Susceptibility to tuberculosis is historically ascribed to an inadequate immune response that fails to control infecting mycobacteria. In zebrafish, we find that susceptibility to Mycobacterium ...marinum can result from either inadequate or excessive acute inflammation. Modulation of the leukotriene A4 hydrolase (LTA4H) locus, which controls the balance of pro- and anti-inflammatory eicosanoids, reveals two distinct molecular routes to mycobacterial susceptibility converging on dysregulated TNF levels: inadequate inflammation caused by excess lipoxins and hyperinflammation driven by excess leukotriene B4. We identify therapies that specifically target each of these extremes. In humans, we identify a single nucleotide polymorphism in the LTA4H promoter that regulates its transcriptional activity. In tuberculous meningitis, the polymorphism is associated with inflammatory cell recruitment, patient survival and response to adjunctive anti-inflammatory therapy. Together, our findings suggest that host-directed therapies tailored to patient LTA4H genotypes may counter detrimental effects of either extreme of inflammation.
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► Conserved eicosanoids are regulated by LTA4H activity and impact inflammatory state ► Genotype-directed modulation of TNF improves outcomes in a zebrafish tuberculosis model ► Drug therapies tailored to lta4h genotype improve infection outcome in zebrafish ► In humans, LTA4H genotype associates with responsiveness to therapy for TB meningitis
A polymorphism in a locus that controls the balance between pro- and anti-inflammatory mediators is predictive of response to anti-inflammatory therapy in tuberculous meningitis.
Summary Tuberculous meningitis is especially common in young children and people with untreated HIV infection, and it kills or disables roughly half of everyone affected. Childhood disease can be ...prevented by vaccination and by giving prophylactic isoniazid to children exposed to infectious adults, although improvements in worldwide tuberculosis control would lead to more effective prevention. Diagnosis is difficult because clinical features are non-specific and laboratory tests are insensitive, and treatment delay is the strongest risk factor for death. Large doses of rifampicin and fluoroquinolones might improve outcome, and the beneficial effect of adjunctive corticosteroids on survival might be augmented by aspirin and could be predicted by screening for a polymorphism in LTA4H , which encodes an enzyme involved in eicosanoid synthesis. However, these advances are insufficient in the face of drug-resistant tuberculosis and HIV co-infection. Many questions remain about the best approaches to prevent, diagnose, and treat tuberculous meningitis, and there are still too few answers.
Data concerning intensive care unit (ICU)-acquired bacterial colonization and infections are scarce from low and middle-income countries (LMICs). ICU patients in these settings are at high risk of ...becoming colonized and infected with antimicrobial-resistant organisms (AROs). We conducted a prospective observational study at the Ho Chi Minh City Hospital for Tropical Diseases, Vietnam from November 2014 to January 2016 to assess the ICU-acquired colonization and infections, focusing on the five major pathogens in our setting: Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), Klebsiella spp., Pseudomonas spp. and Acinetobacter spp., among adult patients with more than 48 hours of ICU stay. We found that 61.3% (223/364) of ICU patients became colonized with AROs: 44.2% (161/364) with rectal ESBL-producing E. coli and Klebsiella spp.; 30.8% (40/130) with endotracheal carbapenemase-producing Acinetobacter spp.; and 14.3% (52/364) with nasal methicillin-resistant S. aureus. The incidence rate of ICU patients becoming colonized with AROs was 9.8 (223/2,276) per 100 patient days. Significant risk factor for AROs colonization was the Charlson Comorbidity Index score. The proportion of ICU patients with HAIs was 23.4% (85/364), and the incidence rate of ICU patients contracting HAIs was 2.3 (85/3,701) per 100 patient days. The vascular catheterization (central venous, arterial and hemofiltration catheter) was significantly associated with hospital-acquired bloodstream infection. Of the 77 patients who developed ICU-acquired infections with one of the five specified bacteria, 44 (57.1%) had prior colonization with the same organism. Vietnamese ICU patients have a high colonization rate with AROs and a high risk of subsequent infections. Future research should focus on monitoring colonization and the development of preventive measures that may halt spread of AROs in ICU settings.
Advances in treatment of bacterial meningitis van de Beek, Diederik, Prof; Brouwer, Matthijs C, MD; Thwaites, Guy E, MD ...
The Lancet (British edition),
11/2012, Volume:
380, Issue:
9854
Journal Article
Peer reviewed
Summary Bacterial meningitis kills or maims about a fifth of people with the disease. Early antibiotic treatment improves outcomes, but the effectiveness of widely available antibiotics is threatened ...by global emergence of multidrug-resistant bacteria. New antibiotics, such as fluoroquinolones, could have a role in these circumstances, but clinical data to support this notion are scarce. Additionally, whether or not adjunctive anti-inflammatory therapies (eg, dexamethasone) improve outcomes in patients with bacterial meningitis remains controversial; in resource-poor regions, where the disease burden is highest, dexamethasone is ineffective. Other adjunctive therapeutic strategies, such as glycerol, paracetamol, and induction of hypothermia, are being tested further. Therefore, bacterial meningitis is a substantial and evolving therapeutic challenge. We review this challenge, with a focus on strategies to optimise antibiotic efficacy in view of increasingly drug-resistant bacteria, and discuss the role of current and future adjunctive therapies.
Staphylococcus aureus bacteraemia remains very difficult to treat, and a large proportion of cases result in potentially lethal metastatic infection. Unpredictable and persistent bacteraemia in the ...face of highly active, usually bactericidal antibiotics is the strongest predictor of death or disseminated disease. Although S. aureus has conventionally been considered an extracellular pathogen, much evidence demonstrates that it can survive intracellularly. In this Opinion article, we propose that phagocytes, and specifically neutrophils, represent a privileged site for S. aureus in the bloodstream, offering protection from most antibiotics and providing a mechanism by which the bacterium can travel to and infect distant sites. Furthermore, we suggest how this can be experimentally confirmed and how it may prompt a change in the current paradigm of S. aureus bacteraemia and identify better treatment options for improved clinical outcomes.
Rapid diagnosis and treatment of acute community-acquired bacterial meningitis reduces mortality and neurological sequelae, but can be delayed by atypical presentation, assessment of lumbar puncture ...safety, and poor sensitivity of standard diagnostic microbiology. Thus, diagnostic dilemmas are common in patients with suspected acute community-acquired bacterial meningitis. History and physical examination alone are sometimes not sufficient to confirm or exclude the diagnosis. Lumbar puncture is an essential investigation, but can be delayed by brain imaging. Results of cerebrospinal fluid (CSF) examination should be interpreted carefully, because CSF abnormalities vary according to the cause, patient's age and immune status, and previous treatment. Diagnostic prediction models that use a combination of clinical findings, with or without test results, can help to distinguish acute bacterial meningitis from other causes, but these models are not infallible. We review the dilemmas in the diagnosis of acute community-acquired bacterial meningitis, and focus on the roles of clinical assessment and CSF examination.
Tuberculous meningitis: where to from here? Donovan, Joseph; Thwaites, Guy E; Huynh, Julie
Current opinion in infectious diseases,
2020-June, Volume:
33, Issue:
3
Journal Article
Peer reviewed
Open access
Tuberculous meningitis (TBM) is associated with significant mortality and morbidity yet is difficult to diagnose and treat. We reviewed original research published in the last 2 years, since 1 ...January 2018, which we considered to have a major impact in advancing diagnosis, treatment and understanding of the pathophysiology of TBM meningitis in children and adults.
Studies have sought to identify a high sensitivity diagnostic test for TBM, with new data on modified Ziehl--Neelsen staining, urinary and cerebrospinal fluid (CSF) lipoarabinomannan and GeneXpert Ultra. Recent studies on CSF biomarkers provide a better understanding of the detrimental inflammatory cascade and neuromarkers of brain damage and suggest potential for novel host-directed therapy. Tryptophan metabolism appears to affect outcome and requires further study. Increased clinical trials activity in TBM focuses on optimizing antituberculosis drug regimens and adjuvant therapy; however, there are few planned paediatric trials.
Tuberculous meningitis still kills or disables around half of sufferers. Although some progress has been made, there remains a need for more sensitive diagnostic tests, better drug therapy, improved management of complications and understanding of host-directed therapy if outcomes are to improve.
There is a paucity of data regarding initial bacterial colonization on admission to Intensive Care Units (ICUs) in low and middle-income countries (LMICs). Patients admitted to ICUs in LMICs are at ...high-risk of subsequent infection with antimicrobial-resistant organisms (AROs). We conducted a prospective, observational study at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam from November 2014 to January 2016 to assess the colonization and antimicrobial susceptibility of Staphylococcus aureus, Escherichia coli, Klebsiella spp., Pseudomonas spp. and Acinetobacter spp. among adult patients within 48 hours of ICU admission. We found the admission colonization prevalence (with at least one of the identified organisms) was 93.7% (785/838) and that of AROs was 63.1% (529/838). The colonization frequency with AROs among patients admitted from the community was comparable to those transferred from other hospitals (62.2% vs 63.8%). Staphylococcus aureus was the most commonly isolated bacteria from nasal swabs (13.1%, 110/838) and the methicillin-resistant Staphylococcus aureus nasal colonization prevalence was 8.6% (72/838). We isolated Escherichia coli from rectal swabs from almost all enrolled patients (88.3%, 740/838) and 52.1% (437/838) of patients were colonized by extended spectrum β-lactamase producing Escherichia coli. Notably, Klebsiella pneumoniae was the most frequently isolated bacteria from the tracheal swabs (11.8%, 18/153). Vietnamese ICU patients have a high rate of colonization with AROs and are thus at risk of subsequent infections with these organisms if good infection control practices are not in place.
Increasing antimicrobial resistance in Salmonella Typhi is a serious public health concern, especially in industrializing countries. Here we review recent clinical and laboratory data concerning the ...evolution of antimicrobial resistance, with particular reference to the emergence resistance against fluoroquinolones, third generation cephalosporins, and azithromycin.
The last 40 years have witnessed the sequential emergence of resistance to all first-line antimicrobials used in the treatment of S. Typhi infections. Multidrug resistance (MDR), defined by resistance to chloramphenicol, amoxicillin, and co-trimoxazole, emerged in the 1990s, followed rapidly by reduced susceptibility to fluoroquinolones. In the current decade, high-level fluoroquinolone resistance has emerged in south Asia and threatens to spread worldwide. Increasing reliance is now being placed on the activity of third generation cephalosporins and azithromycin, but resistance against these agents is developing. Carbapenems and tigecycline may be alternatives, although clinical data are sparse, and in some settings reversion to chloramphenicol and co-trimoxazole susceptibility is occurring. Therefore, older drugs may yet have a role in the treatment of S. Typhi infections.
Good surveillance, improved diagnostics, more prudent use of antimicrobials, and effective vaccines will all be critical to reducing the burden of disease caused by S. Typhi.
Tuberculous meningitis is a devastating brain infection that is caused by Mycobacterium tuberculosis and is notoriously difficult to diagnose and treat. New technologies characterising the ...transcriptome, proteome, and metabolome have identified new molecules and pathways associated with tuberculous meningitis severity and poor outcomes that could offer novel diagnostic and therapeutic targets. The next-generation GeneXpert MTB/RIF Ultra assay, when used on CSF, offers diagnostic sensitivity for tuberculous meningitis of approximately 70%, although it is not widely available and a negative result cannot rule out tuberculous meningitis. Small trials indicate that clinical outcomes might be improved with increased doses of rifampicin, the addition of linezolid or fluoroquinolones to standard antituberculosis therapy, or treatment with adjunctive aspirin combined with corticosteroids. Large phase 3 clinical trials are underway worldwide to address these and other questions concerning the optimal management of tuberculous meningitis; these studies also form a platform for studying pathogenesis and identifying novel diagnostic and treatment strategies, by allowing the implementation of new genomic, transcriptomic, proteomic, and metabolomic technologies in nested substudies.
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