Non-Alcohol Hand Sanitiser Gels with Mandelic Acid and Essential Oils.

Antimicrobial hand gels have become extremely popular in recent years due to the COVID-19 pandemic. Frequent use of hand sanitising gel can lead to dryness and irritation of the skin. This work focuses on the preparation of antimicrobial acrylic acid (Carbomer)-based gels enhanced by non-traditional compounds-mandelic acid and essential oils-as a substitute for irritating ethanol. Physicochemical properties (pH and viscosity), stability and sensory attributes of the prepared gels were investigated. Antimicrobial activity against representative Gram-positive and Gram-negative bacteria and yeasts was determined. The prepared gels with mandelic acid and essential oil (cinnamon, clove, lemon, and thyme) proved to have antimicrobial activity and even better organoleptic properties than commercial ethanol-based antimicrobial gel. Further, results confirmed that the addition of mandelic acid had a desirable effect on gel properties (antimicrobial, consistency, stability). It has been shown that the essential oil/mandelic acid combination can be a dermatologically beneficial hand sanitiser compared to commercial products. Thus, the produced gels can be used as a natural alternative to alcohol-based daily hand hygiene sanitisers.

Evidence of Antimicrobial Resistance in Bats and Its Planetary Health Impact for Surveillance of Zoonotic Spillover Events: A Scoping Review.

As a result of the COVID-19 pandemic, as well as other outbreaks, such as SARS and Ebola, bats are recognized as a critical species for mediating zoonotic infectious disease spillover events. While there is a growing concern of increased antimicrobial resistance (AMR) globally during this pandemic, knowledge of AMR circulating between bats and humans is limited. In this paper, we have reviewed the evidence of AMR in bats and discussed the planetary health aspect of AMR to elucidate how this is associated with the emergence, spread, and persistence of AMR at the human-animal interface. The presence of clinically significant resistant bacteria in bats and wildlife has important implications for zoonotic pandemic surveillance, disease transmission, and treatment modalities. We searched MEDLINE through PubMed and Google Scholar to retrieve relevant studies (n = 38) that provided data on resistant bacteria in bats prior to 30 September 2022. There is substantial variability in the results from studies measuring the prevalence of AMR based on geographic location, bat types, and time. We found all major groups of Gram-positive and Gram-negative bacteria in bats, which are resistant to commonly used antibiotics. The most alarming issue is that recent studies have increasingly identified clinically significant multi-drug resistant bacteria such as Methicillin Resistant Staphylococcus aureus (MRSA), ESBL producing, and Colistin resistant Enterobacterales in samples from bats. This evidence of superbugs abundant in both humans and wild mammals, such as bats, could facilitate a greater understanding of which specific pathways of exposure should be targeted. We believe that these data will also facilitate future pandemic preparedness as well as global AMR containment during pandemic events and beyond.

Impact of COVID-19 pandemic on multidrug resistant gram positive and gram negative pathogens: A systematic review.

BACKGROUND: There is paucity of data describing the impact of COVID-19 pandemic on antimicrobial resistance. This review evaluated the changes in the rate of multidrug resistant gram negative and gram positive bacteria during the COVID-19 pandemic. METHODS: A search was conducted in PubMed, Science Direct, and Google Scholar databases to identify eligible studies. Studies that reported the impact of COVID-19 pandemic on carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Enterobacteriaceae (CRE), extended-spectrum beta-lactamase inhibitor (ESBL)-producing Enterobacteriaceae, vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant Pseudomonas aeruginosa (CPE) were selected. Studies published in English language from the start of COVID-19 pandemic to July 2022 were considered for inclusion. RESULTS: Thirty eligible studies were selected and most of them were from Italy (n = 8), Turkey (n = 3) and Brazil (n = 3). The results indicated changes in the rate of multidrug resistant bacteria, and the changes varied between the studies. Most studies (54.5%) reported increase in MRSA infection/colonization during the pandemic, and the increase ranged from 4.6 to 170.6%. Five studies (55.6%) reported a 6.8-65.1% increase in VRE infection/colonization during the pandemic. A 2.4-58.2% decrease in ESBL E. coli and a 1.8-13.3% reduction in ESBL Klebsiella pneumoniae was observed during the pandemic. For CRAB, most studies (58.3%) reported 1.5-621.6% increase in infection/colonization during the pandemic. Overall, studies showed increase in the rate of CRE infection/colonization during the pandemic. There was a reduction in carbapenem-resistant E. coli during COVID-19 pandemic, and an increase in carbapenem-resistant K. pneumoniae. Most studies (55.6%) showed 10.4 - 40.9% reduction in the rate of CRPA infection during the pandemic. CONCLUSION: There is an increase in the rate of multidrug resistant gram positive and gram negative bacteria during the COVID-19 pandemic. However, the rate of ESBL-producing Enterobacteriaceae and CRPA has decrease during the pandemic. Both infection prevention and control strategies and antimicrobial stewardship should be strengthen to address the increasing rate of multidrug resistant gram positive and gram negative bacteria.

Covid-period-associated changes in organism profile of neonatal sepsis in a tertiary center from East India.

INTRODUCTION: Neonatal sepsis is a major cause of morbidity and mortality with a higher burden from the low- and middle-income countries. The coronavirus disease 2019 (Covid 19) pandemic has impacted healthcare in various ways including healthcare-associated infections (HAI). The objective of the present study was to determine changes in organism profile and incidence rates of HAI in neonates admitted to the index hospital during the pandemic and compared it with the data from the pre-pandemic period. MATERIALS AND METHODS: The study design was a retrospective, observational analysis of data from neonates with culture-positive sepsis, in a tertiary care children's hospital, between January 2018 and December 2021. Pre-Covid (January 2018 to December 2019) and Covid period data (January 2020 to December 2021) were analyzed for the significance of change. RESULTS: The prevalence of culture-positive sepsis, in pre-Covid and Covid periods, was 19.55% [95% confidence interval (95% CI) 17.13-21.52)] and 18.36% (CI 16.05-20.74), respectively. HAI rates/1000 patient days increased slightly during the Covid pandemic [7.2% (95% CI 6.98-10.08) to 9.8% (95% CI 9.78-13.67)] mainly due to an increase in fungal HAI (26% pre- vs. 41.5% Covid period). However, the proportion of Gram-negative (GN) infections fell significantly (70.5% vs. 48.6%) during the same period. In the pre-Covid period, Klebsiella followed by Burkholderia cepacia, Acinetobacter spp and Pseudomonas, were the major HAI isolates. During the Covid period, there was a decline in these isolates and Burkholderia spp was not detected. All fungal isolates were Candida species. The case fatality ratio (CFR) from HAI decreased significantly from 38% to 15.45%, mainly due to a decrease in GN HAI. CONCLUSION: During Covid pandemic, there was a significant decline in GN HAI and CFR from HAI, due to improved compliance with infection control measures in the neonatal intensive care unit (NICU). At the same time, there was a rise in the fungal HAI, possibly because of a higher proportion of premature, and sick neonates with longer hospital stay and more invasive procedures. Consolidations of gains in infection control and restriction of invasive procedures could help to minimize HAI in NICUs.

Blood stream infections in children less than 4 weeks old are known as neonatal sepsis. Several predisposing factors can make a neonate (less than 4 weeks) more prone to sepsis, such as prematurity, male gender, cultural practices, presence of underlying medical or surgical conditions, hospitalization, antibiotic use and invasive treatment. Neonatal sepsis in a hospitalized child can be either­pre-harbored infection (PHI), which means infection acquired prior to hospital admission or it could be healthcare-associated infection (HAI), where the infection is acquired during the hospital stay. Organisms causing neonatal sepsis in hospitalized neonates include bacteria and fungi. The coronavirus disease 2019 (Covid 19) pandemic impacted all aspects of life including healthcare. The investigators conducted the present study to look into the changes in the incidence rate as well as in the type of organisms causing healthcare-associated blood stream infections in neonates in the pre-Covid and during the Covid period.

Healthcare microenvironments define multidrug-resistant organism persistence.

BACKGROUND: Multidrug-resistant organisms (MDROs) colonizing the healthcare environment have been shown to contribute to risk for healthcare-associated infections (HAIs), with adverse effects on patient morbidity and mortality. We sought to determine how bacterial contamination and persistent MDRO colonization of the healthcare environment are related to the position of patients and wastewater sites. METHODS: We performed a prospective cohort study, enrolling 51 hospital rooms at the time of admitting a patient with an eligible MDRO in the prior 30 days. We performed systematic sampling and MDRO culture of rooms, as well as 16S rRNA sequencing to define the environmental microbiome in a subset of samples. RESULTS: The probability of detecting resistant gram-negative organisms, including Enterobacterales, Acinetobacter spp, and Pseudomonas spp, increased with distance from the patient. In contrast, Clostridioides difficile and methicillin-resistant Staphylococcus aureus were more likely to be detected close to the patient. Resistant Pseudomonas spp and S. aureus were enriched in these hot spots despite broad deposition of 16S rRNA gene sequences assigned to the same genera, suggesting modifiable factors that permit the persistence of these MDROs. CONCLUSIONS: MDRO hot spots can be defined by distance from the patient and from wastewater reservoirs. Evaluating how MDROs are enriched relative to bacterial DNA deposition helps to identify healthcare micro-environments and suggests how targeted environmental cleaning or design approaches could prevent MDRO persistence and reduce infection risk.

Multi-target activity of copper complexes: Antibacterial, DNA binding, and molecular docking with SARS-CoV-2 receptor.

A series of pendant-armed mixed-ligand copper(II) complexes of the type [CuL1-3(diimine)] (1-6) have been synthesized by the reaction of pendant-armed ligands N,N-bis(2-(((E)-2-hydroxy-5-methylbenzylidene)amino)ethyl)benzamide (H2L1), N,N-bis(2-(((E)-2-hydroxy-5-methylbenzylidene)amino)ethyl)-4-nitrobenzamide (H2L2) and N,N-bis(2-(((E)-2-hydroxy-5-methylbenzylidene)amino)ethyl)-3,5-dinitrobenzamide (H2L3) with diimine = 2,2'-bipyridyl (bpy) or 1,10-phenanthroline (phen) in the presence of copper(II) chloride and analyzed using various spectroscopic methods. All the spectroscopic results support that the complexes adopt a pentagonal-bipyramidal shape around the copper ion. Gram-positive and Gram-negative bacteria were used to test all the complexes for antibacterial activity and all the complexes had greater potency against gram-negative pathogens. DNA-binding experiments of complexes with calf thymus DNA revealed a major-groove binding pattern, further supported by molecular docking studies. Complexes have significantly interacted with SARS-CoV-2 receptor via π-π, π-σ, π-alkyl, π-anion, π-cation, alkyl, hydrogen bond, van der Waals, and electrostatic interactions. The estimated binding energy and inhibition constant of these complexes are higher than standard drugs, chloroquine, and molnupiravir.

Biogenic nanosilver-fabricated endotracheal tube to prevent microbial colonization in a veterinary hospital.

COVID-19 patients have often required prolonged endotracheal intubation, increasing the risk of developing ventilator-associated pneumonia (VAP). A preventive strategy is proposed based on an endotracheal tube (ETT) modified by the in situ deposition of eucalyptus-mediated synthesized silver nanoparticles (AgNPs). The surfaces of the modified ETT were embedded with AgNPs of approximately 28 nm and presented a nanoscale roughness. Energy dispersive X-ray spectroscopy confirmed the presence of silver on and inside the coated ETT, which exhibited excellent antimicrobial activity against Gram-positive and Gram-negative bacteria, and fungi, including multidrug-resistant clinical isolates. Inhibition of planktonic growth and microbial adhesion ranged from 99 to 99.999% without cytotoxic effects on mammalian cells. Kinetic studies showed that microbial adhesion to the coated surface was inhibited within 2 h. Cell viability in biofilms supplemented with human tracheal mucus was reduced by up to 95%. In a porcine VAP model, the AgNPs-coated ETT prevented adhesion of Pseudomonas aeruginosa and completely inhibited bacterial invasion of lung tissue. The potential antimicrobial efficacy and safety of the coated ETT were established in a randomized control trial involving 47 veterinary patients. The microbial burden was significantly lower on the surface of the AgNPs-coated ETT than on the uncoated ETT (p < 0.05). KEY POINTS: • Endotracheal tube surfaces were modified by coating with green-synthesized AgNPs • P. aeruginosa burden of endotracheal tube and lung was reduced in a porcine model • Effective antimicrobial activity and safety was demonstrated in a clinical trial.

Last resort beta-lactam antibiotics for treatment of New-Delhi Metallo-Beta-Lactamase producing Enterobacterales and other Difficult-to-Treat Resistance in Gram-negative bacteria: A real-life study.

Introduction: Novel last resort beta-lactam antibiotics are now available for management of infections due to New-Delhi Metallo-Beta-Lactamase (NDM) producing Enterobacterales and non-fermenters with Difficult-to-Treat Resistance. However, data regarding the use of imipenem-cilastatin-relebactam (IMI-REL), cefiderocol (CFD) and ceftazidime-avibactam plus aztreonam (CAZ-AVI-ATM) are scarce in real-life settings. This study aimed to describe the use of last resort beta-lactam antibiotics, the microbiology and the outcome, in patients hospitalized in a tertiary hospital. Methods: We conducted a monocentric observational cohort study from 2020/01/01, to 2022/08/31. We screened all patients admitted to Nimes University Hospital who have received ≥ 1 dose of last resort beta-lactam antibiotics during the study period, using the Pharmacy database. We included patients treated with IMI-REL, CFD and CAZ-AVI-ATM. The primary endpoint was the infection-free survival rate. We also calculated rates of microbiological and clinical cure, recurrent infection, death and adverse events. Results: Twenty-seven patients were included in the study and 30 treatment courses were analyzed: CFD (N=24; 80%), CAZ-AVI-ATM (N=3; 10%) and IMI-REL (N=3; 10%). Antibiotics were used in 21 males (70%) and 9 females (30%) with a median age at 65-year-old [50-73.5] and a median Charlson index at 1 [0-2]. Almost all the patients had ≥ 1 risk factor for carbapenem resistant bacteria, a half of them was hospitalized for severe COVID-19, and most of antibiotic courses (N=26; 87%) were associated with ICU admission. In the study population, the probability of infection-free survival at day-90 after last resort beta-lactam therapy initiation was 48.4% CI95% [33.2-70.5]. Clinical failure rate was at 30%, microbiological failure rate at 33% and mortality rate at 23%. Adverse events were documented in 5 antibiotic courses (17%). In details, P. aeruginosa were mainly treated with CFD and IMI-REL, S. maltophilia with CFD and CAZ-AVI-ATM, A. baumannii with CFD, and NDM producing-K. pneumoniae with CAZ-AVI-ATM and CFD. After a treatment course with CFD, CAZ-AVI-ATM and IMI-REL, the probability of infection-free survival was 48% CI95% [10.4-73.5], 33.3% CI95% [6.7-100], 66.7% CI95% [30-100], respectively. Discussion/conclusion: Use of last resort beta-lactam antimicrobials in real-life settings was a safe and efficient therapeutic option for severe infections related to Gram-negative bacteria with Difficult-to-Treat Resistance.

Bacterial profiles and their antibiotic resistance background in superinfections caused by multidrug-resistant bacteria among COVID-19 ICU patients from southwest Iran.

This study investigated the bacterial causes of superinfections and their antibiotic resistance pattern in severe coronavirus disease 2019 (COVID-19) patients admitted to the intensive care unit (ICU) of Razi Hospital in Ahvaz, southwest Iran. In this cross-sectional study, endotracheal tube (ETT) secretion samples of 77 intubated COVID-19 patients, confirmed by reverse transcription-quantitative polymerase chain reaction, were investigated by standard microbiology test and analytical profile index kit. Antibiotic susceptibility testing was performed by disc diffusion. The presence of Haemophilus influenzae and Mycoplasma pneumoniae was investigated by the polymerase chain reaction (PCR). Using culture and PCR methods, 56 (72.7%) of the 77 COVID-19 patients (mean age of 55 years, 29 male and 27 female) had superinfections. Using culture, 67 isolates including 29 (43.2%) Gram-positive and 38 (56.7%) Gram-negative bacteria (GNB) were identified from 49 COVID-19 patients. The GNB were more predominant than the Gram-positive pathogens. Klebsiella pneumoniae (28.4%, n = 19/67) was the most common isolate followed by Staphylococcus aureus (22.4%, n = 15/67). Using PCR, 10.4% (8/77) and 11.7% (9/77) of ETT secretion specimens had H. influenzae and M. pneumoniae amplicons, respectively. Gram-positive and Gram-negative isolates showed high resistance rates (>70.0%) to majority of the tested antibiotics including fluoroquinolone, carbapenems, and cephalosporins and 68.7% (46/67) of isolates were multidrug-resistant (MDR). This study showed a high frequency rate of superinfections by MDR bacteria among COVID-19 patients in southwest Iran. The prevention of long-term consequences caused by COVID-19, demands continuous antibiotic surveillance particularly in management of bacterial superinfections.

Antibacterial and Antiviral Coating on Surfaces through Dopamine-Assisted Codeposition of an Antifouling Polymer and In Situ Formed Nanosilver.

Bacteria and viruses can adhere onto diverse surfaces and be transmitted in multiple ways. A bifunctional coating that integrates both antibacterial and antiviral activities is a promising approach to mitigate bacterial and viral infections arising from a contaminated surface. However, current coating approaches encounter a slow reaction, limited activity against diverse bacteria or viruses, short-term activity, difficulty in scaling-up, and poor adaptation to diverse material surfaces. Here, we report a new one-step strategy for the development of a polydopamine-based nonfouling antibacterial and antiviral coating by the codeposition of various components. The in situ formed nanosilver in the presence of polydopamine was incorporated into the coating and served as both antibacterial and antiviral agents. In addition, the coassembly of polydopamine and a nonfouling hydrophilic polymer was constructed to prevent the adhesion of bacteria and viruses on the coating. The coating was prepared on model surfaces and thoroughly characterized using various surface analytical techniques. The coating exhibited strong antifouling properties with a reduction of nonspecific protein adsorption up to 90%. The coating was tested against both Gram-positive and Gram-negative bacteria and showed long-term antibacterial effectiveness, which correlated with the composition of the coating. The antiviral activity of the coating was evaluated against human coronavirus 229E. A possible mechanism of action of the coating was proposed. We anticipate that the optimized coating will have applications in the development of infection prevention devices and surfaces.

Multidrug resistant bacterial infections in severely ill COVID-19 patients admitted in a national referral and teaching hospital, Kenya.

BACKGROUND: Bacterial infections are a common complication in patients with seasonal viral respiratory tract infections and are associated with poor prognosis, increased risk of intensive care unit admission and 29-55% mortality. Yet, there is limited data on the burden of bacterial infections among COVID-19 patients in Africa, where underdeveloped healthcare systems are likely to play a pertinent role in the epidemiology of the COVID-19 pandemic. Here, we evaluated the etiologies, antimicrobial resistance profiles, risk factors, and outcomes of bacterial infections in severely ill COVID-19 patients. METHODS: A descriptive cross-sectional study design was adopted in severely ill COVID-19 patients at Kenyatta National Hospital, Kenya, from October to December 2021. We used a structured questionnaire and case report forms to collect sociodemographics, clinical presentation, and hospitalization outcome data. Blood, nasal/oropharyngeal swabs and tracheal aspirate samples were collected based on the patient's clinical presentation and transported to the Kenyatta National Hospital microbiology laboratory for immediate processing following the standard bacteriological procedures. RESULTS: We found at least one bacterial infection in 44.2% (53/120) of the patients sampled, with a 31.7% mortality rate. Pathogens were mainly from the upper respiratory tract (62.7%, 42/67), with gram-negative bacteria dominating (73.1%, 49/67). Males were about three times more likely to acquire bacterial infection (p = 0.015). Those aged 25 to 44 years (p = 0.009), immunized against SARS-CoV-2 (p = 0.027), and admitted to the infectious disease unit ward (p = 0.031) for a short length of stay (0-5 days, p < 0.001) were more likely to have a positive outcome. Multidrug-resistant isolates were the majority (64.3%, 46/67), mainly gram-negative bacteria (69.6%, 32/46). The predominant multidrug-resistant phenotypes were in Enterococcus cloacae (42.9%, 3/7), Klebsiella pneumonia (25%, 4/16), and Escherichia coli (40%, 2/5). CONCLUSION: Our findings highlight a high prevalence of multidrug-resistant bacterial infections in severely ill COVID-19 patients, with male gender as a risk factor for bacterial infection. Elderly Patients, non-SARS-CoV-2 vaccination, intensive care unit admission, and long length of hospital stay were associated with poor outcomes. There is a need to emphasize strict adherence to infection and prevention at KNH-IDU and antimicrobial stewardship in line with local and global AMR control action plans.

Acquisition of carbapenem-resistant gram-negative bacilli among intensive care unit (ICU) patients with no previous use of carbapenems: Indirect population impact of antimicrobial use.

OBJECTIVE: To measure the impact of exposure to patients using carbapenem on the acquisition of carbapenem-resistant gram-negative bacilli (CR-GNB) among patients not using carbapenems. DESIGN: An ecological study and a cohort study. SETTING: Two medical surgical intensive care units (ICUs) in inner Brazil. PARTICIPANTS: Patients admitted to 2 ICUs from 2013 through 2018 to whom carbapenem was not prescribed. METHODS: In the ecologic study, the monthly use of carbapenems (days of therapy [DOT] per 1,000 patient days) was tested for linear correlation with the 2-month moving average of incidence CR-GNB among patients to whom carbapenem was not prescribed. In the cohort study, those patients were addressed individually for risk factors (demographics, invasive interventions, use of antimicrobials) for acquisition of CR-GNB, including time at risk and the "carbapenem pressure," described as the aggregate DOT among other ICU patients during time at risk. The analysis was performed in univariate and multivariable Poisson regression models. RESULTS: The linear regression model revealed an association of total carbapenem use and incidence of CR-GNB (coefficient, 0.04; 95% confidence interval [CI], 0.02-0.06; P = .001). In the cohort model, the adjusted rate ratio (RR) for carbapenem DOT was 1.009 (95% CI, 1.001-1.018; P = .03). Other significant risk factors were mechanical ventilation and the previous use of ceftazidime (with or without avibactam). CONCLUSIONS: Every additional DOT of total carbapenem use increased the risk of CR-GNB acquisition by patients not using carbapenems by nearly 1%. We found evidence for a population ("herd effect"-like) impact of antimicrobial use in the ICUs.

Epidemiology of Gram-negative bacteria during coronavirus disease 2019. What is the real pandemic?

PURPOSE OF REVIEW: Bacterial infections play a key role in hospital outcomes during the coronavirus disease 2019 (COVID-19) pandemic. Nonetheless, the global impact on the epidemiology of Gram-negative bacteria (GNB) and antibiotic resistance has not been clearly established. RECENT FINDINGS: Multiple limitations exist in the current literature, in that substantial variability was observed with regard to methodology. Notwithstanding the heterogeneity, the evidence suggests that the COVID-19 pandemic had a substantial negative impact on global epidemiology with an increase in hospital-onset infections, associated with GNB. Similarly, an alarming increase in resistant GNB compared to prepandemic rates, was apparent. This was most evident for carbapenemase-producing Klebsiella pneumoniae (bloodstream infections), carbapenem-resistant Pseudomonas aeruginosa (ventilator-associated pneumonia), and carbapenem-resistant Acinetobacter baumannii (all infections). Significant variations were most apparent in the large, system-wide regional or national comparative assessments, vs. single-centre studies. Categorizing concurrent bacteria as co- or secondary-infections may be paramount to optimize standard of care. SUMMARY: The data from most studies signal the probability that COVID-19 accelerated resistance. However, multiple limitations intrinsic to interpretation of current COVID-19 data, prevents accurately quantifying collateral damage on the global epidemiology and antibiotic resistance amongst GNB. It is likely to be substantial and renewed efforts to limit further increases is warranted.

The health facility as a risk factor for multidrug-resistant gram-negative bacteria in critically ill patients with COVID-19.

BACKGROUND: The relationship between Multidrug Resistant-Gram Negative Bacteria (MDR-GNB) infection and colonization in critically ill COVID-19 patients has been observed, however, it is still poorly understood. This study evaluated the risk factors for acquiring MDR-GNB in patients with severe COVID-19 in Intensive Care Units (ICU). METHODS: This is a nested case-control study in a cohort of 400 adult patients (≥ 18 years old) with COVID-19, hospitalized in the ICU of 4 hospitals in the city of Curitiba, Brazil. Cases were critical COVID-19 patients with one or more MDR GNB from any surveillance and/or clinical cultures were taken during their ICU stay. Controls were patients from the same units with negative cultures for MDR-GNB. Bivariate and multivariate analyses were done. RESULTS: Sixty-seven cases and 143 controls were included. Independent risk factors for MDR bacteria were: male gender (OR = 2.6; 95% CI 1.28‒5.33; p = 0.008); the hospital of admission (OR = 3.24; 95% CI 1.39‒7.57; p = 0.006); mechanical ventilation (OR = 25.7; 95% CI 7.26‒91; p < 0.0001); and desaturation on admission (OR = 2.6; 95% CI 1.27‒5.74; p = 0.009). CONCLUSIONS: Male gender, desaturation, mechanical ventilation, and the hospital of admission were the independent factors associated with MDR-GNB in patients in the ICU with COVID-19. The only modifiable factor was the hospital of admission, where a newly opened hospital posed a higher risk. Therefore, coordinated actions toward a better quality of care for critically ill COVID-19 patients are essential.

Risk stratification for selecting empiric antibiotherapy during and after COVID-19.

PURPOSE OF REVIEW: SARS-CoV-2 deeply modified the risk of bacterial infection, bacterial resistance, and antibiotic strategies. This review summarized what we have learned. RECENT FINDINGS: During the COVID-19 pandemic, we observed an increase in healthcare-acquired infection and multidrug-resistant organism-related infection, triggered by several factors: structural factors, such as increased workload and ongoing outbreaks, underlying illnesses, invasive procedures, and treatment-induced immunosuppression. The two most frequently healthcare-acquired infections described in patients hospitalized with COVID-19 were bloodstream infection, related or not to catheters, health-acquired pneumonia (in ventilated or nonventilated patients). The most frequent species involved in bacteremia were Gram-positive cocci and Gram-negative bacilli in health-acquired pneumonia. The rate of Gram-negative bacilli is particularly high in late-onset ventilator-associated pneumonia, and the specific risk of Pseudomonas aeruginosa- related pneumonia increased when the duration of ventilation was longer than 7 days. A specificity that remains unexplained so far is the increase in enterococci bacteremia. SUMMARY: The choice of empiric antibiotimicrobials depends on several factors such as the site of the infection, time of onset and previous length of stay, previous antibiotic therapy, and known multidrug-resistant organism colonization. Pharmacokinetics of antimicrobials could be markedly altered during SARS-CoV-2 acute respiratory failure, which should encourage to perform therapeutic drug monitoring.

Gearing up for battle: Harnessing adaptive T cell immunity against gram-negative pneumonia.

Pneumonia is one of the leading causes of morbidity and mortality worldwide and Gram-negative bacteria are a major cause of severe pneumonia. Despite advances in diagnosis and treatment, the rise of multidrug-resistant organisms and hypervirulent strains demonstrates that there will continue to be challenges with traditional treatment strategies using antibiotics. Hence, an alternative approach is to focus on the disease tolerance components that mediate immune resistance and enhance tissue resilience. Adaptive immunity plays a pivotal role in modulating these processes, thus affecting the incidence and severity of pneumonia. In this review, we focus on the adaptive T cell responses to pneumonia induced by Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. We highlight key factors in these responses that have potential for therapeutic targeting, as well as the gaps in current knowledge to be focused on in future work.

Study of Novel Peptides for Antimicrobial Protection in Solution and on Cotton Fabric.

Some new N- and C-modified biomolecular peptide analogues of both VV-hemorphin-5 and VV-hemorphin-7 with varied amino acids (Cys, Glu, His), 1-adamantanecarboxylic acid, and niacin (nicotinic acid) were synthesized by solid-phase peptide synthesis-Fmoc (9-fluorenylmethoxy-carbonyl) chemistry and were characterized in water solutions with different pH using spectroscopic and electrochemical techniques. Basic physicochemical properties related to the elucidation of the peptide structure at physiological pH have been also studied. The results showed that the interaction of peptide compounds with light and electricity preserves the structural and conformational integrity of the compounds in the solutions. Moreover, textile cotton fibers were modified with the new compounds and the binding of the peptides to the surface of the material was proved by FTIR and SEM analysis. Washing the material with an alkaline soap solution did not show a violation of the modified structure of the cotton. Antiviral activity against the human respiratory syncytial virus (HRSV-S2) and human adenovirus serotype 5 (HAdV-5), the antimicrobial activity against B. cereus and P. aeruginosa used as model bacterial strains and cytotoxic effect of the peptide derivatives and modified cotton textile material has been evaluated. Antimicrobial tests showed promising activity of the newly synthesized compounds against the used Gram-positive and Gram-negative bacteria. The compounds C-V, H-V, AC-V, and AH-V were found slightly more active than NH7C and NCH7. The activity has been retained after the deposition of the compounds on cotton fibers.

Bacteremia in Children with Solid Tumors: Etiology, Antimicrobial Susceptibility, Factors Associated with Multidrug Resistance, and Mortality.

This retrospective study aims to describe the etiology and resistance patterns of pathogens causing bacteremia in children with solid tumors in a tertiary pediatric hematology-oncology center in Jerusalem, Israel (2011-2019). Factors associated with multidrug-resistant (MDR) bacteremia and mortality were analyzed. A total of 228 pathogens were isolated in 126 patients; 61.0% were gram-negative rods (GNR) and 38.2% were gram-positive cocci (GPC). The most common pathogens were Klebsiella pneumoniae (19.3%), Escherichia coli (17.5%), and coagulase-negative staphylococci (16.2%). The proportion of MDR-GNR was 18.2%, while the proportion of MDR-GPC was 55.2%. In logistic regression analysis, breakthrough bacteremia on a penicillin-group antibiotic (odds ratio [OR] 5.69, [95% confidence interval 1.42-22.76], p-value = 0.014) was associated and underlying diagnosis of neuroblastoma was inversely associated (OR 0.17, [0.04-0.81], p-value = 0.026) with MDR-GNR bacteremia; while the previous hospitalizations' duration (OR 1.032/day, [1.01-1.06], p-value = 0.007) and oncologic treatment intensity (OR 2.19, [1.08-4.45, p-value = 0.03) were associated with MDR-GPC bacteremia. Shock, prolonged profound neutropenia, and pediatric intensive care unit (PICU) admission were associated with 7-day mortality; and relapsed disease, oncologic treatment intensity, prolonged profound neutropenia, and PICU admission-with 30-day mortality in the univariate analyses. Empirical antibiotic choice should be based on factors associated with MDR infections in this specific population.

Sulopenem: An Intravenous and Oral Penem for the Treatment of Urinary Tract Infections Due to Multidrug-Resistant Bacteria.

Sulopenem (formerly known as CP-70,429, and CP-65,207 when a component of a racemic mixture with its R isomer) is an intravenous and oral penem that possesses in vitro activity against fluoroquinolone-resistant, extended spectrum ß-lactamases (ESBL)-producing, multidrug-resistant (MDR) Enterobacterales. Sulopenem is being developed to treat patients with uncomplicated and complicated urinary tract infections (UTIs) as well as intra-abdominal infections. This review will focus mainly on its use in UTIs. The chemical structure of sulopenem shares properties of penicillins, cephalosporins, and carbapenems. Sulopenem is available as an oral prodrug formulation, sulopenem etzadroxil, which is hydrolyzed by intestinal esterases, resulting in active sulopenem. In early studies, the S isomer of CP-65,207, later developed as sulopenem, demonstrated greater absorption, higher drug concentrations in the urine, and increased stability against the renal enzyme dehydropeptidase-1 compared with the R isomer, which set the stage for its further development as a UTI antimicrobial. Sulopenem is active against both Gram-negative and Gram-positive microorganisms. Sulopenem's ß-lactam ring alkylates the serine residues of penicillin-binding protein (PBP), which inhibits peptidoglycan cross-linking. Due to its ionization and low molecular weight, sulopenem passes through outer membrane proteins to reach PBPs of Gram-negative bacteria. While sulopenem activity is unaffected by many ß-lactamases, resistance arises from alterations in PBPs (e.g., methicillin-resistant Staphylococcus aureus [MRSA]), expression of carbapenemases (e.g., carbapenemase-producing Enterobacterales and in Stenotrophomonas maltophilia), reduction in the expression of outer membrane proteins (e.g., some Klebsiella spp.), and the presence of efflux pumps (e.g., MexAB-OprM in Pseudomonas aeruginosa), or a combination of these mechanisms. In vitro studies have reported that sulopenem demonstrates greater activity than meropenem and ertapenem against Enterococcus faecalis, Listeria monocytogenes, methicillin-susceptible S. aureus (MSSA), and Staphylococcus epidermidis, as well as similar activity to carbapenems against Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes. With some exceptions, sulopenem activity against Gram-negative aerobes was less than ertapenem and meropenem but greater than imipenem. Sulopenem activity against Escherichia coli carrying ESBL, CTX-M, or Amp-C enzymes, or demonstrating MDR phenotypes, as well as against ESBL-producing Klebsiella pneumoniae, was nearly identical to ertapenem and meropenem and greater than imipenem. Sulopenem exhibited identical or slightly greater activity than imipenem against many Gram-positive and Gram-negative anaerobes, including Bacteroides fragilis. The pharmacokinetics of intravenous sulopenem appear similar to carbapenems such as imipenem-cilastatin, meropenem, and doripenem. In healthy subjects, reported volumes of distribution (Vd) ranged from 15.8 to 27.6 L, total drug clearances (CLT) of 18.9-24.9 L/h, protein binding of approximately 10%, and elimination half-lives (t½) of 0.88-1.03 h. The estimated renal clearance (CLR) of sulopenem is 8.0-10.6 L/h, with 35.5% ± 6.7% of a 1000 mg dose recovered unchanged in the urine. An ester prodrug, sulopenem etzadroxil, has been developed for oral administration. Initial investigations reported a variable oral bioavailability of 20-34% under fasted conditions, however subsequent work showed that bioavailability is significantly improved by administering sulopenem with food to increase its oral absorption or with probenecid to reduce its renal tubular secretion. Food consumption increases the area under the curve (AUC) of oral sulopenem (500 mg twice daily) by 23.6% when administered alone and 62% when administered with 500 mg of probenecid. Like carbapenems, sulopenem demonstrates bactericidal activity that is associated with the percentage of time that free concentrations exceed the MIC (%f T > MIC). In animal models, bacteriostasis was associated with %f T > MICs ranging from 8.6 to 17%, whereas 2-log10 kill was seen at values ranging from 12 to 28%. No pharmacodynamic targets have been documented for suppression of resistance. Sulopenem concentrations in urine are variable, ranging from 21.8 to 420.0 mg/L (median 84.4 mg/L) in fasted subjects and 28.8 to 609.0 mg/L (median 87.3 mg/L) in those who were fed. Sulopenem has been compared with carbapenems and cephalosporins in guinea pig and murine systemic and lung infection animal models. Studied pathogens included Acinetobacter calcoaceticus, B. fragilis, Citrobacter freundii, Enterobacter cloacae, E. coli, K. pneumoniae, Proteus vulgaris, and Serratia marcescens. These studies reported that overall, sulopenem was non-inferior to carbapenems but appeared to be superior to cephalosporins. A phase III clinical trial (SURE-1) reported that sulopenem was not non-inferior to ciprofloxacin in women infected with fluoroquinolone-susceptible pathogens, due to a higher rate of asymptomatic bacteriuria in sulopenem-treated patients at the test-of-cure visit. However, the researchers reported superiority of sulopenem etzadroxil/probenecid over ciprofloxacin for the treatment of uncomplicated UTIs in women infected with fluoroquinolone/non-susceptible pathogens, and non-inferiority in all patients with a positive urine culture. A phase III clinical trial (SURE-2) compared intravenous sulopenem followed by oral sulopenem etzadroxil/probenecid with ertapenem in the treatment of complicated UTIs. No difference in overall success was noted at the end of therapy. However, intravenous sulopenem followed by oral sulopenem etzadroxil was not non-inferior to ertapenem followed by oral stepdown therapy in overall success at test-of-cure due to a higher rate of asymptomatic bacteriuria in the sulopenem arm. After a meeting with the US FDA, Iterum stated that they are currently evaluating the optimal design for an additional phase III uncomplicated UTI study to be conducted prior to the potential resubmission of the New Drug Application (NDA). It is unclear at this time whether Iterum intends to apply for EMA or Japanese regulatory approval. The safety and tolerability of sulopenem has been reported in various phase I pharmacokinetic studies and phase III clinical trials. Sulopenem (intravenous and oral) appears to be well tolerated in healthy subjects, with and without the coadministration of probenecid, with few serious drug-related treatment-emergent adverse events (TEAEs) reported to date. Reported TEAEs affecting ≥1% of patients were (from most to least common) diarrhea, nausea, headache, vomiting and dizziness. Discontinuation rates were low and were not different than comparator agents. Sulopenem administered orally and/or intravenously represents a potentially well tolerated and effective option for treating uncomplicated and complicated UTIs, especially in patients with documented or highly suspected antimicrobial pathogens to commonly used agents (e.g. fluoroquinolone-resistant E. coli), and in patients with documented microbiological or clinical failure or patients who demonstrate intolerance/adverse effects to first-line agents. This agent will likely be used orally in the outpatient setting, and intravenously followed by oral stepdown in the hospital setting. Sulopenem also allows for oral stepdown therapy in the hospital setting from intravenous non-sulopenem therapy. More clinical data are required to fully assess the clinical efficacy and safety of sulopenem, especially in patients with complicated UTIs caused by resistant pathogens such as ESBL-producing, Amp-C, MDR E. coli. Antimicrobial stewardship programs will need to create guidelines for when this oral and intravenous penem should be used.