Molecular basis of ß-lactam antibiotic resistance of ESKAPE bacterium E. faecium Penicillin Binding Protein PBP5.

Penicillin-binding proteins (PBPs) are essential for the formation of the bacterial cell wall. They are also the targets of ß-lactam antibiotics. In Enterococcus faecium, high levels of resistance to ß-lactams are associated with the expression of PBP5, with higher levels of resistance associated with distinct PBP5 variants. To define the molecular mechanism of PBP5-mediated resistance we leveraged biomolecular NMR spectroscopy of PBP5 - due to its size (>70 kDa) a challenging NMR target. Our data show that resistant PBP5 variants show significantly increased dynamics either alone or upon formation of the acyl-enzyme inhibitor complex. Furthermore, these variants also exhibit increased acyl-enzyme hydrolysis. Thus, reducing sidechain bulkiness and expanding surface loops results in increased dynamics that facilitates acyl-enzyme hydrolysis and, via increased ß-lactam antibiotic turnover, facilitates ß-lactam resistance. Together, these data provide the molecular basis of resistance of clinical E. faecium PBP5 variants, results that are likely applicable to the PBP family.

Penicillin-Binding Proteins and Alternative Dual-Beta-Lactam Combinations for Serious Enterococcus faecalis Infections with Elevated Penicillin MICs.

Ampicillin-ceftriaxone has become a first-line therapy for Enterococcus faecalis endocarditis. We characterized the penicillin-binding protein (PBP) profiles of various E. faecalis strains and tested for synergy to better inform beta-lactam options for the treatment of E. faecalis infections. We assessed the affinity of PBP2B from elevated-MIC strain E. faecalis LS4828 compared to type strain JH2-2 using the fluorescent beta-lactam Bocillin FL. We also characterized pbp4 and pbpA structures and PBP4 and PBP2B expression and used deletion and complementation studies to assess the impact of PBP2B on the levels of resistance. We tested penicillin-susceptible and -resistant E. faecalis isolates against ceftriaxone or ceftaroline combinations with other beta-lactams in 24-h time-kill studies. Two penicillin-susceptible strains (JH2-2 and L2052) had identical pbp sequences and similar PBP expression levels. One reduced-penicillin-susceptibility strain (L2068) had pbp sequences identical to those of the susceptible strains but expressed more PBP4. The second decreased-penicillin-susceptibility strain (LS4828) had amino acid substitutions in both PBP4 and PBP2B and expressed increased quantities of both proteins. PBP2B did not appear to contribute significantly to the elevated beta-lactam MICs. No synergy was demonstrable against the strains with both mutated PBPs and increased expression (L2068 and LS4828). Meropenem plus ceftriaxone or ertapenem plus ceftriaxone demonstrated the most consistent synergistic activity. PBP2B of strain LS4828 does not contribute significantly to reduced penicillin susceptibility. Neither the MIC nor the level of PBP expression correlated directly with the identified synergistic combinations when tested at static subinhibitory concentrations.

Meropenem plus Ceftaroline Is Active against Enterococcus faecalis in an In Vitro Pharmacodynamic Model Using Humanized Dosing Simulations.

The standard of care for serious Enterococcus faecalis infections is ampicillin plus ceftriaxone. Ampicillin's inconvenient dosing schedule, drug instability, allergy potential, along with ceftriaxone's high risk for Clostridioides difficile infection and its promotion of vancomycin-resistant enterococci (VRE), led our team to explore alternative options. This work aimed to understand the role of carbapenems in combination with cephalosporins in these infections. We selected two ampicillin and penicillin susceptible E. faecalis strains (AMP-MIC 0.5-2 µg/mL; PCN-MIC 2 µg/mL) and simulated human therapeutic dosing regimens in a 48-h in vitro pharmacodynamic model (IVPD) with ampicillin (2g q4h), ertapenem (1g q24h), meropenem (2g q8h), ceftriaxone (2g q12h), and ceftaroline (600 mg q8h). As expected, ampicillin plus ceftriaxone demonstrated enhanced activity compared with ampicillin monotherapy with no MIC increases in either isolate. Meropenem and ceftaroline demonstrated significant kill against both isolates, with no regrowth or MIC increases occurring. Meropenem plus ceftriaxone also demonstrated significant kill, and while no MIC increases were identified for meropenem, there was minor regrowth and larger standard deviations. Ertapenem combined with either ceftriaxone or ceftaroline enhanced activity at 24 h, but at 48 h, regrowth occurred, and ertapenem MIC increases were noted. Meropenem-based combination therapy against E. faecalis may provide clinicians with another regimen to treat severe E. faecalis infections. Meropenem plus ceftaroline was as active as the standard of care treatment (ampicillin plus ceftriaxone) and may serve as an alternative for serious E. faecalis infections. Further studies are warranted to determine the clinical efficacy.

Houston, We Have a Problem: Reports of Clostridioides difficile Isolates With Reduced Vancomycin Susceptibility.

During the past 4 decades, oral vancomycin has been a mainstay of Clostridioides difficile infection (CDI) therapy with no reports of treatment failure due to emergence of vancomycin resistance. However, C. difficile isolates with high-level phenotypic resistance to vancomycin have recently been reported in 3 distinct geographic regions. There is an urgent need for surveillance to determine if strains with reduced vancomycin susceptibility are circulating in other areas. In a Cleveland-area hospital, screening of 176 CDI stool specimens yielded no C. difficile isolates with reduced vancomycin susceptibility and highlighted the potential for false-positive results due to contamination with vancomycin-resistant enterococci. Additional studies are needed to clarify whether reduced vancomycin susceptibility is an emerging problem that will alter clinical practice. Clinicians should alert their health department if they observe a substantial increase in the frequency of vancomycin treatment failure in patients diagnosed with CDI with no alternative explanation for diarrhea.

Health, Economic and Social Development Challenges of the COVID-19 Pandemic: Strategies for Multiple and Interconnected Issues.

The COVID-19-pandemic-related economic and social crises are leading to huge challenges for all spheres of human life across the globe. Various challenges highlighted by this pandemic include, but are not limited to, the need for global health cooperation and security, better crisis management, coordinated funding in public health emergencies, and access to measures related to prevention, treatment and control. This systematic review explores health, economic and social development issues in a COVID-19 pandemic context and aftermath. Accordingly, a methodology that focuses on identifying relevant literature with a focus on meta-analysis is used. A protocol with inclusion and exclusion criteria was developed, with articles from 15 December 2019 to 15 March 2022 included in the study. This was followed by a review and data analysis. The research results reveal that non-pharmaceutical measures like social distancing, lockdown and quarantine have created long-term impacts on issues such as changes in production and consumption patterns, market crashes resulting in the closure of business operations, and the slowing down of the economy. COVID-19 has exposed huge health inequalities across most countries due to social stratification and unequal distribution of wealth and/or resources. People from lower socio-economic backgrounds lack access to essential healthcare services during this critical time for both COVID-19 and other non-COVID ailments. The review shows that there is minimal literature available with evidence and empirical backup; similarly, data/studies from all countries/regions are not available. We propose that there is a need to conduct empirical research employing a trans-disciplinary approach to develop the most effective and efficient strategies to combat the pandemic and its aftermath. There is a need to explore the social and ecological determinants of this contagious infection and develop strategies for the prevention and control of COVID-19 or similar infections in future.

The Great Lockdown in the Wake of COVID-19 and Its Implications: Lessons for Low and Middle-Income Countries.

Concern for public health has been growing with the increasing volume of cases of COVID-19 in India. To combat this pandemic, India has implemented nationwide lockdowns, and unlocking phases continue with certain restrictions in different parts of the country. The lockdown has required people to adopt social-distance measures to minimize contacts in order to reduce the risks of additional infection. Nevertheless, the lockdown has already impacted economic activities and other dimensions of the health of individuals and society. Although many countries have helped their people through advanced welfare protection networks and numerous support aids, several emerging economies face specific difficulties to adapt to the pandemic due to vulnerable communities and scarce resources. However, certain lower-income countries need more rigorous analysis to implement more effective strategies to combat COVID-19. Accordingly, the current systematic review addresses the impacts of the COVID-19 pandemic and lockdowns in India in relation to health and the economy. This work also provides further information on health inequalities, eco-nomic and social disparities in the country due to the COVID-19 pandemic and lockdowns and also contributes pragmatic suggestions for overcoming these challenges. These observations will be useful to the relevant local and national officials for improving and adopting novel strategies to face lockdown challenges.

Multistakeholder Participation in Disaster Management-The Case of the COVID-19 Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic is affecting society's health, economy, environment and development. COVID-19 has claimed many lives across the globe and severely impacted the livelihood of a considerable section of the world's population. We are still in the process of finding optimal and effective solutions to control the pandemic and minimise its negative impacts. In the process of developing effective strategies to combat COVID-19, different countries have adapted diverse policies, strategies and activities and yet there are no universal or comprehensive solutions to the problem. In this context, this paper brings out a conceptual model of multistakeholder participation governance as an effective model to fight against COVID-19. Accordingly, the current study conducted a scientific review by examining multi-stakeholder disaster response strategies, particularly in relation to COVID-19. The study then presents a conceptual framework for multistakeholder participation governance as one of the effective models to fight against COVID-19. Subsequently, the article offers strategies for rebuilding the economy and healthcare system through multi-stakeholder participation, and gives policy directions/decisions based on evidence to save lives and protect livelihoods. The current study also provides evidence about multidimensional approaches and multi-diplomatic mechanisms during the COVID-19 crisis, in order to examine dimensions of multi-stakeholder participation in disaster management and to document innovative, collaborative strategic directions across the globe. The current research findings highlight the need for global collaboration by working together to put an end to this pandemic situation through the application of a Multi-Stakeholder Spatial Decision Support System (MS-SDSS).

Enterococcal Physiology and Antimicrobial Resistance: The Streetlight Just Got a Little Brighter.

Enterococcus faecalis differs from many other common human pathogens in its physiology and in its susceptibility to antimicrobial agents. Multiresistant E. faecalis strains owe their phenotypes to a combination of intrinsic and acquired antimicrobial resistance determinants. Acquired resistance is due to E. faecalis frequenting multicultural environments, its capacity to mate with different species, and the nullification of its own defense mechanisms in some lineages. Intrinsic resistance is a complex phenomenon that is intimately tied to the physiology of the species. In their recent study in mBio, Gilmore and colleagues (M. S. Gilmore, R. Salamzade, E. Selleck, N. Bryan, et al., mBio 11:e02962-20, 2020, https://doi.org/10.1128/mBio.02962-20) use functional genomics to explore the genetic underpinnings of E. faecalis physiology and antimicrobial resistance. While they do not come up with many definitive answers, their work points the way toward new and fruitful areas of investigation.

Assessment of groundwater vulnerability using integrated remote sensing and GIS techniques for the West Bengal coast, India.

Groundwater in the coastal districts of West Bengal, India is highly susceptible to various factors such as over-pumping, variations in rainfall, lower elevation and risk due to sea level rise. In addition to these factors, tropical cyclone induced storm surge and saltwater intrusion also induce potential risks to the quality of the coastal aquifers. There are several knowledge gaps, as many of these factors have not previously been systematically and rigorously analysed; furthermore, up-to-date information is either unavailable or insufficient. Accordingly, the present study analysed the groundwater vulnerability during the pre- and post-monsoon months for the period from 2001 to 2010 at three main coastal districts of West Bengal: East Midnapore, South 24 Parganas and North 24 Parganas (administrative regions). The GALDIT index-based model was employed to assess salt-water intrusion into the groundwater using Geographic Information System (GIS). Spatial distribution maps were also generated to identify highly vulnerable groundwater locations. Map removal and single parameter sensitivity analyses were performed to understand the sensitivity of the parameters. The study reveals that the depth of ground-water levels for the three districts increased and also the rainfall exerts a significant effect on the groundwater depth. The chemical constituents TDS and chloride contents in groundwater during the period 2004 to 2010 were analysed. The average TDS range values for pre- and post-monsoon seasons were observed to vary in the range between 100 and 3874 mg/l and 83-1929 mg/l respectively. Reports indicate that, groundwater in the area is highly saturated with iron containing minerals like Fe(OH)3, goethite, and hematite and is also moderately saturated with the calcite, chalcedony, dolomite and quartz, whereas under-saturated with anhydrite and gypsum. The implications of the research points to the urgent need for remedial action and appropriate responses at policy-level to protect groundwater.

An Updated History of Antimicrobial Agents and Chemotherapy: 2000-2020.

Since its inaugural issue nearly half a century ago, Antimicrobial Agents and Chemotherapy has served as a premier source for reports on scientific and clinical advances in the field of antimicrobial chemotherapy. As a follow-up to the previous "History of Antimicrobial Agents and Chemotherapy from 1972 to 1998" written by George A. Jacoby (Antimicrob Agents Chemother 43:999-1002, 1999, https://doi.org/10.1128/AAC.43.5.999), we herein highlight the further evolution of this comprehensive and authoritative journal in response to changing science, demographics, and information technology.

Resistance in Vancomycin-Resistant Enterococci.

Serious infections owing to vancomycin-resistant enterococci have historically proven to be difficult clinical cases, requiring combination therapy and management of treatment-related toxicity. Despite the introduction of new antibiotics with activity against vancomycin-resistant enterococci to the therapeutic armamentarium, significant challenges remain. An understanding of the factors driving the emergence of resistance in vancomycin-resistant enterococci, the dynamics of gastrointestinal colonization and microbiota-mediated colonization resistance, and the mechanisms of resistance to the currently available therapeutics will permit clinicians to be better prepared to tackle these challenging hospital-associated pathogens.

Indicators of Healthy Architecture-a Systematic Literature Review.

The design of the built environment plays an important role as a determinant of health. As a society, we are spending an increasing proportion of our time indoors and now spend over 80% of our life inside, so the design of buildings can greatly impact on human health. Accordingly, architecture health indices (AHIs) are used to evidence the effects on human health associated with the design of buildings. AHIs provide quantitative and empirical data upon which architects, clients, users and other stakeholders might monitor and evaluate the healthiness (or otherwise) of architectural design. A systematic literature review was conducted to reveal the current state of knowledge, reveal gaps, explore potential usage and highlight best practice in this area. Whilst there are a number of different health indicators for the built/urban environments more generally, the scope of this review is limited to the scale of a building and specifically those aspects within the remit of a professional architect. In order to examine the range and characteristics of AHIs currently in use, this review explored three electronic bibliographic databases from January 2008 to January 2019. A two-stage selection was undertaken and screening against eligibility criteria checklist carried out. From 15 included studies, 127 documents were identified, and these included 101 AHI. A sample of the most commonly used AHIs was then analysed at an item level. The review reveals that most AHIs are limited to measuring communicable diseases that directly affect physical health through e.g. air quality or water quality. There are very few indicators focusing on factors affecting mental and social health; given the increase in mental and social health problems, greater focus on AHIs related to these health issues should be included. Furthermore, the research reveals an absence of AHIs that address non-communicable diseases (NCDs). As the majority of all poor health outcomes globally are now related to NCDs, and many are associated with the design of the built environment, there is an urgent need to address this situation.

Fosfomycin for Injection (ZTI-01) Versus Piperacillin-tazobactam for the Treatment of Complicated Urinary Tract Infection Including Acute Pyelonephritis: ZEUS, A Phase 2/3 Randomized Trial.

BACKGROUND: ZTI-01 (fosfomycin for injection) is an epoxide antibiotic with a differentiated mechanism of action (MOA) inhibiting an early step in bacterial cell wall synthesis. ZTI-01 has broad in vitro spectrum of activity, including multidrug-resistant Gram-negative pathogens, and is being developed for treatment of complicated urinary tract infection (cUTI) and acute pyelonephritis (AP) in the United States. METHODS: Hospitalized adults with suspected or microbiologically confirmed cUTI/AP were randomized 1:1 to 6 g ZTI-01 q8h or 4.5 g intravenous (IV) piperacillin-tazobactam (PIP-TAZ) q8h for a fixed 7-day course (no oral switch); patients with concomitant bacteremia could receive up to 14 days. RESULTS: Of 465 randomized patients, 233 and 231 were treated with ZTI-01 and PIP-TAZ, respectively. In the microbiologic modified intent-to-treat (m-MITT) population, ZTI-01 met the primary objective of noninferiority compared with PIP-TAZ with overall success rates of 64.7% (119/184 patients) vs 54.5% (97/178 patients), respectively; treatment difference was 10.2% (95% confidence interval [CI]: -0.4, 20.8). Clinical cure rates at test of cure (TOC, day 19-21) were high and similar between treatments (90.8% [167/184] vs 91.6% [163/178], respectively). In post hoc analysis using unique pathogens typed by pulsed-field gel electrophoresis, overall success rates at TOC in m-MITT were 69.0% (127/184) for ZTI-01 versus 57.3% (102/178) for PIP-TAZ (difference 11.7% 95% CI: 1.3, 22.1). ZTI-01 was well tolerated. Most treatment-emergent adverse events, including hypokalemia and elevated serum aminotransferases, were mild and transient. CONCLUSIONS: ZTI-01 was effective for treatment of cUTI including AP and offers a new IV therapeutic option with a differentiated MOA for patients with serious Gram-negative infections. CLINICAL TRIAL REGISTRATION: NCT02753946.

The Enterococcus: a Model of Adaptability to Its Environment.

The genus Enterococcus comprises a ubiquitous group of Gram-positive bacteria that are of great relevance to human health for their role as major causative agents of health care-associated infections. The enterococci are resilient and versatile species able to survive under harsh conditions, making them well adapted to the health care environment. Two species cause the majority of enterococcal infections: Enterococcus faecalis and Enterococcus faecium Both species demonstrate intrinsic resistance to common antibiotics, such as virtually all cephalosporins, aminoglycosides, clindamycin, and trimethoprim-sulfamethoxazole. Additionally, a remarkably plastic genome allows these two species to readily acquire resistance to further antibiotics, such as high-level aminoglycoside resistance, high-level ampicillin resistance, and vancomycin resistance, either through mutation or by horizontal transfer of genetic elements conferring resistance determinants.