Baseline Predictors of Sputum Culture Conversion in Pulmonary Tuberculosis: Importance of Cavities, Smoking, Time to Detection and W-Beijing Genotype

Abstract

BackgroundTime to detection (TTD) on automated liquid mycobacterial cultures is an emerging biomarker of tuberculosis outcomes. The M. tuberculosis W-Beijing genotype is spreading globally, indicating a selective advantage. There is a paucity of data on the association between baseline TTD and W-Beijing genotype and tuberculosis outcomes.AimTo assess baseline predictors of failure of sputum culture conversion, within the first 2 months of antitubercular therapy, in participants with pulmonary tuberculosis.DesignBetween May 2005 and August 2008 we conducted a prospective cohort study of time to sputum culture conversion in ambulatory participants with first episodes of smear and culture positive pulmonary tuberculosis attending two primary care clinics in Cape Town, South Africa. Rifampicin resistance (diagnosed on phenotypic susceptibility testing) was an exclusion criterion. Sputum was collected weekly for 8 weeks for mycobacterial culture on liquid media (BACTEC MGIT 960). Due to missing data, multiple imputation was performed. Time to sputum culture conversion was analysed using a Cox-proportional hazards model. Bayesian model averaging determined the posterior effect probability for each variable.Results113 participants were enrolled (30.1% female, 10.5% HIV-infected, 44.2% W-Beijing genotype, and 89% cavities). On Kaplan Meier analysis 50.4% of participants underwent sputum culture conversion by 8 weeks. The following baseline factors were associated with slower sputum culture conversion: TTD (adjusted hazard ratio (aHR) = 1.11, 95% CI 1.02; 1.2), lung cavities (aHR = 0.13, 95% CI 0.02; 0.95), ever smoking (aHR = 0.32, 95% CI 0.1; 1.02) and the W-Beijing genotype (aHR = 0.51, 95% CI 0.25; 1.07). On Bayesian model averaging, posterior probability effects were strong for TTD, lung cavitation and smoking and moderate for W-Beijing genotype.ConclusionWe found that baseline TTD, smoking, cavities and W-Beijing genotype were associated with delayed 2 month sputum culture. Larger studies are needed to confirm the relationship between the W-Beijing genotype and sputum culture conversion.

A Time-to-Event Pharmacodynamic Model Describing Treatment Response in Patients with Pulmonary Tuberculosis Using Days to Positivity in Automated Liquid Mycobacterial Culture

“…Our finding that patients with lung cavitation have larger amounts of bacteria that are killed slowly is in accord with previous studies that showed lower 2-month sputum conversion rates (15,25) and a shorter time to detection (or days to positivity) (26,27) for patients with lung cavitation. The small number of patients with HIV infection may explain our failure to identify HIV infection as a significant covariate.…”

“…Indeed, days to a positive MGIT result have been found to be correlated with CFU counts (12), although one study found only a weak correlation between the two (13). Days to culture positivity at baseline have also been shown to predict sputum culture conversion at 8 weeks (14,15), which is a widely accepted surrogate marker of tuberculosis cure (16).…”

Factors associated with sputum conversion in a multinational population of tuberculosis patients

“…The radiological finding of cavitation is observed in severe cases of the disease and is a wellknown factor associated with delayed conversion (Nakamura et al, 2014;Visser et al, 2012;Magee et al, 2014). It is important to consider in the study the following issues.…”

“…The conversion time has been related with multiple factors including nutritional factors such as anemia, magnesium level, and body mass index (Bhargava et al, 2013;Putri et al, 2014;Agrawal, 2017), history of diabetes mellitus and poor metabolic control (Mi et al, 2013;Nakamura et al, 2014;Sharif, 2015), bacillary load in the diagnosis (D'Souza et al, 2018;Kanda et al, 2015;Gunda, 2017), diagnosis delay and radiological lesions suggestive of extensive damage or cavitation (Mi et al, 2013;Nakamura et al, 2014;Unsematham and Kateruttanakul, 2013;Visser et al, 2012) and drug resistance (Kim et al, 2016;Holtz et al, 2006;Kurbatova et al, 2012). A previously published paper identifies the bacillary load in the diagnosis as the main factor related with sputum conversion in patients attended to in a community hospital in Qatar, but the study is limited by the number of patients studied (64 patients) (Guanche et al, 2016).…”

Short-Term Storage Does Not Affect the Quantitative Yield of Mycobacterium tuberculosis in Sputum in Early-Bactericidal-Activity Studies

“…Beyond its clinical purpose, sputum culture can quantify the viable M. tuberculosis sputum load expressed as CFU per ml of sputum counted on agar plates or as times to culture positivity (TTP) of a volume of decontaminated sputum inoculated in liquid mycobacterial culture (8). High sputum mycobacterial loads at diagnosis have been associated with treatment failure and recurrence (9,10). Early-bactericidal-activity (EBA) studies are considered a key step in the clinical evaluation of individual antituberculosis agents and new combination regimens and describe the change in log CFU and TTP on consecutive sputum samples collected over up to 14 treatment days (2,11).…”