Won-Jung Koh

Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients

Dick Menzies and colleagues report findings from a collaborative, individual patient-level meta-analysis of treatment outcomes among patients with multidrug-resistant tuberculosis.

Clinical Significance of Differentiation of Mycobacterium massiliense from Mycobacterium abscessus

RATIONALE Mycobacterium massiliense has been recognized as a separate species from Mycobacterium abscessus; however, little is known regarding the clinical impact of this differentiation. OBJECTIVES To compare clinical features and treatment outcomes between patients with M. abscessus lung disease and those with M. massiliense lung disease. METHODS We performed molecular identification of stored clinical isolates of M. abscessus complex and compared clinical characteristics and treatment outcomes between 64 patients with M. abscessus lung disease and 81 patients with M. massiliense lung disease. MEASUREMENTS AND MAIN RESULTS The clinical and radiographic manifestations of disease caused by each species were similar. Standardized combination antibiotic therapy, including a clarithromycin-containing regimen in combination with an initial 4-week course of cefoxitin and amikacin, was given to 57 patients (24 with M. abscessus and 33 with M. massiliense) for more than 12 months. The proportion of patients with sputum conversion and maintenance of negative sputum cultures was higher in patients with M. massiliense infection (88%) than in those with M. abscessus infection (25%; P < 0.001). Inducible resistance to clarithromycin (minimal inhibitory concentrations ≥ 32 μg/ml) was found in all tested M. abscessus isolates (n = 19), but in none of the M. massiliense isolates (n = 28). CONCLUSIONS Treatment response rates to combination antibiotic therapy including clarithromycin were much higher in patients with M. massiliense lung disease than in those with M. abscessus lung disease. The inducible resistance to clarithromycin could explain the lack of efficacy of clarithromycin-containing antibiotic therapy against M. abscessus lung disease.

Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB : systematic review and meta-analysis

Linezolid is used off-label to treat multidrug-resistant tuberculosis (MDR-TB) in absence of systematic evidence. We performed a systematic review and meta-analysis on efficacy, safety and tolerability of linezolid-containing regimes based on individual data analysis. 12 studies (11 countries from three continents) reporting complete information on safety, tolerability, efficacy of linezolid-containing regimes in treating MDR-TB cases were identified based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analysis was performed using the individual data of 121 patients with a definite treatment outcome (cure, completion, death or failure). Most MDR-TB cases achieved sputum smear (86 (92.5%) out of 93) and culture (100 (93.5%) out of 107) conversion after treatment with individualised regimens containing linezolid (median (inter-quartile range) times for smear and culture conversions were 43.5 (21–90) and 61 (29–119) days, respectively) and 99 (81.8%) out of 121 patients were successfully treated. No significant differences were detected in the subgroup efficacy analysis (daily linezolid dosage ≤600 mg versus >600 mg). Adverse events were observed in 63 (58.9%) out of 107 patients, of which 54 (68.4%) out of 79 were major adverse events that included anaemia (38.1%), peripheral neuropathy (47.1%), gastro-intestinal disorders (16.7%), optic neuritis (13.2%) and thrombocytopenia (11.8%). The proportion of adverse events was significantly higher when the linezolid daily dosage exceeded 600 mg. The study results suggest an excellent efficacy but also the necessity of caution in the prescription of linezolid.

Antibiotic treatment of Mycobacterium abscessus lung disease: a retrospective analysis of 65 patients.

RATIONALE The optimal therapeutic regimen and duration of treatment for Mycobacterium abscessus lung disease is not well established. OBJECTIVES To assess the efficacy of a standardized combination antibiotic therapy for the treatment of M. abscessus lung disease. METHODS Sixty-five patients (11 males, 55 females, median age 55 yr) with M. abscessus lung disease were treated with clarithromycin, ciprofloxacin, and doxycycline, together with an initial regimen of amikacin and cefoxitin for the first 4 weeks of hospitalization. MEASUREMENTS AND MAIN RESULTS Treatment response rates were 83% for symptoms and 74% for high-resolution computed tomography. Sputum conversion and maintenance of negative sputum cultures for more than 12 months was achieved in 38 (58%) patients. These rates were significantly lower in patients whose isolates were resistant to clarithromycin (17%, 2/12) compared with those whose isolates were susceptible or intermediate to clarithromycin (64%, 21/33; P = 0.007). Neutropenia and thrombocytopenia associated with cefoxitin developed in 33 (51%) and 4 (6%) patients, respectively. Drug-induced hepatotoxicity occurred in 10 (15%) patients. Because of these adverse reactions, cefoxitin was discontinued in 39 (60%) patients after treatment for a median of 22 days. CONCLUSIONS Standardized combination antibiotic therapy was moderately effective in treating M. abscessus lung disease. However, frequent adverse reactions and the potential for long-duration hospitalization are important problems that remain to be solved.

Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis

The broadest pattern of tuberculosis drug resistance for which a consensus definition exists is extensively drug-resistant tuberculosis (XDR-TB). It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR-alone and three non-mutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) capreomycin and kanamycin/amikacin (XDR+2sli); XDR plus resistance to second-line injectables and to ≥1 Group 4 drug, i.e. : ethionamide/prothionamide, cycloserine/terizidone or PAS (XDR+sliG4); and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR-alone; 68 XDR+2sli; 48 XDR+sliG4; and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted Odds Ratio (aOR): 0.4; 95% Confidence Interval: 0.2–0.8) compared to XDR-alone, while odds of failure+death were higher in all XDR patients with additional resistance (aOR range: 2.6–2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current DST methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.The broadest pattern of tuberculosis (TB) drug resistance for which a consensus definition exists is extensively drug-resistant (XDR)-TB. It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance in order to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR alone and three nonmutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) and capreomycin and kanamycin/amikacin (XDR+2sli) XDR plus resistance to second-line injectables and to more than one group 4 drug, i.e. ethionamide/protionamide, cycloserine/terizidone or para-aminosalicylic acid (XDR+sliG4) and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR alone, 68 XDR+2sli, 48 XDR+sliG4 and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted OR 0.4, 95% CI 0.2–0.8) compared to XDR alone, while odds of failure and death were higher in all XDR patients with additional resistance (adjusted OR 2.6–2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current drug susceptibility testing methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.

Treatment Outcomes and Long-term Survival in Patients with Extensively Drug-resistant Tuberculosis

RATIONALE The increasing worldwide incidence of extensively drug-resistant tuberculosis (XDR-TB) has emerged as a threat to public health and tuberculosis (TB) control. Treatment outcomes have varied among studies, and data on long-term survival are still scarce. OBJECTIVES To retrospectively assess the burden, clinical characteristics, treatment outcomes, and long-term survival rate of patients with XDR-TB in a cohort of patients with HIV-negative multidrug-resistant tuberculosis (MDR-TB) in South Korea. METHODS Medical records were reviewed of patients newly diagnosed with or retreated for MDR-TB from 2000 to 2002. The cohort was monitored for 3 to 7 years after the initiation of treatment. Initial treatment outcomes and cumulative survival rates were analyzed, and predictors of treatment success and survival were defined. MEASUREMENTS AND MAIN RESULTS Of 1,407 patients with MDR-TB 75 (5.3%) had XDR-TB at treatment initiation. The default rate was high (453/1,407; 32%), and patients with XDR-TB had lower treatment success (29.3 vs. 46.2%; P = 0.004) and higher all-cause (49.3 vs. 19.4%; P < 0.001) and TB-related disease mortality (41.3 vs. 11.8%; P < 0.001) than other patients with MDR-TB. The presence of XDR-TB significantly affected treatment success (odds ratio, 0.23; 95% confidence interval [CI], 0.08-0.64; P = 0.005), all-cause mortality (hazards ratio, 3.25; 95% CI, 1.91-5.53; P < 0.001), and TB-related mortality (hazards ratio, 4.45; 95% CI, 2.48-8.00; P < 0.001) on multivariate analyses. CONCLUSIONS XDR-TB occurred in a substantial proportion of patients with MDR-TB in South Korea, and was the strongest predictor of treatment outcomes and long-term survival in patients with MDR-TB. Adequate TB control policies should be implemented to prevent the further development and spread of drug resistance.

Treatment Outcomes for HIV-Uninfected Patients with Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis

BACKGROUND Multidrug-resistant (MDR) tuberculosis (TB) is more difficult to treat than is drug-susceptible TB. To elucidate the optimal therapy for MDR TB, we assessed the treatment outcomes and prognostic factors for patients with MDR TB. METHODS This study included patients who received an individualized treatment regimen for MDR TB at Samsung Medical Center, a tertiary referral hospital in Seoul, Korea, from January 1995 through December 2004. To identify the prognostic factors related to favorable treatment outcomes, univariate comparison and multiple logistic regression were performed. RESULTS Of 155 patients, 18 (12%) had newly diagnosed MDR TB, 81 (52%) had previously received treatment with first-line drugs, and 56 (36%) had received treatment with second-line drugs. The isolated strains were resistant to a median of 5 drugs. Twenty-seven patients (17%) had extensively drug-resistant (XDR) TB at the start of treatment. Outcome assessment revealed that 102 patients (66%) were cured or completed therapy. The treatment success rates did not differ significantly between patients with non-XDR MDR TB and those with XDR TB (66% vs. 67%). Surgical resection was performed more frequently for patients with XDR TB than for those with non-XDR MDR TB (48% vs. 17%). Combined surgical resection, body mass index >/=18.5 (calculated as the weight in kilograms divided by the square of the height in meters), use of >4 effective drugs, and a negative sputum smear result were independent predictors of a favorable outcome. CONCLUSIONS Early aggressive treatment comprising at least 4 effective drugs and surgical resection, when indicated, may improve the outcome for patients with MDR TB or XDR TB.

Macrolide Treatment for Mycobacterium abscessus and Mycobacterium massiliense Infection and Inducible Resistance

RATIONALE Macrolides, such as clarithromycin (CLR) and azithromycin (AZM), are frequently the only oral antibiotics that are active against Mycobacterium abscessus and M. massiliense infections. OBJECTIVES To compare the activity of CLR and AZM in experimental models. METHODS We compared the treatment efficacies of CLR and AZM and determined the correlation between efficacy and induced erythromycin ribosome methyltransferase gene (erm)(41) expression in experimental models of M. abscessus and M. massiliense infections. MEASUREMENTS AND MAIN RESULTS In all tested M. abscessus isolates, a high level of inducible CLR resistance developed (minimal inhibitory concentration [MIC] on Day 3 versus Day 14; P < 0.001). Whereas the AZM MIC increased on Day 14 (P < 0.01 versus Day 3), the level was significantly lower than the CLR MIC on Day 14 (P < 0.001). However, the MICs of CLR and AZM for the M. massiliense isolates did not change. Compared with CLR, AZM presented greater antibiotic activity against M. abscessus in vitro, ex vivo, and in vivo (P < 0.05), whereas both macrolides were comparably effective against M. massiliense. In M. abscessus infection, the level of erm(41) expression was higher after exposure to CLR than after exposure to AZM (P < 0.001). Experiments using an erm(41)-knockout M. abscessus mutant and an M. massiliense transformant expressing M. abscessus erm(41) confirmed that erm(41) was responsible for inducible CLR resistance. CONCLUSIONS CLR induces greater erm(41) expression and thus higher macrolide resistance than AZM in M. abscessus infection. AZM may be more effective against M. abscessus, whereas both macrolides appear to be equally effective against M. massiliense.

Clinical characteristics and treatment outcomes of chronic necrotizing pulmonary aspergillosis: a review of 43 cases

OBJECTIVES Chronic necrotizing pulmonary aspergillosis (CNPA) is uncommon, and the optimal therapeutic regimen has not been established. In a retrospective cohort study, we investigated the clinical characteristics and treatment outcomes of patients with CNPA. METHODS We reviewed the medical records of all patients who had been diagnosed with CNPA at our institution over the last 10 years. RESULTS Forty-three patients were identified. Their median age was 60 years (interquartile range (IQR) 45-65 years), and 34 (79%) of the patients were men. The most common underlying lung disease was pulmonary tuberculosis (n=40, 93%). After CNPA was diagnosed, all patients were treated with antifungal drugs, including oral itraconazole (n=39, 91%) or intravenous amphotericin B (n=4, 9%). Seventeen (40%) patients discontinued therapy early (<3 months), 14 patients due to death and three to loss of follow-up. Twenty-six (60%) patients received oral itraconazole at a daily dose of 200-400mg for more than 3 months. The median treatment duration was 6 months (IQR 6-12 months). In these 26 patients, clinical improvement was observed in 15 (58%) and radiological improvement was observed in 11 (42%). Ten (38%) patients showed no improvement. Twenty-two (51%) patients died, including 18 (42%) CNPA-related deaths, during a median follow-up of 15 months (IQR 2.5-32 months). The median survival time was 62 months. CONCLUSIONS CNPA is difficult to treat and often has a poor outcome. Further studies with more patients are needed to identify the optimal therapy for patients with CNPA.

Clinical Significance of the Differentiation Between Mycobacterium avium and Mycobacterium intracellulare in M avium Complex Lung Disease

BACKGROUND Mycobacterium avium and Mycobacterium intracellulare are grouped together as the M avium complex; however, little is known about the clinical impact of this species differentiation. This study compared the clinical features and prognoses of patients with M avium and M intracellulare lung disease. METHODS From 2000 to 2009, 590 patients were given a new diagnosis of M avium complex lung disease; 323 (55%) had M avium lung disease, and 267 (45%) had M intracellulare lung disease. RESULTS Compared with the patients with M avium lung disease, the patients with M intracellulare lung disease were more likely to have the following characteristics: older age (64 vs 59 years, P = .002), a lower BMI (19.5 kg/m² vs 20.6 kg/m², P < .001), respiratory symptoms such as cough (84% vs 74%, P = .005), a history of previous treatment for TB (51% vs 31%, P < .001), the fibrocavitary form of the disease (26% vs 13%, P < .001), smear-positive sputum (56% vs 38%, P < .001), antibiotic therapy during the 24 months of follow-up (58% vs 42%, P < .001), and an unfavorable microbiologic response after combination antibiotic treatment (56% vs 74%, P = .001). CONCLUSIONS Patients with M intracellulare lung disease exhibited a more severe presentation and had a worse prognosis than patients with M avium lung disease in terms of disease progression and treatment response. Therefore, species differentiation between M avium and M intracellulare may have prognostic and therapeutic implications.