A major resistance mechanism in Gram-negative bacteria is the production of β-lactamase enzymes. Originally recognized for their ability to hydrolyze penicillins, emergent β-lactamases can now confer ...resistance to other β-lactam drugs, including both cephalosporins and carbapenems. The emergence and global spread of β-lactamase-producing multi-drug-resistant “superbugs” has caused increased alarm within the medical community due to the high mortality rate associated with these difficult-to-treat bacterial infections. To address this unmet medical need, we initiated an iterative program combining medicinal chemistry, structural biology, biochemical testing, and microbiological profiling to identify broad-spectrum inhibitors of both serine- and metallo-β-lactamase enzymes. Lead optimization, beginning with narrower-spectrum, weakly active compounds, provided 20 (VNRX-5133, taniborbactam), a boronic-acid-containing pan-spectrum β-lactamase inhibitor. In vitro and in vivo studies demonstrated that 20 restored the activity of β-lactam antibiotics against carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae. Taniborbactam is the first pan-spectrum β-lactamase inhibitor to enter clinical development.
Antibiotic-resistant bacterial infections arising from acquired resistance and/or through biofilm formation necessitate the development of innovative 'outside of the box' therapeutics. ...Nanomaterial-based therapies are promising tools to combat bacterial infections that are difficult to treat, featuring the capacity to evade existing mechanisms associated with acquired drug resistance. In addition, the unique size and physical properties of nanomaterials give them the capability to target biofilms, overcoming recalcitrant infections. In this Review, we highlight the general mechanisms by which nanomaterials can be used to target bacterial infections associated with acquired antibiotic resistance and biofilms. We emphasize design elements and properties of nanomaterials that can be engineered to enhance potency. Lastly, we present recent progress and remaining challenges for widespread clinical implementation of nanomaterials as antimicrobial therapeutics.
The looming antibiotic-resistance crisis has penetrated the consciousness of clinicians, researchers, policymakers, politicians and the public at large. The evolution and widespread distribution of ...antibiotic-resistance elements in bacterial pathogens has made diseases that were once easily treatable deadly again. Unfortunately, accompanying the rise in global resistance is a failure in antibacterial drug discovery. Lessons from the history of antibiotic discovery and fresh understanding of antibiotic action and the cell biology of microorganisms have the potential to deliver twenty-first century medicines that are able to control infection in the resistance era.
Relebactam (REL MK-7655) is a novel class A/C β-lactamase inhibitor intended for use with imipenem for the treatment of Gram-negative bacterial infections. REL restores imipenem activity against some ...resistant strains of Klebsiella and Pseudomonas In this multicenter, double-blind, controlled trial (NCT01506271), subjects who were ≥18 years of age with complicated intra-abdominal infection were randomly assigned (1:1:1) to receive 250 mg REL, 125 mg REL, or placebo, each given intravenously (i.v.) with 500 mg imipenem-cilastatin (IMI) every 6 h (q6h) for 4 to 14 days. The primary efficacy endpoint was the proportion of microbiologically evaluable (ME) subjects with a favorable clinical response at discontinuation of i.v. therapy (DCIV). A total of 351 subjects were randomized, 347 (99%) were treated, and 255 (73%) were ME at DCIV (55% male; mean age, 49 years). The most common diagnoses were complicated appendicitis (53%) and complicated cholecystitis (17%). Thirty-six subjects (13%) had imipenem-resistant Gram-negative infections at baseline. Both REL doses plus IMI were generally well tolerated and demonstrated safety profiles similar to that of IMI alone. Clinical response rates at DCIV were similar in subjects who received 250 mg REL plus IMI (96.3%) or 125 mg REL plus IMI (98.8%), and both were noninferior to IMI alone (95.2%; one-sided P < 0.001). The treatment groups were also similar with respect to clinical response at early and late follow-up and microbiological response at all visits. Pharmacokinetic/pharmacodynamic simulations show that imipenem exposure at the proposed dose of 500 mg IMI with 250 mg REL q6h provides coverage of >90% of carbapenem-resistant bacterial strains.
Antibiotic resistance in Gram-negative resistance has developed without a commensurate response in the successful development of antibiotic agents, though recent progress has been made.
This review ...aims to provide a summary of the existing evidence on efficacy, spectrum of activity and the development of resistance of new agents that have been licensed or have completed advanced clinical trials and that possess activity against resistant Gram-negative organisms.
A review of the published literature via MEDLINE database was performed. Relevant clinical trials were identified with the aid of the clinicaltrials.gov registry. Further data were ascertained from review of abstracts from recent international meetings and pharmaceutical companies.
Data on the mechanism of action, microbiological spectrum, clinical efficacy and development of resistance are reported for new agents that have activity against Gram-negative organisms. This includes the β-lactam/β-lactamase inhibitor combinations ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam, meropenem/vaborbactam and aztreonam/avibactam; cefiderocol, a siderophore cephalosporin; plazomicin and eravacycline.
The development of new agents with activity against multidrug-resistant Gram-negative pathogens has provided important therapeutic options for clinicians. Polymyxins appear to have been supplanted by new agents as first-line therapy for Klebsiella pneumoniae carbapenemase producers. Cefiderocol and ceftazidime/avibactam/aztreonam are promising options for metallo-β-lactamase producers, and cefiderocol and ceftolozane/tazobactam for multiply resistant Pseudomonas aeruginosa, but definitive data showing clinical efficacy is as yet lacking. Reports of the development of resistance early after the release and use of new agents is of concern. Orally administered options and agents active effective against Acinetobacter baumannii are under-represented in clinical development.
Engineered nanomaterials (ENMs) have gained huge importance in technological advancements over the past few years. Among the various ENMs, silver nanoparticles (AgNPs) have become one of the most ...explored nanotechnology-derived nanostructures and have been intensively investigated for their unique physicochemical properties. The widespread commercial and biomedical application of nanosilver include its use as a catalyst and an optical receptor in cosmetics, electronics and textile engineering, as a bactericidal agent, and in wound dressings, surgical instruments, and disinfectants. This, in turn, has increased the potential for interactions of AgNPs with terrestrial and aquatic environments, as well as potential exposure and toxicity to human health. In the present review, after giving an overview of ENMs, we discuss the current advances on the physiochemical properties of AgNPs with specific emphasis on biodistribution and both in vitro and in vivo toxicity following various routes of exposure. Most in vitro studies have demonstrated the size-, dose- and coating-dependent cellular uptake of AgNPs. Following NPs exposure, in vivo biodistribution studies have reported Ag accumulation and toxicity to local as well as distant organs. Though there has been an increase in the number of studies in this area, more investigations are required to understand the mechanisms of toxicity following various modes of exposure to AgNPs.
Ceftolozane is a novel cephalosporin currently being developed with the β-lactamase inhibitor tazobactam for the treatment of complicated urinary tract infections (cUTIs), complicated intra-abdominal ...infections (cIAIs), and ventilator-associated bacterial pneumonia (VABP). The chemical structure of ceftolozane is similar to that of ceftazidime, with the exception of a modified side-chain at the 3-position of the cephem nucleus, which confers potent antipseudomonal activity. As a β-lactam, its mechanism of action is the inhibition of penicillin-binding proteins (PBPs). Ceftolozane displays increased activity against Gram-negative bacilli, including those that harbor classical β-lactamases (e.g., TEM-1 and SHV-1), but, similar to other oxyimino-cephalosporins such as ceftazidime and ceftriaxone, it is compromised by extended-spectrum β-lactamases (ESBLs) and carbapenemases. The addition of tazobactam extends the activity of ceftolozane to include most ESBL producers as well as some anaerobic species. Ceftolozane is distinguished from other cephalosporins by its potent activity versus
Pseudomonas aeruginosa,
including various drug-resistant phenotypes such as carbapenem, piperacillin/tazobactam, and ceftazidime-resistant isolates, as well as those strains that are multidrug-resistant (MDR). Its antipseudomonal activity is attributed to its ability to evade the multitude of resistance mechanisms employed by
P.
aeruginosa
, including efflux pumps, reduced uptake through porins and modification of PBPs. Ceftolozane demonstrates linear pharmacokinetics unaffected by the coadministration of tazobactam; specifically, it follows a two-compartmental model with linear elimination. Following single doses, ranging from 250 to 2,000 mg, over a 1-h intravenous infusion, ceftolozane displays a mean plasma half-life of 2.3 h (range 1.9–2.6 h), a steady-state volume of distribution that ranges from 13.1 to 17.6 L, and a mean clearance of 102.4 mL/min. It demonstrates low plasma protein binding (20 %), is primarily eliminated via urinary excretion (≥92 %), and may require dose adjustments in patients with a creatinine clearance <50 mL/min. Time-kill experiments and animal infection models have demonstrated that the pharmacokinetic–pharmacodynamic index that is best correlated with ceftolozane’s in vivo efficacy is the percentage of time in which free plasma drug concentrations exceed the minimum inhibitory concentration of a given pathogen (%
fT
>MIC
), as expected of β-lactams. Two phase II clinical trials have been conducted to evaluate ceftolozane ± tazobactam in the settings of cUTIs and cIAIs. One trial compared ceftolozane 1,000 mg every 8 h (q8h) versus ceftazidime 1,000 mg q8h in the treatment of cUTI, including pyelonephritis, and demonstrated similar microbiologic and clinical outcomes, as well as a similar incidence of adverse effects after 7–10 days of treatment, respectively. A second trial has been conducted comparing ceftolozane/tazobactam 1,000/500 mg and metronidazole 500 mg q8h versus meropenem 1,000 mg q8h in the treatment of cIAI. A number of phase I and phase II studies have reported ceftolozane to possess a good safety and tolerability profile, one that is consistent with that of other cephalosporins. In conclusion, ceftolozane is a new cephalosporin with activity versus MDR organisms including
P.
aeruginosa
. Tazobactam allows the broadening of the spectrum of ceftolozane versus β-lactamase-producing Gram-negative bacilli including ESBLs. Potential roles for ceftolozane/tazobactam include empiric therapy where infection by a resistant Gram-negative organism (e.g., ESBL) is suspected, or as part of combination therapy (e.g., with metronidazole) where a polymicrobial infection is suspected. In addition, ceftolozane/tazobactam may represent alternative therapy to the third-generation cephalosporins after treatment failure or for documented infections due to Gram-negative bacilli producing ESBLs. Finally, the increased activity of ceftolozane/tazobactam versus
P.
aeruginosa,
including MDR strains, may lead to the treatment of suspected and documented
P.
aeruginosa
infections with this agent. Currently, ceftolozane/tazobactam is being evaluated in three phase III trials for the treatment of cUTI, cIAI, and VABP.
Background
Antibiotic resistance is a major public health problem. Infections caused by multidrug‐resistant bacteria are associated with prolonged hospital stay and death compared with infections ...caused by susceptible bacteria. Appropriate antibiotic use in hospitals should ensure effective treatment of patients with infection and reduce unnecessary prescriptions. We updated this systematic review to evaluate the impact of interventions to improve antibiotic prescribing to hospital inpatients.
Objectives
To estimate the effectiveness and safety of interventions to improve antibiotic prescribing to hospital inpatients and to investigate the effect of two intervention functions: restriction and enablement.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library), MEDLINE, and Embase. We searched for additional studies using the bibliographies of included articles and personal files. The last search from which records were evaluated and any studies identified incorporated into the review was January 2015.
Selection criteria
We included randomised controlled trials (RCTs) and non‐randomised studies (NRS). We included three non‐randomised study designs to measure behavioural and clinical outcomes and analyse variation in the effects: non‐ randomised trials (NRT), controlled before‐after (CBA) studies and interrupted time series (ITS) studies. For this update we also included three additional NRS designs (case control, cohort, and qualitative studies) to identify unintended consequences. Interventions included any professional or structural interventions as defined by the Cochrane Effective Practice and Organisation of Care Group. We defined restriction as 'using rules to reduce the opportunity to engage in the target behaviour (or increase the target behaviour by reducing the opportunity to engage in competing behaviours)'. We defined enablement as 'increasing means/reducing barriers to increase capability or opportunity'. The main comparison was between intervention and no intervention.
Data collection and analysis
Two review authors extracted data and assessed study risk of bias. We performed meta‐analysis and meta‐regression of RCTs and meta‐regression of ITS studies. We classified behaviour change functions for all interventions in the review, including those studies in the previously published versions. We analysed dichotomous data with a risk difference (RD). We assessed certainty of evidence with GRADE criteria.
Main results
This review includes 221 studies (58 RCTs, and 163 NRS). Most studies were from North America (96) or Europe (87). The remaining studies were from Asia (19), South America (8), Australia (8), and the East Asia (3). Although 62% of RCTs were at a high risk of bias, the results for the main review outcomes were similar when we restricted the analysis to studies at low risk of bias.
More hospital inpatients were treated according to antibiotic prescribing policy with the intervention compared with no intervention based on 29 RCTs of predominantly enablement interventions (RD 15%, 95% confidence interval (CI) 14% to 16%; 23,394 participants; high‐certainty evidence). This represents an increase from 43% to 58% .There were high levels of heterogeneity of effect size but the direction consistently favoured intervention.
The duration of antibiotic treatment decreased by 1.95 days (95% CI 2.22 to 1.67; 14 RCTs; 3318 participants; high‐certainty evidence) from 11.0 days. Information from non‐randomised studies showed interventions to be associated with improvement in prescribing according to antibiotic policy in routine clinical practice, with 70% of interventions being hospital‐wide compared with 31% for RCTs. The risk of death was similar between intervention and control groups (11% in both arms), indicating that antibiotic use can likely be reduced without adversely affecting mortality (RD 0%, 95% CI ‐1% to 0%; 28 RCTs; 15,827 participants; moderate‐certainty evidence). Antibiotic stewardship interventions probably reduce length of stay by 1.12 days (95% CI 0.7 to 1.54 days; 15 RCTs; 3834 participants; moderate‐certainty evidence). One RCT and six NRS raised concerns that restrictive interventions may lead to delay in treatment and negative professional culture because of breakdown in communication and trust between infection specialists and clinical teams (low‐certainty evidence).
Both enablement and restriction were independently associated with increased compliance with antibiotic policies, and enablement enhanced the effect of restrictive interventions (high‐certainty evidence). Enabling interventions that included feedback were probably more effective than those that did not (moderate‐certainty evidence).
There was very low‐certainty evidence about the effect of the interventions on reducing Clostridium difficile infections (median ‐48.6%, interquartile range ‐80.7% to ‐19.2%; 7 studies). This was also the case for resistant gram‐negative bacteria (median ‐12.9%, interquartile range ‐35.3% to 25.2%; 11 studies) and resistant gram‐positive bacteria (median ‐19.3%, interquartile range ‐50.1% to +23.1%; 9 studies). There was too much variance in microbial outcomes to reliably assess the effect of change in antibiotic use.
Heterogeneity of intervention effect on prescribing outcomes
We analysed effect modifiers in 29 RCTs and 91 ITS studies. Enablement and restriction were independently associated with a larger effect size (high‐certainty evidence). Feedback was included in 4 (17%) of 23 RCTs and 20 (47%) of 43 ITS studies of enabling interventions and was associated with greater intervention effect. Enablement was included in 13 (45%) of 29 ITS studies with restrictive interventions and enhanced intervention effect.
Authors' conclusions
We found high‐certainty evidence that interventions are effective in increasing compliance with antibiotic policy and reducing duration of antibiotic treatment. Lower use of antibiotics probably does not increase mortality and likely reduces length of stay. Additional trials comparing antibiotic stewardship with no intervention are unlikely to change our conclusions. Enablement consistently increased the effect of interventions, including those with a restrictive component. Although feedback further increased intervention effect, it was used in only a minority of enabling interventions. Interventions were successful in safely reducing unnecessary antibiotic use in hospitals, despite the fact that the majority did not use the most effective behaviour change techniques. Consequently, effective dissemination of our findings could have considerable health service and policy impact. Future research should instead focus on targeting treatment and assessing other measures of patient safety, assess different stewardship interventions, and explore the barriers and facilitators to implementation. More research is required on unintended consequences of restrictive interventions.
The wound healing process of the diabetic wound is often hindered by excessive oxygen free radicals and infection. An ideal wound dressing should possess great reactive oxygen species (ROS) ...scavenging property and considerable antibacterial ability. In this study, we facilely constructed a novel hydrogel dressing with excellent ROS scavenging property and outstanding antibacterial performance by introducing tannic acid (TA) into quaternized chitosan (QCS) matrix. Attributing to the suitable physical crosslinking between TA and QCS, this QCS/TA hydrogel was endowed with injectable and self-healing properties, which could avoid the various external squeezing on the irregular shape by wound dressing. The results showed that it could promote coagulation, suppress inflammation and expedite collagen deposition in the skin defect model of diabetic rats. This study provides a facile and convenient method for constructing injectable hydrogel dressing, which has application potentials in the clinical management of diabetic wounds.
•An injectable hydrogel (QT) composed of quaternized chitosan and tannic acid was designed.•One-step fabrication of QT hydrogel was achieved via alkali neutralization strategy.•QT hydrogel possessed robust antibacterial and ROS scavenging capabilities.•QT hydrogel significantly accelerated skin tissue regeneration in diabetic wounds.
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