Delayed Sputum Culture Conversion Research Articles

Pharmacokinetics and pharmacodynamics of high-dose isoniazid for the treatment of rifampicin- or multidrug-resistant tuberculosis in Indonesia.

Pharmacokinetic data on high-dose isoniazid for the treatment of rifampicin-/multidrug-resistant tuberculosis (RR/MDR-TB) are limited. We aimed to describe the pharmacokinetics of high-dose isoniazid, estimate exposure target attainment, identify predictors of exposures, and explore exposure-response relationships in RR/MDR-TB patients. We performed an observational pharmacokinetic study, with exploratory pharmacokinetic/pharmacodynamic analyses, in Indonesian adults aged 18-65 years treated for pulmonary RR/MDR-TB with standardized regimens containing high-dose isoniazid (10-15 mg/kg/day) for 9-11 months. Intensive pharmacokinetic sampling was performed after ≥2 weeks of treatment. Total plasma drug exposure (AUC0-24) and peak concentration (Cmax) were assessed using non-compartmental analyses. AUC0-24/MIC ratio of 85 and Cmax/MIC ratio of 17.5 were used as exposure targets. Multivariable linear and logistic regression analyses were used to identify predictors of drug exposures and responses, respectively. We consecutively enrolled 40 patients (median age 37.5 years). The geometric mean isoniazid AUC0-24 and Cmax were 35.4 h·mg/L and 8.5 mg/L, respectively. Lower AUC0-24 and Cmax values were associated (P < 0.05) with non-slow acetylator phenotype, and lower Cmax values were associated with male sex. Of the 26 patients with MIC data, less than 25% achieved the proposed targets for isoniazid AUC0-24/MIC (n = 6/26) and Cmax/MIC (n = 5/26). Lower isoniazid AUC0-24 values were associated with delayed sputum culture conversion (>2 months of treatment) [adjusted OR 0.18 (95% CI 0.04-0.89)]. Isoniazid exposures below targets were observed in most patients, and certain risk groups for low isoniazid exposures may require dose adjustment. The effect of low isoniazid exposures on delayed culture conversion deserves attention.

Low body mass index as a predictor of sputum culture conversion and treatment outcomes among patients receiving treatment for multidrug-resistant tuberculosis in Lesotho

ABSTRACT Background A low body mass index (BMI) at the start of treatment for rifampicin- or multidrug-resistant tuberculosis (MDR/RR-TB) is associated with poor treatment outcomes and may contribute to delayed sputum culture conversion, thereby prolonging the period of potential transmission to others. Whether the relative importance of low BMI in predicting treatment outcomes differs by HIV status is unclear. Objectives We evaluated the association between low BMI and two dependent variables, sputum culture conversion and end-of-treatment outcome, among patients receiving treatment for MDR/RR-TB in Lesotho, a setting with a high prevalence of HIV infection. Methods Secondary data from a prospective cohort of patients initiating a longer (18–20 months) treatment containing bedaquiline and/or delamanid under routine programmatic conditions in Lesotho were analysed. Risk ratios and differences were adjusted for potential confounders using multivariable logistic regression, and estimates were stratified by HIV status. Results Of 264 patients, 105 and 250 were eligible for culture conversion and end-of-treatment analyses, respectively. Seventy-one per cent of patients (74/105) experienced culture conversion within six months, while 74% (184/250) experienced a favourable end-of-treatment outcome. Low BMI was associated with a lower frequency of culture conversion at six months among those who were not living with HIV (relative risk [RR]: 0.50 [95% CI: 0.21, 0.79]); this association was attenuated among those living with HIV (RR: 0.88 [95% CI: 0.68, 1.23]). A low BMI was moderately associated with a lower frequency of treatment success (RR = 0.89 [95% CI: 0.77, 1.03]), regardless of HIV status. Conclusions Low BMI was common and associated with the frequency of six-month culture conversion and end-of-treatment outcomes. The association with culture conversion was more pronounced among those not living with HIV. Addressing the myriad factors that drive low BMI in this setting could hasten culture conversion and improve end-of-treatment outcomes. This will require a multipronged approach focused on alleviating food insecurity and enabling prompt diagnosis and treatment of HIV and TB.

INTENSIVE CASE FINDINGS OF TUBERCULOSIS AND DIABETES MELLITUS IN PATIENTS ATTENDING TERTIARY CARE HOSPITAL IN TRIBAL AREA IN GUJARAT

Tuberculosis (TB) in association with Diabetes Mellitus (DM), TB may get worsen as increased relapse rates, delayed sputum culture conversion, increase in the case fatality rates etc. Conversely, TB may increase the incidence of DM, and worsen glycaemic control in diabetes patients. A cross-sectional cohort study conducted at Medicine and Pulmonology department of ZMCH DAHOD for a period of nine months in June 2020- February 2021. All TB patients were screened for DM and vice versa. All TB patients were followed-up for treatment outcome of TB and all DM patients were followed-up for glycaemic control. Relative risk was calculated using incidence of outcome or control of disease in TB with DM patients to TB patients and DM with TB patients to DM patients. Of 256 TB patients, 38 (14.8%) were TB with DM cases. All 256 patients were followed-up for TB treatment outcome, 100% TB patients without DM had recovery, whereas 97.3% TB patients with DM had recovery after two months of therapy. Relative risk of DM on TB outcome was 0.97. Of 256 DM patients screened, 9 (3.5%) had been newly diagnosed with TB. All 256 people were followed-up for impact on glycaemic control. Relative risk of TB on glycemic control was 1.87. Bidirectional screening would potentially improve care and prevention of TB and DM.

Therapeutic drug monitoring and TB treatment outcomes in patients with diabetes mellitus.

BACKGROUND: Diabetes mellitus (DM) increases the risk of TB disease and poor treatment outcomes such as delayed sputum culture conversion due to inadequate drug exposure. Therapeutic drug monitoring (TDM) has improved these outcomes in some settings.METHODS: To compare treatment outcomes in programs with routine TDM vs. programs that did not use TDM, we conducted a retrospective study among people with DM and TB at health departments in four US states.RESULTS: A total of 170 patients were enrolled (73 patients in the non-TDM group and 97 patients in the TDM group). Days to sputum culture conversion and total treatment duration were significantly shorter in the TDM group vs. the non-TDM group. In adjusted analyses, patients who underwent TDM were significantly more likely to achieve sputum culture conversion at 2 months (P = 0.007).CONCLUSION: TDM hastened microbiological cure from TB among people with DM and a high risk for poor treatment outcomes in the programmatic setting.

Intensive Case Finding of Tuberculosis and Diabetes Mellitus-Bidirectional Screening of Patients Attending a Tertiary Teaching Hospital in Rural Telangana, India

Introduction: Tuberculosis (TB) is a communicable disease of global public health threat. Poor and vulnerable populations are mainly affected with it. In association with Diabetes Mellitus (DM), TB may get worsen as increased relapse rates, delayed sputum culture conversion, increase in the case fatality rates etc. Conversely, TB may increase the incidence of DM, and worsen glycaemic control in diabetes patients. Aim: To study the effectiveness of bidirectional screening for TB and DM in rural hospital. Materials and Methods: A cross-sectional cohort study conducted at Medicine and Pulmonology department of MediCiti Institute of Medical Sciences (MIMS) for a period of nine months in June 2019-February 2020. All TB patients were screened for DM and vice versa. All TB patients were followed-up for treatment outcome of TB and all DM patients were followed-up for glycaemic control. Relative risk was calculated using incidence of outcome or control of disease in TB with DM patients to TB patients and DM with TB patients to DM patients. Results: Of 256 TB patients, 38 (14.8%) were TB with DM cases. All 256 patients were followed-up for TB treatment outcome, 100% TB patients without DM had recovery, whereas 97.3% TB patients with DM had recovery after two months of therapy. Relative risk of DM on TB outcome was 0.97. Of 256 DM patients screened, 9 (3.5%) had been newly diagnosed with TB. All 256 people were followed-up for impact on glycaemic control. Relative risk of TB on glycemic control was 1.87. Conclusion: Bidirectional screening would potentially improve care and prevention of TB and DM.

Time for culture conversion and its associated factors in multidrug-resistant tuberculosis patients at a tertiary level hospital in Peshawar, Pakistan.

Objectives:This study aimed to assess the time to sputum culture conversion (SCC) and its determinants among multidrug-resistant tuberculosis (MDR-TB) patients.Methods:This cross-sectional study was conducted from January 2019 to January 2020. A total of 252 MDR-TB patients presenting at a tertiary level teaching hospital in Peshawar, Khyber Pakhtunkhwa (KP), were included. The patient’s demographic and clinical data were collected using a structured questionnaire. Time to SCC was calculated from the initiation of treatment till the patient had two consecutive negative cultures. The Cox proportional-hazards analysis was performed to check strength and association between the determinants and time for SCC.Results:Out of 252 MDR-TB patients enrolled, sputum culture conversion was observed in 76.6% of the patients by the end of six months. While, 19.0% of the patients failed to achieve negative culture and remained positive after interim report of their treatment. Age > 45 years (HR = 15.22; 95% CI: 7.27-31.83; p<0.001), female gender (6.22; 2.90-13.36; p<0.001), BMI < 18.5 kg/m2 (10.28; 5.25-20.11; p<0.001), weight loss (0.03; 0.01-0.06; p<0.001), smoking (0.10; 0.05-0.21; p<0.001), diabetes mellitus (0.02; 0.00-0.04 p<0.001) and disease severity on chest X-ray (CXR) (0.03; 0.01-0.09; p<0.001) were the significant determinants of delayed sputum culture conversion.Conclusion:MDR-TB patients with older age, low BMI, weight loss, diabetes, smokers and those with disease severity on CXR are less likely to respond to treatment as they displayed delayed SCC. Therefore, such patients should be meticulously followed up for successful management.

Malnutrition is Associated with Delayed Sputum Culture Conversion Among Patients Treated for MDR-TB.

BackgroundClinicians use sputum culture conversion as an interim indicator of the efficacy of multi-drug resistant tuberculosis (MDR-TB) treatment and to determine treatment duration. Yet, limited studies have been published in Ethiopia.ObjectiveThe objective of this study was to determine the predictors of delayed culture conversion among patients receiving MDR-TB treatment at selected treatment centers in Ethiopia.Patients and MethodsA multi-center observation study was conducted among MDR-TB patients in South and Southwestern Ethiopia from April 14 to May 14, 2019. The data of patients treated from January 2013 to July 2019 were reviewed using a data abstraction tool. The data were analyzed. Descriptive statistics was computed using SPSS version 21 software program. Cox regression was used to identify predictors of delayed culture conversion. Hazard ratios with a two-sided p-value <0.05 were considered statistically significant.ResultsOf 200 included MDR-TB patients, 108 (54%) were males. Majority,159 (79.5%) of the patients had a culture conversion time of less than two months, while 15 (7.5%) had delayed culture conversion (greater than 120 days). Patient’s registration group (after loss to follow- (adjusted hazard ratio (AHR)=16.215, 95% CI [3.839, 68.498]), after treatment failure (AHR=12.161, 95% CI [2.516, 58.793]), history of previous TB treatment (AHR=4.007, 95% CI [3.115, 62.990])) and low BMI (AHR= 1.257; 95% CI [0.725,1.547] were identified as a risk factors for delayed culture conversion.ConclusionOur finding showed that nearly 80% of the patients achieve sputum culture conversion by the second month of treatment. Delayed culture conversion was more likely among patients with malnutrition (BMI<18.5kg/m2), after treatment failure, previous TB treatment, and after lost to follow-up.

Association of the Clinico-Demographic and Laboratory Profile with Treatment Outcomes in Patients with Drug-Resistant Pulmonary Tuberculosis

Background:Drug-resistant tuberculosis (DR-TB) is a significant public health problem, especially in the developing and underdeveloped countries; its treatment is relatively expensive, of longer duration, and associated with more adverse effects.Objective:The objective of this study was to report the treatment outcomes in patients with DR-TB and determine if a few selected clinico-demographic parameters and baseline laboratory values, done as part of the pre-treatment evaluation, have any impact on sputum culture conversion and outcomes. The aim was to identify the potential factors associated with unfavourable outcomes prior to starting the treatment.Methods:A retrospective analysis of data of patients diagnosed with DR-TB admitted at our centre from January 2015 to May 2016 was done. Of the 114 patients included, culture reports were available in 85 and 72 patients at the end of the third and sixth month, respectively. The clinicodemographic and laboratory parameters were compared with the sputum culture report at the end of the third and sixth month and final treatment outcomes.Results:Favorable outcome (cured) was seen in 33.3% (38/114) patients. Female gender was associated with delayed sputum culture conversion at three months (P = 0.020). A positive culture at the end of the sixth month was significantly associated with unfavourable outcomes (P = 0.002). A low body mass index (BMI) (15.86 [IQR, 14.10-18.11]) and a higher platelet count (358 × 109/L [IQR, 282-4.85]) at the initiation of treatment were independently and significantly associated with unfavorable outcomes.Conclusion:Patients with a low BMI and high platelet count are more likely to have unfavourable treatment outcomes. Identifying patients with these risk factors during the pre-treatment phase, more intensive follow-up during the treatment course could be advocated.

Plasma Chemokines Are Baseline Predictors of Unfavorable Treatment Outcomes in Pulmonary Tuberculosis.

Plasma chemokines are biomarkers of greater disease severity, higher bacterial burden, and delayed sputum culture conversion in pulmonary tuberculosis (PTB). Whether plasma chemokines could also serve as biomarkers of unfavorable treatment outcomes in PTB is not known. A cohort of newly diagnosed, sputum smear- and culture-positive adults with drug-sensitive PTB were recruited under the Effect of Diabetes on Tuberculosis Severity study in Chennai, India. Plasma chemokine levels measured before treatment initiation were compared between 68 cases with unfavorable outcomes (treatment failure, death, or recurrence) and 136 control individuals who had recurrence-free cure. A second validation cohort comprising newly diagnosed, culture-positive adults with drug-sensitive TB was used to measure plasma chemokine levels in 20 cases and 40 controls. Six chemokines (CCL2, CCL3, CCL4, CXCL8, CXCL10, and CX3CL1) were associated with increased risk, while CXCL1 was associated with decreased risk of unfavorable outcomes in unadjusted and adjusted analyses in the test cohort. Similarly, CCL3, CXCL8, and CXCL10 were associated with increased risk of unfavorable treatment outcomes in the validation cohort. Receiver operating characteristic analysis revealed that combinations of CCL3, CXCL8, and CXCL10 exhibited very high sensitivity and specificity in differentiating cases vs controls. Our study reveals a plasma chemokine signature that can be used as a novel biomarker for predicting adverse treatment outcomes in PTB.

Time to sputum culture conversion and its associated factors among multidrug-resistant tuberculosis patients in Eastern Africa: A systematic review and meta-analysis

ObjectiveThis study aimed to consider the estimated time to multi-resistant tuberculosis culture conversion, and associated factors, in order to enhance evidence utilization in eastern Africa. MethodsWe systematically identified available articles on multidrug-resistant tuberculosis culture conversion using PubMed, Scopus, Cochrane Library, Web of Science core collection, and Science Direct databases. A random-effects model was employed using the R 3.6.1 version and Stata/se 14 software. ResultsNine articles with a sample size of 2458 multidrug-resistant tuberculosis patients were included. The two-month culture conversion rate was 75.4%, with a median time of 61.2 days (interquartile range: 48.6-73.8). In the included studies, favorable treatment outcomes of MDR-TB patients were seen in 75% of the cases, while unfavorable treatment outcomes were seen in 18% (10% deaths, 7% defaulted, and 1% treatment failure) of the cases. The independent factor for delayed sputum culture conversion was body mass index below 18.5kg/m2 (HR=3.1, 95% CI: 2.0, 6.7). ConclusionThe median time to sputum culture conversion was 61.2 days, which is a reasonably short time. Body mass index was the identified associated factor leading to delayed culture conversion. Therefore, there is a need for awareness of how to improve the nutritional status of multidrug-resistant tuberculosis patients through appropriate nutritional supports.

Plasma chemokines are biomarkers of disease severity, higher bacterial burden and delayed sputum culture conversion in pulmonary tuberculosis

Plasma cytokines are biomarkers of disease extent and mycobacterial burden in pulmonary tuberculosis (PTB). Whether chemokines can perform the same role in PTB is not known. We examined the plasma levels of chemokines in individuals with PTB, latent TB (LTB) or healthy controls (HC) and their association with disease severity and mycobacterial burdens in PTB. We also examined the chemokines in PTB individuals at the end of anti-tuberculous chemotherapy (ATT). PTB individuals exhibited significantly higher levels of CCL1, CCL3, CXCL1, CXCL2, CXCL9 and CXCL10 in comparison to LTB and/or HC individuals. PTB individuals with bilateral or cavitary disease displayed significantly elevated levels of CCL1, CCL3, CXCL1, CXCL10 and CXCL11 compared to those with unilateral or non-cavitary disease and also exhibited a significant positive relationship with bacterial burdens. In addition, PTB individuals with slower culture conversion displayed significantly elevated levels of CCL1, CCL3, CXCL1 and CXCL9 at the time of PTB diagnosis and prior to ATT. Finally, the chemokines were significantly reduced following successful ATT. Our data demonstrate that PTB is associated with elevated levels of chemokines, which are partially reversed followed chemotherapy. Our data demonstrate that chemokines are markers of disease severity, predicting increased bacterial burden and delayed culture conversion in PTB.

Predictors of time to sputum culture conversion in multi-drug-resistant tuberculosis and extensively drug-resistant tuberculosis in patients at Tshepong-Klerksdorp Hospital

SettingKlerksdorp-Tshepong Hospital Complex MDR-TB Unit, North-West Province, South Africa.BackgroundTo determine the time to sputum culture conversion (TTSCC) and factors predictive of TTSCC in patients with multi-drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) in the North-West Province.MethodsA retrospective cohort study, abstracting patient demographic and clinical data, laboratory results, dates of sputum testing and sputum culture conversion results, from medical records of 526 MDR-TB and 47 XDR-TB patients started on TB treatment between 01 January 2012 and 31 December 2014. Predictors of TTSCC were determined by Cox proportional hazards regression.ResultsThe median age was 38 years (interquartile range 31–47) with 64% being male. Overall, 79% (449) were Human Immunodeficiency Virus (HIV)-infected. The median TTSCC was 56.5 days and 162.5 days for MDR-TB and XDR-TB patients, respectively. In the multivariate analysis, age [hazard ratio (HR): 0.89, 95% confidence interval (CI): 0.96–0.99], being underweight (HR: 0.631.61, 95% CI: 0.451.03–0.882.51), Acid Fast Bacilli (AFB) positivity (HR: 0.72, 95 % CI: 0.51–1.01) and having XDR-TB (HR: 0.36. 95% CI: 0.19–0.69) were predictive of longer TTSCC.ConclusionPredictors of TTSC allow for MDR-TB- and XDR-TB-diagnosed patients to be identified early for effective management. Those with risk factors for delayed sputum culture conversion which are being underweight and having XDR-TB should be monitored carefully during treatment so that they can achieve sputum culture conversion early.

Efficacy and safety of delamanid in combination with an optimised background regimen for treatment of multidrug-resistant tuberculosis: a multicentre, randomised, double-blind, placebo-controlled, parallel group phase 3 trial

Delamanid is one of two recently approved drugs for the treatment of multidrug-resistant tuberculosis. We aimed to evaluate the safety and efficacy of delamanid in the first 6 months of treatment. This randomised, double-blind, placebo-controlled, phase 3 trial was done at 17 sites in seven countries (Estonia, Latvia, Lithuania, Moldova, Peru, the Philippines, and South Africa). We enrolled eligible adults (>18 years) with pulmonary multidrug-resistant tuberculosis to receive, in combination with an optimised background regimen developed according to WHO and national guidelines, either oral delamanid (100 mg twice daily) for 2 months followed by 200 mg once daily for 4 months or placebo (same regimen). Patients were centrally randomised (2:1) and stratified by risk category for delayed sputum culture conversion. Primary outcomes were the time to sputum culture conversion over 6 months and the difference in the distribution of time to sputum culture conversion over 6 months between the two groups, as assessed in the modified intention-to-treat population. The trial is registered at ClinicalTrials.gov, number NCT01424670. Between Sept 2, 2011, and Nov 27, 2013, we screened 714 patients, of whom 511 were randomly assigned (341 to delamanid plus optimised background regimen [delamanid group] and 170 to placebo plus optimised background regimen [placebo group]) and formed the safety analysis population. 327 patients were culture-positive for multidrug-resistant tuberculosis at baseline and comprised the efficacy analysis population (226 in the delamanid group and 101 in the placebo group). Median time to sputum culture conversion did not differ between the two groups (p=0·0562; modified Peto-Peto), with 51 days (IQR 29-98) in the delamanid group and 57 days (43-85) in the placebo group; the hazard ratio was 1·17 (95% CI 0·91-1·51, p=0·2157). 501 (98·0%) of 511 patients had at least one treatment-emergent adverse event. 136 (26·6%) of 511 patients had at least one serious treatment-emergent adverse event; the incidence was similar between treatment groups (89 [26·1%] of 341 patients for delamanid and 47 [27·6%] of 170 for placebo). Deaths related to treatment-emergent adverse events were similar between groups (15 [4·4%] of 341 for delamanid and six [3·5%] of 170 for placebo). No deaths were considered to be related to delamanid. The reduction in median time to sputum culture conversion over 6 months was not significant in the primary analysis. Delamanid was well tolerated with a highly characterised safety profile. Further evaluation of delamanid is needed to determine its role in a rapidly evolving standard of care. Otsuka Pharmaceutical.

Impact of Diabetes Mellitus on the Presentation and Response to Treatment of Adults With Pulmonary Tuberculosis in Qatar.

BackgroundPersons with diabetes mellitus (DM) have a 3-fold increased risk of tuberculosis (TB). Atypical radiographic findings and differences in bacteriologic response during anti-TB treatment have been reported in earlier studies; however, the findings have varied. We evaluated the effect of DM on manifestations and response to treatment in adults with pulmonary TB in Qatar.MethodsThe impact of DM on the clinical and radiographic presentations of pulmonary TB and bacteriologic response during anti-TB treatment was evaluated between January 2007 and December 2011, comparing patients with and without DM. This is a retrospective unmatched case-control study conducted at a large national hospital. Cases and controls were randomly selected from patients diagnosed with pulmonary TB over a 5-year period. Sputum culture conversion was assessed after 2 months of anti-TB treatment.ResultsClinical symptoms were similar between patients with and without DM. Patients with DM had a higher initial sputum acid-fast bacillus (AFB) smear grade and were less likely to have cavitary lesions on initial chest radiographs than patients without DM. Of 134 adults with DM and TB, 71 (53%) remained sputum culture positive after 2 months of anti-TB treatment, compared with 36 (27%) patients without DM.ConclusionsDM was associated with atypical radiographic findings and delayed sputum culture conversion at 2 months in adults with pulmonary TB in Qatar. Increased health education of patients with DM about symptoms of TB, low thresholds for evaluation for active TB, and close monitoring of bacteriologic response to treatment among patients with TB and DM are warranted.

Communicable and non-communicable diseases: connections, synergies and benefits of integrating care.

Communicable and non-communicable diseases: connections, synergies and benefits of integrating care.

Improvement in plasma drug activity during the early treatment interval among Tanzanian patients with multidrug-resistant tuberculosis.

BackgroundIndividual pharmacokinetic variability may be common in patients treated for multidrug-resistant tuberculosis (MDR-TB) but data are sparse from resource-limited settings and across the early treatment interval.MethodsPlasma drug activity, as measured by the TB Drug Activity (TDA) assay at 2 and 4 weeks of treatment with a standardized MDR-TB regimen was performed in patients with pulmonary MDR-TB from Tanzania. TDA values were correlated with measures of early treatment outcome including every two week collection of sputum for time-to-positivity (TTP) in liquid culture from the MGIT 960 automated system. Patients were evaluated at 24 weeks and those surviving without delayed sputum culture conversion (>8 weeks), culture reversion after previously negative, or weight loss were defined as having a favorable outcome.ResultsTwenty-five patients were enrolled with a mean age of 37 ±12 years. All were culture positive from the pretreatment sputum sample with a mean TTP in MGIT of 257 ±134 hours, and the median time to culture conversion on treatment was 6 weeks. Twenty patients (80%) had an increase in TDA, with the overall mean TDA at 2 weeks of 2.1 ±0.7 compared to 2.4 ±0.8 at 4 weeks (p = 0.005). At 2 weeks 13 subjects (52%) had a TDA value > 2-log killing against their own M. tuberculosis isolate compared to 17 subjects (68%) at 4 weeks (McNemar’s exact test p = 0.29). An interim treatment outcome was able to be determined in 23 patients (92%), of whom 7 had a poor outcome (30%). An increase in TDA from week 2 to week 4 was associated with favorable outcome, [unadjusted OR = 20.0, 95% CI: 1.61–247.98, exact p = 0.017 and adjusted OR = 19.33, 95% CI: 1.55–241.5, exact p = 0.023].ConclusionsThe majority of patients with MDR-TB in Tanzania had an increase in plasma drug activity from week 2 to week 4 of treatment as measured by the TDA assay. Understanding the etiology and full impact of this dynamic may inform therapeutic intervention.

Tuberculosis, Pulmonary Cavitation, and Matrix Metalloproteinases

Tuberculosis (TB), a chronic infectious disease of global importance, is facing the emergence of drug-resistant strains with few new drugs to treat the infection. Pulmonary cavitation, the hallmark of established disease, is associated with very high bacillary burden. Cavitation may lead to delayed sputum culture conversion, emergence of drug resistance, and transmission of the infection. The host immunological reaction to Mycobacterium tuberculosis is implicated in driving the development of TB cavities. TB is characterized by a matrix-degrading phenotype in which the activity of proteolytic matrix metalloproteinases (MMPs) is relatively unopposed by the specific tissue inhibitors of metalloproteinases. Proteases, in particular MMPs, secreted from monocyte-derived cells, neutrophils, and stromal cells, are involved in both cell recruitment and tissue damage and may cause cavitation. MMP activity is augmented by proinflammatory chemokines and cytokines, is tightly regulated by complex signaling paths, and causes matrix destruction. MMP concentrations are elevated in human TB and are closely associated with clinical and radiological markers of lung tissue destruction. Immunomodulatory therapies targeting MMPs in preclinical and clinical trials are potential adjuncts to TB treatment. Strategies targeting patients with cavitary TB have the potential to improve cure rates and reduce disease transmission.

Smoking and 2-month culture conversion during anti-tuberculosis treatment

To investigate risk factors for delayed sputum culture conversion to negative during anti-tuberculosis treatment, with an emphasis on smoking. Nested case-control study of adults with non-cavitary, culture-confirmed pulmonary tuberculosis (TB) participating in an anti-tuberculosis treatment trial in Brazil. A case of delayed culture conversion was a patient who remained culture-positive after 2 months of treatment. Odds ratios with 95% confidence intervals were calculated. Fifty-three cases and 240 control patients were analyzed. Smokers had three-fold greater odds of remaining culture-positive after 2 months of treatment (P = 0.007) than non-smokers, while smokers and ex-smokers who smoked >20 cigarettes a day had two-fold greater odds of remaining culture-positive after 2 months of treatment (P = 0.045). Cigarette smoking adversely affects culture conversion during anti-tuberculosis treatment. Support for smoking cessation should be considered to improve outcomes in TB control programs.

Shorter treatment duration for selected patients with multidrug-resistant tuberculosis

To the Editors: Tuberculosis (TB) is still an infectious disease of public health importance today [1]. Of particular concern is the occurrence of multidrug-resistant (MDR)-TB with resistance to at least isoniazid and rifampicin, and extensively drug-resistant (XDR)-TB with additional resistance to any fluoroquinolone and at least one of the second-line injectable drugs, including kanamycin, amikacin and capreomycin. MDR- and XDR-TB need prolonged treatment duration, from 18 to 24 months after sputum culture conversion, as recommended by the World Health Organization (WHO) [2]. A prolonged duration of treatment may lead to poor adherence, higher cost and undue toxicity. In our previous studies, we found that the use of ofloxacin/levofloxacin-containing regimens had a favourable effect on MDR-TB outcome [3, 4]. Our studies also suggested that shorter treatment duration (mean duration 14 months) might be feasible in selected MDR-TB patients. Based on this finding, the treatment duration of selected MDR-TB patients under programmatic management in Hong Kong was changed from the rigid enforcement of ≥18 months after sputum conversion to an individualised duration tailored by the physician's judgement. The determinants favouring longer treatment included extensive drug resistance, delayed sputum culture conversion, greater extent of radiographic disease (including cavities), presence of diabetes or silicosis, and extrapulmonary disease. Out of these factors, the extent of drug resistance was the most important. Ofloxacin-resistant MDR-TB was arbitrarily given a prolonged treatment based on our previous studies [3, 4]. Despite a relatively high TB incidence (76 cases per 100,000 population in 2009), both TB and MDR-TB rates are actually decreasing under the local TB control programme [5]. Therefore, we conducted a retrospective evaluation of the long-term outcomes of our MDR-TB patients, focusing on the factors affecting the efficacy and relapse rate of a shorter treatment duration. …

Geographic Differences in Time to Culture Conversion in Liquid Media: Tuberculosis Trials Consortium Study 28. Culture Conversion Is Delayed in Africa

BackgroundTuberculosis Trials Consortium Study 28, was a double blind, randomized, placebo-controlled, phase 2 clinical trial examining smear positive pulmonary Mycobacterium tuberculosis. Over the course of intensive phase therapy, patients from African sites had substantially delayed and lower rates of culture conversion to negative in liquid media compared to non-African patients. We explored potential explanations of this finding.MethodsIn TBTC Study 28, protocol-correct patients (n = 328) provided spot sputum specimens for M. tuberculosis culture in liquid media, at baseline and weeks 2, 4, 6 and 8 of study therapy. We compared sputum culture conversion for African and non-African patients stratified by four baseline measures of disease severity: AFB smear quantification, extent of disease on chest radiograph, cavity size and the number of days to detection of M. tuberculosis in liquid media using the Kaplan-Meier product-limit method. We evaluated specimen processing and culture procedures used at 29 study laboratories serving 27 sites.ResultsAfrican TB patients had more extensive disease at enrollment than non-African patients. However, African patients with the least disease by the 4 measures of disease severity had conversion rates on liquid media that were substantially lower than conversion rates in non-African patients with the greatest extent of disease. HIV infection, smoking and diabetes did not explain delayed conversion in Africa. Some inter-site variation in laboratory processing and culture procedures within accepted practice for clinical diagnostic laboratories was found.ConclusionsCompared with patients from non-African sites, African patients being treated for TB had delayed sputum culture conversion and lower sputum conversion rates in liquid media that were not explained by baseline severity of disease, HIV status, age, smoking, diabetes or race. Further investigation is warranted into whether modest variation in laboratory processes substantially influences the efficacy outcomes of phase 2 TB treatment trials or if other factors (e.g., nutrition, host response) are involved.Trial RegistrationClinicalTrials.gov NCT00144417