Global Burden Of Antimicrobial Resistance Research Articles

Investigating the feasibility and potential of combining industry AMR monitoring systems: a comparison with WHO GLASS

Background Efforts to estimate the global burden of antimicrobial resistance (AMR) have highlighted gaps in existing surveillance systems. Data gathered from hospital networks globally by pharmaceutical industries to monitor antibiotic efficacy in different bacteria represent an additional source to track the temporal evolution of AMR. Here, we analysed available industry monitoring systems to assess to which extent combining them could help fill the gaps in our current understanding of AMR levels and trends. Methods We analysed six industry monitoring systems (ATLAS, GEARS, SIDERO-WT, KEYSTONE, DREAM, and SOAR) obtained from the Vivli platform and reviewed their respective isolates collection and analysis protocols. Using the R software, we designed a pipeline to harmonise and combine these into a single dataset. We assessed the reliability of resistance estimates from these sources by comparing the combined dataset to the publicly available subset of WHO GLASS for shared bacteria-antibiotic-country-year combinations. Results Combined, the industry monitoring systems cover 18 years (4 years for GLASS), 85 countries (71), 412 bacterial species (8), and 75 antibiotics (25). Although all industry systems followed a similar centralised testing approach, the criteria for isolate collection were unclear (patients selection, associated sampling periods…). For E.coli, K. pneumoniae and S. aureus, at least 65% of comparable resistance proportions were within 0.1 of the corresponding estimate in GLASS. We did not identify systemic bias towards resistance in industry systems compared to GLASS. Conclusions Combining industry monitoring systems can substantially strengthen our knowledge of global AMR burden across bacterial species and countries. High agreement values for available comparisons with GLASS suggest that data for other bacteria-antibiotic-country-year combinations only present in industry systems could complement GLASS, particularly for Priority Pathogens currently not covered. This valuable information on resistance levels could help clinicians and stakeholders prioritize testing and select appropriate antibiotics in settings with limited surveillance data.

Development of a new antibiotic-induced dysbiosis model of the canine colonic microbiota

As in humans, antibiotics are widely used in dogs to treat gastrointestinal infections, contributing to the global burden of antimicrobial resistance on both human and animal health. Close contact between pets and their owners can lead to horizontal transfer of gut microbes, including transmission of antibiotic resistance. Nevertheless, until now, the impact of antibiotics on the canine gut microbiota has been poorly described. The aim of this study was to adapt the canine mucosal artificial colon (CANIM-ARCOL) model, reproducing the main nutritional, physicochemical and microbial parameters found in the large intestine of the dog to simulate an antibiotic-induced perturbation. Following initial investigation of five antibiotic cocktails at in-field doses, a 5-day regimen of metronidazole/enrofloxacin (ME) was selected for further model development. Two CANIM-ARCOL bioreactors were inoculated with a faecal sample (n=2 donors) and run in parallel for 26 days under control or antibiotic conditions. ME reduced microbial diversity and induced major shifts in bacterial populations, leading to a state of dysbiosis characterized by an increase in the relative abundance of Streptococcaceae, Lactobacillaceae and Enterobacteriaceae, and a decrease in the relative abundance of Bacteroidaceae, Fusobacteriota and Clostridiaceae. Overall, mucus-associated microbiota were less impacted by antibiotics than luminal microbes. Microbial alterations were associated with drastic decreases in gas production and short-chain fatty acid concentrations. Finally, the model was well validated through in-vitro-in-vivo comparisons in a study in dogs. The CANIM-ARCOL model provides a relevant platform as an alternative to in-vivo assays for an in-depth understanding of antibiotic-microbiota interactions and further testing of restoration strategies at individual level.

Methicillin resistant Staphylococcus aureus in the United Arab Emirates: a 12-year retrospective analysis of evolving trends.

Methicillin resistant Staphylococcus aureus (MRSA) is a major contributor to the global burden of antimicrobial resistance (AMR). As MRSA continues to evolve, the need for continued surveillance to evaluate trends remains crucial. This study was carried out to assess MRSA trends in the United Arab Emirates (UAE) based on analysis of data from the national AMR surveillance program. We carried out a 12-year (2010-2021) retrospective analysis of MRSA demographic and microbiological data collected as part of the UAE national AMR surveillance program. Participating centers from across the country routinely submit AMR surveillance data collected by trained personnel to the National AMR Surveillance Committee, where data is analyzed using a unified WHONET platform. Data on non-duplicate isolates associated with clinical infections were obtained and included in the analysis. A total of 29,414 non-duplicate MRSA isolates associated with clinical infections were reported between 2010 and 2021 (2010: n = 259; 2021: n = 4,996). MRSA represented 26.4% of all S. aureus (n = 111,623) isolates identified during the study period. In 2010, among the S. aureus isolates with reported oxacillin testing, 21.9% (n/N = 259/1,181) were identified as MRSA and this showed an increase to 33.5% (n/N = 4,996/14,925) in 2021. Although there was variation in the distribution of MRSA across the seven emirates of the country, most had an upward trend. Patient demographics reflected a male preponderance, with most being adults and from the outpatient setting. Isolates were mostly from skin and soft tissue infection specimens (72.5%; n/N = 21,335/29,414). Among the inpatients (N = 8,282), a total of 3,313 MRSA isolates were from specimens obtained ≤ 48 h after admission indicative of community acquired infection. Increasing resistance trends were observed for most antibiotics including ciprofloxacin, levofloxacin, moxifloxacin, erythromycin, gentamicin, trimethoprim-sulfamethoxazole, and quinupristin/dalfopristin. Low levels of resistance (0.0-0.8%) were sustained for linezolid except for 2015, 2016, and 2017 with 2.5, 2.6, and 2.9%, respectively. No confirmed vancomycin resistance was reported. The increasing trend of MRSA isolates associated with clinical infections in the hospital and community settings is a concern. Continued monitoring including incorporation of genomic surveillance and infection control measures are recommended to stem the dissemination.

The global burden of antimicrobial resistance - urinary tract infections.

Antimicrobial resistance (AMR) has emerged as a significant global healthcare problem. Antibiotic use has accelerated the physiologic process of AMR, particularly in Gram-negative pathogens. Urinary tract infections (UTIs) are predominantly of a Gram-negative nature. Uropathogens are evolutionarily highly adapted and selected strains with specific virulence factors, suggesting common mechanisms in how bacterial cells acquire virulence and AMR factors. The simultaneous increase in resistance and virulence is a complex and context-dependent phenomenon. Among known AMR mechanisms, the plenitude of different β-lactamases is especially prominent. The risk for AMR in UTIs varies in different patient populations. A history of antibiotic consumption and the physiology of urinary flow are major factors that shape AMR prevalence. The urinary tract is in close crosstalk with the microbiome of other compartments, including the gut and genital tracts. In addition, pharmacokinetic properties and the physiochemical composition of urinary compartments can contribute to the emergence of AMR. Alternatives to antibiotic treatment and a broader approach to address bacterial infections are needed. Among the various alternatives studied, antimicrobial peptides and bacteriophage treatment appear to be highly promising approaches. We herein summarize the present knowledge of clinical and microbiological AMR in UTIs and discuss innovative approaches, namely new risk prediction tools and the use of non-antibiotic approaches to defend against uropathogenic microbes.

Inhibition of β-lactamase function by de novo designed peptide.

Antimicrobial resistance is a great public health concern that is now described as a "silent pandemic". The global burden of antimicrobial resistance requires new antibacterial treatments, especially for the most challenging multidrug-resistant bacteria. There are various mechanisms by which bacteria develop antimicrobial resistance including expression of β-lactamase enzymes, overexpression of efflux pumps, reduced cell permeability through downregulation of porins required for β-lactam entry, or modifications in penicillin-binding proteins. Inactivation of the β-lactam antibiotics by β-lactamase enzymes is the most common mechanism of bacterial resistance to these agents. Although several effective small-molecule inhibitors of β-lactamases such as clavulanic acid and avibactam are clinically available, they act only on selected class A, C, and some class D enzymes. Currently, none of the clinically approved inhibitors can effectively inhibit Class B metallo-β-lactamases. Additionally, there is increased resistance to these inhibitors reported in several bacteria. The objective of this study is to use the Resonant Recognition Model (RRM), as a novel strategy to inhibit/modulate specific antimicrobial resistance targets. The RRM is a bio-physical approach that analyzes the distribution of energies of free electrons and posits that there is a significant correlation between the spectra of this energy distribution and related protein biological activity. In this study, we have used the RRM concept to evaluate the structure-function properties of a group of 22 β-lactamase proteins and designed 30-mer peptides with the desired RRM spectral periodicities (frequencies) to function as β-lactamase inhibitors. In contrast to the controls, our results indicate 100% inhibition of the class A β-lactamases from Escherichia coli and Enterobacter cloacae. Taken together, the RRM model can likely be utilized as a promising approach to design β-lactamase inhibitors for any specific class. This may open a new direction to combat antimicrobial resistance.

Antimicrobial Resistance (AMR).

Antimicrobial resistance (AMR) has now emerged as a chronic public health problem globally, with the forecast of 10 million deaths per year globally by 2050. AMR occurs when viruses, bacteria, fungi and parasites do not respond to antimicrobial treatments in humans and animals, thus allowing the survival of the microorganism within the host. The prominent cause contributing to the current crisis remains to be the overuse and misuse of antimicrobials, particularly the inappropriate usage of antibiotics, increasing the global burden of antimicrobial resistance. The global consumption and usage of antibiotics are therefore closely monitored at all times. This review provides a current overview of the implications of strategies used by international governmental organisations, including the UN's 17 Sustainable Development Goals (SDGs), to address the problem of antibiotic resistance, as well as the "One Health Approach," a system incorporating a multidisciplinary effort to achieve the best possible health outcome by acknowledging the clear connections between humans, animals and their shared environment. The importance of public awareness and health literacy of lay audiences still needs to be further emphasised as part of global and local action plans. Antimicrobial resistance continues to be a major global public health dilemma of the 21st century. Already this topic is receiving substantial political input from the G7 countries and continues to be on the agenda of numerous political conferences. The consequences of failure to adequately address AMR are profound, with estimations of a return to the pre-antibiotic era, where everyday infections relating to childbirth, surgery and open fractured limbs could be potentially life-threatening. AMR itself represents a microcosm of factors, including social anthropology, civil unrest/war, diasporas, ethnic displacement, political systems, healthcare, economics, societal behaviour both at a population and individual level, health literacy, geoclimatic events, global travel and pharmaceutical innovation and investment, thus finding a solution that adequately addresses AMR and which helps stem further AMR emergence is complicated. Success will involve individuals, communities and nations all working together to ensure that the world continues to possess a sufficient armamentarium of effective antimicrobials that will sustain human and animal health, both now and in the future.

Phages against Noncapsulated Klebsiella pneumoniae: Broader Host range, Slower Resistance.

Klebsiella pneumoniae (Kp), a human gut colonizer and opportunistic pathogen, is a major contributor to the global burden of antimicrobial resistance. Virulent bacteriophages represent promising agents for decolonization and therapy. However, the majority of anti-Kp phages that have been isolated thus far are highly specific to unique capsular types (anti-K phages), which is a major limitation to phage therapy prospects due to the highly polymorphic capsule of Kp. Here, we report on an original anti-Kp phage isolation strategy, using capsule-deficient Kp mutants as hosts (anti-Kd phages). We show that anti-Kd phages have a broad host range, as the majority are able to infect noncapsulated mutants of multiple genetic sublineages and O-types. Additionally, anti-Kd phages induce a lower rate of resistance emergence in vitro and provide increased killing efficiency when in combination with anti-K phages. In vivo, anti-Kd phages are able to replicate in mouse guts colonized with a capsulated Kp strain, suggesting the presence of noncapsulated Kp subpopulations. The original strategy proposed here represents a promising avenue that circumvents the Kp capsule host restriction barrier, offering promise for therapeutic development. IMPORTANCE Klebsiella pneumoniae (Kp) is an ecologically generalist bacterium as well as an opportunistic pathogen that is responsible for hospital-acquired infections and a major contributor to the global burden of antimicrobial resistance. In the last decades, limited advances have been made in the use of virulent phages as alternatives or complements to antibiotics that are used to treat Kp infections. This work demonstrates the potential value of an anti-Klebsiella phage isolation strategy that addresses the issue of the narrow host range of anti-K phages. Anti-Kd phages may be active in infection sites in which capsule expression is intermittent or repressed or in combination with anti-K phages, which often induce the loss of capsule in escape mutants.

Community carriage of ESBL-producing Escherichia coli and Klebsiella pneumoniae: a cross-sectional study of risk factors and comparative genomics of carriage and clinical isolates.

The global prevalence of infections caused by extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) is increasing, and for Escherichia coli, observations indicate that this is partly driven by community-onset cases. The ESBL-E population structure in the community is scarcely described, and data on risk factors for carriage are conflicting. Here, we report the prevalence and population structure of fecal ESBL-producing E. coli and Klebsiella pneumoniae (ESBL-Ec/Kp) in a general adult population, examine risk factors, and compare carriage isolates with contemporary clinical isolates. Fecal samples obtained from 4,999 participants (54% women) ≥40 years in the seventh survey of the population-based Tromsø Study, Norway (2015, 2016), were screened for ESBL-Ec/Kp. In addition, we included 118 ESBL-Ec clinical isolates from the Norwegian surveillance program in 2014. All isolates were whole-genome sequenced. Risk factors associated with carriage were analyzed using multivariable logistic regression. ESBL-Ec gastrointestinal carriage prevalence was 3.3% [95% confidence interval (CI) 2.8%-3.9%, no sex difference] and 0.08% (0.02%-0.20%) for ESBL-Kp. For ESBL-Ec, travel to Asia was the only independent risk factor (adjusted odds ratio 3.46, 95% CI 2.18-5.49). E. coli ST131 was most prevalent in both collections. However, the ST131 proportion was significantly lower in carriage (24%) versus clinical isolates (58%, P < 0.001). Carriage isolates were genetically more diverse with a higher proportion of phylogroup A (26%) than clinical isolates (5%, P < 0.001), indicating that ESBL gene acquisition occurs in a variety of E. coli lineages colonizing the gut. STs commonly related to extraintestinal infections were more frequent in clinical isolates also carrying a higher prevalence of antimicrobial resistance, which could indicate clone-associated pathogenicity.IMPORTANCEESBL-Ec and ESBL-Kp are major pathogens in the global burden of antimicrobial resistance. However, there is a gap in knowledge concerning the bacterial population structure of human ESBL-Ec/Kp carriage isolates in the community. We have examined ESBL-Ec/Kp isolates from a population-based study and compared these to contemporary clinical isolates. The large genetic diversity of carriage isolates indicates frequent ESBL gene acquisition, while those causing invasive infections are more clone dependent and associated with a higher prevalence of antibiotic resistance. The knowledge of factors associated with ESBL carriage helps to identify patients at risk to combat the spread of resistant bacteria within the healthcare system. Particularly, previous travel to Asia stands out as a major risk factor for carriage and should be considered in selecting empirical antibiotic treatment in critically ill patients.

Livestock producers' knowledge, attitude, and behavior (KAB) regarding antimicrobial use in Ethiopia.

Inappropriate antimicrobial use (AMU) in livestock production is an important aspect of the global burden of antimicrobial resistance (AMR). In Ethiopia, a low-income country with a large and increasing livestock population, AMU in food animals is not properly regulated. Hence, farmers are fully free to use antimicrobials to their (perceived) benefit. Therefore, understanding farmers' mindsets is important to improve antimicrobial stewardship in the livestock sector. This cross-sectional study was conducted to assess livestock disease management practices and knowledge, attitude, and behavior (KAB) among livestock producers regarding AMU, residues, and resistance, as well as factors potentially explaining differences in KAB. We determined the KAB of livestock owners of three selected districts of central and western Ethiopia (n = 457), using a pretested questionnaire administered through face-to-face interviews. Logistic regression was used to evaluate the association between potential explanatory variables and the KAB scores of the respondents. The results showed that 44% of the farmers used antimicrobials in the past few years, where antibiotics (21%) and trypanocides (11%) were most widely used to manage livestock diseases. Furthermore, most farmers showed poor knowledge about AMU, residues, and AMR (94%) and unfavorable attitudes (<50% correct answers) toward contributing factors for AMR (97%). On the contrary, 80% of the respondents had overall good behavior scores (≥50% correct answers) related to AMU. Multivariate analysis results showed that having good knowledge, keeping ≥2 animal species, and the occurrence of ≥4 livestock diseases on the farm in a year were strong predictors of bad behavior scores (p < 0.05). The findings of the current investigation also revealed that the incidence of livestock diseases on the farm and a higher level of formal education significantly contributed to better knowledge and desirable attitudes but bad AMU behavior. A low level of awareness about and undesirable attitudes toward AMU and AMR could potentially affect farmers' behavior toward judicious AMU, thus requiring awareness creation efforts on livestock disease management practices.

Antimicrobial Agents and Chemotherapy Launches a New Section Focused on Innovative Antimicrobial Stewardship Studies.

In response to the global burden of antimicrobial resistance (AMR) and the critical role antimicrobial stewardship plays in optimizing antibiotic use and reducing the subsequent emergence of AMR, Antimicrobial Agents and Chemotherapy is excited to add a new section to the journal focused on antimicrobial stewardship studies. Combatting the devastating burden of AMR requires novel, multipronged approaches from clinicians and scientists alike. Launching this new section is an important step in disseminating cutting-edge research that will have notable implications in the global fight against antimicrobial-resistant pathogens.

Increased growth temperature and vitamin B12 supplementation reduces the lag time for rapid pathogen identification in BHI agar and blood cultures.

Background: Rapid diagnostics of pathogens is essential to prescribe appropriate antibiotic therapy. The current methods for pathogen detection require the bacteria to grow in a culture medium, which is time-consuming. This increases the mortality rate and global burden of antimicrobial resistance. Culture-free detection methods are still under development and are not common in the clinical routine. Therefore, decreasing the culture time for accurately detecting infection and resistance is vital for diagnosis. Methods: This study investigated easy-to-implement factors (in a minimal laboratory set-up), including inoculum size, incubation temperature, and additional supplementation ( e.g., vitamin B12 and trace metals), that can significantly reduce the bacterial lag time (t lag). These factors were arranged in simple two-level factorial designs using Gram-positive cocci ( Staphylococcus aureus), Gram-positive bacilli ( Bacillus subtilis), and Gram-negative bacilli ( Escherichia coli and Pseudomonas aeruginosa) bacteria, including clinical isolates with known antimicrobial resistance profiles. Blood samples spiked with a clinical isolate of E. coli CCUG 17620 (Culture Collection University of Gothenburg) were also tested to see the effect of elevated incubation temperature on bacterial growth in blood cultures. Results: We observed that increased incubation temperature (42°C) along with vitamin B12 supplementation significantly reduced the t lag (10 - 115 minutes or 4% - 49%) in pure clinical isolates and blood samples spiked with E. coli CCUG17620. In the case of the blood sample, PCR results also detected bacterial DNA after only 3h of incubation and at three times the CFU/mL. Conclusion: Enrichment of bacterial culture media with growth supplements such as vitamin B12 and increased incubation temperature can be a cheap and rapid method for the early detection of pathogens. This proof-of-concept study is restricted to a few bacterial strains and growth conditions. In the future, the effect of other growth conditions and difficult-to-culture bacteria should be explored to shorten the lag phase.

Increased growth temperature and vitamin B12 supplementation reduces the lag time for rapid pathogen identification in BHI agar and blood cultures.

Background: The rapid diagnostics of pathogens is essential to prescribe appropriate and early antibiotic therapy. The current methods for pathogen detection require the bacteria to grow in a culture medium, which is time-consuming. This increases the mortality rate and the global burden of antimicrobial resistance. Culture-free detection methods are still under development and are not used in the clinical routine. Therefore decreasing the culture time for accurate detection of infection and resistance is vital for diagnosis. Methods: In this study, we wanted to investigate easy-to-implement factors (in a minimal laboratory set-up), including inoculum size, incubation temperature, and additional supplementation ( e.g., vitamin B12 and trace metals), that can significantly reduce the lag time (t lag). These factors were arranged in simple two-level factorial designs using Gram-positive ( Escherichia coli and Pseudomonas aeruginosa) and Gram-negative ( Staphylococcus aureus and Bacillus subtilis) bacteria, including clinical isolates with known antimicrobial resistance profiles. Blood samples spiked with a clinical isolate of E. coli CCUG17620 were also tested to see the effect of elevated incubation temperature on bacterial growth in blood cultures. Results: We observed that increased incubation temperature (42°C) along with vitamin B12 supplementation significantly reduced the t lag (10 - 115 minutes or 4% - 49%) in pure clinical isolates and blood samples spiked with E. coli CCUG17620. In the case of the blood sample, PCR results also detected bacterial DNA after only 3h of incubation and at three times the CFU/mL. Conclusions: Enrichment of bacterial culture media with growth supplements such as vitamin B12 and increased incubation temperature can be a cheap and rapid method for the early detection of pathogens. This is a proof-of-concept study restricted to a few bacterial strains and growth conditions. In the future, the effect of other growth conditions and difficult-to-culture bacteria should be explored to shorten the lag phase.

Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019

Reducing the burden of death due to infection is an urgent global public health priority. Previous studies have estimated the number of deaths associated with drug-resistant infections and sepsis and found that infections remain a leading cause of death globally. Understanding the global burden of common bacterial pathogens (both susceptible and resistant to antimicrobials) is essential to identify the greatest threats to public health. To our knowledge, this is the first study to present global comprehensive estimates of deaths associated with 33 bacterial pathogens across 11 major infectious syndromes. We estimated deaths associated with 33 bacterial genera or species across 11 infectious syndromes in 2019 using methods from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, in addition to a subset of the input data described in the Global Burden of Antimicrobial Resistance 2019 study. This study included 343 million individual records or isolates covering 11 361 study-location-years. We used three modelling steps to estimate the number of deaths associated with each pathogen: deaths in which infection had a role, the fraction of deaths due to infection that are attributable to a given infectious syndrome, and the fraction of deaths due to an infectious syndrome that are attributable to a given pathogen. Estimates were produced for all ages and for males and females across 204 countries and territories in 2019. 95% uncertainty intervals (UIs) were calculated for final estimates of deaths and infections associated with the 33 bacterial pathogens following standard GBD methods by taking the 2·5th and 97·5th percentiles across 1000 posterior draws for each quantity of interest. From an estimated 13·7 million (95% UI 10·9-17·1) infection-related deaths in 2019, there were 7·7 million deaths (5·7-10·2) associated with the 33 bacterial pathogens (both resistant and susceptible to antimicrobials) across the 11 infectious syndromes estimated in this study. We estimated deaths associated with the 33 bacterial pathogens to comprise 13·6% (10·2-18·1) of all global deaths and 56·2% (52·1-60·1) of all sepsis-related deaths in 2019. Five leading pathogens-Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae, and Pseudomonas aeruginosa-were responsible for 54·9% (52·9-56·9) of deaths among the investigated bacteria. The deadliest infectious syndromes and pathogens varied by location and age. The age-standardised mortality rate associated with these bacterial pathogens was highest in the sub-Saharan Africa super-region, with 230 deaths (185-285) per 100 000 population, and lowest in the high-income super-region, with 52·2 deaths (37·4-71·5) per 100 000 population. S aureus was the leading bacterial cause of death in 135 countries and was also associated with the most deaths in individuals older than 15 years, globally. Among children younger than 5 years, S pneumoniae was the pathogen associated with the most deaths. In 2019, more than 6 million deaths occurred as a result of three bacterial infectious syndromes, with lower respiratory infections and bloodstream infections each causing more than 2 million deaths and peritoneal and intra-abdominal infections causing more than 1 million deaths. The 33 bacterial pathogens that we investigated in this study are a substantial source of health loss globally, with considerable variation in their distribution across infectious syndromes and locations. Compared with GBD Level 3 underlying causes of death, deaths associated with these bacteria would rank as the second leading cause of death globally in 2019; hence, they should be considered an urgent priority for intervention within the global health community. Strategies to address the burden of bacterial infections include infection prevention, optimised use of antibiotics, improved capacity for microbiological analysis, vaccine development, and improved and more pervasive use of available vaccines. These estimates can be used to help set priorities for vaccine need, demand, and development. Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Health and Social Care, using UK aid funding managed by the Fleming Fund.

Isolation and Characterization of a Phapecoctavirus Infecting Multidrug-Resistant Acinetobacter baumannii in A549 Alveolar Epithelial Cells.

Multidrug-resistant Acinetobacter baumannii (MDR A. baumannii) is an emerging pathogen in the ESKAPE group. The global burden of antimicrobial resistance has led to renewed interest in alternative antimicrobial treatment strategies, including phage therapy. This study isolated and characterized a phage vB_AbaM_ ABPW7 (vABPW7) specific to MDR A. baumannii. Morphological analysis showed that phage vABPW7 belongs to the Myoviridae family. Genome analysis showed that the phage DNA genome consists of 148,647 bp and that the phage is a member of the Phapecoctavirus genus of the order Caudovirales. A short latent period and a large burst size indicated that phage vABPW7 was a lytic phage that could potentially be used in phage therapy. Phage vABPW7 is a high-stability phage that has high lytic activity. Phage vABPW7 could effectively reduce biofilm formation and remove preformed biofilm. The utility of phage vABPW7 was investigated in a human A549 alveolar epithelial cell culture model. Phage vABPW7 was not cytotoxic to A549 cells, and the phage could significantly reduce planktonic MDR A. baumannii and MDR A. baumannii adhesion on A549 cells without cytotoxicity. This study suggests that phage vABPW7 has the potential to be developed further as a new antimicrobial agent against MDR A. baumannii.

Globalisation of antibiotic-resistant bacteria at recurring mass gathering events

Antimicrobial resistance is associated with an estimated 4·95 million deaths annually and is currently a leading cause of death worldwide. 1 Murray CJL Ikuta KS Sharara F et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022; 399: 629-655 Summary Full Text Full Text PDF PubMed Scopus (867) Google Scholar Despite numerous global initiatives to control the surge of antimicrobial resistance, at the current rate of increase, annual deaths from antimicrobial resistance are estimated to rise to 10 million by 2050. This puzzling conundrum indicates that there are unknown factors that continue to increase antimicrobial resistance at a global scale and that identifying them will be crucial in controlling the ongoing antimicrobial resistance pandemic. There are also scarce data about the geographical distribution and evolution of antimicrobial resistance over time in settings outside of health-care facilities, 2 Hay SI Rao PC Dolecek C et al. Measuring and mapping the global burden of antimicrobial resistance. BMC Med. 2018; 16: 78 Crossref PubMed Scopus (89) Google Scholar , 3 Luz CF van Niekerk JM Keizer J et al. Mapping twenty years of antimicrobial resistance research trends. Artif Intell Med. 2022; 123: 102216 Crossref PubMed Scopus (4) Google Scholar and more accurate scientific evidence is required to promote optimal policies to combat antimicrobial resistance.

Prophage induction therapy: Activation of the lytic phase in prophages for the elimination of pathogenic bacteria

The global burden of antimicrobial resistance has resulted in an unmet need to develop novel interventions targeting pathogenic bacteria. Although phage therapy employs lytic phages to cause host-specific killing of target bacteria, regulatory hurdles have impeded its development. It is interesting to note that more significant percentages of bacterial populations harbor dormant phages called prophages. This article proposes a novel approach termed prophage induction therapy to treat bacterial infections, with CI repressor as the therapeutic target. Disruption of CI repressor-operator interaction with a small molecule leads to the activation of the lytic phase in prophages. Post-induction, phages released from lysogenic bacteria can infect their non-lysogenic counterparts, leading to their elimination. A surrogate reporter assay is proposed to screen and identify inducers, followed by a demonstration of proof of principle in the pathogenic bacteria of interest. Further, eliminating a heterogeneous population of lysogenic and non-lysogenic bacteria can be demonstrated using animal models of infectious diseases. Prophage induction therapy can be potentially applied to clinical settings to target antibiotic-resistant strains of bacteria or employed as an alternative to conventional antibiotic-based treatments.

Drug resistant tuberculosis: Implications for transmission, diagnosis, and disease management.

Drug resistant tuberculosis contributes significantly to the global burden of antimicrobial resistance, often consuming a large proportion of the healthcare budget and associated resources in many endemic countries. The rapid emergence of resistance to newer tuberculosis therapies signals the need to ensure appropriate antibiotic stewardship, together with a concerted drive to develop new regimens that are active against currently circulating drug resistant strains. Herein, we highlight that the current burden of drug resistant tuberculosis is driven by a combination of ongoing transmission and the intra-patient evolution of resistance through several mechanisms. Global control of tuberculosis will require interventions that effectively address these and related aspects. Interrupting tuberculosis transmission is dependent on the availability of novel rapid diagnostics which provide accurate results, as near-patient as is possible, together with appropriate linkage to care. Contact tracing, longitudinal follow-up for symptoms and active mapping of social contacts are essential elements to curb further community-wide spread of drug resistant strains. Appropriate prophylaxis for contacts of drug resistant index cases is imperative to limit disease progression and subsequent transmission. Preventing the evolution of drug resistant strains will require the development of shorter regimens that rapidly eliminate all populations of mycobacteria, whilst concurrently limiting bacterial metabolic processes that drive drug tolerance, mutagenesis and the ultimate emergence of resistance. Drug discovery programs that specifically target bacterial genetic determinants associated with these processes will be paramount to tuberculosis eradication. In addition, the development of appropriate clinical endpoints that quantify drug tolerant organisms in sputum, such as differentially culturable/detectable tubercle bacteria is necessary to accurately assess the potential of new therapies to effectively shorten treatment duration. When combined, this holistic approach to addressing the critical problems associated with drug resistance will support delivery of quality care to patients suffering from tuberculosis and bolster efforts to eradicate this disease.

Recent Advances in the Development of Semisynthetic Glycopeptide Antibiotics: 2014-2022.

The accelerated appearance of drug-resistant bacteria poses an ever-growing threat to modern medicine’s capacity to fight infectious diseases. Gram-positive species such as methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae continue to contribute significantly to the global burden of antimicrobial resistance. For decades, the treatment of serious Gram-positive infections relied upon the glycopeptide family of antibiotics, typified by vancomycin, as a last line of defense. With the emergence of vancomycin resistance, the semisynthetic glycopeptides telavancin, dalbavancin, and oritavancin were developed. The clinical use of these compounds is somewhat limited due to toxicity concerns and their unusual pharmacokinetics, highlighting the importance of developing next-generation semisynthetic glycopeptides with enhanced antibacterial activities and improved safety profiles. This Review provides an updated overview of recent advancements made in the development of novel semisynthetic glycopeptides, spanning the period from 2014 to today. A wide range of approaches are covered, encompassing innovative strategies that have delivered semisynthetic glycopeptides with potent activities against Gram-positive bacteria, including drug-resistant strains. We also address recent efforts aimed at developing targeted therapies and advances made in extending the activity of the glycopeptides toward Gram-negative organisms.

In Silico Docking, Resistance Modulation and Biofilm Gene Expression in Multidrug-Resistant Acinetobacter baumannii via Cinnamic and Gallic Acids.

Despite the mounting global burden of antimicrobial resistance (AMR), the generation of new classes of effective antimicrobials still lags far behind. The interplay between multidrug resistance and biofilm formation in Acinetobacter baumannii has drastically narrowed the available therapeutic choices. The use of natural compounds holds promise as an alternate option for restoring the activity of existing antibiotics and attenuating virulence traits through reduced biofilm formation. This study aimed to evaluate the modulatory effect of combining cinnamic and gallic acids at ½MIC with various antibiotics against multidrug-resistant (MDR) A. baumannii clinical isolates as well as study the effect on the expression of the biofilm-associated genes (bap, csuE, ompA) via quantitative, real-time PCR. Combining cinnamic or gallic acid with imipenem, amikacin or doxycycline resulted in significant reduction of resistance (p < 0.05). On the contrary, no effect was recorded when both acids were combined with levofloxacin, and only cinnamic acid had a synergistic effect with colistin. The transcriptomic changes of biofilm-related genes in the presence of gallic acid at ½MIC were compared with untreated control samples. The fold expression values proved that gallic acid substantially down-regulated the respective genes in all five strong biofilm formers. Molecular docking studies of gallic and cinnamic acids on target genes revealed good binding affinities and verified the proposed mechanism of action. To the best of our knowledge, this is the first report on the effect of gallic acid on the expression of bap, csuE and ompA genes in A. baumannii, which may permit its use as an adjunct anti-virulence therapeutic strategy.

It is time to define an organizational model for the prevention and management of infections along the surgical pathway: a worldwide cross-sectional survey

BackgroundThe objectives of the study were to investigate the organizational characteristics of acute care facilities worldwide in preventing and managing infections in surgery; assess participants’ perception regarding infection prevention and control (IPC) measures, antibiotic prescribing practices, and source control; describe awareness about the global burden of antimicrobial resistance (AMR) and IPC measures; and determine the role of the Coronavirus Disease 2019 pandemic on said awareness.MethodsA cross-sectional web-based survey was conducted contacting 1432 health care workers (HCWs) belonging to a mailing list provided by the Global Alliance for Infections in Surgery. The self-administered questionnaire was developed by a multidisciplinary team. The survey was open from May 22, 2021, and June 22, 2021. Three reminders were sent, after 7, 14, and 21 days.ResultsThree hundred four respondents from 72 countries returned a questionnaire, with an overall response rate of 21.2%. Respectively, 90.4% and 68.8% of participants stated their hospital had a multidisciplinary IPC team or a multidisciplinary antimicrobial stewardship team. Local protocols for antimicrobial therapy of surgical infections and protocols for surgical antibiotic prophylaxis were present in 76.6% and 90.8% of hospitals, respectively. In 23.4% and 24.0% of hospitals no surveillance systems for surgical site infections and no monitoring systems of used antimicrobials were implemented. Patient and family involvement in IPC management was considered to be slightly or not important in their hospital by the majority of respondents (65.1%). Awareness of the global burden of AMR among HCWs was considered very important or important by 54.6% of participants. The COVID-19 pandemic was considered by 80.3% of respondents as a very important or important factor in raising HCWs awareness of the IPC programs in their hospital. Based on the survey results, the authors developed 15 statements for several questions regarding the prevention and management of infections in surgery. The statements may be the starting point for designing future evidence-based recommendations.ConclusionAdequacy of prevention and management of infections in acute care facilities depends on HCWs behaviours and on the organizational characteristics of acute health care facilities to support best practices and promote behavioural change. Patient involvement in the implementation of IPC is still little considered. A debate on how operationalising a fundamental change to IPC, from being solely the HCWs responsibility to one that involves a collaborative relationship between HCWs and patients, should be opened.