Efficacy and safety of fluoroquinolone-containing regimens in treating pulmonary Mycobacterium avium complex disease: A propensity score analysis.

BACKGROUND: Although combination therapy using clarithromycin, rifampicin, and ethambutol is recommended for patients with pulmonary Mycobacterium avium complex (MAC) disease, some patients do not tolerate it because of adverse effects or underlying diseases. The efficacy and safety of fluoroquinolone-containing combination regimens as an alternative remain uncertain. This study aimed to compare the efficacy and safety of fluoroquinolone-containing regimens with those of the standard regimens for treating pulmonary MAC disease. METHODS: We retrospectively included consecutive MAC patients who were treated in our hospital between January 2011 and May 2019. Patients treated with fluoroquinolone-containing regimens who had relapsed after treatment with standard regimens were excluded. A propensity score analysis was conducted to reduce selection bias, and the proportions of clinical improvement, defined by chest imaging findings and sputum conversion, were compared between the fluoroquinolone-containing regimen and standard regimen groups. RESULTS: We analyzed 28 patients who received fluoroquinolone-containing regimens and 46 who received the standard regimen. Fluoroquinolone-containing regimens were more likely selected for patients with cavitary lesions, diabetes mellitus, culture negativity, a low daily physical activity level, a decreased lymphocyte count and an increased CRP level. The propensity score was calculated using these variables (C-statistic of the area under the receiver operating characteristic curve of the propensity score: 0.807, p < 0.0001). The fluoroquinolone-containing regimens were significantly inferior to the standard regimen in clinical improvements (p = 0.002, Log-rank test) in the univariate analysis, but the significance was lost after adjusting for the propensity score (HR 0.553, 95% CI 0.285-1.074, p = 0.080). Six (21%) patients in the fluoroquinolone-containing regimen group and ten (22%) patients in the standard regimen group experienced low-grade adverse effects. CONCLUSIONS: There was no significant difference in clinical improvement between these regimens after propensity score adjustment. A large-scale prospective study is required to validate these results.

The impact of performance status on tuberculosis-related death among elderly patients with lung tuberculosis: A competing risk regression analysis.

While advanced age is a main prognostic factor in patients with tuberculosis, the factors that specifically affect tuberculosis-related death are unclear because elderly people are at a risk for other age-related lethal diseases. We aimed to assess the impact of performance status on tuberculosis-related death among elderly patients with lung tuberculosis. Elderly patients (≥65 years of age) admitted to our hospital for bacteriologically-diagnosed lung tuberculosis were included, and analyzed the influence of performance status on tuberculosis-related in-hospital death, with non-tuberculosis-related death as a competing risk. Forty and 19 of the 275 patients died from tuberculosis-related causes and non-tuberculosis-related causes, respectively. The tuberculosis-related death group had a greater number of patients with a poor performance status (defined as category 3 and 4 [HR 21.022; 95%CI 2.881-153.414; p = 0.003]), a lower serum albumin level (HR 0.179; 95%CI 0.090-0.359; p < 0.001) and a higher C-reactive protein level (HR1.076; 95%CI 1.026-1.127; p = 0.002). A multivariate competing risk regression analysis showed that a poor performance status (HR 7.311; 95%CI 1.005-53.181; p = 0.049) and low albumin level (HR 0.228; 95%CI 0.099-0.524); p = 0.001) significantly predicted tuberculosis-related death. Performance status can be a useful scale for predicting tuberculosis-related death among elderly patients with pulmonary tuberculosis.

A high C-reactive protein level and poor performance status are associated with delayed sputum conversion in elderly patients with pulmonary tuberculosis in Japan.

INTRODUCTION: Although the aging population had been increasing in many countries, the factors associated with sputum conversion in elderly patients with pulmonary tuberculosis have not been fully elucidated. OBJECTIVES: We aimed to identify the predictors of delayed sputum conversion and to assess the impact of non-conversion on mortality during tuberculosis treatment in elderly patients. METHODS: Elderly patients (>65 years) admitted at our hospital in Japan for sputum smear-positive pulmonary tuberculosis were included. The risk factors for sputum non-conversion after 2 months of treatment were determined using multiple logistic regression. Cox hazard regression was used to assess the influence of non-conversion on mortality. RESULTS: We included 185 patients, with median age of 82 years (IQR, 79-88 years). The median time to conversion was 47 (95% CI 43-51) days, and 62 (34%) were identified as non-converters. Multivariate analysis showed that high pretreatment smear grade, high C-reactive protein level and poor performance status were associated with non-conversion. Non-conversion did not contribute to death during treatment. CONCLUSIONS: In elderly patients, inflammation level and physical activity level, along with initial smear grade may have a significant impact on delayed sputum conversion. Non-conversion after two months of treatment might not be related with mortality.

Factors associated with atypical radiological findings of pulmonary tuberculosis.

BACKGROUND: Unusual radiological images may delay diagnosis of pulmonary tuberculosis. This study aimed to analyze the risk factors for an atypical radiological image in patients with pulmonary tuberculosis. METHODS: We retrospectively analyzed data from patients admitted to one hospital from January 2013 to December 2016 for sputum smear-positive lung tuberculosis who underwent chest computed tomography (CT) on admission. Patients whose sputum cultures were positive for general bacteria were excluded. Patient characteristics and laboratory data were compared between patients with cavity and those without and between patients with upper predominant lung involvement and those without. RESULTS: This study included 94 (93%) of 101 patients who underwent chest CT. The non-cavity group was older, had a greater number of females, had a lower C-reactive protein (CRP) level, and had a lower glomerular filtration rate. Multivariate analysis showed that a low CRP level (OR 0.808; 95% CI 0.674-0.967; p = 0.020) significantly predicted non-cavity pulmonary tuberculosis. The non-upper predominant lung involvement group was older and had a greater number of females, poorer performance status, a higher CRP level, and a lower serum albumin level. A poor performance status (OR 2.155; 95% CI 1.257-3.693; p = 0.005) was found to significantly predict pulmonary tuberculosis with non-upper predominant lung distributions. CONCLUSIONS: A low CRP level and poor performance status were associated with non-cavity and non-upper predominant lung distribution, respectively, in patients with pulmonary tuberculosis. Tuberculosis patients with these characteristics may present unusual chest images.

Impact of additional antibiotics on in-hospital mortality in tuberculosis isolated general bacteria: A propensity score analysis.

Whether or not additional antibiotics with anti-tuberculosis agents are required to treat bacterial co-infection with pulmonary tuberculosis is unclear. We aimed to assess the impact of additional antibiotics on mortality in pulmonary tuberculosis patients whose sputum cultures were positive for general bacteria as a surrogate definition of bacterial pneumonia. This study was a single-center retrospective cohort using a propensity score analysis. We included patients who were admitted for pulmonary tuberculosis and whose sputum cultures were positive for general bacteria. The mortality of patients who received additional antibiotics was analyzed after adjusting for other variables, including the propensity score predicting treatment with additional antibiotics. We assessed 68 and 55 tuberculosis patients treated with and without general antibiotics, respectively. Additional antibiotics tended to be administered to patients with a high level of C-reactive protein and neutrophil count, poor performance status, hypoxemia and hypoalbuminemia (C-statistics of area under receiver operating characteristic curve to the propensity score; 0.884, p < 0.001). In the multivariate analysis, advanced age and not the use of additional antibiotics was associated with in-hospital mortality. Additional antibiotics with anti-tuberculosis agents may not improve the prognosis of pulmonary tuberculosis patients whose sputum cultures were positive for general bacteria. Isolation of general bacteria does not equate to complication with bacterial pneumonia, so physicians should not administer general antibiotics to TB patients based solely on the results of sputum culture for general bacteria. A prospective study is needed to verify these results using a more accurate definition of pulmonary tuberculosis complicated with bacterial pneumonia.

[Clinical features of foreign-born tuberculosis patients treated at our hospital].

INTRODUCTION: There has been an increase in the number of foreign-born tuberculosis (TB) patients residing in Japan. The purpose of this study is to clarify the clinical features of the foreign-born TB patients treated at our hospital. MATERIALS AND METHODS: This study included foreign-born TB patients treated at our hospital between 2000 and 2009. A comparison was performed with Japanese TB patients in the same age group who were treated in the same period. RESULTS: There were 44 patients (17 males and 27 females; mean age: 23.6 +/- 5.1). These patients originated from 13 different countries, 12 of which were Asian countries such as China and the Philippines, and 8 of which were WHO-designated high-burden TB countries. The period between the patient's entry into Japan and the onset of TB was less than a year for half of the cases. As compared with the Japanese patients group, the foreign patients group included a significantly higher proportion of students and a significantly large number of cases found by periodic health examination. In terms of clinical findings, no significant difference was observed in the proportion of cavitary cases (37.5%) and of smear positive cases (37.5%); however, the frequency of drug-resistant cases (30.4%) was significantly higher among the foreign patients than the Japanese patients. The cure rate was 75% among foreign-born patients, and there were no defaulters. CONCLUSION: Compared with Japanese patients with the same ages, the foreign-born TB patients treated at our hospital included a high proportion of students from high-burden TB countries who were detected by periodic health examination and a higher proportion of drug-resistant cases. The treatment outcome was satisfactory without any defaulters. Periodic mass health examinations and drug susceptibility tests are important, and careful health examination is necessary for all individuals from high-burden TB countries when they enter Japan.

The Mycobacterium tuberculosis SigD sigma factor controls the expression of ribosome-associated gene products in stationary phase and is required for full virulence.

During infection Mycobacterium tuberculosis is exposed to several environmental conditions depending on the stage and severity of the disease. To survive, M. tuberculosis uses alternate sigma factors to regulate its gene expression in response to the changing host environment. In order to better understand the way in which stress response genes are regulated, the extracytoplasmic sigma factor gene sigD was deleted and subsequently complemented in the CDC1551 strain of M. tuberculosis. The DeltasigD mutant strain exhibited an in vitro growth rate in rich medium identical to that of both the sigD-complemented and wild-type CDC1551 strains. Additionally, no differences were observed in short-term intracellular growth between the mutant, complemented, and wild-type bacteria within the J774A.1 macrophage cell line. However, tumour necrosis factor (TNF)-alpha levels in macrophages infected with the DeltasigD mutant were decreased as compared to levels observed in macrophages infected with the wild-type bacteria. In time-to-death studies, C3H mice infected with the DeltasigD mutant exhibited a mortality delay compared to those infected with either the complemented or wild-type strains. Although mice infected with the DeltasigD mutant died at a reduced rate, the bacillary loads in the lungs and spleen of these mice were comparable to those seen in mice infected with either the complemented or wild-type strains. Microarray analysis of the DeltasigD mutant relative to wild type revealed that SigD directs the expression of a small set of ribosomal genes and adenosine triphosphate transporters whose expression is normally induced during stationary phase growth in vitro. Altered expression of a subset of these genes was confirmed by quantitative reverse transcription polymerase chain reaction analysis. Promoter-like elements resembling the consensus sequence AGAAAG-N16-20-CGTTAA were found upstream of 19 of the genes underexpressed in the DeltasigD mutant suggesting this may be the recognition sequence for the M. tuberculosis SigD-holoenzyme, EsigmaD. These data indicate that the M. tuberculosis SigD sigma factor governs the expression of a small set of ribosomal genes typically expressed in stationary phase during in vitro growth and that loss of sigD reduces macrophage TNF-alpha secretion as well as the lethality of M. tuberculosis infection in mice.

Dormancy phenotype displayed by extracellular Mycobacterium tuberculosis within artificial granulomas in mice.

Mycobacterium tuberculosis residing within pulmonary granulomas and cavities represents an important reservoir of persistent organisms during human latent tuberculosis infection. We present a novel in vivo model of tuberculosis involving the encapsulation of bacilli in semidiffusible hollow fibers that are implanted subcutaneously into mice. Granulomatous lesions develop around these hollow fibers, and in this microenvironment, the organisms demonstrate an altered physiologic state characterized by stationary-state colony-forming unit counts and decreased metabolic activity. Moreover, these organisms show an antimicrobial susceptibility pattern similar to persistent bacilli in current models of tuberculosis chemotherapy in that they are more susceptible to the sterilizing drug, rifampin, than to the bactericidal drug isoniazid. We used this model of extracellular persistence within host granulomas to study both gene expression patterns and mutant survival patterns. Our results demonstrate induction of dosR (Rv3133c) and 20 other members of the DosR regulon believed to mediate the transition into dormancy, and that rel(Mtb) is required for Mycobacterium tuberculosis survival during extracellular persistence within host granulomas. Interestingly, the dormancy phenotype of extracellular M. tuberculosis within host granulomas appears to be immune mediated and interferon-gamma dependent.

Moxifloxacin-containing regimens of reduced duration produce a stable cure in murine tuberculosis.

In a recent experimental study using the mouse model of tuberculosis, treatment with a combination of rifampin, moxifloxacin, and pyrazinamide was able to shorten the time to negative lung cultures by up to 2 months compared with the standard regimen of rifampin, isoniazid, and pyrazinamide. To confirm that this substitution of moxifloxacin for isoniazid permits a shorter duration of treatment, a second study was performed in which mice were assessed for relapse after treatment with combination therapy for 3, 4, 5, or 6 months. Although no relapse was observed among mice treated for at least 4 months with rifampin, moxifloxacin, and pyrazinamide, mice treated with rifampin, isoniazid, and pyrazinamide required 6 months of treatment before no relapse could be detected. For mice treated with rifampin, moxifloxacin, and pyrazinamide, similar efficacy was noted whether pyrazinamide was administered for 1 month, 2 months, or the entire duration of therapy. These results suggest that the use of rifampin, moxifloxacin, and pyrazinamide may substantially shorten the duration of therapy needed to cure human tuberculosis and that the full benefit of pyrazinamide in this regimen may be realized after just 1 month of treatment.

Moxifloxacin-containing regimen greatly reduces time to culture conversion in murine tuberculosis.

Tuberculosis continues to be a major cause of morbidity and mortality in the world. The expansion of tuberculosis control programs has been limited by the lengthy and cumbersome nature of current chemotherapeutic regimens. A new drug that improves the sterilizing activity of current regimens would reduce the duration of therapy without sacrificing efficacy, thereby enhancing treatment completion rates and preserving precious public health resources. The new 8-methoxyfluoroquinolone moxifloxacin has potent activity against both actively multiplying and nonactively multiplying tubercle bacilli. Using a murine model that is representative of chemotherapy for human tuberculosis, we show that the combination of moxifloxacin, rifampin, and pyrazinamide reduced the time needed to eradicate Mycobacterium tuberculosis from the lungs of infected mice by up to 2 months when compared with the standard regimen of isoniazid, rifampin, and pyrazinamide. The findings suggest that this regimen has the potential to substantially shorten the duration of therapy needed to cure human tuberculosis.

Deletion of Mycobacterium tuberculosis sigma factor E results in delayed time to death with bacterial persistence in the lungs of aerosol-infected mice.

The stress-induced extracytoplasmic sigma factor E (SigE) of Mycobacterium tuberculosis shows increased expression after heat shock, sodium dodecyl sulfate treatment, and oxidative stress, as well as after phagocytosis in macrophages. We report that deletion of sigE results in delayed lethality in mice without a significant reduction of bacterial numbers in lungs.

Reduced immunopathology and mortality despite tissue persistence in a Mycobacterium tuberculosis mutant lacking alternative sigma factor, SigH.

The pathogenesis of tuberculosis involves multiple phases and is believed to involve both a carefully deployed series of adaptive bacterial virulence factors and inappropriate host immune responses that lead to tissue damage. A defined Mycobacterium tuberculosis mutant strain lacking the sigH-encoded transcription factor showed a distinctive infection phenotype. In resistant C57BL/6 mice, the mutant achieved high bacterial counts in lung and spleen that persisted in tissues in a pattern identical to those of wild-type bacteria. Despite a high bacterial burden, the mutant produced a blunted, delayed pulmonary inflammatory response, and recruited fewer CD4(+) and CD8(+) T cells to the lung in the early stages of infection. In susceptible C3H mice, the mutant again showed diminished immunopathology and was nonlethal at over 170 days after intravenous infection, in contrast to isogenic wild-type bacilli, which killed with a median time to death of 52 days. Complete genomic microarray analysis revealed that M. tuberculosis sigH may mediate the transcription of at least 31 genes directly and that it modulates the expression of about 150 others; the SigH regulon governs thioredoxin recycling and may be involved in the maintenance of intrabacterial reducing capacity. These data show that the M. tuberculosis sigH gene is dispensable for bacterial growth and survival within the host, but is required for the production of immunopathology and lethality. This phenotype demonstrates that beyond an ability to grow and persist within the host, M. tuberculosis has distinct virulence mechanisms that elicit deleterious host responses and progressive pulmonary disease.

Bactericidal activity of increasing daily and weekly doses of moxifloxacin in murine tuberculosis.

Moxifloxacin (MXF) is a new 8-methoxyquinolone with potent activity against Mycobacterium tuberculosis and a half-life of 9 to 12 h in humans. Previous in vivo studies using daily doses of 100 mg/kg of body weight have demonstrated bactericidal activity comparable to that of isoniazid (INH) in a murine model of tuberculosis (TB). Recent pharmacokinetic data suggest that MXF may have been underadministered in these studies and that a 400-mg/kg dose in mice better approximates the area under the concentration-time curve obtained in humans after a 400-mg oral dose. Therefore, the bactericidal activity of MXF in doses up to 400 mg/kg given daily or weekly for 28 days was assessed in mice infected intravenously with 5 x 10(6) CFU of M. tuberculosis. INH was used as a positive control. After 3 days of daily therapy, the CFU counts from splenic homogenates for mice treated with MXF in doses of 100 to 400 mg/kg/day were lower than those from pretreatment controls. No significant differences in CFU counts were seen when mice receiving INH or MXF at 50 mg/kg/day were compared to pretreatment controls. After 28 days of therapy, dose-dependent reductions in CFU counts in splenic homogenates were seen for daily MXF therapy. The maximum bactericidal effect was seen with daily doses of 400 mg/kg, which resulted in a reduction in CFU counts of 1 log(10) greater than that with INH treatment, although the difference was not statistically significant. CFU counts from lung homogenates after 28 days of therapy were significantly lower in all treatment groups than in untreated controls. The weekly administration of MXF in doses ranging from 50 to 400 mg/kg resulted in no significant bactericidal activity. Mice receiving daily MXF doses of 200 and 400 mg/kg/day failed to gain weight and appeared ill after 28 days of therapy, findings suggestive of drug toxicity. In conclusion, MXF has dose-dependent bactericidal activity against M. tuberculosis in the mouse when given in doses up to 400 mg/kg, where its pharmacokinetic profile better approximates that of standard human dosages. Combination regimens which take advantage of the enhanced pharmacodynamic profile of MXF at these doses have the potential to shorten the course of antituberculous therapy or allow more intermittent (i.e., once-weekly) therapy and should be evaluated in the mouse model of TB.