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International Journal of... 2023Difficult-to-treat mycobacterial infections are increasing globally. There is an urgent need of new treatment alternatives for multidrug-resistant Mycobacterium... (Review)
Review
Difficult-to-treat mycobacterial infections are increasing globally. There is an urgent need of new treatment alternatives for multidrug-resistant Mycobacterium tuberculosis (MTB), as well as nontuberculous mycobacteria such as the Mycobacterium abscessus complex (MABC) and Mycobacterium avium complex (MAC). Recently, new carbapenems and combinations of carbapenems with β-lactamase inhibitors have become available, but activity data in vitro against mycobacteria are so far scarce. Therefore, we performed a systematic review collating the minimum inhibitory concentrations (MICs) of carbapenems, with or without a β-lactamase inhibitors for MTB, MABC, and MAC. The databases PubMed and Web of Science were searched for the relevant articles in English up until September 21, 2022. Screening of studies was performed by two independent reviewers. MIC data by recommended methods with at least five individual MICs were included. Data were reported as MIC range, MIC, modal MIC, and/or histograms when individual MICs were available. The study protocol was registered at PROSPERO (CRD42021258537). After screening, a total of 75 studies with MIC data for carbapenems with or without β-lactamase inhibitors were included in the review. For MTB, the oral carbapenem tebipenem combined with the β-lactamase inhibitor clavulanic acid resulted in the most significant reduction of MICs. For MABC, the addition of avibactam to tebipenem resulted in a 64-fold reduction of modal MIC. Data were insufficient for the analysis of MAC. Carbapenems, and in particular the novel oral compound tebipenem, in combination with clavulanic acid for MTB and avibactam for MABC may be an untapped potential for difficult-to-treat mycobacterial infections.
Topics: Humans; beta-Lactamase Inhibitors; Mycobacterium abscessus; Mycobacterium avium Complex; Mycobacterium tuberculosis; Carbapenems; Penicillins; Clavulanic Acid; Microbial Sensitivity Tests; Anti-Bacterial Agents; Mycobacterium Infections, Nontuberculous
PubMed: 37721224
DOI: 10.4103/ijmy.ijmy_131_23 -
Veterinary Research Feb 2021Animal tuberculosis (TB) is a multi-host disease caused by members of the Mycobacterium tuberculosis complex (MTC). Due to its impact on economy, sanitary standards of...
Animal tuberculosis (TB) is a multi-host disease caused by members of the Mycobacterium tuberculosis complex (MTC). Due to its impact on economy, sanitary standards of milk and meat industry, public health and conservation, TB control is an actively ongoing research subject. Several wildlife species are involved in the maintenance and transmission of TB, so that new approaches to wildlife TB diagnosis have gained relevance in recent years. Diagnosis is a paramount step for screening, epidemiological investigation, as well as for ensuring the success of control strategies such as vaccination trials. This is the first review that systematically addresses data available for the diagnosis of TB in wildlife following the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The article also gives an overview of the factors related to host, environment, sampling, and diagnostic techniques which can affect test performance. After three screenings, 124 articles were considered for systematic review. Literature indicates that post-mortem examination and culture are useful methods for disease surveillance, but immunological diagnostic tests based on cellular and humoral immune response detection are gaining importance in wildlife TB diagnosis. Among them, serological tests are especially useful in wildlife because they are relatively inexpensive and easy to perform, facilitate large-scale surveillance and can be used both ante- and post-mortem. Currently available studies assessed test performance mostly in cervids, European badgers, wild suids and wild bovids. Research to improve diagnostic tests for wildlife TB diagnosis is still needed in order to reach accurate, rapid and cost-effective diagnostic techniques adequate to a broad range of target species and consistent over space and time to allow proper disease monitoring.
Topics: Animals; Animals, Wild; Disease Reservoirs; Mycobacterium bovis; Mycobacterium tuberculosis; Tuberculosis
PubMed: 33627188
DOI: 10.1186/s13567-020-00881-y -
Do HLA class II genes protect against pulmonary tuberculosis? A systematic review and meta-analysis.European Journal of Clinical... Oct 2016Pulmonary tuberculosis (PTB) develops by a complex combination of environmental, immunological and socioeconomic factors and genetic susceptibility. The human leukocyte... (Meta-Analysis)
Meta-Analysis Review
Pulmonary tuberculosis (PTB) develops by a complex combination of environmental, immunological and socioeconomic factors and genetic susceptibility. The human leukocyte antigen (HLA) is the most polymorphic biological system and plays an essential role in the immune response against PTB. The aim of this study was to carry out a systematic review and meta-analysis evaluating the relationship between HLA-DRB1, HLA-DQB1 and HLA-DQA1 gene polymorphisms as possible risk or protective factors for PTB. A systematic search of the PubMed and Scopus databases was conducted following the guidelines described in the PRISMA statement. Fifty-six alleles were included in the meta-analysis. In the total pooled results, HLA-DRB1*08:03 (OR 1.95, CI 1.29-2.96), HLA-DQB1*06:01 (OR 1.78, CI 1.39-2.28), HLA-DQB1*06:09 (OR 2.27, 95 % CI 1.04-4.96) and HLA-DQA1*01:01 (OR 2.12, CI 1.11-4.03) genes were related to higher susceptibility to PTB. Conversely, the presence of the genes HLA-DRB1*07:01 (OR 0.74, CI 0.56-0.97), HLA-DQB1*03:01 (OR 0.77, CI 0.61-0.97), HLA-DQB1*04:02 (OR 0.57, CI 0.39-0.83), HLA-DQA1*04:01 (OR 0.50, CI 0.26-0.95) and HLA-DQA1*05:01 (OR 0.66, CI 0.48-0.92) demonstrated protection against PTB. In an analysis by ethnic subgroups, we found more genetic associations in Caucasians than in Asians. These findings suggest that HLAs may be used as markers for acquisition and development of PTB. To strengthen PTB susceptibility/resistance, we recommend further multicentric studies in different geographic regions, with certainty of controls' exposure to M. tuberculosis by use of marker of latent or active PTB, with analysis stratified by ethnic groups, with descriptions of specific alleles and carrying out immunological functionality tests.
Topics: Asian People; Gene Frequency; Genes, MHC Class II; Genetic Predisposition to Disease; Humans; Mycobacterium tuberculosis; Phosphoproteins; Tuberculosis, Pulmonary; White People
PubMed: 27412154
DOI: 10.1007/s10096-016-2713-x -
International Journal of Antimicrobial... Sep 2023Pyrazinamide (PZA) is a first-line antituberculosis drug with potent sterilising activity. Variability in drug exposure may translate into suboptimal treatment... (Review)
Review
Pyrazinamide (PZA) is a first-line antituberculosis drug with potent sterilising activity. Variability in drug exposure may translate into suboptimal treatment responses. This systematic review, conducted according to PRISMA guidelines, aimed to evaluate the concentration-effect relationship. In vitro/in vivo studies had to contain information on the infection model, PZA dose and concentration, and microbiological outcome. Human studies had to present information on PZA dose, measures of drug exposure and maximum concentration, and microbiological response parameter or overall treatment outcome. A total of 34 studies were assessed, including in vitro (n = 2), in vivo (n = 3) and clinical studies (n = 29). Intracellular and extracellular models demonstrated a direct correlation between PZA dose of 15-50 mg/kg/day and reduction in bacterial count between 0.50-27.7 log CFU/mL. Consistent with this, higher PZA doses (>150 mg/kg) were associated with a greater reduction in bacterial burden in BALB/c mice models. Human pharmacokinetic studies displayed a linear positive correlation between PZA dose (i.e. 21.4-35.7 mg/kg/day) and drug exposure (AUC range 220.6-514.5 mg·h/L). Additionally, human studies confirmed a dose-effect relationship, with an increased 2-month sputum culture conversion rate at AUC/MIC targets of 8.4-11.3 with higher exposure/susceptibility ratios leading to greater efficacy. A 5-fold variability in AUC was observed at PZA dose of 25 mg/kg. A direct concentration-effect relationship and increased treatment efficacy with higher PZA exposure to susceptibility ratios was observed. Taking into account variability in drug exposure and treatment response, further studies on dose optimisation are justified.
Topics: Animals; Mice; Humans; Pyrazinamide; Mycobacterium tuberculosis; Tuberculosis; Antitubercular Agents; Mice, Inbred BALB C; Microbial Sensitivity Tests
PubMed: 37419292
DOI: 10.1016/j.ijantimicag.2023.106914 -
Tuberculosis (Edinburgh, Scotland) May 2015The ability to monitor response to therapy for tuberculosis (TB) and confirm adequate treatment would be a major advance. The low reversion rate of interferon-gamma... (Review)
Review
The ability to monitor response to therapy for tuberculosis (TB) and confirm adequate treatment would be a major advance. The low reversion rate of interferon-gamma based assays means that they are unlikely to be useful for monitoring therapy. Several exploratory studies have evaluated the diagnostic potential of cytokine biomarkers other than interferon-gamma for monitoring anti-tuberculous therapy. A systematic review of these studies was performed to identify the most promising candidate biomarkers. TNF-α, IL-2, IL-6, IL-10 and IL-12 were the most extensively investigated cytokines. There was significant heterogeneity between studies in relation to study design and laboratory methodology, complicating direct comparisons. There was marked variation between studies in the observed changes during treatment for many of the biomarkers. Further longitudinal studies in sufficiently large patient cohorts with rigorous methodology are needed to determine the true potential of individual cytokine biomarkers, or combinations, for monitoring TB treatment.
Topics: Antitubercular Agents; Biomarkers; Cytokines; Humans; Mycobacterium tuberculosis; Predictive Value of Tests; Reproducibility of Results; Treatment Outcome; Tuberculosis
PubMed: 25797612
DOI: 10.1016/j.tube.2015.01.003 -
Annals of Vascular Surgery Jul 2022Bacillus Calmette-Guerin (BCG) is a live attenuated strain of Mycobacterium bovis that has been used as immunotherapy against several malignancies. In particular,... (Review)
Review
BACKGROUND
Bacillus Calmette-Guerin (BCG) is a live attenuated strain of Mycobacterium bovis that has been used as immunotherapy against several malignancies. In particular, intravesical instillation of BCG has become a well-accepted adjuvant treatment for bladder cancer. BCG vascular infections are a rare complication of BCG therapy. Many aspects of these infections, including the presentations, risk factors, and treatment strategies, are poorly understood. Through a systematic review of the existing literature, we aimed to identify potential associations between this condition and patient characteristics, presentations, its treatments, and outcomes.
METHODS
We searched the PubMed, MEDLINE, and Embase databases for cases of BCG vascular infections from inception to June 2021. English-language reports of BCG vascular infections were included.
RESULTS
A total of 74 cases of BCG vascular infections were included. Seventy-three (99%) cases were male patients, all of whom were exposed to BCG through bladder instillation. Fifty (68%) cases were diagnosed more than 12 months after exposure to BCG. Twenty-six (35%) cases presented with arterial rupture at the time of diagnosis. Concurrent BCG infections in nonvascular locations were present in 37 (50%) cases. The most common locations of BCG vascular infection were the abdominal aorta (57%), prosthetic grafts (15%), and thoracic aorta (12%). The most common treatment for BCG infection was open repair with synthetic graft in situ replacement for the abdominal aorta and endovascular repair for the thoracic aorta. The 30-day mortality, among the 59 cases where these data were reported, was 10%.
CONCLUSIONS
We observed that many aspects of BCG vascular infections are similar to other forms of vascular infections. The high incidence of rupture or fistulation and the propensity toward abdominal aortic involvement and its prognosis are similar to those described in other vascular infections. However, our study also highlights 2 idiosyncratic features of BCG vascular infections: association with male sex and concurrent musculoskeletal infections.
Topics: Administration, Intravesical; BCG Vaccine; Female; Humans; Male; Mycobacterium bovis; Treatment Outcome; Urinary Bladder Neoplasms
PubMed: 35248739
DOI: 10.1016/j.avsg.2022.01.027 -
The Lancet. Infectious Diseases Oct 2014Tuberculous meningitis disproportionately affects young children. We aimed to characterise treatment outcomes for this deadliest and most debilitating form of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Tuberculous meningitis disproportionately affects young children. We aimed to characterise treatment outcomes for this deadliest and most debilitating form of tuberculosis.
METHODS
We did a systematic review and meta-analysis of childhood tuberculous meningitis studies published up to Oct 12, 2012. We included study reports that applied predefined diagnostic criteria and described treatment regimens and outcomes. We pooled risks of death during treatment and neurological sequelae among survivors. As secondary objectives, we assessed study-level characteristics as sources of heterogeneity, and we pooled frequencies of presenting symptoms and diagnostic findings. For all meta-analyses we used random-effects models with the exact binomial likelihood method.
FINDINGS
19 studies met our inclusion criteria, with reported treatment outcomes for 1636 children. Risk of death was 19·3% (95% CI 14·0-26·1) and probability of survival without neurological sequelae was 36·7% (27·9-46·4). Among survivors, risk of neurological sequelae was 53·9% (95% CI 42·6-64·9). Diagnosis in the most advanced disease stage (3) occurred in 307 (47%) of 657 patients and was associated with worse outcomes than was earlier diagnosis. The most common findings at presentation were cerebrospinal fluid (CSF) leucocytosis (frequency 99·9%, 95% CI 68·5-100·0), CSF lymphocytosis (97·9%, 51·9-100·0), fever (89·8%, 79·8-95·2), and hydrocephalus (86·1%, 68·6-94·6). Frequency of CSF acid-fast-bacilli smear positivity was 8·9% (95% CI 5·0-15·4), and frequency of CSF culture positivity for Mycobacterium tuberculosis was 35·1% (16·8-59·2).
INTERPRETATION
Despite treatment, childhood tuberculous meningitis has very poor outcomes. Poor prognosis and difficult early diagnosis emphasise the importance of preventive therapy for child contacts of patients with tuberculosis and low threshold for empirical treatment of tuberculous meningitis suspects. Implementation of consensus definitions, standardised reporting of data, and high-quality clinical trials are needed to clarify optimum therapy.
FUNDING
None.
Topics: Child; Early Diagnosis; Humans; Likelihood Functions; Mycobacterium tuberculosis; Risk; Treatment Outcome; Tuberculosis, Meningeal
PubMed: 25108337
DOI: 10.1016/S1473-3099(14)70852-7 -
The International Journal of... Sep 2017Systematic screening for active pulmonary tuberculosis (PTB) is recommended for high-risk populations, including people living with the human immunodeficiency virus... (Meta-Analysis)
Meta-Analysis Review
SETTING
Systematic screening for active pulmonary tuberculosis (PTB) is recommended for high-risk populations, including people living with the human immunodeficiency virus (PLHIV); however, currently recommended TB screening tools are inadequate for most high-burden settings.
OBJECTIVE
To determine whether C-reactive protein (CRP) possesses the necessary test characteristics to screen individuals for active PTB.
DESIGN
We performed a systematic review and meta-analysis of studies evaluating the diagnostic accuracy of CRP (10 mg/l cut-off point) for culture-positive PTB. Pooled diagnostic accuracy estimates were generated using random-effects meta-analysis for out-patients and in-patients, and for pre-specified subgroups based on HIV status and test indication.
RESULTS
We identified nine unique studies enrolling 1793 adults from out-patient (five studies, 1121 patients) and in-patient settings (five studies, 672 patients), 72% of whom had confirmed HIV infection. Among out-patients, CRP had high sensitivity (93%, 95%CI 88-98) and moderate specificity (60%, 95%CI 40-75) for active PTB. Specificity was lowest among in-patients (21%, 95%CI 6-52) and highest among out-patients undergoing TB screening (range 58-81%). There was no difference in summary estimates by HIV status.
CONCLUSION
CRP, which is available as a simple, inexpensive and point-of-care test, can be used to screen PLHIV presenting for routine HIV/AIDS (acquired immune-deficiency syndrome) care for active TB.
Topics: C-Reactive Protein; HIV Infections; Humans; Mass Screening; Mycobacterium tuberculosis; Outpatients; Point-of-Care Testing; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary
PubMed: 28826451
DOI: 10.5588/ijtld.17.0078 -
PloS One 2015Pyrazinamide (PZA) is crucial for tuberculosis (TB) treatment, given its unique ability to eradicate persister bacilli. The worldwide burden of PZA resistance remains... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Pyrazinamide (PZA) is crucial for tuberculosis (TB) treatment, given its unique ability to eradicate persister bacilli. The worldwide burden of PZA resistance remains poorly described.
METHODS
Systematic PubMed, Science Direct and Scopus searches for articles reporting phenotypic (liquid culture drug susceptibility testing or pyrazinamidase activity assays) and/or genotypic (polymerase chain reaction or DNA sequencing) PZA resistance. Global and regional summary estimates were obtained from random-effects meta-analysis, stratified by presence or risk of multidrug resistant TB (MDR-TB). Regional summary estimates were combined with regional WHO TB incidence estimates to determine the annual burden of PZA resistance. Information on single nucleotide polymorphisms (SNPs) in the pncA gene was aggregated to obtain a global summary.
RESULTS
Pooled PZA resistance prevalence estimate was 16.2% (95% CI 11.2-21.2) among all TB cases, 41.3% (29.0-53.7) among patients at high MDR-TB risk, and 60.5% (52.3-68.6) among MDR-TB cases. The estimated global burden is 1.4 million new PZA resistant TB cases annually, about 270,000 in MDR-TB patients. Among 1,815 phenotypically resistant isolates, 608 unique SNPs occurred at 397 distinct positions throughout the pncA gene.
INTERPRETATION
PZA resistance is ubiquitous, with an estimated one in six incident TB cases and more than half of all MDR-TB cases resistant to PZA globally. The diversity of SNPs across the pncA gene complicates the development of rapid molecular diagnostics. These findings caution against relying on PZA in current and future TB drug regimens, especially in MDR-TB patients.
Topics: Antitubercular Agents; Humans; Mycobacterium tuberculosis; Pyrazinamide; Tuberculosis, Multidrug-Resistant
PubMed: 26218737
DOI: 10.1371/journal.pone.0133869 -
The European Respiratory Journal May 2021The World Health Organization (WHO) recommends following up passengers after possible exposure to a case of infectious tuberculosis (TB) during air travel. This is... (Meta-Analysis)
Meta-Analysis Review
The World Health Organization (WHO) recommends following up passengers after possible exposure to a case of infectious tuberculosis (TB) during air travel. This is time-consuming and difficult, and increasingly so with higher numbers each year of flights and passengers to and from countries with high TB endemicity. This paper systematically reviews the literature on contact tracing investigations after a plane exposure to active pulmonary TB. Evidence for in-flight transmission was assessed by reviewing the positive results of contacts without prior risk factors for latent TB.A search of Medline, EMBASE, BIOSIS, Cochrane Library and Database of Systematic Reviews was carried out, with no restrictions on study design, index case characteristics, duration of flight or publication date.In total, 22 papers were included, with 469 index cases and 15 889 contacts. Only 26.4% of all contacts identified completed screening after exposure. The yield of either a single positive tuberculin skin test (TST) or a TST conversion attributable to in-flight transmission was between 0.19% (95% CI 0.13%-0.27%) and 0.74% (95% CI 0.61%-0.88%) of all contacts identified (0.00%, 95% CI 0.00%-0.00% and 0.13%, 95% CI 0.00%-0.61% in random effects meta-analysis). The main limitation of this study was heterogeneity of reporting.The evidence behind the criteria for initiating investigations is weak and it has been widely demonstrated that active screening of contacts is labour-intensive and unlikely to be effective. Based on our findings, formal comprehensive contact tracing may be of limited utility following a plane exposure.
Topics: Air Travel; Contact Tracing; Humans; Mycobacterium tuberculosis; Travel-Related Illness; Tuberculin Test; Tuberculosis
PubMed: 33214208
DOI: 10.1183/13993003.00013-2020