MDR-TB Infection Research Articles

P27 A challenging case of MDR TB infection following a holiday in India

Abstract Background TB is an infection caused by Mycobacterium tuberculosis. MDR TB is caused by strains of M. tuberculosis resistant to isoniazid and rifampicin.1 XDR TB refers to strains resistant to one or more second-line injectable drugs and any fluoroquinolone, whereas pre-XDR TB refers to strains resistant to either a second-line injectable drug or a fluoroquinolone.1 The implications of MDR TB include prolonged treatment requirements, increased morbidity and mortality, and risk of onward transmission to others.2 Case history A woman in her forties with poorly controlled diabetes was admitted to hospital three times in 3 months with respiratory symptoms and pulmonary consolidation. She was treated for recurrent community acquired pneumonia (CAP). On her fourth admission, sputum and stool microscopy detected acid fast bacilli (AFB) and PCR using Xpert MTB/RIF (Cepheid® GeneXpert® systems) confirmed M. tuberculosis with resistance to rifampicin. She had no known TB contacts but had had a 5 week holiday in Goa, India, 2 years prior. Management Phenotypic testing confirmed the M. tuberculosis isolate was resistant to rifampicin, isoniazid and aminoglycosides but susceptible to fluoroquinolones. Following discussion with the British Thoracic Society (BTS) MDR TB advice service she was empirically initiated on linezolid 600 mg BD, bedaquiline 200 mg OD, levofloxacin 1000 mg OD, clofazimine 200 mg OD, cycloserine 250 mg BD, pyrazinamide 2000mg OD, ethambutol 1000 mg OD and pyridoxine 10 mg OD. The isolate was later identified as of New Delhi Central Asia lineage, with additional resistance to pyrazinamide (which was then stopped). This is the first case of this lineage reported in the UK. Therapeutic drug monitoring of linezolid, levofloxacin and cycloserine was performed. Cycloserine was changed to terizidone 250 mg BD after 1 month, due to a national supply issue. She suffered from medication side effects including diarrhoea, nausea, derangement in liver functions tests, worsening of pre-existing peripheral neuropathy, myalgia, hypercalcaemia, itch, renal tubular acidosis and acute kidney injury. These were managed pharmacologically and through cessation of terizidone after 2 months and dose reduction, then cessation, of linezolid after 4 months. Outcomes Clinically she improved and repeat imaging showed gradual resolution of consolidation and C-reactive protein levels decreased. She is 10 months into an anticipated 18–24 month treatment regimen, recommended due to her extensive pulmonary disease. Medication side effects are currently well controlled. The infection prevention and control team screened all contacts from this and prior admissions, with no further cases identified. Conclusions This case highlights the importance of suspicion of TB in patients with chronic cough and radiological changes, particularly with risk factors for TB such as relevant travel history and diabetes. MDR TB infection has significant consequences and treatment remains challenging with the burden of multiple drugs, and their side effects, leading to further patient morbidity.

Low serum vitamin D in North Indian multi-drug resistant pulmonary tuberculosis patients: the role of diet and sunlight

Background: Tuberculosis (TB) and malnutrition are major global health problems, with multidrug-resistant (MDR) TB complicating international efforts. The role of vitamin D in susceptibility to and as an adjunctive treatment for TB is being studied extensively, although no study has included MDR-TB patients in context to dietary profile with vitamin D levels and sunlight exposure.Objective: This study aimed to estimate vitamin D serum levels and examine their association with dietary intake of vitamin D and sun exposure in patients with MDR-TB.Methods: North Indian participants were enrolled in three groups: MDR-TB, drug-susceptible pulmonary TB (DS-PTB), and healthy controls. All consenting participants underwent the estimation of macro- and micronutrient intake and sunlight exposure using structured questionnaires. Serum biochemistry, including 25-hydroxyvitamin D and calcium levels, was measured, and the correlation between variables was determined.Results: 747 participants were enrolled. Significant differences among the three groups were found in mean serum 25-hydroxyvitamin D levels, body mass index, macronutrient intake, dietary vitamin D and calcium content, and sun exposure index (SEI). All except sun exposure (SEI was highest in DS-PTB patients) were found to follow the trend: MDR-TB < DS-PTB < healthy controls. The mean serum vitamin D levels of all groups were deficient and correlated positively with dietary intake and SEI.Conclusion: In this study’s we found significant association of serum vitamin D concentrations, dietary intake and sunlight exposure in MDR-TB, DS-PTB patients and healthy controls. Dietary intake may be more important than sun exposure in determining serum levels. However, the significance of this finding is uncertain. Further studies are required to confirm the association, direction, and potential for vitamin D supplementation to treat or prevent MDR-TB infection.

Resistance patterns among drug-resistant tuberculosis patients and trends-over-time analysis of national surveillance data in Gabon, Central Africa

ObjectiveRoutinely generated surveillance data are important for monitoring the effectiveness of MDR-TB control strategies. Incidence of rifampicin-resistant tuberculosis (RR-TB) is a key indicator for monitoring MDR-TB.MethodsIn a longitudinal nationwide retrospective study, 8 years (2014–2021) of sputum samples from presumptively drug-resistant tuberculosis patients from all regions of Gabon were referred to the national tuberculosis reference laboratory. Samples were analysed using GeneXpert MTB/RIF and Genotype MTBDRsl version 2/Line Probe Assay.ResultsOf 3057 sputum samples from presumptive tuberculosis patients, both from local hospital and from referral patients, 334 were RR-TB. The median patient age was 33 years (interquartile range 26–43); one third was newly diagnosed drug-resistant tuberculosis patients; one-third was HIV-positive. The proportion of men with RR-TB was significantly higher than that of women (55% vs 45%; p < 0.0001). Patients aged 25–35 years were most affected (32%; 108/334). The cumulative incidence of RR-TB was 17 (95% CI 15–19)/100,000 population over 8 years. The highest incidences were observed in 2020 and 2021. A total of 281 samples were analysed for second-line drug resistance. The proportions of study participants with MDR-TB, pre-XDR-TB and XDR-TB were 90.7% (255/281), 9% (25/281) and 0.3% (1/281), respectively. The most-common mutations in fluoroquinolones resistance isolates was gyrA double mutation gyrA MUT3B and MUT3C (23%; 4/17). Most (64%; 6/8) second-line injectable drugs resistance isolates were characterised by missing both rrs WT2 and MUT2 banding.ConclusionThe increasing incidence of MDR-TB infection in Gabon is alarming. It is highest in the 25–35 years age category. The incidence of MDR-TB infection in treatment-naïve patients calls for case finding and contact tracing strategy improvement.

Correlation expression Toll-like receptor 4 with multidrugs resistant tuberculosis in diabetes mellitus condition

BackgroundToll-like receptor (TLR) are ligand homologous protein in the APC cell membrane that has functions as a receptor to triger leukocytes and innate immune responses. When there is a Microbacterium tuberculosis (MTB) infection enters from droplets to the lungs, the alveolar macrophages perform a phagocytic function. The interaction between M. tuberculosis and the TLR macrophage receptors produces chemokines which induce migration of monocytes and dendrite cells for destruction. Diabetes militus (DM) has become risk factor for developing tuberculosis. DM condition will reduce immunity and the ability of immune cell phagocytes bactery and triger severe infections. The consequences of more severe infection and metabolic disorders that occur make a person more likely to experience Multidrugs resistant MTB. Not much data that reports on the expression of TLR4 as a ligand that triggers an immune response in conditions of MDR and DM. We try to find out correlation between TLR-4 in MDR MTB, diabetes and level of MTB bacteria in experimental animals. MethodsWe conducted an experimental study on 30 experimental mice weighing 25 grams consisting of negative control grub, infected with MTB, infected with MDR MTB, negative control diabetes, MTB DM, MDR MTB DM. DM animals were induced by streptozosin to experience DM, then in the treatment of infection, intraperitoneal MTB and MDR MTB bacterial injections were given. Termination was carried out on day 14. We count number of bacteria level in the lungs and perform evaluation TLR4 from blood sampel. ResultsThe negative control group had mean TLR value of 1.47 (± 0.46) while the MTB group showed an increase in TLR 9.22 (± 0.39) followed by MDR MTB 9.50 (± 0.29), DM negative control 9, 21 (± 0.24) and more increasing in conditions of DM MTB 13.36 (± 0.32) and DM MDR MTB 13.35 (± 0.34). ANOVA analysis showed a significant difference (P = 0.00). pearson correlation analysis find strong correlation TLR4 in MTB and MDR MTB with diabetes. Conclusionthere were a significant difference level TLR4 between MTB and MDR TB infection with diabetes. higher TLR4 level higher in DM MTB, DM MDR MTB. TLR 4 strong correlates with an increase in the number of MTB bacteria.

Genetic Diversity and Drug Susceptibility Profiles of Multidrug-Resistant Tuberculosis Strains in Southeast China.

BackgroundMultidrug-resistant tuberculosis (MDR-TB) isolates collected from Fujian province, China were assessed for molecular epidemiological characteristics. Analysis of isolate genotype profiles revealed that the Beijing genotype was associated with especially high drug resistance and community transmission rates.MethodsA total of 119 MDR-TB isolates obtained from TB patients in Fujian province were typed using 24–locus mycobacterium interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) typing and spoligotyping. Drug susceptibility testing of all isolates was conducted using the L-J proportion method, with pyrazinamide (PZA) susceptibility testing conducted using the Mycobacterium Growth Indicator Tube System 960 (MGIT 960).ResultsWe obtained 26 spoligotypes for the 119 isolates examined in this work. Spoligotyping results revealed that 80 (67.2%) isolates possessed the Beijing family genotypic profiles. Patients aged 25–44 years and ≥45 years were most likely to be infected by non-Beijing genotypes. The percentage of clustered cases with both PZA and ofloxacin (OFLX) resistance was significantly greater than the corresponding percentage for non-clustered cases. Of 44 PZA-resistant isolates, 28 isolates (63.6%) harbored pncA mutations, while pncA mutations were only detected in 7 (9.3%) PZA-susceptible isolates.ConclusionOur data demonstrate that the Beijing genotype is the dominant lineage among MDR-TB strains circulating in Fujian. Thus, MDR-TB infections occurring within this province are not likely associated with recent transmission events. PZA and fluoroquinolone resistance profiles were found to be associated with clustered isolates. Mutation of pncA is the main driver of MDR-TB PZA resistance and is associated with mutation sites scattered throughout the entire pncA protein-coding region.

Prediction of Multidrug-Resistant Tuberculosis Using Machine Learning Algorithms in SWAT, Pakistan.

In this paper, we have focused on machine learning (ML) feature selection (FS) algorithms for identifying and diagnosing multidrug-resistant (MDR) tuberculosis (TB). MDR-TB is a universal public health problem, and its early detection has been one of the burning issues. The present study has been conducted in the Malakand Division of Khyber Pakhtunkhwa, Pakistan, to further add to the knowledge on the disease and to deal with the issues of identification and early detection of MDR-TB by ML algorithms. These models also identify the most important factors causing MDR-TB infection whose study gives additional insights into the matter. ML algorithms such as random forest, k-nearest neighbors, support vector machine, logistic regression, leaset absolute shrinkage and selection operator (LASSO), artificial neural networks (ANNs), and decision trees are applied to analyse the case-control dataset. This study reveals that close contacts of MDR-TB patients, smoking, depression, previous TB history, improper treatment, and interruption in first-line TB treatment have a great impact on the status of MDR. Accordingly, weight loss, chest pain, hemoptysis, and fatigue are important symptoms. Based on accuracy, sensitivity, and specificity, SVM and RF are the suggested models to be used for patients' classifications.

Lung Tuberculosis with Multi Drug Resistant Risk in Tertiary Hospital in Middle Java

World TB report from World Health Organization (WHO) in 2017 informed that Indonesia was second country with TB case. Multi Drug Resistance pulmonary infection’s case in Indonesia were 12.000. Kariadi hospital is one of tertiary hospital for pulmonary MDR-TB treatment but, there is no study about risk factor of it yet, so it needed to find risk factors of MDR-TB pulmonary infection in Kariadi hospital. Cross Sectional design using secondary data from Medical Record from January 1st - December 31, 2017 with result of Mycobacterium tuberculosis on GeneXpert sputum examination. Bivariate analysis with Chi square test and multivariate analysis was done by multiple logistic regression. The p value was considered significant if &lt;0.05, all analyzes were 2-tailed. Totally 110 patients were obtained during periode, 55 samples for case and 55 samples for control. There were correlation between smoking habit OR = 3,1 (CI 95% 1,1-8,7), malnutrition OR = 2,9 (CI 95% 1,3-6,3), contact with patient with MDR pulmonary TB infection OR = 12,0 (CI 95% 1,5-97,3), past treatment OR = 81,7(CI 95% 23,4-285,2) and ≥6months past treatment OR = 94,5 (CI 95% 12,1-736,2. Risk factor that could influence together were contact with patient with MDR pulmonary TB infection OR = 34,5 (CI 95% 2,6-464,5), past treatment OR = 39,4 (CI 95% 8,3-186,3) and ≥ 6months past treatment OR = 12,4 (CI 95% 1,3-117,7). Risk factors for the incidence of pulmonary MDR TB infection are past contact with patient with MDR pulmonary TB infection, past treatment and ≥ 6months past treatment.

Recurrences of multidrug-resistant tuberculosis: Strains involved, within-host diversity, and fine-tuned allocation of reinfections.

Recurrent tuberculosis occurs due to exogenous reinfection or reactivation/persistence. We analysed 90 sequential MDR Mtb isolates obtained in Argentina from 27 patients with previously diagnosed MDR-TB that recurred in 2018 (1-10years, 2-10 isolates per patient). Three long-term predominant strains were responsible for 63% of all MDR-TB recurrences. Most of the remaining patients were infected by strains different from each other. Reactivation/persistence of the same strain caused all but one recurrence, which was due to a reinfection with a predominant strain. One of the prevalent strains showed marked stability in the recurrences, while in another strain higher SNP-based diversity was observed. Comparisons of intra- versus inter-patient SNP distances identified two possible reinfections with closely related variants circulating in the community. Our results show a complex scenario of MDR-TB infections in settings with predominant MDR Mtb strains.

Tuberculosis outcomes related to the Mycobacterium tuberculosis genotype

Mycobacterium tuberculosis strains of different phylogenetic lineages and genetic families differ in biological properties that determine, to some extent, epidemiological features and clinical manifestation in tuberculosis (TB) patients.The aim of the study was to assess the risk of an adverse outcome of the disease in TB patients caused by various M. tuberculosis genotypes.Materials and methods. A total of 425 patients with respiratory TB were enrolled in this study. They were registered at phthisiatric facilities in the Omsk region from March 2015 to June 2017 period and included: males — 73.1%, mean age 39.9 years, females — 26.9%, mean age 42.0 years. M. tuberculosis culture and drug susceptibility testing and DNA extraction were performed in accordance with standard methods. Strains were assigned to the M. tuberculosis Beijing genotype and its epidemiologically relevant clusters B0/W148 and 94-32 by PCR based detection of specific markers. Non-Beijing strains were subjected to spoligotyping.Results. We found that 66.5% isolates belonged to the Beijing genotype, 12.8% — to LAM, 10.1% — to T, and 4.7% — to the Ural genotype. Multi-drug resistance (MDR) to anti-TB drugs was observed in 195 M. tuberculosis strains (45.9%). Moreover, Beijing genotype was more often isolated from patients with MDR-TB infection (PR = 2.09 (95% CI 1.6–2.74) and TB infection associated with HIV infection (PR = 1.14 (95% CI 1.01–1.31). Lethal outcome was double higher in patients infected with Beijing vs. non-Beijing strains, 28.6% vs. 14.0% (PR = 2.03; 95% CI 1.3–3.17). The risk factors were identified as follows: young age 18–44 years (RR = 1.7; 95% CI 1.18–2.7), co-morbidity with HIV (RR = 5.0; 95% CI 3.39–7.45), multiple (RR = 1.7; 95% CI 1.14–2.55) and extensive drug resistance (RR = 2.57; 95% CI 1.35–4.92), and association with the Beijing genotype (RR = 2.0, 95% CI 1.3–3.17).Conclusion. M. tuberculosis spread in the Omsk region is characterised by significant prevalence of the Beijing genotype, associated with multiple and extensive drug resistance. A significant association of adverse clinical outcomes and various factors, including association with the Beijing genotype, requires development of new approaches in the fight against tuberculosis.

Hepatitis C virus infection: a challenge in the complex management of two cases of multidrug-resistant tuberculosis

BackgroundMultidrug-resistant tuberculosis (MDR-TB) requires lengthy use of second-line drugs, burdened by many side effects. Hepatitis C virus (HCV) chronic infection increases risk of drug-induced liver injury (DILI) in these patients. Data on MDR-TB patients with concurrent HCV chronic infection treated at the same time with second-line antitubercular drugs and new direct-acting antivirals (DAAs) are lacking. We evaluate if treating at the same time HCV infection and pulmonary MDR-TB is feasible and effective.Cases presentationIn this study, we described two cases of patients with pulmonary MDR-TB and concurrent HCV chronic infection cured with DAAs at a Tertiary Infectious Diseases Hospital in Italy. During antitubercular treatment, both patients experienced a DILI before treating HCV infection.After DAAs liver enzymes normalized and HCV RNA was undetectable. Then antitubercular regimen was started according to the institutional protocol, drawn up following WHO MDR-TB guidelines. It was completed without further liver side effects and patients were declared cured from both HCV infection and MDR-TB.ConclusionsWe suggest to consider treatment of chronic hepatitis C with DAAs as a useful intervention for reintroduction of second-line antitubercular agents in those patients who developed DILI, reducing the risk of treatment interruption when re-exposed to these drugs.

The Correlation Between Interleukin-10 1082G/A Gene Polimorphism Late Onset with Nephrotoxicity Secondary to Antituberculosis Treatment in Multidrug Resistant Tuberculosis Patients

Backgrounds: Tuberculosis controlling programme has become more complex with MDR-TB problem. Interleukin 10 (IL-10) 1082G/A gene polimorphism correlates with IL-10 secretion as anti-inflammatory cytokine which plays important role in pathogenesis of MDR-TB infection. The management of MDR-TB which used aminoglycosides could cause nephrotoxic effect to the patients. The protective role of IL-10 from IL-10 1082 G/A genotype to nephrotoxicity due to kanamycin still becomes a prolem nowadays.&#x0D; Methods: This study was a retorspective cohort study of MDR-TB patients who underwent treatment in Dr. Moewardi Hospital in 2011-2015.&#x0D; Results: Subjects of the study were 89 MDR-TB patients with IL-10 1082 G/A genotype polimorphism. The proportions of IL-10 1082 G/A genotype were AA genotype of 13.48%, GG of 4.49%, and GA of 82.2%. Statistic test showed that the onset of nephrotoxicity in GG genotype was faster than GA and AA genotype &#x0D; Conclusions: Interleukin 10 1082 G/A gene polymorphism had no significant correlation with nephrotoxicity onset in MDR-TB patients treated with kanamycin in Dr. Moewardi hospital. (J Respir Indo. 2019; 39(4): 215-9)

Mutational analysis of gyrB at amino acids: G481A & D505A in multidrug resistant (MDR) tuberculosis patients

BackgroundThe MDR (multidrug resistance) tuberculosis is a serious public health concern. Fluoroquinolones are in use to treat tuberculosis, but M. tuberculosis strains have now become resistant due to several mutations in different genes. We evaluated mutations in gyrB gene at amino acid positions G481A and D505A of M. tuberculosis by semi-multiplex allele specific (MAS) PCR. MethodsThe information on gender, age, type of tuberculosis (TB), positive/negative for MDR-TB and HIV infection was gathered. The genomic DNA isolation from sputum culture samples (n=53) was carried out by non-column based method. The gyrB mutations were investigated by using self-designed primers in semi MAS-PCR, at mentioned amino acid positions. ResultsThere were 38% male patients and 62% were female patients. Most of MDR-TB patients (58.5%) were in the age between 16–30years. There were 90.5% cases of pulmonary TB and 9.4% cases of extra pulmonary TB. Only 1.8% patients were co-infected with HIV. The 24 samples had mutation in gyrB gene out of 53 (45.28%), on both of positions of amino acids Gly481Ala and Asp505Ala. All samples had mutations at Gly481Ala, whereas, 24 samples (45.28%) had mutations at Asp505Ala. ConclusionMutations at amino acids positions 481 and 505 were involved in MDR-TB, which could further develop into an extensively-drug resistance (XDR) TB. Therefore, there is a need to explore all mutations in gyrB gene in MDR-TB, because it can result in a Fluoroquinolones resistance.

Mortality in hospitalized patients with tuberculous meningitis

BackgroundTo evaluate the mortality in hospitalized patients with tuberculous meningitis and describe factors associated with an increased risk of mortality.MethodsRetrospective study of hospitalized patients with tuberculous meningitis between 2006 and 2015 in Peru performing a generalized linear regression to identify factors predictive of in-hospital mortality.ResultsOf 263 patients, the median age was 35 years, 72.6% were men, 38% were positive for HIV upon admission, 24% had prior TB infections and 2.3% had prior MDR-TB infections. In-hospital mortality was 30.4% of all study patients with a final diagnosis of TBM. When multivariable analysis was applied, significant associations with in-hospital mortality were seen among patients with HIV (RR 2.06; Confidence Interval 95% (95% CI) 1.44–2.94), BMRC II (RR 1.78; 95% CI 1.07–2.97), BMRC III (RR 3.11; 95% CI 1.78–5.45) and positive CSF cultures (RR 1.95; 95% CI 1.39–2.74).ConclusionsIn-hospital mortality is higher among patients with HIV infections, age over 40 years, positive CSF TB culture and BMRC stage II or III.

Levofloxacin versus placebo for the prevention of tuberculosis disease in child contacts of multidrug-resistant tuberculosis: study protocol for a phase III cluster randomised controlled trial (TB-CHAMP)

BackgroundMultidrug-resistant (MDR) tuberculosis (TB) presents a challenge for global TB control. Treating individuals with MDR-TB infection to prevent progression to disease could be an effective public health strategy. Young children are at high risk of developing TB disease following infection and are commonly infected by an adult in their household. Identifying young children with household exposure to MDR-TB and providing them with MDR-TB preventive therapy could reduce the risk of disease progression. To date, no trials of MDR-TB preventive therapy have been completed and World Health Organization guidelines suggest close observation with no active treatment.MethodsThe tuberculosis child multidrug-resistant preventive therapy (TB-CHAMP) trial is a phase III cluster randomised placebo-controlled trial to assess the efficacy of levofloxacin in young child contacts of MDR-TB cases. The trial is taking place at three sites in South Africa where adults with MDR-TB are identified. If a child aged < 5 years lives in their household, we assess the adult index case, screen all household members for TB disease and evaluate any child aged < 5 years for trial eligibility. Eligible children are randomised by household to receive daily levofloxacin (15–20 mg/kg) or matching placebo for six months. Children are closely monitored for disease development, drug tolerability and adverse events. The primary endpoint is incident TB disease or TB death by one year after recruitment. We will enrol 1556 children from approximately 778 households with an average of two eligible children per household. Recruitment will run for 18–24 months with all children followed for 18 months after treatment. Qualitative and health economic evaluations are embedded in the trial.DiscussionIf the TB-CHAMP trial demonstrates that levofloxacin is effective in preventing TB disease in young children who have been exposed to MDR-TB and that it is safe, well tolerated, acceptable and cost-effective, we would expect that that this intervention would rapidly transfer into policy.Trial registrationISRCTN Registry, ISRCTN92634082. Registered on 31 March 2016.

769. An Outbreak of Multidrug-Resistant Tuberculosis, Minnesota 2016–2017

BackgroundMultidrug-resistant tuberculosis (MDR TB) is more difficult to treat and outcomes are worse than for drug-susceptible TB disease. MDR TB cases in Minnesota increased from zero in 2015 to nine in 2016. Case investigations suggested an outbreak. We describe the public health response, challenges of contact investigations (CIs), and ongoing management of contacts.MethodsCDC performed whole-genome sequencing (WGS) to evaluate relatedness of MDR TB isolates. We conducted CIs for infectious cases. We created outbreak specific guidelines for screening and management of contacts, and partnered with various agencies to increase MDR TB awareness.ResultsWGS results were consistent with an MDR TB outbreak that included 10 cases (70% pulmonary) as of April 2018. Limited provider awareness about TB contributed to delayed diagnoses. CIs identified 588 contacts; 8.7% (n = 51) of contacts had previously documented positive TB infection test results, and 14% (n = 74) were newly positive for TB infection (median age: 72 years). Eight cases were epidemiologically linked to one Hmong adult day center. Sixty-two contacts started a fluoroquinolone for latent MDR TB infection. Contacts who declined treatment began a 2-year clinical monitoring program.ConclusionIn this outbreak, delayed diagnoses resulted in long infectious periods and hundreds of contacts. WGS results were consistent with recent transmission. We discovered adult day centers are an overlooked congregate setting. CIs were complicated by limited public health funding and high underlying TB infection prevalence in the affected community. Increased community and provider awareness and intensified screening of contacts resulted in additional case finding and prevention interventions.Disclosures All authors: No reported disclosures.

Treatment of Multidrug-Resistant Tuberculosis Infection in Children.

Treatment of Multidrug-Resistant Tuberculosis Infection in Children.

Treatment of Multidrug-resistant Tuberculosis Infection in Children.

Treatment of Multidrug-resistant Tuberculosis Infection in Children.

Extraspinal osteoarticular multidrug-resistant tuberculosis in children: A case series.

South Africa (SA) is known to have a high disease burden of tuberculosis (TB). Extraspinal osteoarticular multidrug-resistant tuberculosis (ESOA MDR-TB) in children has only been described in a few case reports worldwide. To describe the epidemiology and highlight the potential problem of ESOA MDR-TB infections as seen in children from a single academic hospital in SA. A retrospective record review was performed on all children diagnosed with ESOA TB infection at Chris Hani Baragwanath Academic Hospital, Johannesburg, between 1 January 2006 and 31 December 2015. All patients with a positive TB culture (fluid or tissue) from the surgical site of biopsy (bone or joint) and who were hospitalised were included. Organism culture and drug sensitivity testing were performed. Overall 19 cases of ESOA TB were identified. Areas involved included the shoulder (2 cases), elbow (2 cases), hip (7 cases), knee (4 cases), ankle (3 cases) and humerus (1 case). The mean age of the population was 7.7 (range 2.0 - 14.0) years. The mean white cell count was 11.3 (range 5 - 28.9) × 109/L, the mean C-reactive protein level 53.8 (range 1.0 - 364.0) mg/L and the mean erythrocyte sedimentation rate 35.5 (range 4.0 - 85.0) mm/h. Two cases (10.5%) were MDR, and a further case (5.3%) was resistant to isoniazid only. Four of 12 patients tested positive for HIV. One of the HIV-positive patients was isoniazid resistant. The two positive ESOA MDR-TB cases are discussed in detail. These findings indicate that ESOA MDR-TB is a reality in this paediatric population (10.5%) and a high index of suspicion should be maintained, especially when cultures are negative in children with signs and symptoms of ESOA TB. The effect of HIV infection on the incidence of ESOA MDR-TB requires further study.

Diphenylether-Modified 1,2-Diamines with Improved Drug Properties for Development against Mycobacterium tuberculosis.

New treatments for tuberculosis infection are critical to combat the emergence of multidrug- and extensively drug-resistant Mycobacterium tuberculosis (Mtb). We report the characterization of a diphenylether-modified adamantyl 1,2-diamine that we refer to as TBL-140, which has a minimal inhibitory concentration (MIC99) of 1.2 μg/mL. TBL-140 is effective against drug-resistant Mtb and nonreplicating bacteria. In addition, TBL-140 eliminates expansion of Mtb in cell culture infection assays at its MIC. To define the mechanism of action of this compound, we performed a spontaneous mutant screen and biochemical assays. We determined that TBL-140 treatment affects the proton motive force (PMF) by perturbing the transmembrane potential (ΔΨ), consistent with a target in the electron transport chain (ETC). As a result, treated bacteria have reduced intracellular ATP levels. We show that TBL-140 exhibits greater metabolic stability than SQ109, a structurally similar compound in clinical trials for treatment of MDR-TB infections. Combined, these results suggest that TBL-140 should be investigated further to assess its potential as an improved therapeutic lead against Mtb.

Treatment Outcomes of Patients with Multidrug-Resistant Tuberculosis (MDR- TB) Compared with Non-MDR-TB Infections in Peninsular Malaysia.

Treating patients with multidrug-resistant tuberculosis (MDR-TB) strains is more complicated, complex, toxic, expensive, than treating patients with susceptible TB strains. This study aims to compare the treatment outcomes and potential factors associated between patients with MDR-TB and non MDR TB infections in peninsular Malaysia. This study was a retrospective cohort study. Data were collected from the medical records of all registered MDR-TB patients and Non-MDR-TB patients at five TB hospitals in peninsular Malaysia from January 2010 to January 2014. A total of 314 subjects were studied, including 105 MDR-TB cases and 209 non-MDR-TB. After TB treatment, 24.8% of the MDR-TB patients and 17.7% of non MDR TB relapsed; 17.1% of the MDR-TB patients and 16.3% of non MDR TB defaulted from TB treatment. A significant difference seen in treatment success rate 17.1% for MDR-TB; 63.1% for non MDR TB (P < 0.001)). Mortality rate were 8.9% for MDR-TB; 13.2% for non MDR TB. Multivariable analysis showed the potential factors associated with poor treatment outcomes were presence of HIV infection (AOR, 1.09; 95%CI: 1.05, 1.75; P = 0.001) and previous TB treatment (AOR, 4.87; 95%CI: 2.84, 8.38; P = 0.001). This study revealed that the treatment success rate in patients with non MDR TB infection was higher than MDR-TB. Unsuccessful treatment was seen in MDR-TB associated with potential factors such as history of TB treatment, and presence of HIV infection.