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Antimicrobials are among the most important and commonly prescribed drugs in the management of critically ill patients and beta-lactams are the most common antibiotic class used. Critically ill patient’s pathophysiological factors lead to altered pharmacokinetics and pharmacodynamics of beta-lactams. A comprehensive bibliographic search in PubMed database of all English language articles published from January 2000 to December 2017 was performed, allowing the selection of articles addressing the pharmacokinetics or pharmacodynamics of beta-lactam antibiotics in critically ill patients. In critically ill patients, several factors may increase volume of distribution and enhance renal clearance, inducing high intra- and inter-patient variability in beta-lactam concentration and promoting the risk of antibiotic underdosing. The duration of infusion of beta-lactams has been shown to influence the fT > minimal inhibitory concentration and an improved beta-lactam pharmacodynamics profile may be obtained by longer exposure with more frequent dosing, extended infusions, or continuous infusions. The use of extracorporeal support techniques in the critically ill may further contribute to this problem and we recommend not reducing standard antibiotic dosage since no drug accumulation was found in the available literature and to maintain continuous or prolonged infusion, especially for the treatment of infections caused by multidrug-resistant bacteria. Prediction of outcome based on concentrations in plasma results in overestimation of antimicrobial activity at the site of infection, namely in cerebrospinal fluid and the lung. Therefore, although no studies have assessed clinical outcome, we recommend using higher than standard dosing, preferably with continuous or prolonged infusions, especially when treating less susceptible bacterial strains at these sites, as the pharmacodynamics profile may improve with no apparent increase in toxicity. A therapeutic drug monitoring-guided approach could be particularly useful in critically ill patients in whom achieving target concentrations is more difficult, such as obese patients, immunocompromised patients, those infected by highly resistant bacterial strains, patients with augmented renal clearance, and those undergoing extracorporeal support techniques.

IntroductionWithin the context of antimicrobial stewardship programmes, de-escalation of antimicrobial therapy is one of the proposed strategies for reducing the unnecessary use of broad-spectrum antibiotics (BSA). The empirical treatment of nosocomial and some healthcare-associated bloodstream infections (BSI) frequently includes a beta-lactam with antipseudomonal activity as monotherapy or in combination with other drugs, so there is a great opportunity to optimise the empirical therapy based on microbiological data. De-escalation is assumed as standard of care for experts in infectious diseases. However, it is less frequent than it would desirable.Methods and analysisThe SIMPLIFY trial is a multicentre, open-label, non-inferiority phase III randomised controlled clinical trial, designed as a pragmatic ‘real-practice’ trial. The aim of this trial is to demonstrate the non-inferiority of de-escalation from an empirical beta-lactam with antipseudomonal activity to a targeted narrow-spectrum antimicrobial in patients with BSI due to Enterobacteriaceae. The primary outcome is clinical cure, which will be assessed at the test of cure visit. It will be conducted at 19 Spanish public and university hospitals.Ethics and disseminationEach participating centre has obtained the approval of the ethics review committee, the agreement of the directors of the institutions and authorisation from the Spanish Regulatory Agency (Agencia Española del Medicamento y Productos Sanitarios). Data will be presented at international conferences and published in peer-reviewed journals.DiscussionStrategies to reduce the use of BSA should be a priority. Most of the studies that support de-escalation are observational, retrospective and heterogeneous. A recent Cochrane review stated that well-designed clinical trials should be conducted to assess the safety and efficacy of de-escalation.Trial registration numberThe European Union Clinical Trials Register: EudraCT number 2015-004219-19. Clinical trials.gov: NCT02795949. Protocol version: V.2.0, dated 16 May 2016. All items from the WHO Trial Registration Data Set are included in the registry.

Background. Previous studies indicate that vancomycin is inferior to beta-lactams for treatment of methicillinsusceptible Staphylococcus aureus (MSSA) bloodstream infections. However, it is unclear if this association is true for empiric and definitive therapy. Here, we compared beta-lactams with vancomycin for empiric and definitive therapy of MSSA bloodstream infections among patients admitted to 122 hospitals. Methods. This retrospective cohort study included all patients admitted to Veterans Affairs hospitals from 2003 to 2010 who had positive blood cultures for MSSA. Hazard ratios (HR) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression. Empiric therapy was defined as starting treatment 2 days before and up to 4 days after the first MSSA blood culture was collected. Definitive therapy was defined as starting treatment between 4 and 14 days after the first positive blood culture was collected. Results. Patients who received empiric therapy with a beta-lactam had similar mortality compared with those who received vancomycin (HR, 1.03; 95% CI, .89–1.20) after adjusting for other factors. However, patients who received definitive therapy with a beta-lactam had 35% lower mortality compared with patients who received vancomycin (HR, 0.65; 95% CI, .52–.80) after controlling for other factors. The hazard of mortality decreased further for patients who received cefazolin or antistaphylococcal penicillins compared with vancomycin (HR, 0.57; 95% CI, .46–.71). Conclusions. For patients with MSSA bloodstream infections, beta-lactams are superior to vancomycin for definitive therapy but not for empiric treatment. Patients should receive beta-lactams for definitive therapy, specifically antistaphylococcal penicillins or cefazolin.

The treatment of bacterial infections is hindered by the presence of biofilms and metabolically inactive persisters. Here, we report the synthesis of an enantiomeric block co-beta-peptide, poly(amido-D-glucose)- block -poly(beta-L-lysine), with high yield and purity by one-shot one-pot anionic-ring opening (co)polymerization. The co-beta-peptide is bactericidal against methicillin-resistant Staphylococcus aureus (MRSA), including replicating, biofilm and persister bacterial cells, and also disperses biofilm biomass. It is active towards community-acquired and hospital-associated MRSA strains which are resistant to multiple drugs including vancomycin and daptomycin. Its antibacterial activity is superior to that of vancomycin in MRSA mouse and human ex vivo skin infection models, with no acute in vivo toxicity in repeated dosing in mice at above therapeutic levels. The copolymer displays bacteria-activated surfactant-like properties, resulting from contact with the bacterial envelope. Our results indicate that this class of non-toxic molecule, effective against different bacterial sub-populations, has promising potential for the treatment of S. aureus infections. The authors report the synthesis of an enantiomeric block co-beta-peptide that kills methicillin-resistant Staphylococcus aureus , including biofilm and persister bacterial cells, and disperses biofilms. The copolymer displays antibacterial activity in human ex vivo and mouse in vivo infection models without toxicity.

Broad-spectrum β-lactam antibiotic resistance in Staphylococcus aureus is a global healthcare burden 1 , 2 . In clinical strains, resistance is largely controlled by BlaR1 3 , a receptor that senses β-lactams through the acylation of its sensor domain, inducing transmembrane signalling and activation of the cytoplasmic-facing metalloprotease domain 4 . The metalloprotease domain has a role in BlaI derepression, inducing blaZ (β-lactamase PC1) and mecA (β-lactam-resistant cell-wall transpeptidase PBP2a) expression 3 – 7 . Here, overcoming hurdles in isolation, we show that BlaR1 cleaves BlaI directly, as necessary for inactivation, with no requirement for additional components as suggested previously 8 . Cryo-electron microscopy structures of BlaR1—the wild type and an autocleavage-deficient F284A mutant, with or without β-lactam—reveal a domain-swapped dimer that we suggest is critical to the stabilization of the signalling loops within. BlaR1 undergoes spontaneous autocleavage in cis between Ser283 and Phe284 and we describe the catalytic mechanism and specificity underlying the self and BlaI cleavage. The structures suggest that allosteric signalling emanates from β-lactam-induced exclusion of the prominent extracellular loop bound competitively in the sensor-domain active site, driving subsequent dynamic motions, including a shift in the sensor towards the membrane and accompanying changes in the zinc metalloprotease domain. We propose that this enhances the expulsion of autocleaved products from the active site, shifting the equilibrium to a state that is permissive of efficient BlaI cleavage. Collectively, this study provides a structure of a two-component signalling receptor that mediates action—in this case, antibiotic resistance—through the direct cleavage of a repressor. Cryo-electron microscopy structures of Staphylococcus aureus BlaR1 reveal dynamic signalling states regulating broad spectrum β-lactam antibiotic resistance through cleavage of the transcriptional repressor BlaI and induced expression of the β-lactamase blaZ and the β-lactam-resistant cell-wall transpeptidase mecA .

Antibiotics are commonly used in aquaculture and they can change the environmental resistome by increasing antibiotic resistance genes (ARGs). Sediment samples were collected from two fish farms located in the Northern Baltic Sea, Finland, and from a site outside the farms (control). The sediment resistome was assessed by using a highly parallel qPCR array containing 295 primer sets to detect ARGs, mobile genetic elements and the 16S rRNA gene. The fish farm resistomes were enriched in transposon and integron associated genes and in ARGs encoding resistance to antibiotics which had been used to treat fish at the farms. Aminoglycoside resistance genes were also enriched in the farm sediments despite the farms not having used aminoglycosides. In contrast, the total relative abundance values of ARGs were higher in the control sediment resistome and they were mainly genes encoding efflux pumps followed by beta-lactam resistance genes, which are found intrinsically in many bacteria. This suggests that there is a natural Baltic sediment resistome. The resistome associated with fish farms can be from native ARGs enriched by antibiotic use at the farms and/or from ARGs and mobile elements that have been introduced by fish farming. Antibiotic resistome associated with fish farms can be from native antibiotic resistance genes (ARGs) enriched by antibiotic use at the farms and/or from ARGs and mobile elements that have been introduced by fish farming. Graphical Abstract Figure. Antibiotic resistome associated with fish farms can be from native antibiotic resistance genes (ARGs) enriched by antibiotic use at the farms and/or from ARGs and mobile elements that have been introduced by fish farming.

For the first time since 2015, the World Health Organization’s (WHO) global Antimicrobial Resistance and Use Surveillance (GLASS) featured both global reports for antimicrobial resistance (AMR) and antimicrobial consumption (AMC) data in its annual reports. In this study we investigated the relationship of AMR with AMC within participating countries reported in the GLASS 2022 report. Our analysis found a statistically significant correlation between beta-lactam/cephalosporin and fluoroquinolones consumption and AMR to these antimicrobials associated with bloodstream E . coli and Klebsiella pneumoniae among the participating countries (P<0.05). We observed that for every 1 unit increase in defined daily dose DDD of beta-lactam/cephalosporins and quinolone consumptions among the countries, increased the recoveries of bloodstream-associated beta-lactam/cephalosporins-resistant E . coli / Klebsiella spp. by 11–22% and quinolone-resistant E . coli / Klebsiella spp. by 31–40%. When we compared the antimicrobial consumptions between the antimicrobial ATC (Alphanumeric codes developed by WHO) groups and countries, we observed a statistically significant higher daily consumption of beta-lactam-penicillins (J01C, DDD difference range: 5.23–8.13) and cephalosporins (J01D, DDD difference range: 2.57–5.13) compared to other antimicrobial groups among the countries (adjusted for multiple comparisons using Tukey’s method). Between the participating countries, we observed a statistically significant higher daily consumption of antimicrobial groups in Iran (DDD difference range: 3.63–4.84) and Uganda (DDD difference range: 3.79–5.01) compared to other participating countries (adjusted for multiple comparisons using Tukey’s method). Understanding AMC and how it relates to AMR at the global scale is critical in the global AMR policy development and implementation of global antimicrobial stewardship.

Understanding the nuances of AmpC β-lactamase–mediated resistance can be challenging, even for the infectious diseases specialist. AmpC resistance can be classified into 3 categories: (1) inducible chromosomal resistance that emerges in the setting of a β-lactam compound, (2) stable derepression due to mutations in ampC regulatory genes, or (3) the presence of plasmid-mediated ampC genes. This review will mainly focus on inducible AmpC resistance in Enterobacteriaceae. Although several observational studies have explored optimal treatment for AmpC producers, few provide reliable insights into effective management approaches. Heterogeneity within the data and inherent selection bias make inferences on effective β-lactam choices problematic. Most experts agree it is prudent to avoid expanded-spectrum (ie, third-generation) cephalosporins for the treatment of organisms posing the greatest risk of ampC induction, which has best been described in the context of Enterobacter cloacae infections. The role of other broad-spectrum β-lactams and the likelihood of ampC induction by other Enterobacteriaceae are less clear. We will review the mechanisms of resistance and triggers resulting in AmpC expression, the species-specific epidemiology of AmpC production, approaches to the detection of AmpC production, and treatment options for AmpC-producing infections.

Antibiotic resistance of bacteria is considered one of the most alarming developments in modern medicine. While varied pathways for bacteria acquiring antibiotic resistance have been identified, there still are open questions concerning the mechanisms underlying resistance. Here, we show that alpha phenol-soluble modulins (PSMαs), functional bacterial amyloids secreted by Staphylococcus aureus , catalyze hydrolysis of β-lactams, a prominent class of antibiotic compounds. Specifically, we show that PSMα2 and, particularly, PSMα3 catalyze hydrolysis of the amide-like bond of the four membered β-lactam ring of nitrocefin, an antibiotic β-lactam surrogate. Examination of the catalytic activities of several PSMα3 variants allowed mapping of the active sites on the amyloid fibrils’ surface, specifically underscoring the key roles of the cross-α fibril organization, and the combined electrostatic and nucleophilic functions of the lysine arrays. Molecular dynamics simulations further illuminate the structural features of β-lactam association upon the fibril surface. Complementary experimental data underscore the generality of the functional amyloid-mediated catalytic phenomenon, demonstrating hydrolysis of clinically employed β-lactams by PSMα3 fibrils, and illustrating antibiotic degradation in actual S. aureus biofilms and live bacteria environments. Overall, this study unveils functional amyloids as catalytic agents inducing degradation of β-lactam antibiotics, underlying possible antibiotic resistance mechanisms associated with bacterial biofilms. A number of mechanisms are known to mediate bacterial antibiotic resistance. Here, Arad et al show that amyloid fibrils produced by Staphylococcus aureus rapidly degrade common antibiotic molecules.

β-lactam antibiotics have been prescribed for most bacterial infections since their discovery. However, resistance to β-lactams, mediated by β-lactamase (Bla) enzymes such as extended spectrum β-lactamases (ESBLs), has become widespread. Bla inhibitors can restore the efficacy of β-lactams against resistant bacteria, an approach which preserves existing antibiotics despite declining industry investment. However, the effects of combination treatment on selection for β-lactam resistance are not well understood. Bla production confers both private benefits for resistant cells and public benefits which faster-growing sensitive cells can also exploit. These benefits may be differentially impacted by Bla inhibitors, leading to non-intuitive selection dynamics. In this study, we demonstrate strain-to-strain variation in effective combination doses, with complex growth dynamics in mixed populations. Using modeling, we derive a criterion for the selection outcome of combination treatment, dependent on the burden and effective private benefit of Bla production. We then use engineered strains and natural isolates to show that strong private benefits of Bla are associated with increased selection for resistance. Finally, we demonstrate that this parameter can be coarsely estimated using high-throughput phenotyping of clonal populations. Our analysis shows that quantifying the phenotypic responses of bacteria to combination treatment can facilitate resistance-minimizing optimization of treatment. The authors derive a criterion for when β-lactam/β-lactamase inhibitor combinations can select against a β-lactam-resistant bacterial strain. In particular, the private benefit of resistance is shown to be estimable from clonal growth curves and predictive of selection outcomes.