Novel drugs against tuberculosis: a clinician's perspective.

The United Nations Millennium Development Goal of reversing the global spread of tuberculosis by 2015 has been offset by the rampant re-emergence of drug-resistant tuberculosis, in particular fluoroquinolone-resistant multidrug-resistant and extensively drug-resistant tuberculosis. After decades of quiescence in the development of antituberculosis medications, bedaquiline and delamanid have been conditionally approved for the treatment of drug-resistant tuberculosis, while several other novel compounds (AZD5847, PA-824, SQ109 and sutezolid) have been evaluated in phase II clinical trials. Before novel drugs can find their place in the battle against drug-resistant tuberculosis, linezolid has been compassionately used with success in the treatment of fluoroquinolone-resistant multidrug-resistant tuberculosis. This review largely discusses six novel drugs that have been evaluated in phase II and III clinical trials, with focus on the clinical evidence for efficacy and safety, potential drug interactions, and prospect for using multiple novel drugs in new regimens.

WHO global research priorities for antimicrobial resistance in human health.

The WHO research agenda for antimicrobial resistance (AMR) in human health has identified 40 research priorities to be addressed by the year 2030. These priorities focus on bacterial and fungal pathogens of crucial importance in addressing AMR, including drug-resistant pathogens causing tuberculosis. These research priorities encompass the entire people-centred journey, covering prevention, diagnosis, and treatment of antimicrobial-resistant infections, in addition to addressing the overarching knowledge gaps in AMR epidemiology, burden and drivers, policies and regulations, and awareness and education. The research priorities were identified through a multistage process, starting with a comprehensive scoping review of knowledge gaps, with expert inputs gathered through a survey and open call. The priority setting involved a rigorous modified Child Health and Nutrition Research Initiative approach, ensuring global representation and applicability of the findings. The ultimate goal of this research agenda is to encourage research and investment in the generation of evidence to better understand AMR dynamics and facilitate policy translation for reducing the burden and consequences of AMR.

Peripheral nervous system involvement associated with COVID-19. A systematic review of literature.

There is increasing evidence of both central and peripheral nervous system (PNS) involvement in COVID-19. We conducted this systematic literature review to investigate the characteristics, management and outcomes of patients with PNS, including the types and severity of cranial nerves (CN) involvement. We systematically searched on PubMed for studies reporting adult patients diagnosed with COVID-19 and PNS involvement until July 2021. From 1670 records, 225 articles matched the inclusion criteria, with a total of 1320 neurological events, in 1004 patients. There were 805 (61%) CN, 350 (26.5%) PNS, and 165 (12.5%) PNS plus CN events. The most frequently involved CN were the facial, vestibulo-cochlear and olfactory nerve in 27.3%, 25.4% and 16.1%, respectively. Guillain-Barre syndrome spectrum was identified in 84.2% of PNS events. We analysed 328 patients reported in 225 articles with CN, PNS, and PNS plus CN involvement. The patients with CN involvement were younger (mean age 46.2±17.1, p = .003), and were more frequently treated as outpatients (p < .001), mostly with glucocorticoids (p < .001). Patients that had PNS with or without CN involvement were more likely to be hospitalized (p < .001), and to receive intravenous immunoglobulins (p = .002) or plasma exchange (p = .002). Patients with CN, PNS, and PNS plus CN had severe COVID -19 disease in 24.8%, 37.3%, 34.9% respectively. The most common neurological outcome was mild/moderate sequelae in patients with CN, PNS, and PNS plus CN in 54.7%, 67.5% and 67.8% respectively (p = .1) and no significant difference was found between the three categories regarding death, disease severity, time from disease onset to neurological symptoms, lack of improvement and complete recovery. CN involvement was the most frequent PNS finding. All three categories of PNS involvement were rather associated to non-severe COVID-19 but it may be an important cause of hospitalization and post COVID-19 sequelae.

Global knowledge gaps on antimicrobial resistance in the human health sector: A scoping review.

OBJECTIVES: To identify and summarize existing global knowledge gaps on antimicrobial resistance (AMR) in human health, focusing on the World Health Organization (WHO) bacterial priority pathogens, Mycobacterium tuberculosis, and selected fungi. METHODS: We conducted a scoping review of gray and peer-reviewed literature, published in English from January 2012 through December 2021, that reported on the prevention, diagnosis, treatment, and care of drug-resistant infections. We extracted relevant knowledge gaps and, through an iterative process, consolidated those into thematic research questions. RESULTS: Of 8409 publications screened, 1156 were included, including 225 (19.5%) from low- and middle-income countries. A total of 2340 knowledge gaps were extracted, in the following areas: antimicrobial research and development, AMR burden and drivers, resistant tuberculosis, antimicrobial stewardship, diagnostics, infection prevention and control, antimicrobial consumption and use data, immunization, sexually transmitted infections, AMR awareness and education, policies and regulations, fungi, water sanitation and hygiene, and foodborne diseases. The knowledge gaps were consolidated into 177 research questions, including 78 (44.1%) specifically relevant to low- and middle-income countries and 65 (36.7%) targeting vulnerable populations. CONCLUSION: This scoping review presents the most comprehensive compilation of AMR-related knowledge gaps to date, informing a priority-setting exercise to develop the WHO Global AMR Research Agenda for the human health sector.

Diagnostic yield of urine lipoarabinomannan and sputum tuberculosis tests in people living with HIV: a systematic review and meta-analysis of individual participant data.

BACKGROUND: Sputum is the most widely used sample to diagnose active tuberculosis, but many people living with HIV are unable to produce sputum. Urine, in contrast, is readily available. We hypothesised that sample availability influences the diagnostic yield of various tuberculosis tests. METHODS: In this systematic review and meta-analysis of individual participant data, we compared the diagnostic yield of point-of-care urine-based lipoarabinomannan tests with that of sputum-based nucleic acid amplification tests (NAATs) and sputum smear microscopy (SSM). We used microbiologically confirmed tuberculosis based on positive culture or NAAT from any body site as the denominator and accounted for sample provision. We searched PubMed, Web of Science, Embase, African Journals Online, and clinicaltrials.gov from database inception to Feb 24, 2022 for randomised controlled trials, cross-sectional studies, and cohort studies that assessed urine lipoarabinomannan point-of-care tests and sputum NAATs for active tuberculosis detection in participants irrespective of tuberculosis symptoms, HIV status, CD4 cell count, or study setting. We excluded studies in which recruitment was not consecutive, systematic, or random; provision of sputum or urine was an inclusion criterion; less than 30 participants were diagnosed with tuberculosis; early research assays without clearly defined cutoffs were tested; and humans were not studied. We extracted study-level data, and authors of eligible studies were invited to contribute deidentified individual participant data. The main outcomes were the tuberculosis diagnostic yields of urine lipoarabinomannan tests, sputum NAATs, and SSM. Diagnostic yields were predicted using Bayesian random-effects and mixed-effects meta-analyses. This study is registered with PROSPERO, CRD42021230337. FINDINGS: We identified 844 records, from which 20 datasets and 10 202 participants (4561 [45%] male participants and 5641 [55%] female participants) were included in the meta-analysis. All studies assessed sputum Xpert (MTB/RIF or Ultra, Cepheid, Sunnyvale, CA, USA) and urine Alere Determine TB LAM (AlereLAM, Abbott, Chicago, IL, USA) in people living with HIV aged 15 years or older. Nearly all (9957 [98%] of 10 202) participants provided urine, and 82% (8360 of 10 202) provided sputum within 2 days. In studies that enrolled unselected inpatients irrespective of tuberculosis symptoms, only 54% (1084 of 1993) of participants provided sputum, whereas 99% (1966 of 1993) provided urine. Diagnostic yield was 41% (95% credible interval [CrI] 15-66) for AlereLAM, 61% (95% Crl 25-88) for Xpert, and 32% (95% Crl 10-55) for SSM. Heterogeneity existed across studies in the diagnostic yield, influenced by CD4 cell count, tuberculosis symptoms, and clinical setting. In predefined subgroup analyses, all tests had higher yields in symptomatic participants, and AlereLAM yield was higher in those with low CD4 counts and inpatients. AlereLAM and Xpert yields were similar among inpatients in studies enrolling unselected participants who were not assessed for tuberculosis symptoms (51% vs 47%). AlereLAM and Xpert together had a yield of 71% in unselected inpatients, supporting the implementation of combined testing strategies. INTERPRETATION: AlereLAM, with its rapid turnaround time and simplicity, should be prioritised to inform tuberculosis therapy among inpatients who are HIV-positive, regardless of symptoms or CD4 cell count. The yield of sputum-based tuberculosis tests is undermined by people living with HIV who cannot produce sputum, whereas nearly all participants are able to provide urine. The strengths of this meta-analysis are its large size, the carefully harmonised denominator, and the use of Bayesian random-effects and mixed-effects models to predict yields; however, data were geographically restricted, clinically diagnosed tuberculosis was not considered in the denominator, and little information exists on strategies for obtaining sputum samples. FUNDING: FIND, the Global Alliance for Diagnostics.

Ejaculate for Microbiological Culture: To Wash or Not To Wash?

Bacteria can be associated with male infertility. Antibacterial substances (e.g., zinc-containing proteins, antimicrobial peptides) in ejaculates might impair the growth of bacteria in culture. We therefore wanted to test if removing antibacterial substances by washing the ejaculate could improve the detection of bacteria in culture. All ejaculates from patients ≥18 years old, which were obtained for routine diagnostics to assess male infertility were included in this study (no exclusion criteria were applied). Test samples were diluted with 2 mL sterile 0.45% saline, vortexed, and centrifuged (5 min; 7.5 × g). After the removal of 2 mL of the supernatant and resuspension, 10 µL of the pellet was used for aerobic and anaerobic culture. Control samples were cultured identically but without washing. Species identification was done with matrix-assisted laser desorption ionization-time of flight mass spectrometry. A total of 186 samples were included. The data set was stratified into five groups (Gram-negative rods [GNR], anaerobes [AN], Enterococcus spp. [EC], coagulase-negative staphylococci [CNS], and viridans streptococci [VS]). Compared to the control arm, the test arm revealed significant lower proportions for CNS (59.1% versus 44.6%, P < 0.01) and VS (53.8% versus 41.9%, P = 0.03). Similarly, slightly lower proportions of GNR (16.1% versus 15.1%, P = 0.89), AN (19.9% versus 17.2%, P = 0.5), and EC (25.3% versus 23.1%, P = 0.63) were observed. The medians of CFU were lower in test samples compared to the control samples (6.5 × 103 versus 2.5 × 103, P < 0.01) for any bacterial growth. Lower colony counts were also observed for individual bacterial groups. In conclusion, preculture washing of ejaculates results in a decrease in total bacteria count and culture-positive samples. IMPORTANCE This study compares two methods for processing ejaculate samples from men undergoing investigations for infertility. The method of sample washing and centrifugation was compared to the standard method of direct inoculation and culture. The study hypothesis was that preprocessing of samples may increase bacterial yield by removing bactericidal substances from semen. However, we found that washing ejaculate samples before microbiological culture did not improve the detection of bacteria and led to a reduction in colony counts.

The potential of SARS-CoV-2 antigen-detection tests in the screening of asymptomatic persons.

OBJECTIVES: The aim was to assess the performance of antigen-based rapid diagnostic tests (Ag-RDTs) for SARS CoV-2 when implemented for large-scale universal screening of asymptomatic individuals. METHODS: This study was a pragmatic implementation study for universal Ag-RDT-based screening at a tertiary care hospital in Germany where patients presenting for elective procedures and selected personnel without symptoms suggestive of SARS-CoV-2 were screened with an Ag-RDT since October 2020. Test performance was calculated on an individual patient level. RESULTS: In total, 49 542 RDTs were performed in 27 421 asymptomatic individuals over a duration of 5 and a half months. Out of 222 positive results, 196 underwent in-house confirmatory testing with PCR, out of which 170 were confirmed positive, indicating a positive predictive value of 86.7% (95% CI 81.2-91.1%). Negative Ag-RDTs were not routinely tested with PCR, but a total of 94 cases of false negative Ag-RDTs were detected due to PCR tests being performed within the following 5 days with a median cycle threshold value of 33 (IQR 29-35). DISCUSSION: This study provides evidence that Ag-RDTs can have a high diagnostic yield for transmission relevant infections with limited false positives when utilized at the point of care on asymptomatic patients and thus can be a suitable public health test for universal screening.

Evaluation of a Novel Culture System for Rapid Pathogen Identification and Detection of Cephalosporin Resistance in Neonatal Gram-negative Sepsis at a Tertiary Referral Unit in Harare, Zimbabwe.

BACKGROUND: Neonatal sepsis accounts for a large proportion of neonatal deaths in sub-Saharan Africa. The lack of access to diagnostic testing and excessively long turnaround times to result contributes to delays in sepsis identification and initiation of appropriate treatment. This study aims to evaluate the novel InTrays COLOREX Screen and extended-spectrum beta-lactamase for rapid identification of bacterial pathogens causing sepsis and detection of resistance. METHODS: Neonates with suspected sepsis admitted to the Harare Central Hospital were prospectively enrolled. One blood culture was collected and incubated using the BacT/ALERT automated system. Positive blood cultures with potential pathogens identified by Gram stain were inoculated on the InTray COLOREX Screen and extended-spectrum beta-lactamase culture plates. RESULTS: A total of 216 neonates with suspected sepsis were recruited. Pathogens were isolated from blood cultures in 56 (25.9%) neonates of which 54 were Klebsiella pneumoniae. All K. pneumoniae were resistant to ceftriaxone and 53 (98%) were resistant to gentamicin. Sensitivity and specificity for ceftriaxone-resistant K. pneumoniae detection using InTrays were 100%. InTrays results were interpretable as early as 5-10 hours (median 7 hours, interquartile range 7-7) post blood culture positivity enabling rapid identification and notification of result and leading to a 60% reduction in time to result from blood culture collection. CONCLUSIONS: This study shows that the implementation of a novel culture method was feasible and reduced turnaround times for results by 60% compared with standard microbiologic techniques. An impact on patient outcomes and cost-effectiveness of this method needs to be demonstrated.