SASPI Ltd.
Ethical Principle
WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Participants
Authors: World Medical Association, 13A chemin du Levant, 01210 Ferney-Voltaire, France
Abstract
PREAMBLE:
The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical principles for medical research involving human participants, including research using identifiable human material or data.
The Declaration is intended to be read as a whole, and each of its constituent paragraphs should be applied with consideration of all other relevant paragraphs.
While the Declaration is adopted by physicians, the WMA holds that these principles should be upheld by all individuals, teams, and organizations involved in medical research, as these principles are fundamental to respect for and protection of all research participants, including both patients and healthy volunteers.
Technical document
Estimating the impact of vaccines in reducing antimicrobial resistance and antibiotic use: technical report
Authors: World Health Organization
Abstract
This report provides an in-depth evaluation of the potential role of vaccines in reducing antimicrobial resistance (AMR). It outlines the importance of vaccines as a crucial tool in preventing infections and curbing the spread of resistant strains, thus reducing reliance on antibiotics. Historically, the role of vaccines in reducing AMR has not been fully recognized, with the focus primarily on their use for preventing infectious diseases.
This report is unique in its comprehensive assessment of 44 vaccines targeting 24 pathogens, encompassing both licensed vaccines and those in development. It incorporates a robust methodology to estimate the potential impact of these vaccines on AMR-related health outcomes, antibiotic use, and economic costs. What sets this report apart is its detailed modelling of the burden averted by vaccines and the feasibility of development for each pathogen. The findings underscore the critical role vaccines must play in national and global AMR mitigation strategies.
Other specific ASP article suggested by Editorial Board
Routine immunization against Streptococcus pneumoniae and Haemophilus influenzae type B and antibiotic consumption in India: a dynamic modeling analysis
Authors: Chirag K. Kumar et al.,
Abstract
Background: Childhood vaccinations can reduce disease burden and associated antibiotic use, in turn reducing the risk of antimicrobial resistance (AMR). We retrospectively estimated the population-level reductions in antibiotic use in India following the introduction of vaccines against Streptococcus pneumoniae and Haemophilius influenzae type B in the national immunization program for children in the mid-2010s and projected future gains to 2028 if vaccination coverage were to be increased.
Methods: Using IndiaSim, a dynamic agent-based microsimulation model (ABM) for India, we simulated the spread of Streptococcus pneumoniae and Haemophilius influenzae type B (Hib) among children to estimate reductions in antibiotic use under the scenarios of: (i) pneumococcal and Hib vaccine coverage levels equivalent to the national coverage of pentavalent diphtheria-pertussis-tetanus third dose (DPT3) compared to a baseline of no vaccination, and (ii) near-universal (90%) coverage of the vaccines compared to pre-COVID national DPT3-level coverage. Model parameters, including national DPT3 coverage rates, were based on data from the National Family Household Survey 2015–2016 and other published sources. We quantified reductions in antibiotic consumption nationally and by state and wealth quintiles.
Findings: We estimate that coverage of S. pneumoniae and Hib vaccines at the same level as DPT3 in India would translate to a 61.4% [95% UI: 43.8–69.5] reduction in attributable antibiotic use compared to a baseline of zero vaccination coverage. Increases in childhood vaccination coverage between 2004 and 2016 have likely reduced attributable antibiotic demand by as much as 93.4% among the poorest quintile. Increasing vaccination coverage by an additional 11 percentage points from 2016 levels results in mortality and antibiotic use across wealth quintiles becoming increasingly similar (p < 0.05), reducing in health inquities. We project that near-universal vaccine coverage would further reduce inequities in antibiotic demand and may eliminate of outbreak-associated antibiotic use from S. pneumoniae and Hib.
Interpretation: Though vaccination has a complex relationship with antibiotic use because both are modulated by socioeconomic factors, increasing vaccinations for S. pneumoniae and Hib may have a significant impact on reducing antibiotic use and improving health outcomes among the poorest individuals.
Systematic review/Scoping review with large effect size
Antibiotics for Pediatric Acute Bacterial Sinusitis
DOI:- 10.1001/jama.2024.2018
Authors: Kathleen Chiotos et al.,
Abstract
Acute bacterial rhinosinusitis (ABRS), defined as a bacterial infection of the nasal cavity and one or more sinuses persisting for less than 4 weeks, is a common diagnostic consideration in pediatric care. Nearly 5 million US children are prescribed antibiotics for ABRS annually in ambulatory settings. The Infectious Diseases Society of America (IDSA)1 and American Academy of Pediatrics (AAP)2 published guidelines for management of ABRS in 2012 and 2013, respectively. However, these guidelines are more than 10 years old and they differ in their recommendations for first-line antibiotic therapy. The IDSA recommends amoxicillin-clavulanate and the AAP recommends amoxicillin or amoxicillin-clavulanate. This article reviews antibiotic selection for ABRS, considering evidence published since 2013.
Other specific ASP article suggested by Editorial Board
Addressing urgent priorities in antibiotic development: insights from WHO 2023 antibacterial clinical pipeline analyses
Authors: Daniela Melchiorri et al.,
Abstract
Summary: Antimicrobial resistance continues to evolve and remains a leading cause of death worldwide, with children younger than 5 years being among those at the highest risk. Addressing antimicrobial resistance requires a comprehensive response, including infection prevention efforts, surveillance, stewardship, therapy appropriateness and access, and research and development. However, antimicrobial research and development is limited and lags behind the output of other fields, such as that of cancer or HIV research. The 2023 WHO analysis of the global antibacterial clinical pipeline serves as a tool to monitor and guide research and development efforts. The analysis emphasises the remaining gaps in developing a robust and effective antibacterial drug pipeline, drawing insights from trend analyses and assessment of the innovation potential of candidate antimicrobials. In the present analysis, we evaluated the activity of antibiotics against the new WHO bacterial priority pathogens list 2024, which reflects changing trends in resistance patterns, distribution of bacterial infections, and the emergence of new resistance mechanisms.
Multi-centric observational study with large effect
A nationwide mixed methods study of gaps and barriers to implementation of antimicrobial stewardship programs in hospitals in Indonesia
Authors: Robert Sinto et al.,
Abstract
Background: There is an urgent need to understand the implementation barriers of antimicrobial stewardship programs (ASP) in low- and middle-income countries.
Methods: We conducted a mixed-methods study in public and private hospitals across all provinces in Indonesia (March-December 2023). We used a self-assessment questionnaire with a scoring system, and multilevel ordinal regression to assess associations with hospital and district-level characteristics. Focus group discussions (FGD) with hospital stakeholders examined barriers and enablers. We applied a patient safety framework to integrate results.
Results: 575 (19%) of 3026 hospitals completed the self-assessment, of whom 516 (89.7%) had a formal ASP (median 4 [IQR1-5] years), and 14 participated in FGD. The median overall ASP development score was 48.4% (35.9-62.5%), classifying 41 (8.0%) hospitals as inadequate (0-25%), 237 (45.9%) as basic (26-50%), 179 (34.7%) as intermediate (51-75%) and 59 (11.4%) as advanced (76-100%). Scores were highest for hospital leadership support (83.4% [66.7-100%]), followed by ASP team and infectious disease training (66.7% [55.6-77.8%]); education (50% [0.0-75.0%]); ASP interventions (43.8% [18.7-68.7%]); hospital infrastructure (42.9% [14.3-71.4%]); and monitoring, reporting and feedback (40.9% [27.3-54.5%]). A higher ASP development score was associated with higher hospital tiered level, longer ASP duration, and higher district-level public health development index and per capita domestic expenditure, but not with hospital ownership or geographic region. FGDs highlighted barriers related to hospital leadership support, staff technical and behavioral skills, cross-disciplinary collaboration, fear of loss of prescriber autonomy, microbiology and IT support, and hospital accreditation.
Conclusions: Identified implementation barriers can inform actions for context-specific, sustainable improvement of ASPs.
Other specific DSP article suggested by Editorial Board
Approaches to developing and implementing a molecular diagnostics stewardship program for infectious diseases: an ASM Laboratory Practices Subcommittee report
Authors: Frances Valencia-Shelton et al.,
Abstract
Diagnostic stewardship (DxS) for infectious disease testing requires a multi-disciplinary approach to optimize test selection, performance, interpretation and patient treatment. Nucleic acid amplification-based tests for the diagnosis of infectious diseases, or “molecular microbiology tests,” have rapidly expanded over the past two decades. With the increased availability and complexity of these tests, there is also an increased need for collaborative approaches to optimize test use to promote positive impacts on patient care, while mitigating potential negative impact or resource waste. In this review, we provide recommendations on building collaborative DxS teams, including microbiologists and the diverse stakeholders that use and interpret molecular microbiology tests. We then detail approaches to identify high-priority molecular microbiology tests that may need utilization assessment, select appropriate diagnostic stewardship interventions, and monitor the impact of implemented interventions. This strategic process may be employed by laboratories to realize optimal testing for selected tests at their institution.
Other specific DSP article suggested by Editorial Board
Rapid multiplex PCR panel for pneumonia in hospitalised patients with suspected pneumonia in the USA: a single-centre, open-label, pragmatic, randomised controlled trial
Authors: Abinash Virk et al.,
Abstract
Background: The clinical utility of rapid multiplex respiratory specimen PCR panels for pneumonia for patients with suspected pneumonia is undefined. We aimed to compare the effect of the BioFire FilmArray pneumonia panel (bioMérieux, Salt Lake City, UT, USA) with standard of care testing on antibiotic use in a real-world hospital setting.
Methods: We conducted a single-centre, open-label, pragmatic, randomised controlled trial at the Mayo Clinic, Rochester, MN, USA. Hospitalised patients (aged ≥18 years) with suspected pneumonia, from whom expectorated or induced sputum, tracheal secretions, or bronchoalveolar lavage fluid respiratory culture samples (one per individual) could be collected during index hospitalisation, were eligible for inclusion. Samples from eligible participants were randomly assigned (1:1) with a computerised tool to undergo testing with either the BioFire FilmArray pneumonia panel, conventional culture, and antimicrobial susceptibility testing (intervention group) or conventional culture and antimicrobial susceptibility testing alone (control group). Antimicrobial stewardship review in both groups involved an assessment and recommendations for antibiotic modifications based on clinical data and the results from the BioFire FilmArray pneumonia panel, conventional culture, or both. The primary outcome was median time to first antibiotic modification (ie, escalation or de-escalation of antibiotics against Gram-negative and Gram-positive bacteria) within 96 h of randomisation, assessed with the Wilcoxon rank-sum test and analysed in a modified intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT05937126).
Findings: Between Sept 15, 2020, and Sept 19, 2022, 1547 patients were screened for eligibility, of whom 1181 (76·3%) were randomly assigned: 582 (49·3%) to the intervention group and 599 (50·7%) to the control group. In total, 1152 participants were included in the modified intention-to-treat analysis, 589 (51·1%) in the control group and 563 (48·9%) in the intervention group. For the modified intention-to-treat population, median time to any first antibiotic modification was 20·4 h (95% CI 18·0–20·4) in the intervention group and 25·8 h (22·0–28·7) in the control group (p=0·076). Median time to any antibiotic escalation was 13·8 h (9·2–19·0) in the intervention group and 24·1 h (19·5–29·6) in the control group (p=0·0022). Median time to escalation of antibiotics against Gram-positive organisms was 10·3 h (6·2–30·9) in the intervention group and 24·6 h (19·5–37·2) in the control group (p=0·044); median time to escalation of antibiotics against Gram-negative organisms was 17·3 h (10·8–23·3) in the intervention group and 27·2 h (21·3–33·9) in the control group (p=0·010). Median time to any antibiotic de-escalation did not differ between groups (p=0·37). Median time to first de-escalation of antibiotics against Gram-positive organisms was 20·7 h (17·8–24·0) in the intervention group and 27·8 h (22·9–33·0) in the control group (p=0·015); median time to first de-escalation of antibiotics against Gram-negative organisms did not differ between groups (p=0·46).
Interpretation: Clinical use of the BioFire FilmArray pneumonia panel might lead to faster antibiotic escalations, including for Gram-negative or Gram-positive bacteria, and faster antibiotic de-escalations directed at Gram-positive bacteria. Additional research is needed regarding antimicrobial de-escalation, especially when antibiotics with broad Gram-negative spectrum are being used, by use of rapid diagnostics in patients with lower respiratory tract infection..
Systematic review/Scoping review with large effect size
Laboratory‐based molecular test alternatives to RT‐PCR for the diagnosis of SARS‐CoV‐2 infection
Authors: Ingrid Arevalo-Rodriguez et al.,
Abstract
Main results
Only tests specifically designed to omit/adapt RNA extraction/purification and TMA assays with RNA extraction (a type of isothermal test) met WHO‐acceptable standards for confirming and ruling out SARS‐CoV‐2. For illustration, the results of these studies indicate that in a group of 1000 people, 50 of whom (5%) actually have SARS‐CoV‐2:
* For tests specifically designed to omit/adapt RNA extraction/purification:
‐51 people would test positive for SARS‐CoV‐2. Of these, three people (6%) would not have SARS‐CoV‐2 (false‐positive result).
‐949 people would test negative for SARS‐CoV‐2. Of these, two people (0.2%) would actually have SARS‐CoV‐2 (false‐negative result)
*For TMA tests with RNA extraction:
‐55 people would test positive for SARS‐CoV‐2. Of these, six people (10%) would not have SARS‐CoV‐2 (false‐positive result).
‐945 people would test negative for SARS‐CoV‐2. Of these, one person (0.1%) would actually have SARS‐CoV‐2 (false‐negative result)
Other specific ISP article suggested by Editorial Board
Utility of cell index in the diagnosis of healthcare-associated ventriculitis and meningitis: an analytical cross-sectional study
Authors: Jao Jarro B. Garcia et al.,
Abstract
Background: The diagnosis of healthcare-associated ventriculitis and meningitis (HCAVM) can be complex because multiple factors confound the interpretation of cerebrospinal fluid (CSF) tests. The cell index (CI) may help in the diagnosis of HCAVM. It does not incur additional medical cost and it avoids delays from the turnaround time of CSF cultures. It is derived by calculating the ratio of CSF white blood cell (WBC) and red blood cell (RBC) divided by the ratio of peripheral WBC and RBC. This study aimed to evaluate the diagnostic utility of this parameter.
Methods: An analytic, observational, cross-sectional study was conducted at the University of the Philippines – Philippine General Hospital. All admitted pediatric and adult patients from 2015 to 2022 who underwent external ventricular drain (EVD) insertion for hydrocephalus secondary to intracranial hemorrhage (ICH), acute ischemic stroke, intracranial neoplasms, traumatic brain injury, or congenital hydrocephalus were screened. Records of patients fulfilling the inclusion criteria were then reviewed.
Results: A total of 363 patients underwent EVD insertion from 2015 to 2022. Of these, 161 were included in the study. Two-thirds (66.5%) were adults ≥ 19 years old whereas the remaining were pediatric patients 1 to < 19 years old. There were no patients < 12 months old as they fulfilled at least one exclusion criteria. Forty-nine of them were later confirmed to have HCAVM based on the CDC/NHSN criteria. A CI cut-off of ≥ 1.21 gave a maximum sensitivity of 30.6% and specificity of 86.4%. Receiver operating characteristic area under the curve (AUC-ROC) analysis was 0.585. Subgroup analysis by age showed sensitivity of 52.9% in the pediatric age group and 3.13% in adults. Subgroup analysis by neurologic indication showed sensitivity of 27.6% for ICH and 35.0% for neoplasms. Subsequent AUC-ROC analyses, however, showed that CI failed to adequately diagnose HCAVM in these subgroups.
Conclusions: In our population of neurologic patients who underwent EVD insertion, the cell index is not a reliable parameter in the diagnosis of HCAVM.
Other specific DSP article suggested by Editorial Board
Trends of Common Laboratory Biomarkers after SARS-CoV-2 Infection
Authors: Tomer David Meirman et al.,
Abstract
Background: Most studies that explore the long-term effects of COVID-19 are based on subjectively reported symptoms, while laboratory measured biomarkers are mainly examined in studies of relatively small cohorts. This study investigates the long-term effects of SARS-CoV-2 infection on common laboratory biomarkers.
Methods: We utilized a retrospective cohort of SARS-CoV-2 infected individuals and rigorously matched controls based on demographic and clinical characteristics, examining 63 common laboratory biomarkers. Additional lab-specific cohorts were matched with an additional criterion of baseline biomarker values. Differences in biomarkers over a 12-month follow-up were analyzed using standardized mean difference-in-differences.
Results: The general cohort included 361,061 matched pairs, with 26M laboratory results. The effects on most biomarkers lasted 1-4 months and were consistent with anticipated changes after acute viral infections. Some biomarkers presented prolonged effects, consistent across the general and lab-specific cohorts. One group of such findings included a 7-8 month decrease in WBC counts, mainly driven by decreased counts of neutrophils, monocytes, and basophils. Potassium levels were decreased for 3-5 months. Vaccinated individuals’ data suggested potentially smaller effects on WBCs, but cohort sizes limited this analysis.
Conclusions: This study explores SARS-CoV-2 infection effects on common laboratory biomarkers, characterizing the direction and duration of these effects on the largest infected cohort to date. The effects of most biomarkers resolve in the first months following infection. The most notable longer-lasting effects involved the immune system. Further research is required to characterize the magnitude of these effects among specific individuals.
RCTs having large positive / negative effect
Effect of colistin combined with sulbactam: 9 g versus 12 g per day on mortality in the treatment of carbapenems resistant Acinetobacter baumannii pneumonia: a randomized controlled trial.
Authors: Chutchawan Ungthammakhun et al.,
Abstract
Background: The current treatment recommendation involves administering a high dose of sulbactam alongside at least one additional agent. However, there remains a lack of data regarding the optimal dosage of sulbactam. We investigated whether administering sulbactam at a dosage of 12 g/day decreases the mortality rate among patients with CRAB pneumonia compared to 9 g/day.
Methods: The study was an open-label, superiority, randomized controlled trial conducted at Phramongkutklao Hospital between September 2019 and September 2023 in patients diagnosed with CRAB. Participants were randomly assigned to receive a combination of colistin with either 9 or 12 g/day of sulbactam. The primary endpoint was the all-cause mortality rate at 28 days post-randomization.
Results: Among the 138 participants, there was a trend toward a lower mortality rate in the 12 g/day group (59.4% vs. 47.8%; p = 0.158). After adjusting for factors associated with mortality, a lower mortality was observed in the 12 g/day group (adjusted HR 0.54 [95% CI 0.33-0.87]; p = 0.0110). The microbiological cure rate at day 7 was higher in the 12 g/day group (73.2% vs. 89.4%; p = 0.02).
Conclusions: Colistin in combination with sulbactam at a dosage of 12 g/day may improve mortality compared to 9 g/day.
RCTs having large positive / negative effect
Efficacy of extended infusion of β-lactam antibiotics for the treatment of febrile neutropenia in haematologic patients (BEATLE): a randomised, multicentre, open-label, superiority clinical trial
Authors: Julia Laporte-Amargos et al.,
Abstract
Objectives: The efficacy of extended infusions (EI) of β-lactam antibiotics for optimising outcomes in febrile neutropenia is unclear. We assessed whether the administration of β-lactams was more effective in EI than in intermittent infusion (II) for the treatment of febrile neutropenia.
Methods: We performed a randomised, open-label, superiority clinical trial of patients with febrile neutropenia at four Spanish university hospitals. Patients undergoing haematopoietic stem cell transplantation or with acute leukaemia receiving chemotherapy who required empirical antibiotic treatment for febrile neutropenia were randomly assigned (1:1) to receive EI of β-lactam or II after a first dose in bolus. The choice of antipseudomonal β-lactam was left to the discretion of the attending physician. The primary endpoint was treatment success at day 5, defined as defervescence without modifying the antibiotic treatment. Secondary endpoints included adverse events, attainment of the pharmacokinetic/pharmacodynamic target of 50, 75 and 100%ƒuT>MIC, and 30-day mortality.
Results: Between November 19, 2019 and June 22, 2022, 295 patients we screened for eligibility, of whom 150 were randomly assigned to receive EI (n=77) or II (n=73) of the antipseudomonal β-lactam of choice. In the intention-to-treat analysis, treatment success at day 5 was achieved in 39/77 patients (50.6%) receiving EI versus 46/73 patients (63.0%) receiving II (risk difference -12.4%; 95% confidence interval, -29.4 to 4.7, p=0.17). The pharmacokinetic/pharmacodynamic targets of 75 and 100% ƒuT>MIC for empirical treatment were achieved more frequently in the EI group. No statistically-significant differences were found between groups in terms of adverse events or 30-day mortality.
Conclusions: Our findings do not support the routine use of empirical EI of β-lactams in febrile neutropenia. Further studies should consider the clinical heterogeneity of febrile neutropenia and focus on patients with sepsis/septic shock and microbiologically documented infections, particularly those with infections caused by microorganisms less susceptible to β-lactams.
Other specific DSP article suggested by Editorial Board
Candida auris MIC testing by EUCAST and CLSI broth microdilution, and gradient diffusion strips; to be or not to be amphotericin B resistant?
Authors: Arendrup, Maiken Cavling et al.
Abstract
Objectives: Reported amphotericin B resistance rates for Candida auris vary considerably. This may reflect clinically relevant differences in susceptibility, technical issues with testing or adoption of a clinical breakpoint (BP) that bisects the wild-type population. We compared reference methods and two gradient diffusion strips using a shared C. auris strain collection.
Methods: Forty C. auris strains from nine US states and ≥3 clades were included. Fourteen MIC data sets were generated using EUCAST E.Def 7.4, CLSI M27Ed4, Etest and MTS (Liofilchem) strip MICs. MICs ≤1 mg/L were classified as susceptible.
Results: EUCAST and CLSI amphotericin B MIC testing were robust across included method variables. The modal MIC was 1 mg/L, distributions unimodal and narrow with similar GM-MICs (0.745-1.072); however, susceptibility classification varied (0-28% resistance). Gradient diffusion strip testing resulted in wider and bimodal distributions for 8/9 data sets. If adopting, per manufacturer’s protocol, double inoculation for the Etest method, the modal MIC increased to 2-4 mg/L and resistance rates to 45-63% versus 25-30% with the single inoculation. The EUCAST, CLSI, Etest and MTS strip MICs correlated to the OD of drug-free control EUCAST wells suggesting that some isolates grew better than others and that this was associated with MIC.
Conclusions: The EUCAST and CLSI MIC results were in close agreement, whereas the strip test showed wider and bimodal distributions with reader to reader and centre to centre variation. Our study adds to the concern for commercial MIC testing of amphotericin B against C. auris and suggest the current breakpoint leads to random susceptibility classification.
Other specific ASP article suggested by Editorial Board
Linezolid Pharmacokinetic-Anemia Modeling in Children with Rifampicin-Resistant Tuberculosis
Authors: Jordan T Brooks et al.,
Abstract
Background: Linezolid, an important component of rifampicin- and multidrug-resistant tuberculosis (RR/MDR-TB) treatment, is associated with treatment-limiting toxicities, including anemia. Patient-level and linezolid pharmacokinetic risk factors for anemia have not been well described in children treated for RR/MDR-TB.
Methods: We evaluated the pharmacokinetics of linezolid and longitudinal hemoglobin data to validate an existing population linezolid pharmacokinetic model. We assessed the impact of linezolid pharmacokinetics and the risk of developing anemia in a prospectively enrolled cohort of children. The validation of a previously published population pharmacokinetic linezolid model used nonlinear mixed effects modeling. A multivariable ordinal logistic regression model was built to predict the incidence of anemia.
Results: A total of 112 children, median age 7.2 (IQR: 2.2–16.3) years, were included from South Africa (n=87) and India (n=25). Of these, 24 children contributed new linezolid pharmacokinetic data. The population pharmacokinetic model which informs the currently recommended linezolid dosing in children (10-15 mg/kg) was validated with these additional new data. For every 1 g/dL lower baseline hemoglobin, the odds of developing grade 3 or 4 anemia increased by 2.64 (95% CI 1.98-3.62). For every 1 mg/L*h higher linezolid area under the concentration-time curve (AUC), the odds of developing a grade 3 or 4 anemia increased by 1.012 (95% CI 1.007-1.017).
Conclusions: These data taken together, confirm currently recommended linezolid doses in children. The risk of anemia in children should be carefully considered and monitored throughout. Initiating linezolid in children with low baseline hemoglobin increases the probability of experiencing grade 3 or 4 anemia.
Other specific DSP article suggested by Editorial Board
Engineered Mycobacteriophage TM4::GeNL Rapidly Determines Bedaquiline, Pretomanid, Linezolid, Rifampicin, and Clofazimine Sensitivity in Mycobacterium tuberculosis Clinical Isolates
Authors: Saranathan Rajagopalan et al.,
Abstract
Background: Drug-resistant tuberculosis is a growing public health threat, and early characterization of the resistance phenotype is essential for guiding treatment and mitigating the high mortality associated with the disease. However, the slow growth rate of Mycobacterium tuberculosis, the causative agent of tuberculosis, necessitates several weeks for conventional culture-dependent drug susceptibility testing (DST). In addition, there are no widely available molecular diagnostic assays for evaluating resistance to newer tuberculosis drugs or drugs with complex resistance mechanisms.
Methods: We have developed a luciferase-based reporter mycobacteriophage assay that can determine drug resistance within 48 hours. We engineered the TM4 mycobacteriophage to express green enhanced nanoluciferase (GeNL) cassette and optimized DST for bedaquiline, pretomanid, linezolid, clofazimine, and rifampicin using clinical M. tuberculosis isolates.
Results: To assess the feasibility of this assay, we conducted a proof-of-principle study using 53 clinical M. tuberculosis isolates. TM4::GeNL phage DST effectively distinguished between sensitive and resistant isolates for bedaquiline and rifampicin at a concentration of 0.125 μg/mL. Optimal differentiation between sensitive and resistant isolates for pretomanid, clofazimine, and linezolid was achieved at concentrations of 0.5 μg/mL, 0.25 μg/mL, and 1 μg/mL, respectively. Additionally, TM4::GeNL DST identified low-level rifampicin resistance in clinical isolates even though they were classified as sensitive by Mycobacteria Growth Indicator Tube DST.
Conclusions: TM4::GeNL reporter phage DST offers a rapid method to identify M. tuberculosis drug resistance, including resistance to newer tuberculosis drugs.
Other specific ASP article suggested by Editorial Board
The top 10 papers on the treatment of invasive fungal infections, 2018–2023
Authors: Kayla R. Stover et al.,
Abstract
Background: Invasive fungal infections are responsible for a large number of infections in hospitalized patients annually and are responsible for high morbidity and mortality. Familiarity with novel agents or strategies in this area can be challenging.
Objectives: To identify the top 10 manuscripts on the treatment of invasive fungal infections from 2018 to 2023.
Design: Modified Delphi consensus-building technique.
Methods: A three-stage consensus-building approach was used comprised of (1) identifying relevant articles; (2) voting by a panel of experts to establish consensus on the importance of these articles; and (3) finalizing the list of top articles by a small group. Members of the Southeastern Research Group Endeavor network served as content experts. Publications from 2018 to 2023 were evaluated if articles met the following inclusion criteria: (1) published between 2018 and 2023, (2) contained content related to fungal infections, and (3) included an actionable intervention.
Results: A total of 6518 potential publications were assessed. After applying inclusion and exclusion criteria, 82 articles were reviewed. The top 10 publications related to invasive fungal infections, selected by a panel of experts, are summarized in this manuscript and include publications related to the treatment of invasive aspergillosis, candidiasis, and cryptococcosis.
Conclusion: This article highlights the selected publications and may serve as a key resource for teaching and training. Clinicians may also employ these reported interventions to identify new opportunities to optimize antifungal therapeutic strategies within one’s institution