Mycobacterial biofilms: A therapeutic target against bacterial persistence and generation of antibiotic resistance.

Mycobacterium tuberculosis (M. tb) is the causative agent of Tuberculosis, one of the deadliest infectious diseases. According to the WHO Report 2023, in 2022, approximately 10.6 million people got infected with TB, and 1.6 million died. It has multiple antibiotics for treatment, but the major drawback of anti-tuberculosis therapy (ATT) is, its prolonged treatment duration. The major contributors to the lengthy treatment period are mycobacterial persistence and drug tolerance. Persistent M. tb is phenotypically drug tolerant and metabolically slow down which makes it difficult to be eliminated during ATT. These persisting bacteria are a huge reservoir of impending disease, waiting to get reactivated upon the onset of an immune compromising state. Directly Observed Treatment Short-course, although effective against replicating bacteria; fails to eliminate the drug-tolerant persisters making TB still the second-highest killer globally. There are different mechanisms for the development of drug-tolerant mycobacterial populations being investigated. Recently, the role of biofilms in the survival and host-evasion mechanism of persisters has come to light. Therefore, it is crucial to understand the mechanism of adaptation, survival and attainment of drug tolerance by persisting M. tb-populations, in order to design better immune responses and therapeutics for the effective elimination of these bacteria by reducing the duration of treatment and also circumvent the generation of drug-resistance to achieve the goal of global eradication of TB. This review summarizes the drug-tolerance mechanism and biofilms' role in providing a niche to dormant-M.tb. We also discuss methods of targeting biofilms to achieve sterile eradication of the mycobacteria and prevent its reactivation by achieving adequate immune responses.

Acute Large Pericardial Effusion With Haemodynamic Compromise Secondary to Undiagnosed Tuberculosis.

Tuberculous pericardial effusion is uncommon in the developed countries. However, it remains one of the main causes of presentation with a pericardial presentation with pericardial effusion in the developing world. We present the case of a 24-year-old male patient who presented with a weekly history of diarrhoea, vomiting, shortness of breath and feeling hot. Chest computed tomography revealed a large pericardial effusion with significant haemodynamic compromise. The patient underwent emergency pericardiocentesis, and the pericardial fluid interferon-gamma assay result was positive for tuberculosis. He was unable to tolerate endobronchial biopsy under ultrasound despite heavy sedation and was commenced on anti-tuberculous therapy following a discussion in a multidisciplinary team meeting. He was started on four standard anti-tuberculosis medications, including rifampicin, isoniazid, pyrazinamide, ethambutol and prednisolone. The patient had re-accumulation of pericardial fluid on repeat echocardiography in the first few weeks, which eventually resolved with anti-tuberculous therapy.

Unraveling the potential of graphene quantum dots against Mycobacterium tuberculosis infection.

Introduction: The emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains has underscored the urgent need for novel therapeutic approaches. Carbon-based nanomaterials, such as graphene oxide (GO), have shown potential in anti-TB activities but suffer from significant toxicity issues. Methods: This study explores the anti-TB potential of differently functionalized graphene quantum dots (GQDs) - non-functionalized, L-GQDs, aminated (NH2-GQDs), and carboxylated (COOH-GQDs) - alone and in combination with standard TB drugs (isoniazid, amikacin, and linezolid). Their effects were assessed in both axenic cultures and in vitro infection models. Results: GQDs alone did not demonstrate direct mycobactericidal effects nor trapping activity. However, the combination of NH2-GQDs with amikacin significantly reduced CFUs in in vitro models. NH2-GQDs and COOH-GQDs also enhanced the antimicrobial activity of amikacin in infected macrophages, although L-GQDs and COOH-GQDs alone showed no significant activity. Discussion: The results suggest that specific types of GQDs, particularly NH2-GQDs, can enhance the efficacy of existing anti-TB drugs. These nanoparticles might serve as effective adjuvants in anti-TB therapy by boosting drug performance and reducing bacterial counts in host cells, highlighting their potential as part of advanced drug delivery systems in tuberculosis treatment. Further investigations are needed to better understand their mechanisms and optimize their use in clinical settings.

Vigilance Needed in Treating a Child with Disseminated TB: A Case Report.

BACKGROUND: Tuberculosis is still one of the biggest causes of infection-related death around the world. Disseminated tuberculosis is a potentially fatal disease caused by the haematogenous spread of Mycobacterium tuberculosis. First-line anti-tuberculosis drugs in-clude isoniazid, rifampicin, pyrazinamide, and ethambutol. The first three drugs are known to cause hepatotoxicity. CASE PRESENTATION: We have, herein, reported a case of Drug-induced Liver Injury (DILI) due to anti-tuberculosis therapy in a one-year-old male child with disseminated tuberculosis. He was started on a fixed-dose combination of Anti-tuberculosis Therapy (ATT; isoniazid 50 mg, rifampicin 75 mg, and pyrazinamide 150 mg) and pyridoxine 10 mg orally. Initially, liver pa-rameters were normal, but later on with the course of the treatment, there was a rapid rise in liver enzymes, suggesting liver injury. DISCUSSION: The association between liver injury and anti-tuberculosis therapy has been con-firmed by applying various causality association scales. It is obvious that proper treatment of disseminated tuberculosis can avoid the development of drug-resistant strains that can be harm-ful, worsening the prognosis as there are fewer therapeutic alternatives available. At the same time, there is a need to monitor the patient with ATT-induced DILI. CONCLUSION: The diagnosis of tuberculosis in children is difficult because of the mild, nonspe-cific clinical presentation, which usually reflects the implicated underlying organ. In addition to prompt diagnosis and treatment of disseminated TB, careful monitoring is equally important.

Granulomas Galore: Concomitant Granulomatous Infections in a Patient With Crohn's Disease.

Tumor necrosis factor (TNF)-alpha inhibitors are effective biologics in the treatment of inflammatory bowel disease; however, they increase susceptibility to opportunistic infections. We report a case of a 74-year-old female with Crohn's disease who developed concomitant pulmonary tuberculosis (Mycobacterium tuberculosis [MTB]) and Histoplasmosis capsulatum infection while on adalimumab. Co-infection is rare in patients on TNF-alpha inhibitor therapy, and most cases have been reported in patients with human immunodeficiency virus (HIV). This was a challenging case for diagnosis and treatment due to indistinguishable presenting symptoms of both infections, similar laboratory and radiographical findings, and a clinical course complicated by drug-drug interactions and worsening of symptoms despite therapy.

A Case Report of a Cold Chest Wall Abscess Following Bacillus Calmette-Guérin Vaccination.

The Bacillus Calmette-Guérin (BCG) vaccine, a cornerstone in global immunization programs for tuberculosis prevention, has generally proven to be safe and effective. However, rare complications, including localized abscess formation, have been reported. This case report highlights a two-year-old male who developed a painless swelling on the left chest wall, noticed six weeks post-BCG vaccination. Physical and imaging evaluations confirmed a cold abscess. Laboratory tests ruled out alternative diagnoses. Antitubercular therapy led to a favorable response, avoiding surgical intervention. Follow-up revealed complete resolution, showcasing successful management of this rare BCG-related complication in a pediatric patient. The success of antimycobacterial therapy supports a tailored and conservative approach, raising questions about the necessity of surgical intervention. The presented case sheds light on the complex interplay between BCG vaccination, host response, and rare complications, providing valuable insights for further research. Vigilance, robust surveillance, and collaborative efforts are essential to unravel vaccine-related adverse events. This case contributes to a deeper understanding of rare BCG-related complications, guiding clinical practice, and advancing the knowledge base.

Mesenchymal stem cells-derived extracellular vesicles for therapeutics of renal tuberculosis.

Extrapulmonary tuberculosis with a renal involvement can be a manifestation of a disseminated infection that requires therapeutic intervention, particularly with a decrease in efficacy of conventional regimens. In the present study, we investigated the therapeutic potency of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in the complex anti-tuberculosis treatment (ATT). A rabbit model of renal tuberculosis (rTB) was constructed by injecting of the standard strain Mycobacterium tuberculosis H37Rv into the cortical layer of the kidney parenchyma. Isolated rabbit MSC-EVs were intravenously administered once as an addition to standard ATT (isoniazid, pyrazinamide, and ethambutol). The therapeutic efficacy was assessed by analyzing changes of blood biochemical biomarkers and levels of anti- and pro-inflammatory cytokines as well as by renal computed tomography with subsequent histological and morphometric examination. The therapeutic effect of therapy with MSC-EVs was shown by ELISA method that confirmed a statistically significant increase of the anti-inflammatory and decrease of pro-inflammatory cytokines as compared to conventional treatment. In addition, there is a positive trend in increase of ALP level, animal weigh, and normalization of ADA activity that can indicate an improvement of kidney state. A significant reduction of the area of specific and interstitial inflammation indicated positive affect of MSC-EVs that suggests a shorter duration of ATT. The number of MSC-EVs proteins (as identified by mass-spectometry analysis) with anti-microbial, anti-inflammatory and immunoregulatory functions reduced the level of the inflammatory response and the severity of kidney damage (further proved by morphometric analysis). In conclusion, MSC-EVs can be a promising tool for the complex treatment of various infectious diseases, in particularly rTB.

Host factors associated with false negative results in an interferon-γ release assay in adults with active tuberculosis.

Objective: To identify host factors associated with false-negative results of interferon-γ release tests in adults with active tuberculosis. Methods: The clinical data of 943 patients with active tuberculosis diagnosed by acid-fast smear staining, Mycobacterium tuberculosis culture, Mycobacterium tuberculosis PCR and pathological examination at West China Hospital of Sichuan University were retrospectively analysed. According to the results of the interferon γ release test (IGRA), the patients were divided into the IGRA- group and IGRA+ group. Logistic regression was used to analyze the sociodemographic data and clinical characteristics of participants in the IGRA- group and IGRA+ group. Results: Among 943 patients with active tuberculosis, 174 (18.5 %) were IGRA negative (false negative), and 769 (81.5 %) were IGRA positive. Multivariate logistic regression analysis identified the following characteristics independently associated with IGRA negativity: age (OR: 1.02; 95 % CI: 1.01 1.03; p = 0.006), anti-tuberculosis treatment >1 month (OR: 1.68; 95 % CI: 1.12 2.52; p = 0.013), HIV infection (OR: 9.48; 95 % CI: 3.23 27.85; p = 0.000), combined with connective tissue diseases (OR: 2.78; 95 % CI: 1.30 5.94; p = 0.008) and low hemoglobin (OR: 0.99; 95 % CI: 0.98 1.00; p = 0.044) was associated with an increased false-negative probability of IGRA. Conclusion: Age, anti-tuberculosis therapy >1 month, coinfection with HIV, coassociated connective tissue disease and decreased hemoglobin were identified as risk factors for false-negative results of IGRA. Our results suggest a careful interpretation of IGRA in adults with these characteristics.

Basal Ganglia Ischemic Stroke: The Unforeseen Progression of Tuberculosis Epididymo-Orchitis.

Tuberculosis is an infectious disease with broad pulmonary and extrapulmonary clinical manifestations. Central nervous system tuberculosis (CNS-TB) is a complex extrapulmonary infection known for its diverse clinical features including meningitis, tuberculoma, and spinal arachnoiditis. Particularly, tuberculosis meningitis can further lead to complications such as ischemic stroke.  This article presents a challenging case of a 35-year-old male patient initially diagnosed with epididymo-orchitis, followed by viral-like central nervous system symptoms, ultimately complicated by tuberculosis meningitis and basal ganglia ischemic stroke.  This case presentation underscores the diagnostic complexities associated with CNS-TB and emphasizes on the critical need for heightened awareness of the wide-ranging clinical presentations that can potentially delay early disease recognition and management.

Tuberculosis of the Pubic Symphysis: A Case Report.

Tuberculosis of the pubic symphysis is rare; the diagnosis is often difficult but guided by CT and confirmed by histopathological examination. We report the case of a 25-year-old female with no particular past medical history, presenting with pain at the level of the pubic symphysis. Clinical examination showed a small renitent mass and pain on palpation without inflammatory signs. Radiological investigation showed demineralization, lysis, and diastasis of the pubic symphysis with a cystic image in favor of tuberculosis. A biopsy followed by resection was performed, and histopathology confirmed the diagnosis. The patient received medical care for nine months using the 2RHZE/7RH protocol (rifampicin, isoniazid, pyrazinamide, ethambutol), with good results at follow-up. Bone lesions of the pubic symphysis may exceptionally reveal tuberculosis, and the positive diagnosis is based on a histopathological test.

Eradication of Drug-Tolerant Mycobacterium tuberculosis 2022: Where We Stand.

The lungs of tuberculosis (TB) patients contain a spectrum of granulomatous lesions, ranging from solid and well-vascularized cellular granulomas to avascular caseous granulomas. In solid granulomas, current therapy kills actively replicating (AR) intracellular bacilli, while in low-vascularized caseous granulomas the low-oxygen tension stimulates aerobic and microaerophilic AR bacilli to transit into non-replicating (NR), drug-tolerant and extracellular stages. These stages, which do not have genetic mutations and are often referred to as persisters, are difficult to eradicate due to low drug penetration inside the caseum and mycobacterial cell walls. The sputum of TB patients also contains viable bacilli called differentially detectable (DD) cells that, unlike persisters, grow in liquid, but not in solid media. This review provides a comprehensive update on drug combinations killing in vitro AR and drug-tolerant bacilli (persisters and DD cells), and sterilizing Mycobacterium tuberculosis-infected BALB/c and caseum-forming C3HeB/FeJ mice. These observations have been important for testing new drug combinations in noninferiority clinical trials, in order to shorten the duration of current regimens against TB. In 2022, the World Health Organization, following the results of one of these trials, supported the use of a 4-month regimen for the treatment of drug-susceptible TB as a possible alternative to the current 6-month regimen.

Cerebral venous thrombosis (CVT) complicating tubercular meningitis.

BACKGROUND: Tuberculous meningitis (TBM), complicated with cerebral venous thrombosis (CVT), has been sparsely reported and needs to be investigated further. METHODS: Among those with tuberculous meningitis in Haihe Hospital, Tianjin University, 3 patients with venous sinus thrombosis were identified retrospectively. "Tuberculous meningitis" and "cerebral venous thrombosis" were used as keywords, and the retrieved literature was summarized and analyzed. Our data were combined with previously reported case data to describe this new condition. RESULTS: Among 28 patients with a median onset age of 31 years for TBM, 17 were females. The manifestations were fever, headache, and seizure. Magnetic resonance imaging (MRI) venography showed that the most common site of venous sinus thrombosis involved superior sagittal sinus, left transverse sinus, left sigmoid sinus, cavernous sinus, and straight sinus. The abnormalities found on MRI include hydrocephalus, exudates, hemorrhage, meningeal enhancement, infarction, and tuberculoma. In the acute phase, all patients received standard anti-TB treatment, and 14/28 patients received anticoagulant treatment. The mortality rate of these patients was 17.9%, and 21/28 (75%) became functionally independent. CONCLUSIONS: CVT is one of the rare complications of TMB and must be considered a differential diagnosis in patients with TBM who show poor clinical features and/or develop new neurological signs.

A Case of Delusional Disorder With Abuse of Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol, the First-Line Anti-tuberculosis Therapy Drugs in India.

Tuberculosis (TB) and mental illnesses frequently coexist and are both extremely common worldwide. Through the National Program for Elimination of Tuberculosis (NTEP), anti-tuberculosis therapy (ATT) medications are used to treat tuberculosis in India. We want to report a case 45-year-old patient from the state of Andhra Pradesh, India with comorbid delusional disorder leading to daily ATT drug consumption for the past 20 years. This unusual presentation demonstrates that abuse of a Schedule "H" substance like ATT is also conceivable. To stop "Off-label" purchases, strict measures must be taken. Before beginning ATT, evaluating the patient's mental health may be a wise move.

Abdominal Tuberculosis Presenting With Small Bowel Obstruction: A Case Report.

Abdominal tuberculosis (TB) is a common form of extrapulmonary TB (EXPTB). It is being reported increasingly, especially in high-burden regions of the world. We present a case of a 37-year-old male who presented to the emergency department with clinical features suggestive of bowel obstruction. On clinical examination, the patient exhibited generalized tenderness in the abdomen. A subsequent CT scan revealed features consistent with small bowel obstruction. The patient underwent a diagnostic laparoscopy, which was converted to an exploratory laparotomy due to intraoperative findings of adhesions. Notably, there were extensive peritoneal deposits and adhesions between bowel loops. Peritoneal biopsies were obtained and subjected to the acid-fast bacillus (AFB) smear and culture, which demonstrated the growth of the Mycobacterium tuberculosis complex. As a result, the patient was initiated on antituberculous therapy.

A Rare Case of Primary Mycobacterium tuberculosis Myositis of the Thigh in an Immunocompetent Infant.

Mycobacterium tuberculosis (MTB) infection is a serious health condition that affects individuals of all age groups. Although MTB infections are more common in immunocompromised patients, they are frequently diagnosed in healthy individuals without apparent risk factors. Extrapulmonary infection is an uncommon manifestation of MTB infection, especially infection of the musculoskeletal system. Here, we present a rare case of a five-month-old immunocompetent infant who presented with a progressively enlarging swelling of the thigh without any other symptoms. After further evaluation, a diagnosis of primary MTB myositis of the thigh was made, which was treated successfully with first-line anti-tuberculosis therapy for nine months. This case report highlights the need to consider MTB infection in infants and children with unusual clinical findings. Due to its nonspecific symptoms and difficulty in diagnosis, clinicians need to maintain a high index of clinical suspicion for MTB infection, even in infants without risk factors for exposure.

Complex Case Management of Mycobacterium Tuberculosis Extrapulmonary Manifestation to the Right Sacroiliac Joint.

While Mycobacterium tuberculosis is a common bacterial pathogen that infects the respiratory system, especially in endemic regions, it may uncommonly manifest in other organ systems, such as the nervous, gastrointestinal, or musculoskeletal systems. Sacroiliac joint infections are rare, and only 1%-5% of all infections are tuberculous in nature. Given nonspecific inflammatory signs in both laboratory and radiologic examinations, early identification of the causative agent can be difficult. In this report, we present the case of a 29-year-old Eritrean woman who presented with an uncommon extrapulmonary tuberculosis manifestation of the right sacroiliac joint. The patient reported pain for two years before a formal diagnosis with multiple computed tomography scans demonstrated fluid collections about her right hip and thigh. The patient's medical history of developmental delay, psychosis, outdated medication documentation, non-therapeutic use of numerous psychiatric medications contraindicated for traditional anti-tubercular therapy, and socioeconomic history of a lack of social support and treatment arrangements with the patient's caregiver all complicated the treatment course. Given the rise in tuberculosis cases worldwide and vulnerability factors in patients with mental illnesses such as poverty, homelessness, diabetes, and HIV infection that can predispose patients to tuberculosis infections, early diagnosis and treatment are essential to reduce long-term consequences and improve clinical outcomes. Further research in the development of new tuberculosis treatment plans is essential to addressing an equitable treatment course alongside fighting against the recent rise in drug-resistant tuberculosis.

A case of extrapulmonary tuberculosis after use of baricitinib.

Extrapulmonary tuberculosis (TB) can occur in patients treated with Janus kinase (JAK) inhibitors. We present a case of rheumatoid arthritis complicated by extrapulmonary TB following baricitinib treatment. A 45-year-old Japanese woman was diagnosed with rheumatoid arthritis at another hospital, and she subsequently started treatment with methotrexate (MTX) at 6.0 mg/week and prednisolone at 3.0 mg/day at our institute. The MTX dose was increased to 10 mg/week, and clinical remission was achieved; however, the disease activity flared up 6 months after the initial visit. Isoniazid (INH) prophylaxis was started following positive T-SPOT® screening for TB, and baricitinib (Olumiant®) was introduced 3 weeks later because of an insufficient response to MTX. INH prophylaxis was continued for 6 months. Ten months after starting INH treatment, a painless mass was observed on the left side of the patient's neck. Magnetic resonance imaging showed enlarged lymph nodes with calcification. A subsequent biopsy and pathologic examination led to a diagnosis of tuberculous lymphadenitis, and the patient was started on anti-TB therapy. Ten months later, the patient was still in remission and doing well. Extrapulmonary TB can be difficult to diagnose because of inconsistent physical and laboratory findings. When treating patients with JAK inhibitors, physicians should be cognisant of the potential for extrapulmonary TB to develop.

Same Pathogen, Different Manifestations: A Case of Extrapulmonary Tuberculosis.

Tuberculosis (TB) remains the most prevalent contagious disease worldwide and a significant cause of morbidity, ranking as the second most deadly disease globally. The transmission of the disease occurs through aerosols via the respiratory route, predominantly affecting pulmonary tissue. However, the pathogen can disseminate and infect any organ within the body. Up to 15% of patients exhibit extrapulmonary involvement. The case involves a 59-year-old male who presented to the emergency department complaining of abdominal pain and subfebrile episodes, without any other significant symptoms or findings on physical examination. Laboratory investigations revealed elevated inflammatory markers and abnormal liver biochemistry parameters. A computed tomography (CT) scan showed a neoformative lesion in the liver - a collection with a vascularized, thick, irregular wall. This raised the possibility of a potentially hypervascular hepatic neoformation or an encysted inflammatory lesion. The patient was started on empirical broad-spectrum antibiotics and was admitted to the Internal Medicine ward for further investigation. Later, the patient began to exhibit a decline in overall condition, a slowed and less complex speech pattern, loss of balance, and distal tremors in the upper limbs, as well as a symmetric and distal reduction in strength in all four limbs. A cerebral CT scan revealed no significant abnormalities, and a lumbar puncture yielded no immediate notable findings. Simultaneously, a repeated abdominal CT scan showed the previously known hepatic lesion, albeit with features more indicative of a multiloculated collection. An aspirative biopsy of the hepatic abscess was conducted. From the extensive analysis conducted, a positive PCR result for mycobacterium tuberculosis was identified in both the pus from the hepatic abscess and the cerebrospinal fluid. This led to the conclusion that the case presented was an instance of extrapulmonary TB involving the liver and the central nervous system. Following the identification of the causative agent, the patient commenced antibacterial therapy comprising rifampicin, ethambutol, and isoniazid with adjunctive dexamethasone. Despite targeted treatment and instituted supportive therapy, the patient exhibited an unfavorable progression and eventually succumbed 57 days after diagnosis. This case highlights an unusual manifestation of a patient with disseminated extrapulmonary TB, emphasizing the importance of early diagnostic suspicion for clinicians. The unfavorable disease progression despite appropriate targeted treatment prompts reflection on whether the delay in diagnosis and provision of anti-TB drugs may have played a major role in the prognosis of the patient.

Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS) Syndrome Induced by Primary Anti-tubercular Medication: A Case Report.

Drug reaction with eosinophilia and systemic syndrome (DRESS) is a life-threatening hypersensitivity reaction of the skin and visceral organs caused by exposure to certain drugs, often with a latency period of two to eight weeks. A 20-year-old man, previously diagnosed with pulmonary tuberculosis (TB) one month ago and receiving treatment with isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE regimen), presented with symptoms including a maculopapular rash, fever, elevated transaminase levels, an increased white blood cell count with eosinophilia, hepatomegaly, and lymphadenopathy. The patient experienced recovery upon cessation of drug use and was administered corticosteroids and supportive therapeutic interventions. Individuals diagnosed with pulmonary TB who are undergoing treatment with first-line anti-tubercular medications have a heightened susceptibility to DRESS. The timely identification and cessation of the offending agent can effectively mitigate mortality.