Active Multidrug-resistant Tuberculosis Research Articles

Prolonged survival of a patient with active MDR-TB HIV co-morbidity: insights from a Mycobacterium tuberculosis strain with a unique genomic deletion.

Coinfection of HIV and multidrug-resistant tuberculosis (MDR-TB) presents significant challenges in terms of the treatment and prognosis of tuberculosis, leading to complexities in managing the disease and impacting the overall outcome for TB patients. This study presents a remarkable case of a patient with MDR-TB and HIV coinfection who survived for over 8 years, despite poor treatment adherence and comorbidities. Whole genome sequencing (WGS) of the infecting Mycobacterium tuberculosis (Mtb) strain revealed a unique genomic deletion, spanning 18 genes, including key genes involved in hypoxia response, intracellular survival, immunodominant antigens, and dormancy. This deletion, that we have called "Del-X," potentially exerts a profound influence on the bacterial physiology and its virulence. Only few similar deletions were detected in other non-related Mtb genomes worldwide. In vivo evolution analysis identified drug resistance and metabolic adaptation mutations and their temporal dynamics during the patient's treatment course.

Transforming growth factor-β, Interleukin-23 and interleukin-1β modulate TH22 response during active multidrug-resistant tuberculosis.

We previously reported that patients with multidrug-resistant tuberculosis (MDR-TB) showed low systemic and Mtb-induced Th22 responses associated to high sputum bacillary load and severe lung lesions suggesting that Th22 response could influence the ability of these patients to control bacillary growth and tissue damage. In MDR-TB patients, the percentage of IL-22+ cells inversely correlates with the proportion of senescent PD-1+ T cells. Herein, we aimed to evaluate the pathways involved on the regulation of systemic and Mtb-induced Th22 response in MDR-TB and fully drug-susceptible TB patients (S-TB) and healthy donors. Our results show that while IL-1β and IL-23 promote Mtb-induced IL-22 secretion and expansion of IL-22+ cells, TGF-β inhibits this response. Systemic and in vitro Mtb-induced Th22 response inversely correlates with TGF-β amounts in plasma and in PBMC cultures respectively. The number of circulating PD-1+ T cells directly correlates with plasmatic TGF-β levels and blockade of PD-1/PD-L1 signalling enhances in vitro Mtb-induced expansion of IL-22+ cells. Thus, TGF-β could also inhibit Th22 response through upregulation of PD-1 expression in T cells. Higher percentage of IL-23+ monocytes was observed in TB patients. In contrast, the proportion of IL-1β+ monocytes was lower in TB patients with bilateral lung cavities (BCC) compared to those patients with unilateral cavities (UCC). Interestingly, TB patients with BCC showed higher plasmatic and Mtb-induced TGF-β secretion than patients with UCC. Thus, high TGF-β secretion and subtle differences in IL-23 and IL-1β expression could diminish systemic and in vitro Mtb-induced Th22 response along disease progression in TB patients.

Transmission of multidrug-resistant tuberculosis within family households by DTM-PCR and MIRU-VNTR genotyping

BackgroundDrug-resistant tuberculosis (TB) continues to be a public health threat. There are few studies on transmission and genotyping of MDR-TB family households in China. This study aimed to investigate transmission of multidrug-resistant tuberculosis (MDR-TB) within family households by deletion-targeted multiplex polymerase chain reaction (DTM-PCR), mycobacterial interspersed repetitive unit variable number tandem repeats (MIRU-VNTR) genotyping.MethodsAmong 993 MDR-TB patients registered from Wuhan Institute for Tuberculosis Control, drug resistance and the time interval between the index patients and secondary patients were analyzed in 49 MDR-TB patients from 23 families, in which 22 MDR-TB strains from 11 families who had matched strains were genotyped by DTM-PCR and standard 24-loci MIRU-VNTR genotyping method.ResultsThe time interval between the index patients and the secondary patients ranged from half a month to 110 months. Thirteen secondary patients developed active MDR-TB within two years and accounted for 50% (13/26) of all secondary patients. Among eleven pairs of MDR-TB families, six pairs had identical genotypes, the cluster rate was 54.5% (12/22); three pairs had a single MIRU-VNTR locus variation. If a single MIRU-VNTR locus variation was tolerated in the cluster definition, the cluster rate raised to 81.8% (18/22).ConclusionsThe family households of MDR-TB patients are at risk for infection of MDR-TB. To reduce transmission, MDR-TB patients should be diagnosed earlier and promptly treated in an effective manner, meanwhile, the close family contacts should be screened for TB infection.

Greenness exposure and all-cause mortality during multi-drug resistant tuberculosis treatment: A population-based cohort study

BackgroundLiving closer to greenness were thought to benefit various health outcomes. We aimed to assess the association between residential greenness and mortality among patients undergoing multidrug resistant tuberculosis (MDR-TB) treatment. MethodsWe enrolled all local MDR-TB patients reported in Zhejiang, China from 2009 to 2017 and followed them throughout the treatment. We calculated the contemporaneous normalized difference vegetation index (NDVI) in the 250 and 500 m radius around patient’s residence. Cox proportional hazards regression models with time-varying NDVI were used to assess the impact of greenness exposure on all-cause mortality during MDR-TB treatment, adjusting for potential individual and contextual covariates. ResultsWe ascertained 1,621 active MDR-TB cases, which contributed 3036 person-years at risk with an average follow-up of 684 days (s.d. 149 days) per patient. Among them, there were 163 deaths during follow-up, representing a crude mortality rate of 537 deaths per 10,000 person-years. Patients exposed to the second quintile (Q2) of greenness within the 500 m buffer had around 64% reduced mortality risk over the lowest quintile of greenness with hazard ratio (HR) = 0.364 (95% CI: 0.109–1.22). In lower nighttime light (NTL) areas, the hazard ratios (HR) per quintile increase in NDVI within the 500 m buffer were Q2: 0.35 (95% CI: 0.10–1.18), Q3: 0.24 (95% CI: 0.09–0.66), Q4: 0.26 (95% CI: 0.10–0.69), and Q5: 0.26 (95% CI: 0.10–0.71) relevant to the lowest quintile Q1, with a trend of p-value ≤0.01. Patients who were female, younger (<60 years), resided in urban areas, or had high PM2.5 (i.e. particles with diagram ≤2.5 μm) exposure were more likely to benefit from greenness exposure. Associations were neither observed with NDVI in the 250 m buffer nor for patients living in higher NTL areas. There was a non-linear exposure-response relationship between greenness and deaths with p-value ≤0.05. ConclusionIncreasing greenness exposure along with medical treatment reduces all-cause mortality among patients living in lower NTL areas.

Protocol for a case–control study of vitamin D status, adult multidrug-resistant tuberculosis disease and tuberculosis infection in Mumbai, India

IntroductionVitamin D status may be an important determinant of multidrug-resistant tuberculosis (MDR-TB) infection, progression to disease and treatment outcomes. Novel and potentially cost-effective therapies such as vitamin D supplementation are...

The cost-effectiveness of a bedaquiline-containing short-course regimen for the treatment of multidrug-resistant tuberculosis in South Africa

ABSTRACTBackground: Bedaquiline-containing regimens have demonstrated improved outcomes over injectable-containing regimens in the long-term treatment of multidrug-resistant tuberculosis (MDR-TB). Recently, the World Health Organization (WHO) recommended replacing injectables in the standard short-course regimen (SCR) with a bedaquiline-containing regimen. The South African national TB program similarly recommends a bedaquiline-containing regimen. Here, we investigated the cost-effectiveness of a bedaquiline-containing SCR versus an injectable-containing SCR for the treatment of MDR-TB in South Africa.Methods: A Markov model was adapted to simulate the incidence of active patients with MDR-TB. Patients could transition through eight health states: active MDR-TB, culture conversion, cure, follow-up loss, secondary MDR-TB, extensively DR-TB, end-of-life care, and death. A 5% discount was assumed on costs and outcomes. Health outcomes were expressed as disability-adjusted life years (DALYs).Results: Over a 10-year time horizon, a bedaquiline-containing SCR dominated an injectable-containing SCR, with an incremental saving of US $982 per DALY averted. A bedaquiline-containing SCR was associated with lower total costs versus an injectable-containing SCR (US $597 versus $657 million), of which US $3.2 versus $21.9 million was attributed to adverse event management.Conclusions: Replacing an injectable-containing SCR with a bedaquiline-containing SCR is cost-effective, offering a cost-saving alternative with improved patient outcomes for MDR-TB.

Long-Term Effects of Multi-Drug-Resistant Tuberculosis Treatment on Gut Microbiota and Its Health Consequences.

Gut microbiota dysbiosis has adverse health effects on human body. Multi-drug-resistant tuberculosis (MDR-TB) treatment uses a variety of antibiotics typically for more than 20 months, which may induce gut microbiota dysbiosis. The aim of this study is to investigate the long-term effects of MDR-TB treatment on human gut microbiota and its related health consequences. A total of 76 participants were recruited at a hospital in Linyi, China. The study included one active MDR-TB treatment group, one recovered group from MDR-TB and two treatment-naive tuberculosis groups as control. The two treatment-naïve tuberculosis groups were constructed to match the sex and the age of the active MDR-TB treatment and the recovered group, respectively. The fecal and blood samples were collected and analyzed for gut microbiota and metabolic parameters. An altered gut microbiota community and a loss of richness were observed during the MDR-TB treatment. Strikingly, 3–8 years after recovery and discontinuing the treatment, the gut microbiota still exhibited an altered taxonomic composition (p = 0.001) and a 16% decrease in richness (p = 0.018) compared to the gut microbiota before the treatment. The abundance of fifty-eight bacterial genera was significantly changed in the MDR-TB recovered group versus the untreated control group. Although there were persistent and pervasive gut microbiota alterations, no gastrointestinal symptom such as abdominal pain, diarrhea, nausea, flatulence, and constipation was observed in the recovered group. However, chronic disorders may be indicated by the elevated level of low-density lipoprotein cholesterol (LDLC) (p = 0.034) and total cholesterol (TC) (p = 0.017). These adverse lipid changes were associated with the altered gut bacterial taxa, including phylum Firmicutes and Verrucomicrobia and genera Adlercreutzia, Akkermansia, Butyricicoccus, Coprococcus, Clostridioides, Eubacterium, Erysipelatoclostridium, Fusicatenibacter, Klebsiella, Psychrobacter, and Streptococcus. Collectively, MDR-TB treatment induced a lasting gut microbiota dysbiosis, which was associated with unfavorable changes in lipid profile.

A combination of baseline plasma immune markers can predict therapeutic response in multidrug resistant tuberculosis.

ObjectiveTo identify plasma markers predictive of therapeutic response in patients with multidrug resistant tuberculosis (MDR-TB).MethodsFifty HIV-negative patients with active pulmonary MDR-TB were analysed for six soluble analytes in plasma at the time of initiating treatment (baseline) and over six months thereafter. Patients were identified as sputum culture positive or negative at baseline. Culture positive patients were further stratified by the median time to sputum culture conversion (SCC) as fast responders (< 76 days) or slow responders (≥ 76 days). Chest X-ray scores, body mass index, and sputum smear microscopy results were obtained at baseline.ResultsUnsupervised hierarchical clustering revealed that baseline plasma levels of IP-10/CXCL10, VEGF-A, SAA and CRP could distinguish sputum culture and cavitation status of patients. Among patients who were culture positive at baseline, there were significant positive correlations between plasma levels of CRP, SAA, VEGF-A, sIL-2Rα/CD40, and IP-10 and delayed SCC. Using linear discriminant analysis (LDA) and Receiver Operating Curves (ROC), we showed that a combination of MCP-1/CCL2, IP-10, sIL-2Rα, SAA, CRP and AFB smear could distinguish fast from slow responders and were predictive of delayed SCC with high sensitivity and specificity.ConclusionPlasma levels of specific chemokines and inflammatory markers measured before MDR-TB treatment are candidate predictive markers of delayed SCC. These findings require validation in a larger study.

Multidrug-resistant tuberculosis outbreak in an Italian prison: tolerance of pyrazinamide plus levofloxacin prophylaxis and serial interferon gamma release assays.

The optimal treatment for latent tuberculosis infection (LTBI) in subjects exposed to multidrug-resistant (MDR) tuberculosis (TB) remains unclear, and the change in response of the QuantiFERON-TB Gold In-Tube (QTB-IT) test during and after treatment is unknown. Between May 2010 and August 2010, 39 prisoners at the ‘Casa Circondariale’ of Modena, Italy, were exposed to a patient with active pulmonary MDR TB. All contacts were tested with the tuberculin skin test and QTB-IT. Upon exclusion of active TB, subjects positive to both tests were offered 6 months' treatment with pyrazinamide (PZA) and levofloxacin (LVX). QTB-IT testing was repeated at 3 and 6 months after initial testing in all subjects who were offered LTBI treatment. Seventeen (43.5%) of 39 subjects tested positive to both tuberculin skin test and QTB-IT test, and 12 (70.5%) agreed to receive therapy with PZA and LVX at standard doses. Only five (41.6%) of 12 subjects completed 6 months' treatment. Reasons for discontinuation were asymptomatic hepatitis, gastritis and diarrhoea. The QTB-IT values decreased in all subjects who completed the treatment, in two (33%) of six of those who received treatment for less than 3 months and in one (50%) of two patients who discontinued therapy after 3 months. The QTB-IT test results never turned negative. Despite the small number of subjects, the study confirmed that PZA plus LVX is a poorly tolerated option for MDR LTBI treatment. We observed a large degree of variation in the results of the QTB-IT test results among participants. The study confirmed that the interferon gamma release assay is not a reliable tool for monitoring the treatment of MDR LTBI in clinical practice.

CD4+FoxP3+ T regulatory cells in drug-susceptible and multidrug-resistant tuberculosis

Regulatory T cells (Treg) increase in active tuberculosis (TB). However, whether Treg-mediated immune suppression affect the susceptibility to active TB or development of multidrug-resistant (MDR) TB is not yet clear. We compared circulatory Treg frequencies in drug susceptible (DS) and MDR TB before and after anti-TB treatment. Circulatory Treg frequencies were measured in blood samples from 33 DS TB, 7 mycobacterial culture-positive active MDR TB, 16 stable MDR TB who had been culture negative for at least 6 months, and 14 healthy controls before and after treatment. Treg frequency was measured by flow cytometry using cell-surface marker CD4 and intracellular marker FoxP3. Treg frequency was higher in DS TB and active MDR TB patients than in healthy controls (p<0.05), with no significant difference between the former. Treg frequency was higher in patients with sputum acid-fast bacilli smear-positive TB than in patients with smear-negative TB, but the increase did not correlate with the radiologic extent of TB or presence of a cavity. After successful treatment, Treg decreased to control levels in DS TB and MDR TB patents. The pattern of change, in which Treg frequency increased during active infection and normalized to control levels after successful treatment, was similar in DS and MDR TB patients.

Patients with Multidrug-Resistant Tuberculosis Display Impaired Th1 Responses and Enhanced Regulatory T-Cell Levels in Response to an Outbreak of Multidrug-ResistantMycobacterium tuberculosisM and Ra Strains

In Argentina, multidrug-resistant tuberculosis (MDR-TB) outbreaks emerged among hospitalized patients with AIDS in the early 1990s and thereafter disseminated to the immunocompetent community. Epidemiological, bacteriological, and genotyping data allowed the identification of certain MDR Mycobacterium tuberculosis outbreak strains, such as the so-called strain M of the Haarlem lineage and strain Ra of the Latin America and Mediterranean lineage. In the current study, we evaluated the immune responses induced by strains M and Ra in peripheral blood mononuclear cells from patients with active MDR-TB or fully drug-susceptible tuberculosis (S-TB) and in purified protein derivative-positive healthy controls (group N). Our results demonstrated that strain M was a weaker gamma interferon (IFN-gamma) inducer than H37Rv for group N. Strain M induced the highest interleukin-4 expression in CD4+ and CD8+ T cells from MDR- and S-TB patients, along with the lowest cytotoxic T-lymphocyte (CTL) activity in patients and controls. Hence, impairment of CTL activity is a hallmark of strain M and could be an evasion mechanism employed by this strain to avoid the killing of macrophages by M-specific CTL effectors. In addition, MDR-TB patients had an increased proportion of circulating regulatory T cells (Treg cells), and these cells were further expanded upon in vitro M. tuberculosis stimulation. Experimental Treg cell depletion increased IFN-gamma expression and CTL activity in TB patients, with M- and Ra-induced CTL responses remaining low in MDR-TB patients. Altogether, these results suggest that immunity to MDR strains might depend upon a balance between the individual host response and the ability of different M. tuberculosis genotypes to drive Th1 or Th2 profiles.

Exposición a tuberculosis multirresistente: estudio y seguimiento de nueve niños

A world increase in multidrug-resistant tuberculosis (MDR-TB) has been reported over the last few years. A larger number of diagnoses are being seen in Spain, due to the increase of immigration from high endemic TB countries. Articles published on this are anecdotal in children, and there is no clear directives for treatment of MDR-TB, or latent tuberculosis infection (ITBL) or on prophylaxis after exposure to active pulmonary MDR-TB. We present the initial management and progression of nine children after close contact exposure to an Ecuadorian woman diagnosed with active pulmonary TB, resistant to Isoniazid, Rifampicin and Pyrazinamide.

New Challenges in the Clinical Management of Drug-Resistant Tuberculosis

Strains of Mycobacterium tuberculosis are multidrug-resistant when isoniazid and rifampin, the two most powerful antituberculous agents, do not inhibit their growth. Only a decade ago, outbreaks of multidrug-resistant tuberculosis (MDR-TB) occurred in New York, California, and Florida. In each setting, early detection by physicians decreased both transmission of and deaths caused by these strains. Working in Haiti, Peru, and Russia, our team has treated over 1,000 patients sick with MDR-TB. Most infecting strains were resistant to all first-line drugs. Because no new antituberculous drugs have been developed in decades, therapeutic options for such patients are limited. Our own experience suggests, however, that prompt detection and effective therapy can cure the great majority of cases of active MDR-TB. We review below the principles of MDR-TB treatment: 18–24 months of therapy with multidrug regimens, designed with use of drug susceptibility testing, and close attention to the management of adverse effects. We also discuss the treatment of MDR-TB in children, during pregnancy, and in the presence of HIV coinfection. Controversies in the management of MDR-TB are reviewed, including the use of resective surgery, the relative efficacy of different fluoroquinolones, and postexposure prophylaxis for close contacts of patients with pulmonary MDR-TB.

Fatal primary multidrug-resistant tuberculosis in a heart transplant recipient

Abstract The incidence of tuberculosis (TB) worldwide is currently on the rise, not only in the general population but also quite notably among immunosuppressed patients. Its incidence among patients undergoing antirejection therapy is considerably higher than in the general population, and heart transplant recipients have been found to carry the highest risk of TB. There are no reported data, however, on primary TB caused by multidrug-resistant (MDR) Mycobacterium tuberculosis (M. tuberculosis) in heart transplant recipients. We describe the case of a patient who developed active primary MDR TB following the reactivation of a latent tuberculous infection 6 months after transplantation. The patient was most likely infected by M. tuberculosis during a period of time he spent in prison 10 years before undergoing transplantation, but he never developed active tuberculosis, nor did he ever receive antituberculous medication prior to transplantation. Because of the atypical clinical presentation, establishment of the diagnosis was postponed, and the resistance pattern of the isolate grown from bronchoalveolar lavage (BAL) specimens (resistant to isoniazid and rifampicin) led to treatment failure and a fatal outcome. The adoption of the most rapid diagnostic tools for the identification of M. tuberculosis and for a quick screening of drug-resistant isolates is urgently needed in those centers where organ transplantation is carried out.

Drug-resistant tuberculosis.

Multidrug-resistant tuberculosis (MDRTB) is an iatrogenic disease that is emerging as a major infectious disease problem throughout the world. The AIDS pandemic, increased incidence of tuberculosis in populations with easy access to antituberculosis medications, the deterioration of the public health infrastructure, and inadequate training of health care providers in the epidemiology of tuberculosis are some of the factors contributing to the increased incidence of MDRTB. Mortality from MDRTB exceeds 80% in persons infected with human immunodeficiency virus (HIV) but is also high in patients free of HIV. The management of MDRTB is complicated by the lack of methods for rapid detection of resistant strains of Mycobacterium tuberculosis. The risk of infection among close contacts of patients with MDRTB, the probability of the development of active MDRTB after infection, and the likelihood of cure of MDRTB need to be determined quantitatively. Attributable risk estimates for factors associated with MDRTB should be calculated for each community as part of the strategies to prevent MDRTB. Issues regarding chemoprophylaxis in newly infected contacts of MDRTB cases remain unanswered. Basic research on the mechanisms of action of existing antituberculosis drugs may contribute to an understanding of the mechanism of resistance in M. tuberculosis. There is an urgent need to expand the scope of epidemiological, clinical, and laboratory research to address these problems.