Dennis Kunimoto

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a serious and devastating infectious disease worldwide. Approximately a quarter of the world population harbors latent Mtb infection without pathological consequences. Exposure of immunocompetent healthy individuals with Mtb does not result in active disease in more than 90% individuals, suggesting a defining role of host immunity to prevent and/or clear early infection. However, innate immune stimulation strategies have been relatively underexplored for the treatment of tuberculosis. In this study, we used cell culture and mouse models to examine the role of a heat-killed form of a non-pathogenic microbe, Caulobacter crescentus (HKCC), in inducing innate immunity and limiting Mtb infection. We also examined the added benefits of a distinct chemo-immunotherapeutic strategy that incorporates concurrent treatments with low doses of a first-line drug isoniazid and HKCC. This therapeutic approach resulted in highly significant reductions in disseminated Mtb in the lungs, liver, and spleen of mice compared to either agent alone. Our studies demonstrate the potential of a novel innate immunotherapeutic strategy with or without antimycobacterial drugs in controlling Mtb infection in mice and open new avenues for the treatment of tuberculosis in humans.

We evaluated the anti-mycobacterial effect of a flavonoid 5,7-dihydroxy-2-(4-hydroxyphenyl) 4H-chromen-4-one (1) and two pyrimidines, 4-hydroxy-2-dimethylamino-5-nitroso-6-aminopyrimidine (2) and 2-chloro-5-n-nonylpyrimidine (3) in vitro against Mycobacterium tuberculosis (M. tuberculosis, H37Ra) and Mycobacterium avium (M. avium), using a Microplate Alamar Blue Assay (MABA). The effects of the compounds 1–3 in combination with first- and second-line anti-TB drugs isoniazid, rifampicin, cycloserine, and clarithromycin on the growth of M. tuberculosis and M. avium were also evaluated in in vitro assays. As a single agent, compounds 1 and 2 exhibited modest activity while compound 3 was the most effective against M. tuberculosis and M. avium. When compounds 1–3 were evaluated at lower than 50% of their inhibitory concentrations in a two-drug combination with isoniazid or rifampicin, they showed additive to synergistic interactions. This inhibitory effect was improved when each of the three compounds was tested together in a three-drug combination with two of the first-line anti-TB drugs. Compounds 1–3 also demonstrated strong synergistic interaction in combination with cycloserine and clarithromycin in inhibiting the growth of M. tuberculosis and M. avium, respectively. This study demonstrated that compounds 1–3 have potential to be developed as effective anti-TB agents with combined use.

Erythema induratum of Bazin (EIB) – nodular vasculitis associated with Mycobacterium tuberculosis (TB) – and Tuberculosis-Associated Ocular Inflammation (TB-AOI) represent uncommon manifestations of TB. There is limited data and a lack of diagnostic and treatment standards for these conditions. Eleven-year retrospective review of EIB and TB-AOI cases managed in a provincial TB program with prospective phone-based follow-up of anti-tubercular therapy (ATT) recipients. Presumptive TB-AOI and EIB diagnoses were determined by ophthalmologist or dermatologist assessments correlated with positive tuberculin skin test and/or QuantiFERON-TB Gold, along with pathologic criteria in EIB cases. Of 21 EIB and 20 TB-AOI cases that received ATT, 13 and 11, respectively, were reached for follow-up. The majority of EIB and TB-AOI cases were female and immigrated from TB high-burden countries. Median durations of pre-diagnosis symptoms were 2 and 0.8 years (IQR 2.5 & 1.1) for EIB and TB-AOI cases, respectively. Overall, 14 different ATT regimens were used for a median duration of 6 months (range 5–9). ATT related adverse events resulting in treatment discontinuation occurred in 14% of EIB and 10% of TB-AOI cases. On last follow-up, 76% of EIB and 42% of TB-AOI had improvement or resolution of disease. EIB and TB-AOI were uncommon presentations receiving variable therapy. While treatment response was modest for EIB cases, TB-AOI cases had sub-optimal treatment outcomes. The unique diagnostic and management challenges presented by these conditions in TB low-incidence settings highlight a need for improved treatment candidate selection, therapy standardization, and cross-specialty medical collaboration.

Tuberculosis remains a major human health threat that infects one in three individuals worldwide. Infection with Mycobacterium tuberculosis is a standoff between host and bacteria in the formation of a granuloma. This review will introduce a variety of bacterial and host factors that impact individual granuloma fates. The authors describe advances in the development of in vitro granuloma models, current evidence surrounding infection and granuloma development, and the applicability of existing in vitro models in the study of human disease. In vitro models of infection help improve our understanding of pathophysiology and allow for the discovery of other potential models of study.

BACKGROUND: In Alberta provincial tuberculosis (TB) clinics, serum drug concentrations (SDCs) are measured in patients with human immunodeficiency virus, diabetes mellitus or at extremes of weight, or showing slow clinical response to treatment, to guide treatment. DESIGN: A retrospective review was performed of TB cases in Northern Alberta with SDCs measured from 1998 to 2013. Adequacy of SDC was based on the maximum concentration (C_max) achieved in serum, with rifampicin (RMP) values P = 0.0084). A similar trend was seen in the cohort with inadequate concentrations of RMP (39% vs. 21%, P = 0.0725). CONCLUSIONS: Among our study population, low SDCs of INH and, to a lesser extent, RMP, appear to be associated with reduced sputum culture conversion after 2 months of treatment.

OBJECTIVE: To study the laboratory diagnosis of tuberculosis (TB), and relate the findings to its epidemiology in Central Saudi Arabia. METHODS: This retrospective study was carried out at the Department of Pathology/Microbiology, King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia between January 2003 and December 2010. Data were retrieved from the hospital information system on laboratory findings. After adjustment, 9,405 specimens were studied. The specimens were stained by Ziehl-Neelsen (ZN), auramine-rhodamine, and cultured in Bactec alert 960, and Lowenstein-Jensen media. Mycobacterium tuberculosis (M. tuberculosis) complex and non-tuberculous mycobacteria were differentiated by ProbTec system and p-nitrobenzoate medium. The BACTEC MGIT 960 SIRE kit was used for susceptibility testing. RESULTS: A total of 568 (6%) specimens grew M. tuberculosis complex, and 87% were from Saudis with an incidence rate of 55.6/100,000 of TB. Time to positive growth in the Bactec liquid medium was directly related to the acid fast bacilli smear load. Most of the positive patients were from the 18-35 years age group. The percentage of multidrug resistance was 0.7%. CONCLUSION: Most patients (87%) were Saudis showing an incident rate of 55.6/100,000. An increase of TB cases was noticed in the 18-35 age group. Resistance to isoniazid was 10.6%, 1% to Rifampicin, 2-8% to Ethambutol, and streptomycin was 6%.

A limited number of studies have been published that examine treatment completion rates and interventions used to increase treatment completion within an inner‐city population. The purpose of the present study was to determine the rate of latent tuberculosis infection (LTBI) treatment completion in an inner‐city population in Edmonton, Alberta, and to identify factors that correlated with treatment completion. A retrospective chart review was conducted involving patients who started LTBI treatment between January 1, 2005 and December 31, 2010 in Edmonton’s inner city. A total of 77 patients started treatment and 57 (74%) patients completed LTBI treatment. Homelessness was the only variable that was significantly associated with incomplete treatment (OR 8.0 [95% CI 1.4 to 45.6]) and it remained significant when controlling for drug use (adjusted OR 6.5 [95% CI 1.1 to 38.8]). While the present study demonstrated treatment completion rates comparable with or better than those described in the general population, it highlighted the need for continued emphasis on interventions aimed at improving outcomes within homeless populations.

Beijing strains are speculated to have a selective advantage over other Mycobacterium tuberculosis strains because of increased transmissibility and virulence. In Alberta, a province of Canada that receives a large number of immigrants, we conducted a population-based study to determine whether Beijing strains were associated with increased transmission leading to disease compared with non-Beijing strains. Beijing strains accounted for 258 (19%) of 1,379 pulmonary tuberculosis cases in 1991–2007; overall, 21% of Beijing cases and 37% of non-Beijing cases were associated with transmission clusters. Beijing index cases had significantly fewer secondary cases within 2 years than did non-Beijing cases, but this difference disappeared after adjustment for demographic characteristics, infectiousness, and M. tuberculosis lineage. In a province that has effective tuberculosis control, transmission of Beijing strains posed no more of a public health threat than did non-Beijing strains.