Showing papers in "Clinical Microbiology Reviews in 2022"

A Comprehensive Review on the Role of the Gut Microbiome in Human Neurological Disorders

Abstract: The human body is full of an extensive number of commensal microbes, consisting of bacteria, viruses, and fungi, collectively termed the human microbiome. The initial acquisition of microbiota occurs from both the external and maternal environments, and the vast majority of them colonize the gastrointestinal tract (GIT).

A Comprehensive Review on the Role of the Gut Microbiome in Human Neurological Disorders

Abstract: The human body is full of an extensive number of commensal microbes, consisting of bacteria, viruses, and fungi, collectively termed the human microbiome. The initial acquisition of microbiota occurs from both the external and maternal environments, and the vast majority of them colonize the gastrointestinal tract (GIT). SUMMARY The human body is full of an extensive number of commensal microbes, consisting of bacteria, viruses, and fungi, collectively termed the human microbiome. The initial acquisition of microbiota occurs from both the external and maternal environments, and the vast majority of them colonize the gastrointestinal tract (GIT). These microbial communities play a central role in the maturation and development of the immune system, the central nervous system, and the GIT system and are also responsible for essential metabolic pathways. Various factors, including host genetic predisposition, environmental factors, lifestyle, diet, antibiotic or nonantibiotic drug use, etc., affect the composition of the gut microbiota. Recent publications have highlighted that an imbalance in the gut microflora, known as dysbiosis, is associated with the onset and progression of neurological disorders. Moreover, characterization of the microbiome-host cross talk pathways provides insight into novel therapeutic strategies. Novel preclinical and clinical research on interventions related to the gut microbiome for treating neurological conditions, including autism spectrum disorders, Parkinson’s disease, schizophrenia, multiple sclerosis, Alzheimer’s disease, epilepsy, and stroke, hold significant promise. This review aims to present a comprehensive overview of the potential involvement of the human gut microbiome in the pathogenesis of neurological disorders, with a particular emphasis on the potential of microbe-based therapies and/or diagnostic microbial biomarkers. This review also discusses the potential health benefits of the administration of probiotics, prebiotics, postbiotics, and synbiotics and fecal microbiota transplantation in neurological disorders.

COVID-19 Convalescent Plasma and Clinical Trials: Understanding Conflicting Outcomes

Abstract: Convalescent plasma (CP) recurs as a frontline treatment in epidemics because it is available as soon as there are survivors. The COVID-19 pandemic represented the first large-scale opportunity to shed light on the mechanisms of action, safety, and efficacy of CP using modern evidence-based medicine approaches. Studies ranging from observational case series to randomized controlled trials (RCTs) have reported highly variable efficacy results for COVID-19 CP (CCP), resulting in uncertainty. SUMMARY Convalescent plasma (CP) recurs as a frontline treatment in epidemics because it is available as soon as there are survivors. The COVID-19 pandemic represented the first large-scale opportunity to shed light on the mechanisms of action, safety, and efficacy of CP using modern evidence-based medicine approaches. Studies ranging from observational case series to randomized controlled trials (RCTs) have reported highly variable efficacy results for COVID-19 CP (CCP), resulting in uncertainty. We analyzed variables associated with efficacy, such as clinical settings, disease severity, CCP SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) antibody levels and function, dose, timing of administration (variously defined as time from onset of symptoms, molecular diagnosis, diagnosis of pneumonia, or hospitalization, or by serostatus), outcomes (defined as hospitalization, requirement for ventilation, clinical improvement, or mortality), CCP provenance and time for collection, and criteria for efficacy. The conflicting trial results, along with both recent WHO guidelines discouraging CCP usage and the recent expansion of the FDA emergency use authorization (EUA) to include outpatient use of CCP, create confusion for both clinicians and patients about the appropriate use of CCP. A review of 30 available RCTs demonstrated that signals of efficacy (including reductions in mortality) were more likely if the CCP neutralizing titer was >160 and the time to randomization was less than 9 days. The emergence of the Omicron variant also reminds us of the benefits of polyclonal antibody therapies, especially as a bridge to the development and availability of more specific therapies.

Pathogenesis of Respiratory Viral and Fungal Coinfections

Abstract: Individuals suffering from severe viral respiratory tract infections have recently emerged as "at risk" groups for developing invasive fungal infections. Influenza virus is one of the most common causes of acute lower respiratory tract infections worldwide. Fungal infections complicating influenza pneumonia are associated with increased disease severity and mortality, with invasive pulmonary aspergillosis being the most common manifestation. Strikingly, similar observations have been made during the current coronavirus disease 2019 (COVID-19) pandemic. The copathogenesis of respiratory viral and fungal coinfections is complex and involves a dynamic interplay between the host immune defenses and the virulence of the microbes involved that often results in failure to return to homeostasis. In this review, we discuss the main mechanisms underlying susceptibility to invasive fungal disease following respiratory viral infections. A comprehensive understanding of these interactions will aid the development of therapeutic modalities against newly identified targets to prevent and treat these emerging coinfections.

Klebsiella oxytoca Complex: Update on Taxonomy, Antimicrobial Resistance, and Virulence

Abstract: Klebsiella oxytoca is actually a complex of nine species-Klebsiella grimontii, Klebsiella huaxiensis, Klebsiella michiganensis, K. oxytoca, Klebsiella pasteurii, Klebsiella spallanzanii, and three unnamed novel species. Phenotypic tests can assign isolates to the complex, but precise species identification requires genome-based analysis. The K. oxytoca complex is a human commensal but also an opportunistic pathogen causing various infections, such as antibiotic-associated hemorrhagic colitis (AAHC), urinary tract infection, and bacteremia, and has caused outbreaks. Production of the cytotoxins tilivalline and tilimycin lead to AAHC, while many virulence factors seen in Klebsiella pneumoniae, such as capsular polysaccharides and fimbriae, have been found in the complex; however, their association with pathogenicity remains unclear. Among the 5,724 K. oxytoca clinical isolates in the SENTRY surveillance system, the rates of nonsusceptibility to carbapenems, ceftriaxone, ciprofloxacin, colistin, and tigecycline were 1.8%, 12.5%, 7.1%, 0.8%, and 0.1%, respectively. Resistance to carbapenems is increasing alarmingly. In addition to the intrinsic blaOXY, many genes encoding β-lactamases with varying spectra of hydrolysis, including extended-spectrum β-lactamases, such as a few CTX-M variants and several TEM and SHV variants, have been found. blaKPC-2 is the most common carbapenemase gene found in the complex and is mainly seen on IncN or IncF plasmids. Due to the ability to acquire antimicrobial resistance and the carriage of multiple virulence genes, the K. oxytoca complex has the potential to become a major threat to human health.

Environmental, Microbiological, and Immunological Features of Bacterial Biofilms Associated with Implanted Medical Devices

Abstract: The spread of biofilms on medical implants represents one of the principal triggers of persistent and chronic infections in clinical settings, and it has been the subject of many studies in the past few years, with most of them focused on prosthetic joint infections. We review here recent works on biofilm formation and microbial colonization on a large variety of indwelling devices, ranging from heart valves and pacemakers to urological and breast implants and from biliary stents and endoscopic tubes to contact lenses and dental and neurosurgical implants. SUMMARY The spread of biofilms on medical implants represents one of the principal triggers of persistent and chronic infections in clinical settings, and it has been the subject of many studies in the past few years, with most of them focused on prosthetic joint infections. We review here recent works on biofilm formation and microbial colonization on a large variety of indwelling devices, ranging from heart valves and pacemakers to urological and breast implants and from biliary stents and endoscopic tubes to contact lenses and neurosurgical implants. We focus on bacterial abundance and distribution across different devices and body sites and on the role of environmental features, such as the presence of fluid flow and properties of the implant surface, as well as on the interplay between bacterial colonization and the response of the human immune system.

Sensitivity to Vaccines, Therapeutic Antibodies, and Viral Entry Inhibitors and Advances To Counter the SARS-CoV-2 Omicron Variant

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) keeps evolving and mutating into newer variants over time, which gain higher transmissibility, disease severity, and spread in communities at a faster rate, resulting in multiple waves of surge in Coronavirus Disease 2019 (COVID-19) cases. A highly mutated and transmissible SARS-CoV-2 Omicron variant has recently emerged, driving the extremely high peak of infections in almost all continents at an unprecedented speed and scale. SUMMARY Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) keeps evolving and mutating into newer variants over time, which gain higher transmissibility, disease severity, and spread in communities at a faster rate, resulting in multiple waves of surge in Coronavirus Disease 2019 (COVID-19) cases. A highly mutated and transmissible SARS-CoV-2 Omicron variant has recently emerged, driving the extremely high peak of infections in almost all continents at an unprecedented speed and scale. The Omicron variant evades the protection rendered by vaccine-induced antibodies and natural infection, as well as overpowers the antibody-based immunotherapies, raising the concerns of current effectiveness of available vaccines and monoclonal antibody-based therapies. This review outlines the most recent advancements in studying the virology and biology of the Omicron variant, highlighting its increased resistance to current antibody-based therapeutics and its immune escape against vaccines. However, the Omicron variant is highly sensitive to viral fusion inhibitors targeting the HR1 motif in the spike protein, enzyme inhibitors, involving the endosomal fusion pathway, and ACE2-based entry inhibitors. Omicron variant-associated infectivity and entry mechanisms of Omicron variant are essentially distinct from previous characterized variants. Innate sensing and immune evasion of SARS-CoV-2 and T cell immunity to the virus provide new perspectives of vaccine and drug development. These findings are important for understanding SARS-CoV-2 viral biology and advances in developing vaccines, antibody-based therapies, and more effective strategies to mitigate the transmission of the Omicron variant or the next SARS-CoV-2 variant of concern.

Machine Learning for Antimicrobial Resistance Prediction: Current Practice, Limitations, and Clinical Perspective

Abstract: Antimicrobial resistance (AMR) is a global health crisis that poses a great threat to modern medicine. Effective prevention strategies are urgently required to slow the emergence and further dissemination of AMR. SUMMARY Antimicrobial resistance (AMR) is a global health crisis that poses a great threat to modern medicine. Effective prevention strategies are urgently required to slow the emergence and further dissemination of AMR. Given the availability of data sets encompassing hundreds or thousands of pathogen genomes, machine learning (ML) is increasingly being used to predict resistance to different antibiotics in pathogens based on gene content and genome composition. A key objective of this work is to advocate for the incorporation of ML into front-line settings but also highlight the further refinements that are necessary to safely and confidently incorporate these methods. The question of what to predict is not trivial given the existence of different quantitative and qualitative laboratory measures of AMR. ML models typically treat genes as independent predictors, with no consideration of structural and functional linkages; they also may not be accurate when new mutational variants of known AMR genes emerge. Finally, to have the technology trusted by end users in public health settings, ML models need to be transparent and explainable to ensure that the basis for prediction is clear. We strongly advocate that the next set of AMR-ML studies should focus on the refinement of these limitations to be able to bridge the gap to diagnostic implementation.

Worldwide Control and Management of Chagas Disease in a New Era of Globalization: a Close Look at Congenital Trypanosoma cruzi Infection

Abstract: Population movements have turned Chagas disease (CD) into a global public health problem. Despite the successful implementation of subregional initiatives to control vectorial and transfusional Trypanosoma cruzi transmission in Latin American settings where the disease is endemic, congenital CD (cCD) remains a significant challenge. SUMMARY Population movements have turned Chagas disease (CD) into a global public health problem. Despite the successful implementation of subregional initiatives to control vectorial and transfusional Trypanosoma cruzi transmission in Latin American settings where the disease is endemic, congenital CD (cCD) remains a significant challenge. In countries where the disease is not endemic, vertical transmission plays a key role in CD expansion and is the main focus of its control. Although several health organizations provide general protocols for cCD control, its management in each geopolitical region depends on local authorities, which has resulted in a multitude of approaches. The aims of this review are to (i) describe the current global situation in CD management, with emphasis on congenital infection, and (ii) summarize the spectrum of available strategies, both official and unofficial, for cCD prevention and control in countries of endemicity and nonendemicity. From an economic point of view, the early detection and treatment of cCD are cost-effective. However, in countries where the disease is not endemic, national health policies for cCD control are nonexistent, and official regional protocols are scarce and restricted to Europe. Countries of endemicity have more protocols in place, but the implementation of diagnostic methods is hampered by economic constraints. Moreover, most protocols in both countries where the disease is endemic and those where it is not endemic have yet to incorporate recently developed technologies. The wide methodological diversity in cCD diagnostic algorithms reflects the lack of a consensus. This review may represent a first step toward the development of a common strategy, which will require the collaboration of health organizations, governments, and experts in the field.

Clinical and Public Health Implications of Human T-Lymphotropic Virus Type 1 Infection

Abstract: Human T-lymphotropic virus type 1 (HTLV-1) is estimated to affect 5 to 10 million people globally and can cause severe and potentially fatal disease, including adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The burden of HTLV-1 infection appears to be geographically concentrated, with high prevalence in discrete regions and populations. SUMMARY Human T-lymphotropic virus type 1 (HTLV-1) is estimated to affect 5 to 10 million people globally and can cause severe and potentially fatal disease, including adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The burden of HTLV-1 infection appears to be geographically concentrated, with high prevalence in discrete regions and populations. While most high-income countries have introduced HTLV-1 screening of blood donations, few other public health measures have been implemented to prevent infection or its consequences. Recent advocacy from concerned researchers, clinicians, and community members has emphasized the potential for improved prevention and management of HTLV-1 infection. Despite all that has been learned in the 4 decades following the discovery of HTLV-1, gaps in knowledge across clinical and public health aspects persist, impeding optimal control and prevention, as well as the development of policies and guidelines. Awareness of HTLV-1 among health care providers, communities, and affected individuals remains limited, even in countries of endemicity. This review provides a comprehensive overview on HTLV-1 epidemiology and on clinical and public health and highlights key areas for further research and collaboration to advance the health of people with and at risk of HTLV-1 infection.

SARS-CoV-2 Infection and Lung Regeneration

Abstract: The lung is the primary site of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced immunopathology whereby the virus enters the host cells by binding to angiotensin-converting enzyme 2 (ACE2). Sophisticated regeneration and repair programs exist in the lungs to replenish injured cell populations. SUMMARY The lung is the primary site of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced immunopathology whereby the virus enters the host cells by binding to angiotensin-converting enzyme 2 (ACE2). Sophisticated regeneration and repair programs exist in the lungs to replenish injured cell populations. However, known resident stem/progenitor cells have been demonstrated to express ACE2, raising a substantial concern regarding the long-term consequences of impaired lung regeneration after SARS-CoV-2 infection. Moreover, clinical treatments may also affect lung repair from antiviral drug candidates to mechanical ventilation. In this review, we highlight how SARS-CoV-2 disrupts a program that governs lung homeostasis. We also summarize the current efforts of targeted therapy and supportive treatments for COVID-19 patients. In addition, we discuss the pros and cons of cell therapy with mesenchymal stem cells or resident lung epithelial stem/progenitor cells in preventing post-acute sequelae of COVID-19. We propose that, in addition to symptomatic treatments being developed and applied in the clinic, targeting lung regeneration is also essential to restore lung homeostasis in COVID-19 patients.

Helicobacter pylori Infection, Its Laboratory Diagnosis, and Antimicrobial Resistance: a Perspective of Clinical Relevance

Abstract: Despite the recent decrease in overall prevalence of Helicobacter pylori infection, morbidity and mortality rates associated with gastric cancer remain high. The antimicrobial resistance developments and treatment failure are fueling the global burden of H. pylori-associated gastric complications. SUMMARY Despite the recent decrease in overall prevalence of Helicobacter pylori infection, morbidity and mortality rates associated with gastric cancer remain high. The antimicrobial resistance developments and treatment failure are fueling the global burden of H. pylori-associated gastric complications. Accurate diagnosis remains the opening move for treatment and eradication of infections caused by microorganisms. Although several reports have been published on diagnostic approaches for H. pylori infection, most lack the data regarding diagnosis from a clinical perspective. Therefore, we provide an intensive, comprehensive, and updated description of the currently available diagnostic methods that can help clinicians, infection diagnosis professionals, and H. pylori researchers working on infection epidemiology to broaden their understanding and to select appropriate diagnostic methods. We also emphasize appropriate diagnostic approaches based on clinical settings (either clinical diagnosis or mass screening), patient factors (either age or other predisposing factors), and clinical factors (either upper gastrointestinal bleeding or partial gastrectomy) and appropriate methods to be considered for evaluating eradication efficacy. Furthermore, to cope with the increasing trend of antimicrobial resistance, a better understanding of its emergence and current diagnostic approaches for resistance detection remain inevitable.

Group B Streptococcal Neonatal Meningitis

Abstract: Neonatal bacterial meningitis is a devastating disease, associated with high mortality and neurological disability, in both developed and developing countries. Streptococcus agalactiae, commonly referred to as group B Streptococcus (GBS), remains the most common bacterial cause of meningitis among infants younger than 90 days. Maternal colonization with GBS in the gastrointestinal and/or genitourinary tract is the primary risk factor for neonatal invasive disease. SUMMARY Neonatal bacterial meningitis is a devastating disease, associated with high mortality and neurological disability, in both developed and developing countries. Streptococcus agalactiae, commonly referred to as group B Streptococcus (GBS), remains the most common bacterial cause of meningitis among infants younger than 90 days. Maternal colonization with GBS in the gastrointestinal and/or genitourinary tracts is the primary risk factor for neonatal invasive disease. Despite prophylactic intrapartum antibiotic administration to colonized women and improved neonatal intensive care, the incidence and morbidity associated with GBS meningitis have not declined since the 1970s. Among meningitis survivors, a significant number suffer from complex neurological or neuropsychiatric sequelae, implying that the pathophysiology and pathogenic mechanisms leading to brain injury and devastating outcomes are not yet fully understood. It is imperative to develop new therapeutic and neuroprotective approaches aiming at protecting the developing brain. In this review, we provide updated clinical information regarding the understanding of neonatal GBS meningitis, including epidemiology, diagnosis, management, and human evidence of the disease's underlying mechanisms. Finally, we explore the experimental models used to study GBS meningitis and discuss their clinical and physiologic relevance to the complexities of human disease.

Digital PCR Applications in the SARS-CoV-2/COVID-19 Era: a Roadmap for Future Outbreaks

Abstract: The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global public health disaster. The current gold standard for the diagnosis of infected patients is real-time reverse transcription-quantitative PCR (RT-qPCR). SUMMARY The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global public health disaster. The current gold standard for the diagnosis of infected patients is real-time reverse transcription-quantitative PCR (RT-qPCR). As effective as this method may be, it is subject to false-negative and -positive results, affecting its precision, especially for the detection of low viral loads in samples. In contrast, digital PCR (dPCR), the third generation of PCR, has been shown to be more effective than the gold standard, RT-qPCR, in detecting low viral loads in samples. In this review article, we selected publications to show the broad-spectrum applications of dPCR, including the development of assays and reference standards, environmental monitoring, mutation detection, and clinical diagnosis of SARS-CoV-2, while comparing it analytically to the gold standard, RT-qPCR. In summary, it is evident that the specificity, sensitivity, reproducibility, and detection limits of RT-dPCR are generally unaffected by common factors that may affect RT-qPCR. As this is the first time that dPCR is being tested in an outbreak of such a magnitude, knowledge of its applications will help chart a course for future diagnosis and monitoring of infectious disease outbreaks.

Monkeypox Virus Infections in Humans

Abstract: Human monkeypox is a viral zoonosis endemic to West and Central Africa that has recently generated increased interest and concern on a global scale as an emerging infectious disease threat in the midst of the slowly relenting COVID-2019 disease pandemic. The hallmark of infection is the development of a flu-like prodrome followed by the appearance of a smallpox-like exanthem. SUMMARY Human monkeypox is a viral zoonosis endemic to West and Central Africa that has recently generated increased interest and concern on a global scale as an emerging infectious disease threat in the midst of the slowly relenting COVID-2019 disease pandemic. The hallmark of infection is the development of a flu-like prodrome followed by the appearance of a smallpox-like exanthem. Precipitous person-to-person transmission of the virus among residents of 100 countries where it is nonendemic has motivated the immediate and widespread implementation of public health countermeasures. In this review, we discuss the origins and virology of monkeypox virus, its link with smallpox eradication, its record of causing outbreaks of human disease in regions where it is endemic in wildlife, its association with outbreaks in areas where it is nonendemic, the clinical manifestations of disease, laboratory diagnostic methods, case management, public health interventions, and future directions.

Tuberculosis Treatment Monitoring and Outcome Measures: New Interest and New Strategies

Abstract: Despite the advent of new diagnostics, drugs and regimens, tuberculosis (TB) remains a global public health threat. A significant challenge for TB control efforts has been the monitoring of TB therapy and determination of TB treatment success. SUMMARY Despite the advent of new diagnostics, drugs and regimens, tuberculosis (TB) remains a global public health threat. A significant challenge for TB control efforts has been the monitoring of TB therapy and determination of TB treatment success. Current recommendations for TB treatment monitoring rely on sputum and culture conversion, which have low sensitivity and long turnaround times, present biohazard risk, and are prone to contamination, undermining their usefulness as clinical treatment monitoring tools and for drug development. We review the pipeline of molecular technologies and assays that serve as suitable substitutes for current culture-based readouts for treatment response and outcome with the potential to change TB therapy monitoring and accelerate drug development.

Paracoccidioidomycosis: Current Status and Future Trends

Abstract: Paracoccidioidomycosis (PCM), initially reported in 1908 in the city of São Paulo, Brazil, by Adolpho Lutz, is primarily a systemic and neglected tropical mycosis that may affect individuals with certain risk factors around Latin America, especially Brazil. Paracoccidioides brasiliensis sensu stricto, a classical thermodimorphic fungus associated with PCM, was long considered to represent a monotypic taxon. However, advances in molecular taxonomy revealed several cryptic species, including Paracoccidioides americana, P. restrepiensis, P. venezuelensis, and P. lutzii, that show a preference for skin and mucous membranes, lymph nodes, and respiratory organs but can also affect many other organs. SUMMARY Paracoccidioidomycosis (PCM), initially reported in 1908 in the city of São Paulo, Brazil, by Adolpho Lutz, is primarily a systemic and neglected tropical mycosis that may affect individuals with certain risk factors around Latin America, especially Brazil. Paracoccidioides brasiliensis sensu stricto, a classical thermodimorphic fungus associated with PCM, was long considered to represent a monotypic taxon. However, advances in molecular taxonomy revealed several cryptic species, including Paracoccidioides americana, P. restrepiensis, P. venezuelensis, and P. lutzii, that show a preference for skin and mucous membranes, lymph nodes, and respiratory organs but can also affect many other organs. The classical diagnosis of PCM benefits from direct microscopy culture-based, biochemical, and immunological assays in a general microbiology laboratory practice providing a generic identification of the agents. However, molecular assays should be employed to identify Paracoccidioides isolates to the species level, data that would be complemented by epidemiological investigations. From a clinical perspective, all probable and confirmed cases should be treated. The choice of treatment and its duration must be considered, along with the affected organs, process severity, history of previous treatment failure, possibility of administering oral medication, associated diseases, pregnancy, and patient compliance with the proposed treatment regimen. Nevertheless, even after appropriate treatment, there may be relapses, which generally occur 5 years after the apparent cure following treatment, and also, the mycosis may be confused with other diseases. This review provides a comprehensive and critical overview of the immunopathology, laboratory diagnosis, clinical aspects, and current treatment of PCM, highlighting current issues in the identification, treatment, and patient follow-up in light of recent Paracoccidioides species taxonomic developments.

Candidate Phyla Radiation, an Underappreciated Division of the Human Microbiome, and Its Impact on Health and Disease

Abstract: Candidate phyla radiation (CPR) is an emerging division of the bacterial domain within the human microbiota. Still poorly known, these microorganisms were first described in the environment in 1981 as “ultramicrobacteria” with a cell volume under 0.1 μm3 and were first associated with the human oral microbiota in 2007. SUMMARY Candidate phyla radiation (CPR) is an emerging division of the bacterial domain within the human microbiota. Still poorly known, these microorganisms were first described in the environment in 1981 as “ultramicrobacteria” with a cell volume under 0.1 μm3 and were first associated with the human oral microbiota in 2007. The evolution of technology has been paramount for the study of CPR within the human microbiota. In fact, since these ultramicrobacteria have yet to be axenically cultured despite ongoing efforts, progress in imaging technology has allowed their observation and morphological description. Although their genomic abilities and taxonomy are still being studied, great strides have been made regarding their taxonomic classification, as well as their lifestyle. In addition, advancements in next-generation sequencing and the continued development of bioinformatics tools have allowed their detection as commensals in different human habitats, including the oral cavity and gastrointestinal and genital tracts, thus highlighting CPR as a nonnegligible part of the human microbiota with an impact on physiological settings. Conversely, several pathologies present dysbiosis affecting CPR levels, including inflammatory, mucosal, and infectious diseases. In this exhaustive review of the literature, we provide a historical perspective on the study of CPR, an overview of the methods available to study these organisms and a description of their taxonomy and lifestyle. In addition, their distribution in the human microbiome is presented in both homeostatic and dysbiotic settings. Future efforts should focus on developing cocultures and, if possible, axenic cultures to obtain isolates and therefore genomes that would provide a better understanding of these ultramicrobacteria, the importance of which in the human microbiome is undeniable.

Updated Review on Nocardia Species: 2006–2021

Abstract: This review serves as an update to the previous Nocardia review by Brown-Elliott et al. published in 2006 (B. A. SUMMARY This review serves as an update to the previous Nocardia review by Brown-Elliott et al. published in 2006 (B. A. Brown-Elliott, J. M. Brown, P. S. Conville, and R. J. Wallace. Jr., Clin Microbiol Rev 19:259–282, 2006, https://doi.org/10.1128/CMR.19.2.259-282.2006). Included is a discussion on the taxonomic expansion of the genus, current identification methods, and the impact of new technology (including matrix-assisted laser desorption ionization-time of flight [MALDI-TOF] and whole genome sequencing) on diagnosis and treatment. Clinical manifestations, the epidemiology, and geographic distribution are briefly discussed. An additional section on actinomycotic mycetoma is added to address this often-neglected disease.

Bacillus cereus Invasive Infections in Preterm Neonates: an Up-to-Date Review of the Literature

Abstract: Bacillus cereus group species are widespread, Gram-positive, spore-forming environmental bacteria. B. cereus sensu stricto is one of the major causes of food poisoning worldwide. In high-risk individuals, such as preterm neonates, B. cereus infections can cause fatal infections. It is important to note that the phenotypic identification methods commonly used in clinical microbiology laboratories make no distinction between B. cereus sensu stricto and the other members of the group (Bacillus anthracis excluded). SUMMARY Bacillus cereus group species are widespread, Gram-positive, spore-forming environmental bacteria. B. cereus sensu stricto is one of the major causes of food poisoning worldwide. In high-risk individuals, such as preterm neonates, B. cereus infections can cause fatal infections. It is important to note that the phenotypic identification methods commonly used in clinical microbiology laboratories make no distinction between B. cereus sensu stricto and the other members of the group (Bacillus anthracis excluded). As a result, all the invasive infections attributed to B. cereus are not necessarily due to B. cereus sensu stricto but likely to other closely related species of the B. cereus group. Next-generation sequencing (NGS) should be used to characterize the whole genome of the strains belonging to the B. cereus group. This could confirm whether the strains involved in previously reported B. cereus invasive infections preferentially belong to formerly known or emerging individual species. Moreover, infections related to B. cereus group species have probably been overlooked, since their isolation in human bacteriological samples has for a long time been regarded as an environmental contaminant of the cultures. Recent studies have questioned the emergence or reemergence of B. cereus invasive infections in preterm infants. This review reports our current understanding of B. cereus infections in neonates, including taxonomical updates, microbiological characteristics, bacterial identification, clinical features, host-pathogen interactions, environmental sources of contamination, and antimicrobial resistance.

Human Listeriosis

Abstract: Listeria monocytogenes is a Gram-positive facultative intracellular pathogen that can cause severe invasive infections upon ingestion with contaminated food. Clinically, listerial disease, or listeriosis, most often presents as bacteremia, meningitis or meningoencephalitis, and pregnancy-associated infections manifesting as miscarriage or neonatal sepsis. SUMMARY Listeria monocytogenes is a Gram-positive facultative intracellular pathogen that can cause severe invasive infections upon ingestion with contaminated food. Clinically, listerial disease, or listeriosis, most often presents as bacteremia, meningitis or meningoencephalitis, and pregnancy-associated infections manifesting as miscarriage or neonatal sepsis. Invasive listeriosis is life-threatening and a main cause of foodborne illness leading to hospital admissions in Western countries. Sources of contamination can be identified through international surveillance systems for foodborne bacteria and strains’ genetic data sharing. Large-scale whole genome studies have increased our knowledge on the diversity and evolution of L. monocytogenes, while recent pathophysiological investigations have improved our mechanistic understanding of listeriosis. In this article, we present an overview of human listeriosis with particular focus on relevant features of the causative bacterium, epidemiology, risk groups, pathogenesis, clinical manifestations, and treatment and prevention.

Bioengineering Strategies for Developing Vaccines against Respiratory Viral Diseases

Abstract: Respiratory viral pathogens like influenza and coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have caused outbreaks leading to millions of deaths. Vaccinations are, to date, the best and most economical way to control such outbreaks and have been highly successful for several pathogens. Currently used vaccines for respiratory viral pathogens are primarily live attenuated or inactivated and can risk reversion to virulence or confer inadequate immunity. The recent trend of using potent biomolecules like DNA, RNA, and protein antigenic components to synthesize vaccines for diseases has shown promising results. Still, it remains challenging to translate due to their high susceptibility to degradation during storage and after delivery. Advances in bioengineering technology for vaccine design have made it possible to control the physicochemical properties of the vaccines for rapid synthesis, heightened antigen presentation, safer formulations, and more robust immunogenicity. Bioengineering techniques and materials have been used to synthesize several potent vaccines, approved or in trials, against coronavirus disease 2019 (COVID-19) and are being explored for influenza, SARS, and Middle East respiratory syndrome (MERS) vaccines as well. Here, we review bioengineering strategies such as the use of polymeric particles, liposomes, and virus-like particles in vaccine development against influenza and coronaviruses and the feasibility of adopting these technologies for clinical use.

Reassessment of Historical Clinical Trials Supports the Effectiveness of Phage Therapy

Abstract: Phage therapy has become a hot topic in medical research due to the increasing prevalence of antibiotic-resistant bacteria strains. In the treatment of bacterial infections, bacteriophages have several advantages over antibiotics, including strain specificity, lack of serious side effects, and low development costs. SUMMARY Phage therapy has become a hot topic in medical research due to the increasing prevalence of antibiotic-resistant bacteria strains. In the treatment of bacterial infections, bacteriophages have several advantages over antibiotics, including strain specificity, lack of serious side effects, and low development costs. However, scientists dismissed the clinical success of early clinical trials in the 1940s, slowing the adoption of this promising antibacterial application in Western countries. The current study used statistical methods commonly used in modern meta-analysis to reevaluate early 20th-century studies and compare them with clinical trials conducted in the last 20 years. Using a random effect model, the development of disease after treatment with or without phages was measured in odds ratios (OR) with 95% confidence intervals (CI). Based on the findings of 17 clinical trials conducted between 1921 and 1940, phage therapy was effective (OR = 0.21, 95% CI = 0.10 to 0.44, P value < 0.0001). The current study includes a topic review on modern clinical trials; four could be analyzed, indicating a noneffective therapy (OR = 2.84, 95% CI = 1.53 to 5.27, P value = 0.0009). The results suggest phage therapy was surprisingly less effective than standard treatments in resolving bacterial infections. However, the results were affected by the small sample set size. This work also contextualizes the development of phage therapy in the early 20th century and highlights the expansion of phage applications in the last few years. In conclusion, the current review shows phage therapy is no longer an underestimated tool in the treatment of bacterial infections.

Osteoarticular Mycoses

Abstract: Osteoarticular mycoses are chronic debilitating infections that require extended courses of antifungal therapy and may warrant expert surgical intervention. As there has been no comprehensive review of these diseases, the International Consortium for Osteoarticular Mycoses prepared a definitive treatise for this important class of infections. SUMMARY Osteoarticular mycoses are chronic debilitating infections that require extended courses of antifungal therapy and may warrant expert surgical intervention. As there has been no comprehensive review of these diseases, the International Consortium for Osteoarticular Mycoses prepared a definitive treatise for this important class of infections. Among the etiologies of osteoarticular mycoses are Candida spp., Aspergillus spp., Mucorales, dematiaceous fungi, non-Aspergillus hyaline molds, and endemic mycoses, including those caused by Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides species. This review analyzes the history, epidemiology, pathogenesis, clinical manifestations, diagnostic approaches, inflammatory biomarkers, diagnostic imaging modalities, treatments, and outcomes of osteomyelitis and septic arthritis caused by these organisms. Candida osteomyelitis and Candida arthritis are associated with greater events of hematogenous dissemination than those of most other osteoarticular mycoses. Traumatic inoculation is more commonly associated with osteoarticular mycoses caused by Aspergillus and non-Aspergillus molds. Synovial fluid cultures are highly sensitive in the detection of Candida and Aspergillus arthritis. Relapsed infection, particularly in Candida arthritis, may develop in relation to an inadequate duration of therapy. Overall mortality reflects survival from disseminated infection and underlying host factors.

Genotypic Resistance Testing of HIV-1 DNA in Peripheral Blood Mononuclear Cells

Abstract: HIV-1 DNA exists in nonintegrated linear and circular episomal forms and as integrated proviruses. In patients with plasma viremia, most peripheral blood mononuclear cell (PBMC) HIV-1 DNA consists of recently produced nonintegrated virus DNA while in patients with prolonged virological suppression (VS) on antiretroviral therapy (ART), most PBMC HIV-1 DNA consists of proviral DNA produced months to years earlier. SUMMARY HIV-1 DNA exists in nonintegrated linear and circular episomal forms and as integrated proviruses. In patients with plasma viremia, most peripheral blood mononuclear cell (PBMC) HIV-1 DNA consists of recently produced nonintegrated virus DNA while in patients with prolonged virological suppression (VS) on antiretroviral therapy (ART), most PBMC HIV-1 DNA consists of proviral DNA produced months to years earlier. Drug-resistance mutations (DRMs) in PBMCs are more likely to coexist with ancestral wild-type virus populations than they are in plasma, explaining why next-generation sequencing is particularly useful for the detection of PBMC-associated DRMs. In patients with ongoing high levels of active virus replication, the DRMs detected in PBMCs and in plasma are usually highly concordant. However, in patients with lower levels of virus replication, it may take several months for plasma virus DRMs to reach detectable levels in PBMCs. This time lag explains why, in patients with VS, PBMC genotypic resistance testing (GRT) is less sensitive than historical plasma virus GRT, if previous episodes of virological failure and emergent DRMs were either not prolonged or not associated with high levels of plasma viremia. Despite the increasing use of PBMC GRT in patients with VS, few studies have examined the predictive value of DRMs on the response to a simplified ART regimen. In this review, we summarize what is known about PBMC HIV-1 DNA dynamics, particularly in patients with suppressed plasma viremia, the methods used for PBMC HIV-1 GRT, and the scenarios in which PBMC GRT has been used clinically.

Diagnosis, Management, and Future Control of Cholera

Abstract: Cholera, caused by Vibrio cholerae, persists in developing countries due to inadequate access to safe water, sanitation, and hygiene. There are approximately 4 million cases and 143,000 deaths each year due to cholera. SUMMARY Cholera, caused by Vibrio cholerae, persists in developing countries due to inadequate access to safe water, sanitation, and hygiene. There are approximately 4 million cases and 143,000 deaths each year due to cholera. The disease is transmitted fecally-orally via contaminated food or water. Severe dehydrating cholera can progress to hypovolemic shock due to the rapid loss of fluids and electrolytes, which requires a rapid infusion of intravenous (i.v.) fluids. The case fatality rate exceeds 50% without proper clinical management but can be less than 1% with prompt rehydration and antibiotics. Oral cholera vaccines (OCVs) serve as a major component of an integrated control package during outbreaks or within zones of endemicity. Water, sanitation, and hygiene (WaSH); health education; and prophylactic antibiotic treatment are additional components of the prevention and control of cholera. The World Health Organization (WHO) and the Global Task Force for Cholera Control (GTFCC) have set an ambitious goal of eliminating cholera by 2030 in high-risk areas.

Class C β-Lactamases: Molecular Characteristics

Abstract: Class C β-lactamases or cephalosporinases can be classified into two functional groups (1, 1e) with considerable molecular variability (≤20% sequence identity). These enzymes are mostly encoded by chromosomal and inducible genes and are widespread among bacteria, including Proteobacteria in particular. SUMMARY Class C β-lactamases or cephalosporinases can be classified into two functional groups (1, 1e) with considerable molecular variability (≤20% sequence identity). These enzymes are mostly encoded by chromosomal and inducible genes and are widespread among bacteria, including Proteobacteria in particular. Molecular identification is based principally on three catalytic motifs (64SXSK, 150YXN, 315KTG), but more than 70 conserved amino-acid residues (≥90%) have been identified, many close to these catalytic motifs. Nevertheless, the identification of a tiny, phylogenetically distant cluster (including enzymes from the genera Legionella, Bradyrhizobium, and Parachlamydia) has raised questions about the possible existence of a C2 subclass of β-lactamases, previously identified as serine hydrolases. In a context of the clinical emergence of extended-spectrum AmpC β-lactamases (ESACs), the genetic modifications observed in vivo and in vitro (point mutations, insertions, or deletions) during the evolution of these enzymes have mostly involved the Ω- and H-10/R2-loops, which vary considerably between genera, and, in some cases, the conserved triplet 150YXN. Furthermore, the conserved deletion of several amino-acid residues in opportunistic pathogenic species of Acinetobacter, such as A. baumannii, A. calcoaceticus, A. pittii and A. nosocomialis (deletion of residues 304–306), and in Hafnia alvei and H. paralvei (deletion of residues 289–290), provides support for the notion of natural ESACs. The emergence of higher levels of resistance to β-lactams, including carbapenems, and to inhibitors such as avibactam is a reality, as the enzymes responsible are subject to complex regulation encompassing several other genes (ampR, ampD, ampG, etc.). Combinations of resistance mechanisms may therefore be at work, including overproduction or change in permeability, with the loss of porins and/or activation of efflux systems.

The Microbial Etiology of Community-Acquired Pneumonia in Adults: from Classical Bacteriology to Host Transcriptional Signatures

Abstract: All modern advances notwithstanding, pneumonia remains a common infection with substantial morbidity and mortality. Understanding of the etiology of pneumonia continues to evolve as new techniques enable identification of already known organisms and as new organisms emerge. SUMMARY All modern advances notwithstanding, pneumonia remains a common infection with substantial morbidity and mortality. Understanding of the etiology of pneumonia continues to evolve as new techniques enable identification of already known organisms and as new organisms emerge. We now review the etiology of pneumonia (at present often called “community-acquired pneumonia”) beginning with classic bacteriologic techniques, which identified Streptococcus pneumoniae as the overwhelmingly common cause, to more modern bacteriologic studies, which emphasize Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, Enterobacteriaceae, Pseudomonas, and normal respiratory flora. Urine antigen detection is useful in identifying Legionella and pneumococcus. The low yield of bacteria in recent studies is due to the failure to obtain valid sputum samples before antibiotics are administered. The use of high-quality sputum specimens enables identification of recognized (“typical”) bacterial pathogens as well as a role for commensal bacteria (“normal respiratory flora”). Nucleic acid amplification technology for viruses has revolutionized diagnosis, showing the importance of viral pneumonia leading to hospitalization with or without coinfecting bacterial organisms. Quantitative PCR study of sputum is in its early stages of application, but regular detection of high counts of bacterial DNA from organisms that are not seen on Gram stain or grown in quantitative culture presents a therapeutic dilemma. This finding may reflect the host microbiome of the respiratory tract, in which case treatment may not need to be given for them. Finally, host transcriptional signatures might enable clinicians to distinguish between viral and bacterial pneumonia, an important practical consideration.

Controlled Human Infection Models To Accelerate Vaccine Development

Abstract: The timelines for developing vaccines against infectious diseases are lengthy, and often vaccines that reach the stage of large phase 3 field trials fail to provide the desired level of protective efficacy. The application of controlled human challenge models of infection and disease at the appropriate stages of development could accelerate development of candidate vaccines and, in fact, has done so successfully in some limited cases. SUMMARY The timelines for developing vaccines against infectious diseases are lengthy, and often vaccines that reach the stage of large phase 3 field trials fail to provide the desired level of protective efficacy. The application of controlled human challenge models of infection and disease at the appropriate stages of development could accelerate development of candidate vaccines and, in fact, has done so successfully in some limited cases. Human challenge models could potentially be used to gather critical information on pathogenesis, inform strain selection for vaccines, explore cross-protective immunity, identify immune correlates of protection and mechanisms of protection induced by infection or evoked by candidate vaccines, guide decisions on appropriate trial endpoints, and evaluate vaccine efficacy. We prepared this report to motivate fellow scientists to exploit the potential capacity of controlled human challenge experiments to advance vaccine development. In this review, we considered available challenge models for 17 infectious diseases in the context of the public health importance of each disease, the diversity and pathogenesis of the causative organisms, the vaccine candidates under development, and each model’s capacity to evaluate them and identify correlates of protective immunity. Our broad assessment indicated that human challenge models have not yet reached their full potential to support the development of vaccines against infectious diseases. On the basis of our review, however, we believe that describing an ideal challenge model is possible, as is further developing existing and future challenge models.

Human and Animal Fascioliasis: Origins and Worldwide Evolving Scenario

Abstract: Fascioliasis is a plant- and waterborne zoonotic parasitic disease caused by two trematode species: (i) Fasciola hepatica in Europe, Asia, Africa, the Americas, and Oceania and (ii) F. gigantica, which is restricted to Africa and Asia. Fasciolid liver flukes infect mainly herbivores as ruminants, equids, and camelids but also omnivore mammals as humans and swine and are transmitted by freshwater Lymnaeidae snail vectors. SUMMARY Fascioliasis is a plant- and waterborne zoonotic parasitic disease caused by two trematode species: (i) Fasciola hepatica in Europe, Asia, Africa, the Americas, and Oceania and (ii) F. gigantica, which is restricted to Africa and Asia. Fasciolid liver flukes infect mainly herbivores as ruminants, equids, and camelids but also omnivore mammals as humans and swine and are transmitted by freshwater Lymnaeidae snail vectors. Two phases may be distinguished in fasciolid evolution. The long predomestication period includes the F. gigantica origin in east-southern Africa around the mid-Miocene, the F. hepatica origin in the Near-Middle East of Asia around the latest Miocene to Early Pliocene, and their subsequent local spread. The short postdomestication period includes the worldwide spread by human-guided movements of animals in the last 12,000 years and the more recent transoceanic anthropogenic introductions of F. hepatica into the Americas and Oceania and of F. gigantica into several large islands of the Pacific with ships transporting livestock in the last 500 years. The routes and chronology of the spreading waves followed by both fasciolids into the five continents are redefined on the basis of recently generated knowledge of human-guided movements of domesticated hosts. No local, zonal, or regional situation showing disagreement with historical records was found, although in a few world zones the available knowledge is still insufficient. The anthropogenically accelerated evolution of fasciolids allows us to call them “peridomestic endoparasites.” The multidisciplinary implications for crucial aspects of the disease should therefore lead the present baseline update to be taken into account in future research studies.