Children exposed to second-hand smoke have high rates of hospitalization for respiratory illness. These visits represent a "teachable moment" when parental smokers can be motivated to quit. However, pediatric health care practitioners receive little training in tobacco cessation.

The Web-Based Respiratory Education About Tobacco and Health online training program was effective at increasing the provision of an effective tobacco cessation intervention by pediatric hospital-based respiratory therapists, registered nurses, and nurse practitioners to adult smokers. (Read the full article)

Among youth with asthma, tobacco smoke exposure causes increased asthma morbidity. Little is known about changes over time in tobacco smoke exposure among youth with asthma in a national sample.

Our analysis reveals a decrease in environmental tobacco smoke exposure among children and adolescents with current asthma in the United States from 1988–1994 to 2005–2010, but a majority of youth with asthma remain exposed to environmental tobacco smoke. (Read the full article)

Expectations are high that electronic health record–based clinical decision support and performance feedback will improve adherence to guidelines by delivering relevant and actionable information to clinicians. Few studies have evaluated these assertions or examined the combined effects of decision support and feedback.

Clinical decision support customized to a patient’s history and presentation and performance feedback are both effective for improving adherence to guidelines for otitis media. However, the combination of the 2 interventions is no better than either delivered alone. (Read the full article)

Active smoking and secondhand smoke are associated with chronic kidney disease in adults. No data are available for children.

Secondhand smoke and active smoking were associated with decreased estimated glomerular filtration rate in US adolescents. These findings support that tobacco smoke effects on kidney function begin in childhood. (Read the full article)

Before the introduction of conjugate pneumococcal vaccines and routine penicillin prophylaxis, febrile patients with sickle cell disease were known to have a 3% to 5% risk of bacteremia. Consequently, hospitalization rates for febrile episodes are >70%.

We observed no mortality or morbidity among those managed completely as outpatients, and bacteremia occurred in <1%. Physicians should strongly consider outpatient management of febrile children with sickle cell disease if there are no other indications for admission. (Read the full article)

Young adult smokers frequently encounter the health care system as parents coming in for their child’s medical visit. Child health care clinicians, however, do not typically provide smoking cessation assistance to parents.

This national cluster-randomized trial demonstrates that a tobacco dependence intervention for parents can be effectively implemented in routine pediatric outpatient practice. (Read the full article)

Despite declines in cigarette smoking, smokeless tobacco use among youth has remained unchanged in the United States. Modified or novel smokeless tobacco products are being increasingly promoted to youth in the United States as an alternative to smoking.

Among US students in grades 6 through 12, 5.0% used snuff or chewing or dipping tobacco, whereas 2.2% used snus or dissolvable tobacco products. Approximately two-thirds of smokeless tobacco users concurrently smoked combustible tobacco; risk perception of all tobacco products was protective of smokeless tobacco use. (Read the full article)

Prosmoking messages, delivered through marketing and the media, can reach very young children and influence attitudes and behaviors around smoking.

Marketing of tobacco and cigarette brands has successfully reached young children in low- and middle-income countries. More effective measures are needed to restrict the reach of tobacco marketing. (Read the full article)

Bacteremia occurs in 2.2% of febrile infants who have a blood culture drawn. Regional data suggest that Escherichia coli, group B Streptococcus, and Staphylococcus aureus are leading causes; however, the geographic boundaries of these data limit universal applicability.

This is the first national study examining epidemiology of bacteremia in febrile infants admitted to a general inpatient unit. The most common pathogens were Escherichia coli (42%), group B Streptococcus (23%), and Streptococcus pneumoniae (6%). No Listeria monocytogenes was identified. (Read the full article)

Youth are frequent consumers of movies that contain high levels of violence, and violent content in films, especially those rated PG-13, has been increasing over time.

Content analyses seldom examine how violence is portrayed with other health risk behaviors, such smoking, drinking, and sex. This study presents an innovative way to characterize on-screen violent content and demonstrates the extent to which risk behaviors co-occur within films. (Read the full article)

Bacille Calmette-Guerin (BCG) vaccination may provide benefits beyond protecting against pediatric tuberculosis. Evidence suggests links between cell-mediated immunity from tuberculosis and bacterial/viral-related pneumonia but the impact of BCG on acute lower respiratory infection is not fully known.

BCG-vaccinated children had a lower risk of suspected acute lower respiratory infection. Protection was amplified when children were vaccinated against diphtheria-tetanus-pertussis (DTP). Number of DTP doses did not modify this effect, but order in which vaccines were received did. (Read the full article)

There is a perception that Gram-negative bacilli (GNB) bloodstream infection is increasing in the NICU, and those infections caused by a multidrug-resistant (MDR) strain are a growing threat to hospitalized patients.

Exposure to broad-spectrum antibiotics is the most important risk factor for MDR GNB bacteremia, which is associated with higher mortality. Neonates with risk factors for bacteremia caused by a MDR GNB strain may benefit from empirical antimicrobial therapy with carbapenem. (Read the full article)

An estimated 9.5% of children are diagnosed with attention-deficit/hyperactivity disorder (ADHD), which affects academic and social outcomes. We previously found significant improvements in ADHD symptoms immediately after neurofeedback training at school.

This randomized controlled trial included a large sample of elementary school students with ADHD who received in-school computer attention training with neurofeedback or cognitive training. Students who received neurofeedback were reported to have fewer ADHD symptoms 6 months after the intervention. (Read the full article)

Diarrhea still remains as a significant cause of morbidity and mortality. Intervention to reduce this risk are needed. Evidence on the effect of Lactobacillus reuteri DSM 17938 to prevent diarrhea in children is scarce.

In healthy children attending day care centers, daily administration of L reuteri DSM 17938 had a significant effect in reducing episodes and duration of diarrhea and respiratory tract infections, with consequent cost saving for the community. (Read the full article)

Existing data do not demonstrate a need for combination therapy after antimicrobial susceptibility data indicate adequate in vitro activity with β-lactam monotherapy. However, the role of empirical combination therapy for the treatment of Gram-negative bacteremia in children remains unsettled.

We conducted a retrospective, propensity-score matched study demonstrating no improvement in 10-day mortality of children who have Gram-negative bacteremia receiving empirical β-lactam and aminoglycoside combination therapy compared with β-lactam monotherapy, unless the bacteremic episode was attributable to a multidrug-resistant organism. (Read the full article)

The widely disseminated National Institute on Alcohol Abuse and Alcoholism screening tool for adolescent alcohol use was developed based on epidemiologic data. It has not been validated in a clinical sample and does not screen for tobacco or drug use.

This study found that a measure that expanded the National Institute on Alcohol Abuse and Alcoholism adolescent alcohol use tool to include tobacco and drugs was sensitive and specific for identifying substance use disorders in a pediatric clinic patient population. (Read the full article)

Cotinine assays for dried blood spots have been developed but not deployed in a large sample of newborn specimens.

Cotinine levels consistent with active maternal smoking were detectable in 12% of newborn blood spots, although 41% of the mothers reportedly did not smoke. Data confirm that reported smoking during pregnancy is an imperfect measure of prenatal tobacco smoke exposure. (Read the full article)

Cigarette smoking during adolescence causes significant health problems. Health care providers play an important role in promoting tobacco use abstinence among adolescents, but recent data on the prevalence of provider screening and advice to adolescents are lacking.

This study uses nationally representative surveillance data to provide current estimates of self-reported receipt of health professional screening and advice about tobacco use among US adolescents. Cessation behaviors and correlates of past-year quit attempts among smokers were also explored. (Read the full article)

Many pediatric acute respiratory tract infections (ARTI) are viral and do not require antimicrobial treatment. Recent estimates of antimicrobial overprescribing for these infections, defined based on the published bacterial disease prevalence among all ARTI, are not available.

Based on the published bacterial prevalence rates for pediatric ARTI, antimicrobial agents are prescribed almost twice as often as expected to outpatients nationally, amounting to an estimated 11.4 million potentially preventable antimicrobial prescriptions annually. (Read the full article)

Parental smoking cessation helps eliminate children’s exposure to tobacco smoke. A child’s visit to the doctor provides a teachable moment for parental smoking cessation. Effective strategies to help parents quit smoking are available for implementation.

Evidence-based outpatient intervention for parents who smoke can be delivered successfully after the initial implementation. Maximizing parental quit rates in the pediatric context will require more complete and sustained systems-level integration. (Read the full article)

Delivering competent oral case presentations is an important clinical communication skill, yet effective means of improving trainees’ presentations have not been identified.

Oral presentation feedback sessions facilitated by faculty by using an 18-item competency-based evaluation form early in pediatric clerkships improved medical students’ subsequent oral presentations. Medical schools should consider implementing this evidence-supported practice. (Read the full article)

Youth in foster care are at higher risk of health problems at entrance and during their stays in care. Little is known about this group’s risk of health problems in young adulthood, in comparison with other populations of young adults.

This is the first prospective study to our knowledge demonstrating that former foster youth are at higher risk of chronic health problems than economically secure and insecure general population young adults. (Read the full article)

There is a debate about whether e-cigarettes will benefit public health. However, there is little knowledge about how e-cigarette users and dual users (those using both e-cigarettes and tobacco cigarettes) differ from other adolescents on a range of variables.

Teenagers who only used e-cigarettes were intermediate in levels of risk and protective factors between nonusers and those who used both cigarettes and e-cigarettes. This raises a question about whether e-cigarettes recruit low-risk youth to tobacco product use. (Read the full article)

Noncigarette tobacco products are increasingly popular among youth, especially youth who smoke cigarettes. Although youth use of conventional cigarettes is on the decline, use of other tobacco products is rising and multiple product use may be an escalating trend.

More than twice as many youth in the United States currently use 2 or more tobacco products than cigarettes alone. Youth multiple product use is associated with increased nicotine dependence, raising concerns about the additive harms of noncigarette tobacco products. (Read the full article)

Childhood bacteremia caused by vaccine-preventable organisms has substantially declined over the last decade. Recognition of bacteremia in children is difficult, and delayed administration of antibiotics is associated with poor outcomes. Adults with health care–associated Gram-negative bacteremia experience delays in receiving appropriate antibiotics.

Bacteremia in children presenting to the emergency department is increasingly health care associated and resistant to empirical antibiotics. These infections are associated with increased length of stay. Rates of Gram-negative bacteremia have increased, and children with Gram-negative bacteremia experience delayed antibiotic administration. (Read the full article)

The National Math and Science Initiative's new tool aims to help the field look for patterns in STEM data, so educators and policy folks can fill in holes.

Source: www.thestar.com - Saturday, May 09, 2020
Canada approved a verbal demarche to two senior WHO executives that urged them to allow Taiwan to be admitted as an observer to an upcoming meeting because its input would be “meaningful and important.”

England U21 coach Stuart Pearce discusses a position he used to master.

Teachers are the experts of the classroom, so they should be empowered to lead professional development, educators said at a forum that included the two national teachers' union presidents.

The founder and chief of his eponymous investment bank traveled to Riyadh to extol the virtues of friendship. He stood out as many of the titans of U.S. finance sat out the kingdom’s signature investment summit amid international outrage over the killing of government critic Jamal Khashoggi.

For a moment, Wall Street seemed to be inching away from Saudi Arabia. Now, it’s already inching back.

If we continue to focus on student growth and improvement as learners, keep track of that progress, and watch its impact on standard test results, will we be able to know if what we are doing is helping students develop as learners and thinkers.

Objectives. The aim of this study was to assess the safety of early oral switch (EOS) prior to 14 days for low-risk Staphylococcus aureus bacteremia (LR-SAB), which is the primary treatment strategy employed at our institution. Usually recommended therapy is 14 days of intravenous (IV) antibiotics.

Methods. All patients with SAB at our hospital were identified between 1 January 2014 and 31 December 2018. Those meeting low-risk criteria (healthcare-associated, no evidence of deep infection or demonstrated involvement of prosthetic material, and no further positive blood cultures after 72-hours) were included in the study. The primary outcome was occurrence of a SAB-related complication within 90 days.

Results. There were 469 SAB episodes during the study period, 100 (21%) of whom met inclusion criteria. EOS was performed in 84 patients. In this group, line infection was the source in 79%, methicillin-susceptible S. aureus caused 95% of SABs and 74% of patients received IV flucloxacillin. The median duration of IV and oral antibiotics in the EOS group was 5 (IQR 4-6) and 10 days (IQR 9-14), respectively. Seventy-one percent of patients received flucloxacillin as their EOS agent. Overall, 86% of oral step-down therapy was with beta-lactams. One patient (1%) undergoing EOS had SAB relapse within 90 days. No deaths attributable to SAB occurred within 90 days.

Conclusions. In this low MRSA prevalence LR-SAB cohort, EOS was associated with a low incidence of SAB-related complications. This was achieved with oral beta-lactam therapy in most patients. Larger prospective studies are needed to confirm these findings.

Carbapenems are currently the preferred agents for the treatment of serious Acinetobacter infections. However, whether cefepime/cefpirome can be used to treat Acinetobacter bloodstream infection (BSI) if it is active against the causative pathogens is not clear. This study aimed to compare the efficacy of cefepime/cefpirome and carbapenem monotherapy in patients with Acinetobacter BSI. The population included 360 patients with monomicrobial Acinetobacter BSI receiving appropriate antimicrobial therapy admitted to four medical centres in Taiwan in 2012–2017. The predictors of 30-day mortality were determined by Cox regression analysis. The overall 30-day mortality rate in the appropriate antibiotic treatment group was 25.0% (90/360 patients), respectively. The crude 30-day mortality rates for cefepime/cefpirome and carbapenem therapy were 11.5% (7/61 patients) and 26.3% (21/80 patients), respectively. The patients receiving cefepime/cefpirome/carbapenem therapy were infected by Acinetobacter nosocomialis (51.8%), A. baumannii (18.4%) and A. pittii (12.1%). After adjusting for age, Sequential Organ Failure Assessment (SOFA) score, invasive procedures, and underlying diseases, cefepime/cefpirome therapy was not independently associated with a higher or lower 30-day mortality compared to the carbapenem therapy. SOFA score (hazard ratio [HR], 1.324; 95% confidence interval [CI], 1.137–1.543; P < 0.001) and neutropenia (HR, 7.060; 95% CI, 1.607–31.019; P = 0.010) were independent risk factors for 30-day mortality of patients receiving cefepime/cefpirome or carbapenem monotherapy. The incidence density of 30-day mortality for cefepime/cefpirome versus carbapenem therapy was 0.40% versus 1.04%. The therapeutic response of cefepime/cefpirome therapy was comparable to that of carbapenems among patients with Acinetobacter BSI receiving appropriate antimicrobial therapy.

Ceftobiprole medocaril is an advanced-generation cephalosporin prodrug that has qualified infectious disease product status granted by the US-FDA and is currently being evaluated in phase 3 clinical trials in patients with acute bacterial skin and skin structure infections (ABSSSIs) and in patients with Staphylococcus aureus bacteremia. In this study, the activity of ceftobiprole and comparators was evaluated against more than 7,300 clinical isolates collected in the United States from 2016 through 2018 from patients with skin and skin structure infections. The major species/pathogen groups were S. aureus (53%), Enterobacterales (23%), Pseudomonas aeruginosa (7%), β-hemolytic streptococci (6%), Enterococcus spp. (4%), and coagulase-negative staphylococci (2%). Ceftobiprole was highly active against S. aureus (MIC_50/90, 0.5/1 mg/L; 99.7% susceptible by EUCAST criteria; 42% methicillin-resistant S. aureus [lsqb]MRSA[rsqb]). Ceftobiprole also exhibited potent activity against other Gram-positive cocci. The overall susceptibility of Enterobacterales to ceftobiprole was 84.8% (>99.0% susceptible for isolate subsets that exhibited a non-extended-spectrum β-lactamase [lsqb]ESBL[rsqb]-phenotype). A total of 74.4% of P. aeruginosa, 100% of β-hemolytic streptococci and coagulase-negative staphylococci, and 99.6% of Enterococcus faecalis isolates were inhibited by ceftobiprole at ≤4 mg/L. As expected, ceftobiprole was largely inactive against Enterobacterales that contained ESBL genes and Enterococcus faecium. Overall, ceftobiprole was highly active against most clinical isolates from the major Gram-positive and Gram-negative skin and skin structure pathogen groups collected at U.S. medical centers participating in the SENTRY Antimicrobial Surveillance Program during 2016–2018. The broad-spectrum activity of ceftobiprole, including potent activity against MRSA, supports its further evaluation for the potential ABSSSI indication.

Bacteria of the genus Campylobacter are major foodborne pathogens which have become increasingly resistant to clinically important antimicrobial agents (1)....

The Cpx stress response is widespread among Enterobacteriaceae. We have previously reported a mutation in cpxA in a multidrug resistant strain of Klebsiella aerogenes isolated from a patient treated with imipenem. This mutation yields to a single amino acid substitution (Y144N) located in the periplasmic sensor domain of CpxA. In this work, we sought to characterize this mutation in Escherichia coli by using genetic and biochemical approaches. Here, we show that cpxA^Y144N is an activated allele that confers resistance to β-lactams and aminoglycosides in a CpxR-dependent manner, by regulating the expression of the OmpF porin and the AcrD efflux pump, respectively. We also demonstrate the intimate interconnection between Cpx system and peptidoglycan integrity on the expression of an exogenous AmpC β-lactamase by using imipenem as a cell wall active antibiotic or inactivation of penicillin-binding proteins. Moreover, our data indicate that the Y144N substitution abrogates the interaction between CpxA and CpxP and increase phosphotransfer activity on CpxR. Because the addition of a strong AmpC inducer such as imipenem is known to causes abnormal accumulation of muropeptides (disaccharide-pentapeptide, N-acetylglucosamyl-1,6-anhydro-N-acetylmuramyl-l-alanyl-d-glutamy-meso-diaminopimelic-acid-d-alanyl-d-alanine) in the periplasmic space, we propose these molecules activate the Cpx system by displacing CpxP from the sensor domain of CpxA. Altogether, these data could explain why large perturbations to peptidoglycan caused by imipenem lead to mutational activation of the Cpx system and bacterial adaptation through multidrug resistance. These results also validate the Cpx system, in particular the interaction between CpxA and CpxP, as a promising therapeutic target.

QPX7728 is an ultra-broad-spectrum boronic acid beta-lactamase inhibitor that demonstrates inhibition of key serine and metallo beta-lactamases at a nano molar range in biochemical assays with purified enzymes. The broad-spectrum inhibitory activity of QPX7728 observed in biochemical experiments translates into enhancement of the potency of many beta-lactams against strains of target pathogens producing beta-lactamases. The impact of bacterial efflux and permeability on inhibitory potency were determined using isogenic panels of KPC-3 producing isogenic strains of K. pneumoniae and P. aeruginosa and OXA-23-producing strains of A. baumannii with various combinations of efflux and porin mutations. QPX7728 was minimally affected by multi-drug resistance efflux pumps in either Enterobacteriaceae, or in non-fermenters such as P. aeruginosa or A. baumannii. In P. aeruginosa, the potency of QPX7728 was further enhanced when the outer membrane is permeabilized. The potency of QPX7728 in P. aeruginosa is not affected by inactivation of the carbapenem porin OprD. While changes in OmpK36 (but not OmpK35) reduced the potency of QPX7728 (8-16-fold), QPX7728 (4 μg/ml) nevertheless completely reversed KPC-mediated meropenem resistance in strains with porin mutations, consistent with a lesser effect of these mutations on the potency of QPX7728 compared to other agents. The ultra-broad-spectrum beta-lactamase inhibition profile combined with enhancement of the activity of multiple beta-lactam antibiotics with varying sensitivity to the intrinsic resistance mechanisms of efflux and permeability indicate QPX7728 is a useful inhibitor for use with multiple beta-lactam antibiotics.

Third-generation cephalosporin (3GC)-resistant Enterobacteriaceae are classified as critical priority pathogens, with extended-spectrum β-lactamases (ESBLs) as principal resistance determinants. Enmetazobactam (formerly AAI101) is a novel ESBL inhibitor developed in combination with cefepime for empiric treatment of serious Gram-negative infections in settings where ESBLs are prevalent. Cefepime-enmetazobactam has been investigated in a phase 3 trial in patients with complicated urinary tract infections or acute pyelonephritis. This study examined pharmacokinetic-pharmacodynamic (PK-PD) relationships of enmetazobactam, in combination with cefepime, for ESBL-producing isolates of Klebsiella pneumoniae in 26-hour murine neutropenic thigh infection models. Enmetazobactam dose fractionation identified time above a free threshold concentration (fT > C_T) as the PK-PD index predictive of efficacy. Nine ESBL-producing isolates of K. pneumoniae, resistant to cefepime and piperacillin-tazobactam, were included in enmetazobactam dose-ranging studies. The isolates encoded CTX-M-type, SHV-12, DHA-1 and OXA-48 β-lactamases and covered a cefepime-enmetazobactam MIC range from 0.06 to 2 μg/ml. Enmetazobactam restored the efficacy of cefepime against all isolates tested. Sigmoid curve fitting across the combined set of isolates identified enmetazobactam PK-PD targets for stasis and for a 1-log₁₀ bioburden reduction of 8% and 44% fT > 2 μg/ml, respectively, with a concomitant cefepime PK-PD target of 40 – 60% fT > cefepime-enmetazobactam MIC. These findings support clinical dose selection and breakpoint setting for cefepime-enmetazobactam.

Mycobacterium abscessus lung infections remain difficult to treat. Recent studies have recognized the power of new combinations of antibiotics such as bedaquiline and imipenem although in vitro data have questioned this combination. We report that the efficacy of the bedaquiline plus imipenem treatment relies essentially on the activity of bedaquiline in a C3HeB/FeJ mice model of infection with a rough variant of M. abscessus. The addition of imipenem contributed at clearing the infection in the spleen.

Multidrug resistant strains belonging to the Enterobacter cloacae complex (ECC) group, and especially those belonging to clusters C-III, C-IV and C-VIII, have increasingly emerged as a leading cause of healthcare-associated infections, with colistin used as one of the last line of treatment. However, colistin-resistant ECC strains have emerged. The aim of this study was to prove that MgrB, the negative regulator of PhoP/PhoQ two-component regulatory system, is involved in colistin resistance in ECC of cluster C-VIII, formerly referred to as Enterobacter hormaechei subsp. steigerwaltii. An in vitro mutant (Eh22-Mut) was selected from a clinical isolate of Eh22. The sequencing analysis of its mgrB gene showed the presence of one nucleotide deletion leading to the formation of a truncated protein of six instead of 47 amino acids. Wild-type mgrB gene from Eh22, as well as that of a clinical strain of Klebsiella pneumoniae used as controls, were cloned and the corresponding recombinant plasmids were used for complementation assays. Results showed a fully restored susceptibility to colistin, and confirmed for the first time that mgrB gene expression plays a key role in acquired resistance to colistin in ECC strains.

Klebsiella pneumoniae that produce extended spectrum beta lactamases (ESBLs) are a persistent public health threat. There are relatively few therapeutic options and there is undue reliance on carbapenems. Alternative therapeutic options are urgently required. A combination of cefepime and the novel beta lactamase inhibitor enmetazobactam is being developed for treatment of serious infections caused by ESBL-producing organisms. The pharmacokinetics-pharmacodynamics (PK-PD) of cefepime-enmetazobactam against ESBL-producing K. pneumoniae was studied in a neutropenic murine pneumonia model. Dose ranging studies were performed. Dose fractionation studies were performed to define the relevant PD index for the inhibitor. The partitioning of cefepime and enmetazobactam into the lung was determined by comparing area under the concentration time curve (AUC) in plasma and epithelial lining fluid. The magnitude of drug exposure for cefepime-enmetazobactam required for logarithmic killing in the lung was defined using 3 ESBL-producing strains. Cefepime 100 mg/kg q8h i.v. had minimal antimicrobial effect. When this background regimen of cefepime was combined with enmetazobactam half-maximal effect was induced with enmetazobactam 4.71 mg/kg q8h i.v. The dose fractionation study suggest both fT>threshold and fAUC:MIC are potentially relevant PD indices. The AUC_ELF:AUC_plasma for cefepime and enmetazobactam was 73.4% and 61.5%, respectively. A ≥2-log kill in the lung was achieved with a plasma and ELF cefepime fT>MIC of ≥20% and enmetazobactam fT>2 mg/L of ≥20% of the dosing interval. These data and analyses provide the underpinning evidence for the combined use of cefepime and enmetazobactam for nosocomial pneumonia.

Chromosomal and plasmid-borne AmpC cephalosporinases are a major resistance mechanism to β-lactams in Enterobacteriaceae and Pseudomonas aeruginosa. The new β-lactamase inhibitor avibactam effectively inhibits class C enzymes and can fully restore ceftazidime susceptibility. The conserved amino acid residue Asn³⁴⁶ of AmpC cephalosporinases directly interacts with the avibactam sulfonate. Disruption of this interaction caused by the N³⁴⁶Y amino acid substitution in Citrobacter freundii AmpC was previously shown to confer resistance to the ceftazidime-avibactam combination (CAZ-AVI). The aim of this study was to phenotypically and biochemically characterize the consequences of the N³⁴⁶Y substitution in various AmpC backgrounds. Introduction of N³⁴⁶Y into Enterobacter cloacae AmpC (AmpC_cloacae), plasmid-mediated DHA-1, and P. aeruginosa PDC-5, led to 270-, 12,000-, and 79-fold decreases in the inhibitory efficacy (k₂/K_i) of avibactam, respectively. The kinetic parameters of AmpC_cloacaeand DHA-1 for ceftazidime hydrolysis were moderately affected by the substitution. Accordingly, AmpC_cloacaeand DHA-1 harboring N³⁴⁶Y conferred CAZ-AVI resistance (MIC of ceftazidime of 16 µg/ml in the presence of 4 µg/ml of avibactam). In contrast, production of PDC-5 N³⁴⁶Y was associated with a lower MIC (4 µg/ml) since this β-lactamase retained a higher inactivation efficacy by avibactam in comparison to AmpC_cloacaeN³⁴⁶Y. For FOX-3, the I³⁴⁶Y substitution did not reduce the inactivation efficacy of avibactam and the substitution was highly deleterious for β-lactam hydrolysis, including ceftazidime, preventing CAZ-AVI resistance. Since AmpC_cloacaeand DHA-1 display substantial sequence diversity, our results suggest that loss of hydrogen interaction between Asn³⁴⁶ and avibactam could be a common mechanism of acquisition of CAZ-AVI resistance.

Probiotics might provide an alternative approach for the control of oral candidiasis. However, studies on the antifungal activity of probiotics in the oral cavity are based on the consumption of yogurt or other dietary products, and there is a necessary to use appropriate biomaterials and specific strains to obtain probiotic formulations targeting local oral administration. In this study, we impregnated gellan gum, a natural biopolymer used as a food-additive, with a probiotic and investigated its antifungal activity against Candida albicans. Lactobacillus paracasei 28.4, a strain recently isolated from the oral cavity of a caries-free individual, was incorporated in several concentrations of gellan gum (0.6% to 1%). All tested concentrations could incorporate L. paracasei cells while maintaining bacterial viability. Probiotic/gellan formulations were stable for 7 days when stored at room temperature or 4°C. Long-term storage of bacteria-impregnated gellan gum was achieved when L. paracasei 28.4 was lyophilized. The probiotic/gellan formulations provided a release of L. paracasei cells over 24 hours that was sufficient to inhibit the growth of C. albicans with effects dependent on the cell concentrations incorporated into gellan gum. The probiotic/gellan formulations also had inhibitory activity against Candida spp. biofilms by reducing the number of Candida spp. cells (p < 0.0001), decreasing the total biomass (p = 0.0003), and impairing hyphae formation (p = 0.0002), compared to the control group which received no treatment. Interestingly, probiotic formulation of 1% w/v gellan gum provided an oral colonization of L. paracasei in mice with approximately 6 log of CFU/mL after 10 days. This formulation inhibited the C. albicans growth (p < 0.0001), prevented the development of candidiasis lesions (p = 0.0013), and suppressed inflammation (p = 0.0006) when compared to the mice not treated in the microscopic analysis of the tongue dorsum. These results indicate that gellan gum is a promising biomaterial and can be used as a carrier system to promote oral colonization for probiotics that prevent oral candidiasis.

Durlobactam (DUR, also known as ETX2514) is a novel β-lactamase inhibitor with broad activity against Ambler class A, C, and D β-lactamases. Addition of DUR to sulbactam (SUL) in vitro restores SUL activity against clinical isolates of Acinetobacter baumannii. The safety and pharmacokinetics (PK) of DUR alone and with SUL and/or imipenem/cilastatin (IMI/CIL) were evaluated in healthy subjects. This was a randomized, placebo-controlled study. In Part A, subjects including an elderly cohort (DUR 1 g) received single ascending doses of DUR 0.25-8 g. In Part B, multiple ascending dose of DUR 0.25-2 g were administered every 6 hours (q6h) for 29 doses. In Parts C and D, the drug-drug interaction (DDI) potential, including safety, of DUR (1 g) with SUL (1 g) and/or IMI/CIL (0.5/0.5 g) was investigated after single and multiple doses. Plasma and urine concentrations of DUR, SUL, and IMI/CIL were determined. Among 124 subjects, DUR was generally safe and well tolerated either alone or in combination with SUL and/or IMI/CIL. After single and multiple doses, DUR demonstrated linear dose proportional exposure across the studied dose ranges. Renal excretion was a predominant clearance mechanism. No drug:drug interaction potential was identified between DUR and SUL and/or IMI/CIL. SUL-DUR, 1 g (of each component) administered q6h with a 3 hour IV infusion, is under development for the treatment of serious infections due to A. baumannii.