therapeutic drug monitoring, the monitoring of drug interactions and side effects, and patient education to improve compliance are necessary, which suggests the need to extend the role of pharmacists toward the improvement of NTM treatment efficacy and safety (Table 2).

This study reviewed the latest studies on the safety and efficacy of linezolid in the treatment of NTM pulmonary disease and showed that linezolid had notable positive effects in the treatment of MAB pulmonary disease. The limitation of this study, however, is that the studies published so far comprise solely small-scale retrospective studies and case reports. In line with the continuously increasing prevalence of NTM pulmonary disease, it seems necessary to conduct large-scale clinical studies in Korea as with overseas countries, to propose effective drug therapies. Additionally, further studies should find ways to reduce the side effects upon long-term administration of linezolid that pose risks despite positive effects.

In conclusion, our literature review on the safety and efficacy of linezolid in the treatment of NTM pulmonary disease showed that linezolid had notable positive clinical effects on MAB pulmonary disease. However, drug side effects occurred in almost half the patients, which might lead to treatment discontinuation. This suggests the need for further studies related to optimal drug therapies with reduced side effects, so that we will be able to retain or enhance the efficacy of linezolid in the treatment of NTM pulmonary disease through the studies. Furthermore, pharmacists should take part in or develop a greater interest in the journey toward optimal drug therapies for patients in the NTM treatment.

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Article

Review

DTT 2023; 2(2): 145-155

Published online September 30, 2023 https://doi.org/10.58502/DTT.23.0017

Copyright © The Pharmaceutical Society of Korea.

Efficacy and Safety of Linezolid in the Treatment of Nontuberculous Mycobacterial Pulmonary Disease: A Review

Mi Seon Park1,2 , Eun Joo Choi1

1Department of Pharmacy, College of Pharmacy, Chosun University, Gwangju, Korea
2Department of Pharmacy, Jeonbuk National University Hospital, Jeonju, Korea

Correspondence to:Eun Joo Choi, ejchoi@chosun.ac.kr

Received: April 28, 2023; Revised: June 8, 2023; Accepted: June 11, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ((http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The incidence of nontuberculous mycobacteria (NTM) pulmonary disease has been increasing worldwide. However, treatment options for NTM pulmonary disease are limited by the multidrug-resistant nature of these organisms and the toxicities of antibiotics. Although linezolid (LZD) has shown its activity against NTM species in vitro studies, long-term use of LZD may be limited by its side effects. Therefore, we aimed to evaluate the efficacy and safety of LZD in the treatment of NTM pulmonary disease through a literature review. A literature search was conducted using search engines such as PubMed, Embase, and Cochrane library up to March 25, 2022. We evaluated the treatment outcomes including improvement of clinical symptoms, culture conversion, and the incidence of side effects. Of the 1,073 articles searched, 3 retrospective studies and 6 case reports met the inclusion criteria. LZD was mostly used in the treatment of Mycobacterium abscessus as a combination therapy of three or more antibiotics. Treatment success was reported in 2 retrospective studies at 67% and 81%, respectively, and in 4 out of 6 case reports. Discontinuation of LZD due to serious side effects such as myelosuppression and neuropathy was reported in 3 retrospective studies in 0%, 22%, and 39%, respectively, and in 2 out of 6 case reports. In the treatment of NTM pulmonary disease, the majority of patients on combination therapies including LZD had positive outcomes. However, many patients experienced side effects leading to discontinuation of the treatment. All NTM patients with LZD treatment should be monitored closely for the presence of serious side effects.

Keywords: nontuberculous mycobacteria (NTM), linezolid, efficacy, safety, treatment

Introduction

Nontuberculous mycobacteria (NTM) refers to mycobacteria excluding the Mycobacterium tuberculosis complex and Mycobacterium leprae (Jhun and Koh 2019). Currently, there are approximately 200 known species of NTM, and new species are being identified (Daley et al. 2020; Chen et al. 2022). Most NTM is widely distributed in the natural environment, such as water and soil, and although they exhibit low pathogenicity, some species can induce diseases including pulmonary disease, lymphadenitis, skin, and soft tissue osteomyelitis, and disseminated disease (Kang 2021), among which pulmonary disease is the most common type that accounts for ≥ 90% of human diseases caused by NTM (The Korean Academy of Tuberculosis and Respiratory Diseases [KATRD] guideline 2020). Various causal pathogens of NTM pulmonary disease have been reported in numerous countries and regions, but the most frequent ones include the Mycobacterium avium complex (MAC; Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium chimaera), Mycobacterium kansasii, Mycobacterium xenopi, and Mycobacterium abscessus (MAB) (Jeon 2019).

Recently, the incidence of tuberculosis among pulmonary diseases in South Korea has shown a decreasing trend; however, on the contrary, the frequency of NTM isolation from clinical samples has rapidly increased, and the number of patients receiving the diagnosis and treatment of NTM pulmonary disease has increased worldwide, including in South Korea (Yoo et al. 2012; Kwon and Koh 2014; Jhun and Koh 2019; Winthrop et al. 2020). Patients with NTM pulmonary disease vary in symptom and disease progression, and the lack of treatment for pulmonary diseases of the fibrocavitary form or with severe symptoms generally leads to extensive parenchymal destruction and death as the disease progresses (Koh 2011). However, effective treatment for NTM pulmonary disease is yet to be developed, and although the treatment generally necessitates 18-24 months of combined use of antibiotics, the related side effects and drug resistance pose challenges to the current treatment (KATRD 2020).

Linezolid is an oxazolidinone-based antibiotic originally developed for the treatment of Gram-positive bacteria, especially those resistant to conventional antibiotics such as methicillin-resistant Staphylococcus aureus. The drug has subsequently been shown to have an antimicrobial effect against the Mycobacterium tuberculosis complex, and it is thus recommended as the core drug in the treatment of multidrug-resistant tuberculosis (MDR-TB) at present (Tang et al. 2015; Zhang et al. 2015; Agyeman and Ofori-Asenso 2016; World Health Organization [WHO] 2019). NTM species have also shown susceptibility to linezolid in an in vitro test, which prompted clinical treatments using linezolid (Brown-Elliott et al. 2003; Cavusoglu et al. 2007). In South Korea, NTM pulmonary disease has been reported to be most frequently caused by MAC as in overseas countries, where the second-most common causal pathogen is MAB, a relatively rare species (Ko et al. 2018). MAB pulmonary disease, compared to MAC pulmonary disease, shows resistance to several antibiotics, and despite injection therapy over long-term hospitalization, the treatment outcome has been poor (Juhn and Koh 2019). Linezolid is advantageous because it exhibits efficacy against MAB with resistance to other antibiotics and allows oral administration, unlike injected drugs that demand hospitalization (Daley et al. 2020). However, in long-term treatment, linezolid can induce hematological side effects such as anemia and thrombocytopenia, as well as neurological side effects such as peripheral neuritis and optic neuropathy, which can be fatal in the case of NTM pulmonary disease, which requires antibiotic treatment for 18 months or longer (Tang et al. 2015; Zhang et al. 2015; Agyeman and Ofori-Asenso 2016; Daley et al. 2020; KATRD 2020). Despite these side effects, linezolid's health insurance benefits for the use of linezolid in treating NTM pulmonary disease have been expanded in Korea (Health Insurance Review and Assessment Service [HIRA] 2019) due to the lack of other alternative drugs for MAB, which is commonly isolated in Asia (16%) compared to North America (3.2%) and Europe (2.9%) (Zweijpfenning et al. 2018). However, recent guidelines on the use of linezolid published in Korea and overseas (2020 ATS/ERS/ESCMID/IDSA guidelines) vary, and data on ideal drug combinations or administration periods are insufficient (Table 1 and 2) (Ryu et al. 2016; Daley et al. 2020; KATRD 2020, Kims online®; Lexicomp®). Thus, we aimed to contribute to the success of the treatment of NTM pulmonary disease using safe linezolid by conducting a literature review on the efficacy and safety of linezolid based on previously published clinical studies.

Table 1 . Recommended treatment regimens for nontuberculous mycobacterial pulmonary disease.

SpeciesNo. of drugsPreferred regimen
2020 ATS/ERS/ESCMID/IDSA guideline2020 KATRD Korean guidelines
M. avium complex
Nodular-bronchiectatic3AZM (CLR), RIF (RFB), ETBCLR (AZM), RIF, ETB
Cavitary≥ 3AZM (CLR), RIF (RFB), ETB, AMK IV (SM)CLR (AZM), RIF, ETB
Refractory≥ 4AZM (CLR), RIF (RFB), ETB, inhaled AMK (AMK IV or SM)CLR (AZM), RIF, ETB, AMK IV (SM)
M. kansasii3AZM (CLR), RIF (RFB), ETBINH, RIF, ETB
3INH, RIF (RFB), ETB
M. xenopi≥ 3AZM (CLR) and/or MXF, RIF (RFB), ETB, AMKN/A
M. abscessus
Macrolide susceptibleInitial phase ≥ 3Parenteral (choose 1-2): AMK, IPM (or FOX), TGC
Oral (choose 2): AZM (CLR), CLO, LZD
Parenteral (choose 2): AMK, FOX (or IPM), TGC
Continuation phase ≥ 2Oral/inhaled (choose 1-2): AZM (CLR), CLO, LZD, inhaled AMKOral: CLR (AZM)
Macrolide inducible resistanta)Initial phase ≥ 4Parenteral (choose 2-3): AMK, IPM (or FOX), TGC
Oral (choose 2-3): AZM (CLR), CLO, LZD
Continuation phase ≥ 2Oral/inhaled (choose 2-3): AZM (CLR), CLO, LZD, inhaled AMK
Macrolide mutational resistantInitial phase ≥ 4Parenteral (choose 2-3): AMK, IPM (or FOX), TGC
Oral (choose 2-3): AZM (CLR), CLO, LZD
Continuation phase ≥ 2Oral/inhaled (choose 2-3): AZM (CLR), CLO, LZD, inhaled AMK

AMK, amikacin; AZM, azithromycin; CLR, clarithromycin; CLO, clofazimine; ETB, ethambutol; FOX, cefoxitin; INH, isoniazid; IPM, imipenem; IV, intravenous; LZD, linezolid; MXF, moxifloxacin; N/A, not available; RFB, rifabutin; RIF, rifampicin; SM, streptomycin; TGC, tigecycline..

a)Inducible resistance: The organism develops resistance to the macrolides in vitro after prolonged incubation (susceptible at day 3, but resistant at day 14), or by preincubation in macrolide-containing media (Ryu et al. 2016)..

NOTE: This table was modified based on 2020 ATS/ERS/ESCMID/IDSA guideline and 2020 KATRD Korean guidelines (Daley et al. 2020; KATRD 2020)..



Table 2 . Dosing and metabolism of drugs for nontuberculous mycobacterial pulmonary disease (Daley et al. 2020; Kims online®; Lexicomp®).

DrugDaily dosing (day)3 times weekly dosing (day)Hepatic impairmentRenal impairment CrCl (mL/min)Metabolism/transport effect
Oral
Azithromycin200-500 mg500 mgN/AN/A

Substrate of CYP3A4 (minor).

Inhibits P-glycoprotein/ABCB1.

Ciprofloxacin500-750 mg twiceN/AN/ACrCl 30-50: 250-500 mg twice daily

Substrate of OAT1/3, P-glycoprotein/ABCB1 (minor).

Inhibits CYP1A2 (moderate), CYP3A4 (weak).

CrCl < 30: 500 mg once daily
Clarithromycin500 mg twice500 mg twiceN/ACrCl < 30: 500 mg once daily

Substrate of CYP3A4 (major).

Inhibits CYP3A4 (strong), OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/ABCB1.

Clofazimine100-200 mgN/AAdministrationwith cautionN/AN/A
Doxycycline100 mg once or twiceN/AN/AN/AN/A
Ethambutol15 mg/kg25 mg/kgN/ACrCl < 30: increase dosing interval

Substrate of OCT1, OCT2.

Isoniazid5 mg/kg (max: 300 mg)N/AAdministrationwith cautionN/A

Substrate of CYP2E1 (minor).

Inhibits CYP2E1 (moderate), CYP3A4 (weak).

Induces CYP2E1 (weak).

Linezolid600 mg once or twiceN/AN/AN/A

Inhibits monoamine oxidase.

Moxifloxacin400 mgN/AN/AN/AN/A
Trimethoprim-sulfamethoxazole800/160 mg tab twiceN/AAdministrationwith cautionCrCl 15-30: dose reduction to 50%

Substrate of CYP2C9 (minor), CYP3A4 (minor).

Inhibits CYP2C8 (weak), OCT1, OCT2.

CrCl < 15: dose reduction to 25-50%, administration with caution
Rifabutin150-300 mg300 mgAdministrationwith cautionCrCl < 30: dose reduction of 50% if toxicity is suspected

Substrate of CYP1A2 (minor), CYP3A4 (major).

Induces CYP2C9 (weak), CYP3A4 (moderate), UGT1A4.

Rifampicin10 mg/kg (450-600 mg)600 mgAdministrationwith cautionN/A

Substrate of OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/ABCB1 (minor).

Inhibits OATP1B1/1B3 (SLCO1B1/1B3).

Induces BCRP/ABCG2, CYP1A2 (weak), CYP2B6 (moderate), CYP2C19 (strong), CYP2C8 (moderate), CYP2C9 (moderate), CYP3A4 (strong), OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/ABCB1, UGT1A1, UGT1A9.

Parenteral
Amikacin (IV)10-15 mg/kga)15-25 mg/kga)N/AReduce dose or increase dosing intervalN/A
Cefoxitin (IV)2-4 g 2-3 times (max: 12 g/day)N/AN/AReduce dose or increase dosing intervalSubstrate of OAT1/3
Imipenem (IV)500-1,000 mg,
2-3 times
N/AN/AReduce dose or increase dosing intervalN/A
Streptomycin (IV or IM)10-15 mg/kg15-25 mg/kgN/AReduce dose or increase dosing intervalN/A
Tigecycline (IV)25-50 mg
1-2 times
N/A25 mg 1-2 times in severe hepatic impairmentN/AN/A
Inhalation
Amikacin liposome inhalation suspension590 mgN/AN/AN/AN/A
Amikacin, parenteral formulation250-500 mgN/AN/AN/AN/A

CrCl, creatinine clearance; IM, intramuscular; IV, intravenous; N/A, not available..

a)Monitoring of serum concentrations is recommended to ensure efficacy and avoid toxicity..

NOTE: This table was modified and developed based on 2020 ATS/ERS/ESCMID/IDSA guideline (Daley et al. 2020)..


Materials and Methods

Literature search

This study was conducted based on the methodology of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) (Moher et al. 2015). The selected search words were “Linezolid,” “Nontuberculous mycobacteria,” “Mycobacterium avium,” “Mycobacterium intracellulare,” “Mycobacterium abscessus,” “Mycobacterium chelonae,” “Mycobacterium fortuitum,” “Mycobacterium chimaera,” and “Mycobacterium xenopi.” The search was performed by the search formula combining the Boolean operators (Supplementary Table 1). For the literature search, the databases of MEDLINE (source: PubMed), Embase, and Cochrane Library were searched for the period up to March 25, 2022.

Article selection and categorization

After the exclusion of duplicated articles from the search result, two researchers independently performed the selection of articles based on the criteria. According to the inclusion criteria, studies were eligible if they investigated the clinical outcomes of linezolid treatment in patients with NTM pulmonary disease, included the study subjects aged ≥ 18 years, and were published only in English. The title and abstract of each article were reviewed to exclude animal studies, studies on pediatric patients, studies published in languages other than English, studies with only the abstract, and those such as reviews, commentaries, and editorial letters. The full texts of the selected articles were subsequently reviewed to exclude studies that could not evaluate the efficacy and safety of linezolid treatments in patients with NTM pulmonary disease. When the two researchers disagreed during the review of full texts, the inclusion of the respective articles was determined if a mutual agreement could be reached. However, owing to the highly limited number of clinical studies on linezolid treatment regarding NTM pulmonary disease, all clinical studies including case reports were selected for this study.

Data extraction

The data extracted from the retrieved articles included study design, publication year, sample size, demographic characteristics, clinical information associated with linezolid (dosage, treatment duration), and clinical outcomes (culture conversion, clinical cure, and side effects).

Results

With the exclusion of duplicated articles from 1,073 articles presented by the PubMed, Embase, and Cochrane library search engines, 926 studies were selected. Based on the title and abstract, 504 articles that did not meet the inclusion criteria were primarily excluded. After a review of the full text, 20 articles unrelated to NTM, 193 articles unrelated to linezolid, 176 articles regarding the use of linezolid in NTM diseases other than a pulmonary disease, and 24 articles that prevent the determination of independent effects of linezolid owing to various regimen changes, i.e., a total of 413 articles, were excluded. Through the agreement of the two researchers after expert review, 6 case reports and 3 retrospective studies, including 2 articles reporting approximately 78% of pulmonary disease among NTM infections, were selected for this study (Fig. 1).

Figure 1. Flow diagram of study selection. NTM, nontuberculous mycobacteria.

Characteristics of the studies

Table 3 presents the study design and subject characteristics in the final set of nine selected studies. The 9 articles included in this study were clinical studies published between 2004 and 2021, comprising 3 retrospective studies (2 observational studies and 1 cohort study) and 6 case reports, conducted on a total of 133 subjects. For the causal pathogen of NTM pulmonary disease against which linezolid was used, one among three retrospective clinical studies applied linezolid solely for the treatment of MAB, and the other two applied linezolid mainly against MAB but also for the treatment of MAC and M. chelonae. Among the 6 case reports, linezolid was used to treat MAB in 4, M. mucogenicum in 1, and Mycolicibacter kumamotonensis (the M. terrae complex) in 1 (Spellberg et al. 2004; Faulk et al. 2013; Winthrop et al. 2015; Inoue et al. 2017; Li et al. 2019; Singh et al. 2019; Manika et al. 2021; Poon et al. 2021; Wen 2021).

Table 3 . Baseline characteristics of included studies.

StudyPublication (year)CountryNo. of patients receiving linezolidAge (years)Species Identification
Retrospective study
1Winthrop et al.2015North America102Median: 58 (range: 3-88)M. abscessus (44%), M. avium complex (33%), M. chelonae (14%)
2Li et al.2019China16Median: 39.5 (IQR: 36-43.8)M. abscessus
3Poon et al. (retrospective cohort)2021USA9Median: 66 (IQR: 61-72)M. abscessus complex (56 %)
Case report
1Spellberg et al.2004USA164M. abscessus
2Faulk et al.2013USA156M. abscessus
3Inoue et al.2017Japan151M. abscessus
4Singh et al.2019India156M. abscessus
5Wen et al.2021China132M. mucogenicum
6Manika et al.2021Greece168Mycolicibacter kumamotonensis (M. terrae complex)


Efficacy evaluation for linezolid

The treatment of NTM pulmonary disease commenced with the final diagnosis based on clinical symptoms, microbiological analysis, and radiological test (Table 4). Drug susceptibility tests were subsequently performed in certain studies, and in some cases, linezolid was combined with other antibiotics even when the susceptibility test result indicated intermediate susceptibility or resistance. The initial daily dose deviated across 300, 600, or 1,200 mg, and the dose was either reduced according to drug tolerance or side effects or discontinued and then readministered depending on the patient’s status. In the combined treatment, linezolid was mainly administered with three or more different drugs including macrolides (e.g., clarithromycin and azithromycin), aminoglycosides (e.g., amikacin and tobramycin), quinolones (e.g., levofloxacin and moxifloxacin), and other antibiotic drugs such as cefoxitin. The duration of linezolid treatment varied across studies: 21.4 weeks (median, range: 1-201 weeks) and 13 months (median) in two retrospective observational studies; 29 days (IQR: 19-79 days) in one retrospective cohort study; and 53 days to 12 months in the case reports.

Table 4 . Efficacy and safety of linezolid in the treatment of nontuberculous mycobacterial pulmonary disease.

StudySusceptibility testSusceptibility resultsInitial daily LZD doseDuration of LZD treatmentOther medications for NTM treatmentClinical outcomeSafety, AEsDiscontinuation of LZD due to AEs
Retrospective study
1Winthropet al.--300 mg (12%), 600 mg (79%), 1,200 mg (5%)Mean: 21.4 wks (range: 1-201 wks)Macrolides (80%), aminoglycosides (45%) and fluoroquinolones (33%)-AEs: 46/102 (45%) attributed to LZD after a median 19.9 wks (range 0.1-107 wks). Peripheral neuropathy (24%), gastro-intestinal intolerance (9%), anemia (8%), thrombocytopenia (6%)39% (40/102)
2Li et al.--600 mgMedian: 13 months (IQR: 13-13 months)FOX (initial 4 wks), AMK (initial 12 wks), AZM, MXF and LZD for last 12 months after the first sputum conversionCulture conversion rate: 81% at 18 monthsAEs: 10/16 (62%)
leukopenia (38%), hepatotoxicity (25%), gastrointestinal symptoms (13%), anemia (6%)
Severe SEs: 1 (6.2%, leukopenia)
0% (0/16)
3Poon et al.Yes-300 mg (11%), 600 mg (33%), 1,200 mg (56%)Median (IQR): 24 days (19-79 days)LZD with other antibiotics67% (2/3) patients were clinically cured (efficacy assessment)Discontinuation due to hematologic AEs (2/9, 22%), non-AEs (2/9, 22%), Loss to follow-up (1/9, 11%)22.2% (2/9)
Case report
1Spellberg et al.YesSusceptible to AMK, CLR, LZD; intermediate to FOX; resistant to CIP, LVX, DOX, TMP/SMX1,200 mg26 wksAMK, CLR, FOX, LZD for 3 wks → CLR, LZD for 26 wks-AEs: Anemia, severe neuropathy leading to discontinuation of LZD100% (1/1)
2Faulk et al.YesSusceptible to AMK, TGC-2 monthsTOB, CLR for 4 month, LVX (initial 3 wks) → IPM, CLR for 4 months → FOX, TGC, LZD for 3 days (discontinued because of severe intolerance) → restarted on AMK, FOX, LZD for 2 monthsStill on treatmentSevere intolerance leading to discontinuation of LZD100% (1/1)
3Inoue et al.Yes-600 mg6 monthsMEM, AMK, CLR add STFX on day 6 and LZD on day 18 (for 35 days) → CLR, LZD, FARO for 6 monthsClinical improvement-N/A
4Singh et al.YesSusceptible to CLR; resistance to AMK, IPM, MXF, LZD300 mg12 monthsAMK 8 wks, CLR, FARO, LZD, ETB for 1 yrsCulture negative conversion and clinical improvement-N/A
5Wen et al.--1,200 mg53 daysCLR, LZD (TGC and CZA for the treatment of Klebsiella pneumoniae)Clinical improvement-N/A
6Manika et al.YesSusceptible to CLR, AMK, DOX, RFB, ETB, TMP/SMX; intermediate susceptible to LZD; resistance to RIF, CIP, MXF600 mg12 monthsAZM, AMK, MXF, LZDClinical improvement-N/A

AEs, adverse events; AMK, amikacin; AZM, azithromycin; CZA, ceftazidime-avibactam; CIP, ciprofloxacin; CLR, clarithromycin; DOX, doxycycline; ETB, ethambutol; FARO, faropenem; FOX, cefoxitin; IPM, imipenem; LVX, levofloxacin; LZD, linezolid; MEM, meropenem; MIN, minocycline; MXF, moxifloxacin; N/A, not available; RFB, rifabutin; RIF, rifmpicin; wks, weeks; STFX, sitafloxacin; TOB, tobramycin; TMP/SMX, trimethoprim-sulfamethoxazole; TGC, tigecycline; yrs, years..



The clinical improvement after linezolid treatment, including culture conversion and improvement in clinical symptoms, was reported as 67% and 81% in two retrospective studies (Li et al. 2019; Poon et al. 2021). In the retrospective study by Winthrop et al. (2015), the efficacy of linezolid treatment could not be verified because the study focused on drug tolerance. Four among six case reports showed clinical improvements, whereas one reported ongoing treatment and one did not indicate clear results.

Safety evaluation for linezolid

The side effects that frequently occurred owing to the administration of linezolid were hematological side effects, such as anemia, thrombocytopenia, and leukopenia; neurological side effects, such as peripheral neuritis and optic neuropathy; gastrointestinal side effects such as nausea and vomiting; and hepatotoxicity. In the retrospective observational study on drug tolerance, conducted by Winthrop et al. (2015), linezolid-related side effects occurred in approximately 45% of patients during the period between 0.1-107 weeks of linezolid administration, which caused treatment discontinuation in 39% of patients. The frequent side effects were peripheral neuritis (24%), side effects in the digestive system (9%), anemia (8%), and thrombocytopenia (6%) (Winthrop et al. 2015). In the other retrospective observational study, drug side effects occurred in approximately 62% of patients, with severe leukopenia in 6.2% of patients, which nevertheless did not lead to discontinuation (Li et al. 2019). In the retrospective cohort study, linezolid treatment was discontinued in two out of nine patients (22%) owing to a hematological side effect (Poon et al. 2021). In two out of six case reports, side effects caused the discontinuation of linezolid treatment in each study were anemia and peripheral neuritis in one and intolerance to antibiotics including linezolid in the other (Table 4).

Discussion

According to the 2020 ATS/ERS/ESCMID/IDSA guidelines and KATRD guidelines for the treatment of NTM pulmonary disease, both guidelines recommend the combination of macrolides, rifampicin, and ethambutol for MAC treatment. In MAB treatment, oral drugs are recommended in combination with intravenous amikacin, imipenem (or cefoxitin), or tigecycline in the initial phase. However, in selecting oral drugs, ATS/ERS/ESCMID/IDSA recommends in combination with macrolides, clofazimine, linezolid, or inhaled amikacin according to the results of the macrolide resistance, but KATRD did not mention the use of drugs other than macrolide (Tables 1 and 2) (Ryu et al. 2016; Daley et al. 2020; KATRD 2020). For this reason, we conducted a literature review to verify the efficacy and safety of linezolid in the treatment of NTM pulmonary disease. The results showed that linezolid was used in combination with other antibiotics in the treatment of MAB pulmonary disease as well as NTM pulmonary disease with various pathogenic species, including MAC and M. chelonae. A notable positive effect of linezolid was observed in the treatment of MAB. However, the findings of this study also indicated that long-term administration of linezolid caused frequent side effects, especially hematological side effects such as anemia and thrombocytopenia as well as neurological side effects such as peripheral neuritis, which led to discontinuation.

The second-most common causal pathogen of NTM pulmonary disease in South Korea is MAB. However, there is still insufficient evidence for the ideal drug combination in MAB treatment, although the guidelines for MAB treatment in South Korea and overseas have been revised in 2020 (Jhun and Koh 2019; Daley et al. 2020). MAB shows inducible resistance related to the erythromycin resistance methylase (erm) (41) gene against macrolides as the core drugs, in addition to resistance against most antibiotics including moxifloxacin and cefoxitin as the core drugs (Ryu et al. 2016; Cho et al. 2019; Daley et al. 2020). However, MAB exhibited relatively high susceptibility at 74.7% to amikacin and 62.1% to linezolid (Cho et al. 2019). Despite its good outcomes on MAB, amikacin has limitations including side effects such as renal toxicity upon long-term administration and demands hospitalization for intravenous injection (Ballarino et al. 2009; Leber and Marras 2011; Jhun and Koh 2019). Linezolid was found to ensure high clinical and symptomatic improvements at 67% and 81%, respectively, in two retrospective studies that applied the drug primarily for MAB treatment, as reviewed in this study. Four out of six case reports reviewed in this study also revealed the efficacy of linezolid with clinical and symptomatic improvements. Through a review of this literature, including the studies published after the revision of the NTM treatment guideline, positive clinical effects that can support the use of linezolid in MAB treatment, which is common in Korea, were confirmed (Daley et al. 2020). There remains, however, the need to verify the efficacy of linezolid through large-scale prospective studies, as the currently available studies are mostly small-scale observational studies and case reports.

An obstacle in the NTM treatment despite the positive effects of linezolid is the hematological or neurological side effect that occurs upon long-term administration. In a retrospective observational study of tolerability to linezolid by Winthrop et al. (2015), approximately half of the patients experienced side effects. A similar trend of side effects upon the long-term use of linezolid was shown by a relatively larger volume of studies on MDR-TB compared to NTM (Agyeman and Ofori-Asenso 2016; Oehadian et al. 2022; Zhang et al. 2022). A study by Sotgiu G et al. reported that the administration of linezolid (> 600 mg/day) significantly increased the incidence of side effects (Sotgiu et al. 2012), and a study by Oehadian A. et al. reported the risk factors as the dose of linezolid, duration of linezolid treatment, renal function, and reduction of platelet counts before treatment (Oehadian et al. 2022). Recently, new methods have been tested to reduce the side effects, such as low-dose linezolid treatment (≤ 600 mg/day), ≤ 2 mg/L of linezolid blood concentration, and combined treatment with pyridoxine (Spellberg et al. 2004; Soriano et al. 2007; Winthrop et al. 2015; Cheng et al. 2021; Tietjen et al. 2022; Wasserman et al. 2022; Zhang et al. 2022). There is a possibility of applying the methods used to reduce the side effects of linezolid in the treatment of tuberculosis or NTM pulmonary disease that shares the need for long-term linezolid administration; however, as linezolid shows higher minimum inhibitory concentration against most NTM species than against the M. tuberculosis complex, the treatment could fail with the dose used in the treatment of tuberculosis (Wallace et al. 2001; Brown-Elliott et al. 2003). Thus, further studies should find ways to ensure the safety of linezolid and increase its efficacy in the treatment of NTM pulmonary disease.

For the successful outcome of the treatment of NTM pulmonary disease, the prescribed drugs must be regularly and continuously administered for the assigned period in addition to the selection of suitable drugs based on the NTM species and susceptibility test results. However, patients may readily receive drugs irregularly due to various side effects during the long-term administration of multiple drugs such as tuberculosis treatment (Munro et al. 2007). The positive influence of pharmacists in the management of tuberculosis has been verified in overseas studies, such as the improvement of drug compliance through related education provided by pharmacists, the monitoring of drug interactions, and the improvement of lifestyle (Juan et al. 2006; Clark et al. 2007; Mitrzyk 2008). In South Korea, however, there is a general lack of studies regarding the role of pharmacists in tuberculosis and NTM treatments. With the steady increase in the specialization and extension of the role of pharmacists in South Korea, what pharmacists could do regarding the monitoring of drug interactions, therapeutic drug monitoring, and intervention to support appropriate antibiotic prescribing have been emphasized, and positive effects have been shown across numerous studies (Ah et al. 2020; Wang et al. 2021; Park et al. 2022). In the treatment of NTM pulmonary disease, likewise, not only linezolid but most other drugs for NTM treatment also exhibit a high incidence of side effects. Therefore, the appropriate drug monitoring following renal or hepatic function, therapeutic drug monitoring, the monitoring of drug interactions and side effects, and patient education to improve compliance are necessary, which suggests the need to extend the role of pharmacists toward the improvement of NTM treatment efficacy and safety (Table 2).

This study reviewed the latest studies on the safety and efficacy of linezolid in the treatment of NTM pulmonary disease and showed that linezolid had notable positive effects in the treatment of MAB pulmonary disease. The limitation of this study, however, is that the studies published so far comprise solely small-scale retrospective studies and case reports. In line with the continuously increasing prevalence of NTM pulmonary disease, it seems necessary to conduct large-scale clinical studies in Korea as with overseas countries, to propose effective drug therapies. Additionally, further studies should find ways to reduce the side effects upon long-term administration of linezolid that pose risks despite positive effects.

In conclusion, our literature review on the safety and efficacy of linezolid in the treatment of NTM pulmonary disease showed that linezolid had notable positive clinical effects on MAB pulmonary disease. However, drug side effects occurred in almost half the patients, which might lead to treatment discontinuation. This suggests the need for further studies related to optimal drug therapies with reduced side effects, so that we will be able to retain or enhance the efficacy of linezolid in the treatment of NTM pulmonary disease through the studies. Furthermore, pharmacists should take part in or develop a greater interest in the journey toward optimal drug therapies for patients in the NTM treatment.

Acknowledgements

None.

Supplementary Materials

Supplementary Materials can be found via https://doi.org/10.58502/DTT.23.0017.

Conflict of interest

The authors declare that they have no conflict of interest.

Fig 1.

Figure 1.Flow diagram of study selection. NTM, nontuberculous mycobacteria.
Drug Targets and Therapeutics 2023; 2: 145-155https://doi.org/10.58502/DTT.23.0017

Table 1 Recommended treatment regimens for nontuberculous mycobacterial pulmonary disease

SpeciesNo. of drugsPreferred regimen
2020 ATS/ERS/ESCMID/IDSA guideline2020 KATRD Korean guidelines
M. avium complex
Nodular-bronchiectatic3AZM (CLR), RIF (RFB), ETBCLR (AZM), RIF, ETB
Cavitary≥ 3AZM (CLR), RIF (RFB), ETB, AMK IV (SM)CLR (AZM), RIF, ETB
Refractory≥ 4AZM (CLR), RIF (RFB), ETB, inhaled AMK (AMK IV or SM)CLR (AZM), RIF, ETB, AMK IV (SM)
M. kansasii3AZM (CLR), RIF (RFB), ETBINH, RIF, ETB
3INH, RIF (RFB), ETB
M. xenopi≥ 3AZM (CLR) and/or MXF, RIF (RFB), ETB, AMKN/A
M. abscessus
Macrolide susceptibleInitial phase ≥ 3Parenteral (choose 1-2): AMK, IPM (or FOX), TGC
Oral (choose 2): AZM (CLR), CLO, LZD
Parenteral (choose 2): AMK, FOX (or IPM), TGC
Continuation phase ≥ 2Oral/inhaled (choose 1-2): AZM (CLR), CLO, LZD, inhaled AMKOral: CLR (AZM)
Macrolide inducible resistanta)Initial phase ≥ 4Parenteral (choose 2-3): AMK, IPM (or FOX), TGC
Oral (choose 2-3): AZM (CLR), CLO, LZD
Continuation phase ≥ 2Oral/inhaled (choose 2-3): AZM (CLR), CLO, LZD, inhaled AMK
Macrolide mutational resistantInitial phase ≥ 4Parenteral (choose 2-3): AMK, IPM (or FOX), TGC
Oral (choose 2-3): AZM (CLR), CLO, LZD
Continuation phase ≥ 2Oral/inhaled (choose 2-3): AZM (CLR), CLO, LZD, inhaled AMK

AMK, amikacin; AZM, azithromycin; CLR, clarithromycin; CLO, clofazimine; ETB, ethambutol; FOX, cefoxitin; INH, isoniazid; IPM, imipenem; IV, intravenous; LZD, linezolid; MXF, moxifloxacin; N/A, not available; RFB, rifabutin; RIF, rifampicin; SM, streptomycin; TGC, tigecycline.

a)Inducible resistance: The organism develops resistance to the macrolides in vitro after prolonged incubation (susceptible at day 3, but resistant at day 14), or by preincubation in macrolide-containing media (Ryu et al. 2016).

NOTE: This table was modified based on 2020 ATS/ERS/ESCMID/IDSA guideline and 2020 KATRD Korean guidelines (Daley et al. 2020; KATRD 2020).


Table 2 Dosing and metabolism of drugs for nontuberculous mycobacterial pulmonary disease (Daley et al. 2020; Kims online®; Lexicomp®)

DrugDaily dosing (day)3 times weekly dosing (day)Hepatic impairmentRenal impairment CrCl (mL/min)Metabolism/transport effect
Oral
Azithromycin200-500 mg500 mgN/AN/A

Substrate of CYP3A4 (minor)

Inhibits P-glycoprotein/ABCB1

Ciprofloxacin500-750 mg twiceN/AN/ACrCl 30-50: 250-500 mg twice daily

Substrate of OAT1/3, P-glycoprotein/ABCB1 (minor)

Inhibits CYP1A2 (moderate), CYP3A4 (weak)

CrCl < 30: 500 mg once daily
Clarithromycin500 mg twice500 mg twiceN/ACrCl < 30: 500 mg once daily

Substrate of CYP3A4 (major)

Inhibits CYP3A4 (strong), OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/ABCB1

Clofazimine100-200 mgN/AAdministrationwith cautionN/AN/A
Doxycycline100 mg once or twiceN/AN/AN/AN/A
Ethambutol15 mg/kg25 mg/kgN/ACrCl < 30: increase dosing interval

Substrate of OCT1, OCT2

Isoniazid5 mg/kg (max: 300 mg)N/AAdministrationwith cautionN/A

Substrate of CYP2E1 (minor)

Inhibits CYP2E1 (moderate), CYP3A4 (weak)

Induces CYP2E1 (weak)

Linezolid600 mg once or twiceN/AN/AN/A

Inhibits monoamine oxidase

Moxifloxacin400 mgN/AN/AN/AN/A
Trimethoprim-sulfamethoxazole800/160 mg tab twiceN/AAdministrationwith cautionCrCl 15-30: dose reduction to 50%

Substrate of CYP2C9 (minor), CYP3A4 (minor)

Inhibits CYP2C8 (weak), OCT1, OCT2

CrCl < 15: dose reduction to 25-50%, administration with caution
Rifabutin150-300 mg300 mgAdministrationwith cautionCrCl < 30: dose reduction of 50% if toxicity is suspected

Substrate of CYP1A2 (minor), CYP3A4 (major)

Induces CYP2C9 (weak), CYP3A4 (moderate), UGT1A4

Rifampicin10 mg/kg (450-600 mg)600 mgAdministrationwith cautionN/A

Substrate of OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/ABCB1 (minor)

Inhibits OATP1B1/1B3 (SLCO1B1/1B3)

Induces BCRP/ABCG2, CYP1A2 (weak), CYP2B6 (moderate), CYP2C19 (strong), CYP2C8 (moderate), CYP2C9 (moderate), CYP3A4 (strong), OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/ABCB1, UGT1A1, UGT1A9

Parenteral
Amikacin (IV)10-15 mg/kga)15-25 mg/kga)N/AReduce dose or increase dosing intervalN/A
Cefoxitin (IV)2-4 g 2-3 times (max: 12 g/day)N/AN/AReduce dose or increase dosing intervalSubstrate of OAT1/3
Imipenem (IV)500-1,000 mg,
2-3 times
N/AN/AReduce dose or increase dosing intervalN/A
Streptomycin (IV or IM)10-15 mg/kg15-25 mg/kgN/AReduce dose or increase dosing intervalN/A
Tigecycline (IV)25-50 mg
1-2 times
N/A25 mg 1-2 times in severe hepatic impairmentN/AN/A
Inhalation
Amikacin liposome inhalation suspension590 mgN/AN/AN/AN/A
Amikacin, parenteral formulation250-500 mgN/AN/AN/AN/A

CrCl, creatinine clearance; IM, intramuscular; IV, intravenous; N/A, not available.

a)Monitoring of serum concentrations is recommended to ensure efficacy and avoid toxicity.

NOTE: This table was modified and developed based on 2020 ATS/ERS/ESCMID/IDSA guideline (Daley et al. 2020).


Table 3 Baseline characteristics of included studies

StudyPublication (year)CountryNo. of patients receiving linezolidAge (years)Species Identification
Retrospective study
1Winthrop et al.2015North America102Median: 58 (range: 3-88)M. abscessus (44%), M. avium complex (33%), M. chelonae (14%)
2Li et al.2019China16Median: 39.5 (IQR: 36-43.8)M. abscessus
3Poon et al. (retrospective cohort)2021USA9Median: 66 (IQR: 61-72)M. abscessus complex (56 %)
Case report
1Spellberg et al.2004USA164M. abscessus
2Faulk et al.2013USA156M. abscessus
3Inoue et al.2017Japan151M. abscessus
4Singh et al.2019India156M. abscessus
5Wen et al.2021China132M. mucogenicum
6Manika et al.2021Greece168Mycolicibacter kumamotonensis (M. terrae complex)

Table 4 Efficacy and safety of linezolid in the treatment of nontuberculous mycobacterial pulmonary disease

StudySusceptibility testSusceptibility resultsInitial daily LZD doseDuration of LZD treatmentOther medications for NTM treatmentClinical outcomeSafety, AEsDiscontinuation of LZD due to AEs
Retrospective study
1Winthropet al.--300 mg (12%), 600 mg (79%), 1,200 mg (5%)Mean: 21.4 wks (range: 1-201 wks)Macrolides (80%), aminoglycosides (45%) and fluoroquinolones (33%)-AEs: 46/102 (45%) attributed to LZD after a median 19.9 wks (range 0.1-107 wks). Peripheral neuropathy (24%), gastro-intestinal intolerance (9%), anemia (8%), thrombocytopenia (6%)39% (40/102)
2Li et al.--600 mgMedian: 13 months (IQR: 13-13 months)FOX (initial 4 wks), AMK (initial 12 wks), AZM, MXF and LZD for last 12 months after the first sputum conversionCulture conversion rate: 81% at 18 monthsAEs: 10/16 (62%)
leukopenia (38%), hepatotoxicity (25%), gastrointestinal symptoms (13%), anemia (6%)
Severe SEs: 1 (6.2%, leukopenia)
0% (0/16)
3Poon et al.Yes-300 mg (11%), 600 mg (33%), 1,200 mg (56%)Median (IQR): 24 days (19-79 days)LZD with other antibiotics67% (2/3) patients were clinically cured (efficacy assessment)Discontinuation due to hematologic AEs (2/9, 22%), non-AEs (2/9, 22%), Loss to follow-up (1/9, 11%)22.2% (2/9)
Case report
1Spellberg et al.YesSusceptible to AMK, CLR, LZD; intermediate to FOX; resistant to CIP, LVX, DOX, TMP/SMX1,200 mg26 wksAMK, CLR, FOX, LZD for 3 wks → CLR, LZD for 26 wks-AEs: Anemia, severe neuropathy leading to discontinuation of LZD100% (1/1)
2Faulk et al.YesSusceptible to AMK, TGC-2 monthsTOB, CLR for 4 month, LVX (initial 3 wks) → IPM, CLR for 4 months → FOX, TGC, LZD for 3 days (discontinued because of severe intolerance) → restarted on AMK, FOX, LZD for 2 monthsStill on treatmentSevere intolerance leading to discontinuation of LZD100% (1/1)
3Inoue et al.Yes-600 mg6 monthsMEM, AMK, CLR add STFX on day 6 and LZD on day 18 (for 35 days) → CLR, LZD, FARO for 6 monthsClinical improvement-N/A
4Singh et al.YesSusceptible to CLR; resistance to AMK, IPM, MXF, LZD300 mg12 monthsAMK 8 wks, CLR, FARO, LZD, ETB for 1 yrsCulture negative conversion and clinical improvement-N/A
5Wen et al.--1,200 mg53 daysCLR, LZD (TGC and CZA for the treatment of Klebsiella pneumoniae)Clinical improvement-N/A
6Manika et al.YesSusceptible to CLR, AMK, DOX, RFB, ETB, TMP/SMX; intermediate susceptible to LZD; resistance to RIF, CIP, MXF600 mg12 monthsAZM, AMK, MXF, LZDClinical improvement-N/A

AEs, adverse events; AMK, amikacin; AZM, azithromycin; CZA, ceftazidime-avibactam; CIP, ciprofloxacin; CLR, clarithromycin; DOX, doxycycline; ETB, ethambutol; FARO, faropenem; FOX, cefoxitin; IPM, imipenem; LVX, levofloxacin; LZD, linezolid; MEM, meropenem; MIN, minocycline; MXF, moxifloxacin; N/A, not available; RFB, rifabutin; RIF, rifmpicin; wks, weeks; STFX, sitafloxacin; TOB, tobramycin; TMP/SMX, trimethoprim-sulfamethoxazole; TGC, tigecycline; yrs, years.


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