Especially critically ill children are exposed to antibiotic overtreatment, mainly caused by the fear of missing out a severe bacterial infection. Potential adverse effects and selection of multi-drug resistant bacteria play minor roles in decision making. This narrative review first describes harm from antibiotics and second focuses on different aspects that could help to reduce antibiotic overtreatment without harming the patient: harm from antibiotic treatment, diagnostic approaches, role of biomarkers, timing of antibiotic therapy, empiric therapy, targeted therapy, and therapeutic drug monitoring. Wherever possible, we linked the described evidence to the current Surviving Sepsis Campaign guidelines. Antibiotic stewardship programs should help guiding antibiotic therapy for critically ill children.Critically ill children can be harmed by inadequate or overuse of antibiotics.Hemodynamically unstable children with a suspicion of infection should be immediately treated with broad-spectrum antibiotics. In contrast, in hemodynamically stable children with sepsis and organ dysfunction, a time frame of 3 h for proper diagnostics may be adequate before starting antibiotics if necessary.Less and more targeted antibiotic treatment can be achieved via antibiotic stewardship programs. Bloodstream infections caused by MDR bacteria are associated with high mortality.3Additionally, the proportion of chronically ill children with bacterial infections requiring antibiotic treatment rose in recent years,4 A point prevalence investigation showed inappropriate antimicrobial therapy in 16–61% of cases on a cardiac and pediatric intensive care unit (PICU).5 The ARPEC point prevalence study including more than 1000 PICU patients worldwide revealed that 61% received at least one antibiotic (combination therapy in 51%).6 Prolonged (inappropriate) surgical prophylaxis was documented in 78% of patients.7 Overprescription of antibiotics can be driven, e.g., by the anxiety of missing an infection or not-challenging decisions of colleagues.8Keeping the burden of severe bacterial infections in mind, the care for critically ill children presenting with systemic inflammation frequently includes antibacterial treatment, even if the viral infection is proven.9 recommend fast initiation of antimicrobial therapy within the first hour of recognition in case of septic shock but leave 3 h of appropriate evaluation in children with sepsis-associated organ dysfunction without shock.As antibiotic overuse in PICU is frequent and adverse effects of antibiotics are well-known, a rational approach is needed. The Surviving Sepsis Campaign guidelines from 2020In this narrative review, we aim to summarize important aspects of antibiotic therapy in critically ill children that may help to reduce overtreatment. From these findings, we developed key questions for pediatric intensive care physicians that can support rational antibiotic decision-making in critically ill children. Wherever applicable, we put the existing evidence into context with the current Surviving Sepsis Campaign guidelines.This review is based on an extensive search of scholarly/peer-reviewed literature. We conducted a PubMed search for literature published between 2000 and 2021. Articles were screened for relevance if they included an English abstract and the full text in either English, German or French. Search items included “critically ill children”, “PICU” and “antibiotic”, “therapeutic drug monitoring”, “biomarker”, “time to antibiotic”, “procalcitonin”, “sepsis”, “septic shock”, “surveillance”, “adverse events”. Relevant articles referenced in publications identified from our search were also reviewed. We included original research and reviews as well as expert opinions if they addressed one of the topics of our review.n = 6/2), diagnostic approaches (n = 7/5), role of biomarkers (n = 6/3), timing of antibiotic therapy (n = 8/5), empiric therapy (n = 16), targeted therapy (n = 26/19), therapeutic drug monitoring (n = 14)), created a tabular overview over the studies  or the bone marrow .20 In non-critically ill adult inpatients receiving antibiotics, an average of 20% experienced at least one ADE, with risk increasing according to the longer duration of treatment.21 Among pediatric outpatients, an estimated 70,000 emergency department visits due to antibiotic ADEs occur annually in the United States of America, accounting for 46% of emergency department visits for ADEs.22Several antibiotics have organ toxic side effects such as nephro-, oto-, and hepatotoxicity. Serum levels of antibiotics that exert dose-dependent organ toxicity, like aminoglycosides, glycopeptides, and polymyxins, are commonly subject to therapeutic drug monitoring.24 In these mechanisms, the common phylogenetic origin of mitochondria and bacteria may play a role, as important effectors of the innate immune response to pathogen infection are located at the mitochondrial surface.25 Antibiotics that fit mitochondrial carriers have the potential to impair the activity of the electron transport chain in mitochondria, thereby possibly attenuating immune cell function.28 However, the importance of these potential modulations of the immune system remains uninvestigated in critically ill patient, calling for further research.12Detrimental effects of antibiotics on the innate and adaptive immune reaction have long been acknowledged.30 In children, the majority of antibiotic ADE visits to emergency departments were due to allergic or idiosyncratic reactions in a retrospective study.22While dose-dependent ADEs to antibiotics can be anticipated, immune-mediated idiosyncratic reactions are unpredictable. These immune reactions include anaphylaxis, eosinophilic skin rash, toxic epidermal necrolysis, Stevens–Johnson syndrome, and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome.33 even in neonates when using micro blood samples (100 µl).34 However, it remains unclear if the higher rate of detection leads to better outcomes or even less antibiotic usage. The risk of contamination, limited number of detectable pathogens, lack of resistance testing, and high costs have to be outweighed against the undetermined clinical benefit.The gold standard for diagnostics of severe bacterial infections remain blood cultures or cultures of body fluids acquired from the infected organ system. Definite results are available 24–72 h after preservation and aid in modifying or terminating antibiotic treatment but not in the initial decision. Due to difficulties to obtain sufficiently sized samples in small children, it is not always possible to receive meaningful results. To tackle this problem, molecular diagnostics have been considered as promising tools to enhance pathogen detection. In several studies, a multiplex-polymerase chain reaction in addition to routine blood cultures detected more relevant pathogens than blood cultures alone,36 and a small single-center trial in immunocompromised children.37 However, the interpretation of results might be even more challenging than in multiplex-PCRs. More trials are on the way to scrutinize if NGS can contribute to a rational antibiotic therapy. High costs and limited availability must also be addressed before NGS can become clinical routine.Next-generation sequencing (NGS) for the detection of cell-free DNA in blood was developed as another promising approach to molecular detection of pathogens. The clinical value of NGS has been studied with promising first results in adults38 In high-quality studies in adults, the use of PCT-guided algorithms reduced both mortality and antibiotic therapies in critically ill patients.41Currently used biomarkers for detection and follow-up of bacterial infections in children are C-reactive protein (CrP), Procalcitonin (PCT), leukocyte count, and especially in neonatology interleukin 6 and 8 . Here we focus on the use of PCT to guide antibiotic therapy. Procalcitonin as a biomarker is characterized by an early first peak in the course of a bacterial infection and a close relation to the clinical course and resolution of infection.42 There was no difference in mortality, which was attributed to the fact that no sepsis-related deaths occurred during the study.42 The results are limited by the fact that PCT was not compared to other biomarkers like CrP. In late-onset sepsis, the use of CrP showed fair discriminative power in a recent meta-analysis.43A randomized controlled trial on the value of PCT for treatment guidance in neonatal early-onset sepsis showed a reduction of antibiotic treatment duration (64 vs. 51 h).44 One difference to other studies was the integration of Antibiotic Stewardship recommendations in both study arms . This might have led to shorter antibiotic courses per se (at mean 6 days). A recent review gives a comprehensive overview on the utility and the challenges of PCT measurement in children with sepsis.45 When PCT was used for detection of bacterial infections thresholds, of 0.5 or 1 ng/ml were often used. For the cessation of antibiotic therapy, a threshold of a reduction of at least 80% from peak PCT levels is recommended.45The results of a randomized prospective trial in PICU patients did not confirm the reduction of antibiotic treatment duration as previously described.9The current SSC guidelines review the value of procalcitonin (but not CrP) in the context of antimicrobial therapy duration. A daily clinical assessment including laboratory analyses for the possibility of antibiotic de-escalation is recommended. The authors conclude that PCT shows promise, but there is still insufficient evidence for algorithm-based treatment decisions.48 In children there is less evidence on the tolerable delay of treatment initiation. In one study conducted on a PICU, the critical threshold for a significantly increased mortality was three hours (adjusted odds ratio (OR) 4.8  1.5–16.2)).49 Children with neutropenia after chemotherapy are especially prone to bacterial infections. In this population, administration of antibiotics within the first hour of check-in to hospital as a result of improved in-hospital processes significantly reduced the need for ICU consultation or admission.50In patients with suspected systemic infection and arterial hypotension or life-threatening organ dysfunction, immediate initiation of antibiotic treatment is undisputed. In adults, some studies report linear increases of mortality with every hour of treatment delay, other studies report increased mortality after a certain delay, mostly between one and six hours.9These studies highlight the importance of fast initiation of causal treatment in children with neutropenic fever, septic shock, or sepsis with organ dysfunction. Accordingly, the Surviving Sepsis Campaign calls for the initiation of empiric broad-spectrum antibiotic treatment within the first hour in septic shock and within three hours in sepsis-associated organ dysfunction.52 another study found 2.9-fold (CI 1.2–7.0) increased adjusted odds for 30-day mortality if the empirical treatment was discordant.53 A retrospective cohort study of over 10,000 preterm infants found that non-indicated antibiotic treatment was associated with increased mortality.54 In a quasi-experimental pre-post design study, 101 adults with intensive care unit acquired infections treated on an intensive care unit immediately received antibiotic treatment during the first period of the study.55 During the second period, diagnostic work-up was completed and antibiotic treatment was only initiated after obtaining positive culture results in 100 patients. During first the period, days with antibiotic treatment (17.7 vs. 12.5 days) and adjusted odds for mortality (OR 2.5 (95% CI 1.4–4.0)) were significantly higher.If completing the diagnostic work-up combined with watchful waiting may be justified in less critically ill patients remains yet to be answered: While some retrospective studies on bacteriemia in children failed to identify inadequate empirical antibiotic treatment as an independent risk factor for adverse outcome,Some of these findings might support a watchful waiting strategy if no signs of septic shock or organ dysfunction are present. However, further evidence in this area is needed before a recommendation can be made.Broad-spectrum therapy is recommended in pediatric septic shock or sepsis-associated organ dysfunction to increase the likelihood that initial empirical treatment is effective. The number one choice in this context is broad-spectrum beta-lactams. However, choosing the adequate empirical antibiotic treatment becomes increasingly difficult if the prevalence of MDR bacteria is high, for example in hospital-acquired infections. To broaden the antimicrobial spectrum, a beta-lactam can be combined with an aminoglycoside if a gram-negative MDR infection is suspected, or with a glycopeptide, if gram-positive MDR bacteria are likely.56 In another retrospective study, odds for acute kidney injury were doubled in children with gram-negative bacteremia receiving combination therapy with a beta-lactam and aminoglycoside compared to beta-lactam monotherapy.57 Mortality after 30 days was not affected.57 Even in severely ill  or profoundly neutropenic (≤100 cells/ml) patients with gram-negative bacteremia, no 10-days survival benefit was reported for empirical combination therapy with a beta-lactam and an aminoglycoside.58 However, patients with MDR gram-negative bacteremia had reduced 10-days mortality  and would benefit from empirical combination therapy.58 This study shows that the identification of patients at risk for MDR is extremely important to avoid the adverse effects of combination therapy and achieve the best outcomes at the same time.Treating all patients at risk for MDR infections sufficiently without exposing low-risk patients to unneeded organ toxicity drugs remains a challenge. For example, one retrospective study found a significant association of acute kidney injury with concomitant piperacillin/tazobactam and vancomycin treatment in children with suspected nosocomial infection.59 Nevertheless, some studies with mainly adult ICU patients assessed the relationship between preceding colonization and the probability of an infection. In general, critically ill patients with MDR carriage (mainly extended-spectrum β-lactamase pathogens) are at a clinically important risk for an invasive infection with the same bacteria.63 As a consequence, knowledge of colonization status could help improve the rate of adequate empiric antibiotic therapy. Whether this quality improvement leads to a better outcome in terms of survival, remains uncertain. Two of the four studies reported similar mortality rates but the number of patients was rather low, and mortality was not the primary outcome.62 The value of routine screening programs might also depend on the local incidence of MDR pathogens. A study by Jalalzai et al. in a low-endemicity ICU showed that it was safe to withdraw the routine screening program without harm.64 Additionally, the use of carbapenems was reduced during the period without screening.Screening for carriage of multi-drug resistant bacteria has become routine in many health care facilities who care for critically ill child. Data on the association of positive swabs with subsequent invasive infection with the same pathogen are anecdotal to our knowledge.9 However, even in these patients, combination therapy with a glycopeptide is recommended in settings with a high prevalence of methicillin-resistant Staphylococcus aureus or ceftriaxone-resistant pneumococci. If ceftriaxone resistance is common in gram-negative bacteria, the addition of an aminoglycoside or substitution with a carbapenem is considered appropriate.9 In hospital-acquired sepsis or immunocompromised patients, the clinical history including comorbidities, recent antibiotic exposure, known colonization, and indwelling devices have to be considered for antibiotic choice. Initial antimicrobial treatment should consist of a broad-spectrum therapy with a single- or multi-drug regimen.9 If the patient is considered at risk for an MDR infection the above-described combination therapy should be applied.9The Surviving Sepsis Campaign recommends monotherapy with a third-generation cephalosporin for previously healthy children with community-acquired sepsis as initial empirical treatment.Antibiotics are initiated because of a suspected infection. After obtaining results from cultures, an important strategy to avoid the development of MDR strains and reduce individual organ toxicity is a de-escalation of the initial empiric treatment. This includes targeted antimicrobial therapy whenever possible, discontinuation of treatment if no infection is confirmed, definition of treatment duration, and source control.65 Highlighting the adverse effects of unindicated antibiotic exposure, the failure to de-escalate initial empiric antibiotic treatment was associated with higher 90-days mortality in adults with severe sepsis or septic shock.66In a prospective multicenter study, children with neutropenic fever were stratified into groups with high, intermediate, and low risk for bacterial infection based on clinical findings and laboratory results. Patients in the high-risk group were treated empirically with antibiotics. Interleukin-8 was determined to distinguish between intermediate and low risk. Intermediate-risk patients received antibiotics and were re-evaluated after 72 h. In 41% of these patients, antibiotic treatment was discontinued following re-evaluation—without a case of sepsis relapse. Low-risk patients were clinically observed and discharged after 12 h without fever. However, 13% of the low-risk patients turned out to have an infection with coagulase-negative staphylococci requiring antibiotic treatment.67 Similar findings have been reported on antimicrobial time-outs in non-critically ill children.68A possible way to reduce antimicrobial exposure is the regular reassessment of indication for antibiotic treatment. In a tertiary pediatric intensive care unit, an antimicrobial time-out 48–72 h after treatment initiation led to defined treatment duration (63%) or discontinuation of treatment (29%) in most cases. Additionally, the time-out significantly reduced days of therapy per 1000 patient-days for vancomycin and meropenem compared to the pre-implementation period and reduced total acquisition cost for piperacillin/tazobactam, vancomycin, and meropenem.9 It is important to point out that infections causing more severe initial illness or organ dysfunction do not generally require longer courses of treatment. In numerous studies, similar clinical outcomes were achieved after short courses compared to long courses of antibiotics.77 Long exposure to antibiotics can cause secondary complications such as necrotizing enterocolitis in very preterm infants, candidemia, infections with C. difficile, and development of antibiotic resistance, making unnecessarily long exposure to antibiotics obsolete.82The duration of treatment should be determined with respect to the site of infection, causative pathogen, response to treatment, and the possibility to control the source by surgical interventions or removal of infected catheters.85Besides the administration of antimicrobials, source control has been shown to be an important part of sepsis treatment also in children and should be intended whenever possible.9These studies show that antibiotic treatment should be administered only as long as indicated, tailored to the patient’s needs, and de-escalated whenever possible. According to the Surviving Sepsis Campaign, assessment for de-escalation of antimicrobial therapy should be performed daily.89 These conditions typically occur during the initial phase of critical illness and resolve over time, thereby interfering with rigid dosing regimens that do not account for intraindividual pharmacokinetic variability.90If a decision in favor of antibiotic treatment has been made—be it adequate or not—an appropriate dosage should be administered to ensure an effective treatment. The adequacy of antimicrobial drug exposure is mainly determined by the volume of distribution and clearance. Sepsis patients are at risk for altered pharmacokinetics and pharmacodynamics due to shifts in distribution volume caused by fluid resuscitation, capillary leak, augmented or reduced renal clearance, and low serum albumin.94 While therapeutic drug monitoring is well-established in clinical practice for vancomycin and aminoglycosides, evidence is increasing that there may also be a role for monitoring beta-lactam plasma concentrations. A retrospective study in critically ill children found that augmented renal clearance, early phase of sepsis, and severity of sepsis-associated illness were associated with subtherapeutic levels of beta-lactams.86 In this study, no case of concentrations above the threshold or clinical toxicity was observed and children receiving continuous infusion had adequate plasma concentrations.86 Further studies have linked augmented renal clearance and critical illness in children to subtherapeutic treatment exposure to beta-lactams.102Several reports highlight the role of augmented renal clearance for subtherapeutic drug exposure to antibiotics with renal elimination profiles, such as glycopeptides, aminoglycosides, and beta-lactams.Therapeutic drug monitoring of beta-lactams not only helps to avoid organ toxicity but may also be a useful tool to assure adequate plasma concentrations of antimicrobial agents. Given the rapid changes in pharmacokinetics and pharmacodynamics children undergo during critical illness and subsequent recovery, individualized dosing strategies and monitoring of plasma concentrations of antimicrobial agents including beta-lactams seem inevitable in pediatric intensive care patients. Even though therapeutic drug monitoring will not reduce antibiotic overuse, it can help to reduce organ toxicity and ensure that the conducted treatments are effective.Antibiotics can save lives, but at the same time exert harm to the individual by multiple mechanisms, ranging from direct impairment of cellular function to disturbance of physiological homeostasis and even contributing to the development of new diseases. Awareness of these potential harms must become an essential part of physician’s decision-making for or against antibiotic treatment.Critically ill children may be a patient group that needs wise decision-making on antibiotic therapies even more than others. Important aspects to consider on the path to adequate antibiotic treatment are diagnostic approaches to identify pathogens and guide antibiotic treatment, timing of antibiotics, empiric and targeted therapy, and therapeutic drug monitoring. To guide decision-making, we developed 6 key questions to answer before the initiation of antibiotic therapy in critically ill children.Supplementary Table 1Supplementary Table 2Supplementary Table 3Supplementary Table 4Supplementary Table 5Supplementary Table 6Supplementary Table 7


Pseudomonas aeruginosa chronically infects in the lungs of people with cystic fibrosis and other forms of lung disease. Infections are treated with antibiotics, but over time, the bacteria acquire mutations that reduce their antibiotic susceptibility. The effects of inhibitory amounts of antibiotics in selecting for antibiotic-resistant mutants have been well studied. However, the concentrations of antibiotics that reach infecting bacteria can be sub-inhibitory and but may nonetheless promote emergence of antibiotic-resistant bacteria. Therefore, the aim of this research was to investigate the effects of sub-inhibitory concentrations of antibiotics on the antibiotic susceptibility of P. aeruginosa. Two P. aeruginosa reference strains, PAO1 and PA14, and six isolates from individuals with cystic fibrosis were studied. The bacteria were passaged in the presence of antibiotics  at sub-inhibitory amounts. Fifteen populations of bacteria (up to five per strain) were exposed to each of the four antibiotics. Antibiotic susceptibility was determined following 10 passages on agar supplemented with antibiotic and compared with susceptibility prior to antibiotic exposure. Antibiotic exposure resulted in susceptibility being significantly (>2-fold) reduced for 13 of the 60 populations. Seven samples had reduced susceptibility to ciprofloxacin, three to tobramycin, two to ceftazidime and one to meropenem. Whole-genome sequencing revealed the mutations arising following antibiotic exposure. Mutants with reduced antibiotic susceptibility had mutations in genes known to affect antibiotic resistance, including regulators of efflux pumps  and the fusA1 gene that is associated with aminoglycoside resistance. Genes not previously associated with resistance, including gacS, sigX and crfX and two genes with no known function, were also mutated in some isolates with reduced antibiotic susceptibility. Our results show that exposure to sub-inhibitory amounts of antibiotics can select for mutations that reduce the susceptibility of P. aeruginosa to antibiotics and that the profile of mutations is different from that arising during selection with inhibitory antibiotic concentrations. It is likely that exposure to sub-inhibitory amounts of antibiotics during infection contributes to P. aeruginosa becoming antibiotic-resistant. Pseudomonas aeruginosa is a widespread environmental bacterium that commonly infects the lungs of individuals with cystic fibrosis (CF) and other forms of lung disease (CF will have chronic P. aeruginosa respiratory infections (P. aeruginosa is associated with increased occurrence of sudden worsening of pulmonary symptoms (exacerbations), accelerated rate of lung function decline and decreased quality of life and reduced life expectancy  of the mutants identified the underlying resistance-causing mutations [oprD (carbapenem resistance) and gyrAB (fluoroquinolone resistance), and also in previously unrecognised resistance-associated genes, such as ftsI (carbapenem resistance) and fusA1 (aminoglycoside resistance).Once long-term infections are established, antibiotic treatment is rarely sufficient to eradicate survival . To bettP. aeruginosa even though the bacteria likely encounter this situation during chronic infection. There is evidence that sub-lethal doses of antibiotics can increase the antimicrobial resistance of P. aeruginosa  agar plates (Difco) supplemented with doubling concentrations of antibiotic. The SIC was defined as being ¼ of the lowest antibiotic concentration that inhibited visible growth after overnight incubation at 37°C (Ciprofloxacin (Ciplox), ceftazidime and tobramycin  and meropenem  were used. Overnight cultures grown in Luria Bertani broth  and inoculated onto an LB agar plate. ETEST strips were added and plates incubated at 37°C for 18 h under aerobic conditions. The minimum inhibitory concentration (MIC) was determined at the point where the inhibition ellipse intersected the side of the antibiotic strip. In some cases, replicate tests were undertaken to confirm reproducibility.Antibiotic sensitivity testing was carried out using ETEST strips  in accordance with the manufacturer’s instructions. Briefly, bacteria from an overnight culture grown in LB broth were diluted to ODSIC concentrations. In a subset of experiments, half or twice the SIC concentration was used. Briefly, a single colony inoculum in antibiotic-free LB broth was cultured overnight and adjusted to OD600nm 0.1. An MH plate was surface flooded with a 750 μl aliquot of the prepared inoculum and excess culture removed. Following aerobic incubation , bacteria were harvested from the plate and used to inoculate antibiotic-free LB broth which was incubated overnight. This process was repeated for 10 passages. Four strains were also passaged 10 times under antibiotic-free conditions to assess any effect of passaging itself on changes to MIC or occurrence of genetic mutations.Bacteria underwent 10 passages in the presence of antibiotic at ® Microbial DNA isolation kit) underwent sequencing on the Illumina MiSeq platform with a minimum of 40-fold coverage across each genome. Raw sequence reads were trimmed using Trimmomatic version 0.36  of each of four antibiotics. There were no significant changes in the MIC following passaging with tobramycin, ceftazidime or meropenem, where a significant change was defined as being a difference of more than one doubling dilution  and one replicate of strain DUN-003B (2.5-fold). One DUN-003B replicate had a 3.5-fold increase in the MIC following passaging in the presence of ceftazidime.To determine whether these findings were applicable to clinical isolates of SIC levels on clinical isolates. Similar to the results for the initial two clinical isolates, exposure to antibiotics at SIC generally had no significant impact on the MIC. As exceptions, exposure to ceftazidime, ciprofloxacin and meropenem resulted in a 2.7–16- and 6.3-fold increase in the MIC for one replicate of DUN-015A, DUN-009B and DUN-036-1, respectively.Passaging of an additional four isolates  was undertaken to further assess the impact of antibiotics at n = 7), followed by tobramycin (n = 3), ceftazidime (n = 2) and meropenem (n = 1). None of the increases in MIC were sufficiently high to cause the bacteria to be classified as clinically resistant  increase in MIC. Most of these were for ciprofloxacin , to determine whether passaging alone resulted in a change to MIC. None of the passaged bacteria had a significant change in MIC .SIC. In one of these experiments, half of the SIC resulted in an increased MIC for tobramycin in isolate DUN-003B. The MIC did not change in other experiments where passaging was carried out with different amounts of antibiotic , consissigX gene or the crfX gene. So far as we are aware, these genes have not previously been associated with antibiotic resistance. A mutation in the cmpX gene, that is operonic with crfX and likely to have a related function, reduces expression of sigX  associated with alginate biosynthesis following passaging in the presence of antibiotics. Clinical isolates frequently undergo changes in mucoidy that are associated with altered alginate production during subculture . It is therefore likely that the mucA mutations are associated with adaptation of the bacteria to growth under laboratory conditions.Derivatives of clinical isolates S2239_16 and DUN-003B had mutations in genes  and the Health Research Council of New Zealand (17/372). SW was supported by a Postgraduate Scholarship from the University of Otago.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This paper presents an investigation of the bond mechanism between carbon fibre reinforced polymer (CFRP) laminates, concrete and steel in the near-surface mounted (NSM) CFRP-strengthened reinforced concrete (RC) beam-bond tests. The experimental program consisting of thirty modified concrete beams flexurally strengthened with NSM CFRP strips was published in. The effects of five parameters and their interactions on the ultimate load carrying capacities and the associated bond mechanisms of the beams are investigated in this paper with consideration of the following investigated parameters: beam span, beam depth, longitudinal tensile steel reinforcement ratio, the bond length of the CFRP strips and compressive concrete strength. The longitudinal steel reinforcement was cut at the beam mid-span in four beams to investigate a better assessment of the influence of the steel reinforcement ratio on the bond behaviour of CFRP to concrete bond behaviour. The numerical analysis implemented in this paper is based on a nonlinear micromechanical finite element model (FEM) that was used for investigation of the flexural behaviour of NSM CFRP-strengthened members. The 3D model based on advanced CFRP to concrete bond responses was introduced to modelling of tested specimens. The FEM procedure presents the orthotropic behaviour of the CFRP strips and the bond response between the CFRP and concrete. Comparison of the experimental and numerical results revealed an excellent agreement that confirms the suitability of the proposed FE model. In the last two decades, an enormous amount of research work and numerous innovative applications have been published in the field of externally bonded (EB) fibre-reinforced polymer (FRP) concrete structures. The near-surface mounted technology has become very effective for flexural strengthening in single-span and double-span members, especially in the negative moment regions, where externally bonded FRP reinforcement is sensitive to environmental and mechanical impacts. Due to much better anchorage, the near-surface mounted (NSM) reinforcement is more safe and efficient than EB FRP applications ,7,8,9,10The key factor affecting the performance of CFRP-strengthened structures is the bond phenomenon between the CFRP bars or strips and concrete. Although the bond mechanisms have been extensively studied over the last few years ,17,18,19The flexural behaviour of CFRP-strengthened concrete beams and slabs has been deeply investigated in RC members, which confirmed significantly higher efficiency compared to the EB configuration ,35,36,37This is why the modified beam-bond tests according to the RILEM  have beeThe bond mechanisms of CFRP to concrete joints depend on the interfacial crack widths along with the interface, which means that the steel reinforcement ratio can significantly affect the bond performance between the CFRP and concrete ,60,61,62The interesting test results of the NSM technique extended with Steel Reinforced Grout (SRG) materials published in  indicateThe effectiveness of the strengthening technique using either externally bonded reinforcement (EBR) or NSM procedures was found to be dependent on various parameters, such as the steel reinforcement ratio, distribution of the bending moments along the beam span, a number of layers of the externally bonded CFRP laminates, their axial stiffness and the bond length.As far as related theoretical work is concerned, to achieve an accurate prediction for the bond strength, one must first understand the shear stress transfer mechanisms along the interface, and also determine the multiaxial state of stress to which a point inside the interface is subjected.The finite element simulations based on a fairly sophisticated micromechanics material description, known as the microplane theory, were used to model the behaviour of tested specimens. Adopting such a concrete theory has been taken foremost because this approach leads to great success in representing the concrete behaviour under the complex stress–strain state. The flexural failure modes and the associated concrete cover splitting can be simulated using a major discrete crack approach along with the microplane concrete models ,66,67,68In the finite element model proposed in this study, an accurate bond-slip relationship is used to represent the interfacial behaviour of CFRP to concrete interfaces. The relations were developed by  and accoThe purpose of the research is the comparative analysis of the numerical and experimental results to show the compatibility of the presented model in reference to obtained test results of the NSM CFRP-strengthened concrete members.Two different concrete batches with the concrete mix proportions for cylinder compressive strength 20 MPa and 40 MPa, summarized in The beams were reinforced in the tensile zone with longitudinal steel ribbed bars of nominal diameters: 8 mm or 16 mm, and steel stirrups of a nominal diameter of 8 mm at a spacing of 100 mm . The rei®30 epoxy adhesive was used to bond the CFRP strips to the concrete.CFRP strips (Type XS1.524) of 2.41 mm thickness and 15 mm width were used for the NSM strengthening of the RC specimens and their mechanical characteristics are presented in The experimental tests were carried out on four main series consisting of thirty single-span, simply supported, modified RC beams published in . The RILThe test specimens described in  had two Twenty-one beams were strengthened with a single CFRP strip with the bond length ranging from 80 mm to 160 mm. Three beams were strengthened with double strips at a spacing of 50 mm and the bond length of 80 mm . The objective of these specimens was to address the effect of double NSM CFRP strip areas comparing to the single CFRP strip on the flexure capacity of the tested specimens. The last six beams in the experimental program were tested as unstrengthened .The first number in the specimen ID  had the internal steel bars cut at the mid-span to investigate the effect of a lack of continuity of the internal reinforcement on the CFRP bond strength. Cutting the internal steel bars at the mid-span was designed to simulate the case of the direct shear test where the forces transferred from the CFRP strips to the concrete without any interaction of the internal steel bars. However, as the result of the fact that the internal reinforcement remained inside the concrete beams, it was expected to affect the flexural cracks at the NSM CFRP cut-off point. The objective of testing these two particular beams was to better understand the role of the internal steel bars on the bond performance.The test specimens were cast in a horizontal steel mould. The reinforcing skeletons for the beams were prepared in the laboratory of the Concrete Structures (TUL) . PreparaAll specimens were tested in an upside-down position to observe cracking patterns of the beams and to monitor the strain readings of the CFRP strips. The beams were tested in a four-point bending static scheme using hydraulic servomotors, as is shown in Axial concrete strains in the tensile (R1–R5) and compressive (R6–R10) zones were monitored with the linear variable displacement transducers . The LVDT measurements were transferred to strain readings using the special Data Acquisition System (DAS) collecting the test data. The compressive and tensile strain measurements were registered in the level of the longitudinal steel hinge axis and in the level of the longitudinal steel reinforcement, respectively. The locations of all gauges are shown in The experimental results are presented with respect to the failure modes, ultimate loads and strain measurements published in detail in .Failure modes of the tested NSM CFRP strengthened beams occurred by the strip debonding together with the surrounding concrete cover along or slightly above the level of the steel reinforcement . In the The specimens with cut steel bars at the mid-span indicated the CFRP strip’s debonding between the CFRP end and the adhesive layer. In several beams, a significant slip of 5 mm between the CFRP strip and concrete occurred . Once the internal reinforcement yielded at this specific location, the major flexural crack at the cut-off point of the NSM CFRP strips merged with the horizontal crack that was initiated at the steel-concrete interface. This indicated that, for a longer bond length, the failure mode began as flexural failure due to steel yielding followed by bond failure in the plane located between the bottom of the CFRP strips and the upper surface of the internal steel bars, or at the level of the steel–concrete interface. On the other hand, for the shorter bond length, the failure mode was typically bond failure at the adhesive and concrete interface.The observed crack patterns for all tested specimens were similar to those reported in the literature for the CFRP—strengthened beams. The crack concentration area was located in the bonded CFRP region; however, cracks first initiated at unbonded locations. The first crack appeared at the cross section of the CFRP cut–off with the shorter bond length at the beam’s mid-span. Then, the flexural cracks followed at the beginning of the CFRP laminates on the other beam side  compare a,b. ThisThe experimental ultimate loads for the strengthened and unstrengthened beams , the shear stress, ications ,75,76. TA detailed 3D brick element with 8-node used for simulation of the behaviour of the concrete with three DOF at each node used in publications ,58 for tInterface elements were used to connect the CFRP nodes and the concrete nodes. These elements were aligned in two perpendicular directions. The interface elements were used in both the longitudinal and vertical beam directions  is presented in With an increase in the NSM bond length, both the debonding and flexural loads increased. For the beam strengthened with a lower bond length than 270 mm, debonding of the NSM strips from the concrete occurred. However, because there was no significant difference between the debonding load .Moreover, the numerical analysis is very sensitive to the bond stiffness of the vertical interface elements connecting the CFRP element nodes and the concrete nodes. The influence of the concrete fracture energy used to constitute the bond behaviour of the major discrete crack interface element was caused by changing the concrete tensile strength for these interface elements from 1.6 to 3.2 MPa (beam NISA/20/85).For the beams with a small bond length and failure due to debonding of the strip, it was found that the material properties of the discrete crack model did not affect the prediction. However, for a relatively long bond length .–The enhancement in the ultimate load-carrying capacity of the tested specimens was in the range of 6% to 24% of the corresponding control specimens for the short beams (NIS) with lower reinforcement (2 bars of 8 mm diameter) and in the range of 20% to 73% of the corresponding control specimens for the long beams (NIL) depending on the bond length of the NSM CFRP strips and concrete compressive strength.–It was unexpected that short strengthened beams with the higher reinforcement ratio (NIIS) failed under lower loading than the reference beam. It confirms that the reason for this failure mode is much stiffer behaviour of the beams reinforced with much higher internal reinforcement that caused such brittle behaviour of the strengthened beams after CFRP debonding.–The cutting of the longitudinal rebars delayed the debonding of the NSM laminates, thus significantly increasing the CFRP strains at failure. However, the beams with cut steel reinforcement at the mid-span indicated a 57% higher ultimate strain in the strengthening NSM CFRP strip (for the beams NILA/40/120 and NILA/40/120s). However, the ultimate load for the beam NILA/40/120s with cut reinforcement was 82% lower than this one with longitudinal reinforcement.–A slightly different situation was observed in the short beams with the higher reinforcement (NILB/40/120 and NILB/40/120s). The cutting of the longitudinal bars delayed the debonding of the NSM laminates and significantly increased the CFRP strains’ failure by 76%. However, the ultimate load for the beam with cut reinforcement NILB/40/120s was unexpectedly lower by 452% than this one with longitudinal reinforcement.–The experimental results showed that the steel reinforcement ratio is the most dominant parameter affecting the bond behaviour between the CFRP strips and concrete. Furthermore, it was observed that the final failure modes are mainly controlled by the effect of the internal steel bars .–The proposed finite element model represents an advanced numerical tool based on micromechanics materials. The prediction of the ultimate load-carrying capacities was based on the major discrete crack approach to represent the flexural failure mode. The finite element analysis revealed a good efficiency of the predicted ultimate loads compared to the experimental ones with an average ratio of numerical and experimental maximum load and its standard deviation equal to 1.02 and 0.13, respectively.–The interfacial stiffness and the bond strength had a small influence on the overall structural stiffness when they were used to constitute the horizontal interface elements. However, they did have a significant effect when they were defined by the interfacial behaviour of interface elements in the vertical direction.–For the beams with a small bond length and failure due to strip debonding, the material properties of the discrete crack model did not affect the numerical predictions. For the specimens with a bond length higher than 270 mm, the concrete fracture energy significantly affected the ultimate load. The numerical simulations revealed that using the concrete tensile strength to define the concrete–steel bond strength with the discrete crack interface element underestimates the predicted values. The bond strength that gave quite good predictions was between 1.5–2.0 times the concrete tensile strength.The paper presents the selected test results published in  and a di


Intensive care units (ICU) constitute a high-risk setting for antimicrobial resistance (AMR).Staphylococcus aureus (MRSA), glycopeptide-resistant enterococci (GRE), extended-spectrum cephalosporin-resistant Escherichia coli (ESCR-EC) and Klebsiella pneumoniae (ESCR-KP), carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa (CRPA) from Swiss ICU. We assessed time trends of antibiotic consumption and identified factors associated with CRE and CRPA.We aimed to describe secular AMR trends including meticillin-resistant We analysed patient isolate and antibiotic consumption data of Swiss ICU sent to the Swiss Centre for Antibiotic Resistance (2009–2018). Time trends were assessed using linear logistic regression; a mixed-effects logistic regression was used to identify factors associated with CRE and CRPA.Enterobacter spp., increased from 1% to 5% ; CRPA remained stable at 27% . Antibiotic consumption in 58 ICU increased from 2009 to 2013 (82.5 to 97.4 defined daily doses (DDD)/100 bed-days) and declined until 2018 (78.3 DDD/100 bed-days). Total institutional antibiotic consumption was associated with detection of CRE in multivariable analysis .Among 52 ICU, MRSA decreased from 14% to 6% ; GRE increased from 1% to 3% . ESCR-EC and ESCR-KP increased from 7% to 15%  and 5% to 11% , respectively. CRE, mostly Enterobacterales have been steadily increasing over the last decade. The emergence of CRE, associated with institutional antibiotic consumption, is of particular concern and calls for reinforced surveillance and antibiotic stewardship in this setting.In Swiss ICU, antibiotic-resistant  Enterobacterales (CRE) and Pseudomonas aeruginosa (CRPA) [Intensive care units (ICU) are considered high-risk settings for antimicrobial resistance (AMR) . This caa (CRPA) ,5. The Ca (CRPA) .Staphylococcus aureus (MRSA) are declining [Surveillance is considered a cornerstone in the fight against AMR . Specifieclining ,10. Antieclining .In this study, we describe secular trends of AMR and antibiotic consumption from Swiss ICU using surveillance data from ANRESIS. For CRE and CRPA, we sought to identify patient-level and institutional factors associated with resistance, including institutional antibiotic consumption. We also assessed the representativeness of ANRESIS for the ICU setting in Switzerland.www.anresis.ch). ANRESIS, led by the Institute for Infectious Diseases at the University of Bern, is the national centre for surveillance of antibiotic resistance and antibiotic consumption and is supported by the Swiss Federal Office of Public Health. Antimicrobial susceptibility testing is performed at local laboratories according to guidelines from the Clinical and Laboratory Standards Institute (CLSI) or the European Committee on Antimicrobial Susceptibility Testing (EUCAST) [https://ukneqas.org.uk) or the Swiss quality control programme of the Institute for Medical Microbiology, University of Zurich (www.imm.uzh.ch/de/services/qc.html). This laboratory-based surveillance study was conducted using antimicrobial resistance and antibiotic consumption data from ANRESIS ((EUCAST) ,13. All www.sgi-ssmi.ch/de/zertifizierte-is.html). Because several small-size ICU have been closed or have been incorporated into larger institutions over the last decade, representativeness was only assessed for the year 2018. This was done by calculating the percentage of ICU beds represented in ANRESIS among all registered ICU beds in Switzerland, stratified by administrative subdivisions (i.e. cantons) speaking mostly French or Italian  or German . In order to detect differences in microbiological sampling frequencies between geographical regions, we calculated the sampling density, defined as the number of microbiological samples per represented ICU bed.ANRESIS continuously collects routine antibiotic resistance data  from 33 laboratories distributed homogeneously all over Switzerland and representing 89% of all hospital samples in 2020. Antibiotic consumption data are collected once yearly from around 70 hospital pharmacies across Switzerland. For the analysis of AMR in ICU, we assessed the representativeness of ANRESIS for ICU registered by the Swiss Society for Intensive Care  from the same patient in a specific calendar year. If patients contributed both resistant and susceptible isolates (per species) in the same year, only the resistant isolate was included. Therefore, each patient contributed only one sample per species, institution and year. Bacterial isolates from non-specified swabs  were excluded in order to minimise the impact of patients colonised with resistant pathogens before ICU admission.For the analysis of antibiotic consumption, we extracted consumption data for the same time period (2009 to 2018) from those ICU where these data were available. Of note, antibiotic consumption data were only available on the institutional level (per year) and not on the patient level.For the analysis of risk factors for CRE and CRPA, we included only data from years where institutions provided AMR data along with corresponding antibiotic consumption data.Resistance to a particular substance was defined as either an intermediate or a resistant phenotype in susceptibility testing according to the individual laboratories. Group resistance  was defined as resistance or intermediate susceptibility to at least one antibiotic of the respective group; extended-spectrum cephalosporin-resistance was defined as resistance or intermediate susceptibility to at least one third or fourth generation cephalosporin.Enterococcus faecalis/faecium (GRE). Non-multidrug-resistant MRSA was used as a surrogate for community-associated MRSA (caMRSA), defined as being susceptible to at least three of the following agents: ciprofloxacin, clindamycin, tetracycline and trimethoprim-sulfamethoxazole [Escherichia coli (ESCR-EC) and Klebsiella pneumoniae (ESCR-KP), CRE , CRPA , carbapenem-resistant Acinetobacter baumannii complex (CRAB) and trimethoprim-sulfamethoxazole-resistant Stenotrophomonas maltophilia (TSRSM).Among Gram-positive bacteria, we analysed MRSA and glycopeptide-resistant hoxazole . The folWe expressed AMR as a percentage of all isolates and consumption of systemic antibiotics as defined daily doses (DDD) per 100 bed-days (BD), compliant with the World Health Organization (WHO) definition from 2019 . CategorFor the analysis of risk factors for CRE and CRPA, we performed a mixed model with ICU as random effect, considering the hierarchical data structure. Patient-level variables included age group , sex and site of sample collection . Institutional variables included geographical region (south-west vs east), hospital type  and total annual antibiotic consumption. All co-variables were entered into multivariable analysis. Two-sided p values ≤ 0.05 were considered statistically significant. All statistical analyses were performed using R statistical software version 3.5.2 .Sensitivity analyses were performed for the assessment of temporal trends for AMR and antibiotic consumption, including only those ICU that provided data for at least 8 years between 2009 and 2018, in order to eliminate potential selection bias.Because ANRESIS contains routinely collected anonymised surveillance data, ethical consent was not required according to the Swiss law for research on human beings.Supplementary Figure S1). By 2018, 11 of 52 ICU did no longer exist, resulting in 41 ICU represented in our database for the analysis of AMR. Of these 41 ICU (with a median bed number of nine), 17 were located in south-western, and 24 in eastern Switzerland; the median bed number was 39 (range: 34–64) for the five university and eight (range: 6–42) for the 36 non-university ICU (listed in Supplementary Table S1).Over the 10-year period, we included 52 and 58 ICU for the analysis of AMR and antibiotic consumption, respectively  of all Swiss ICU beds. Coverage was higher for south-western  than for eastern Switzerland  (p < 0.001). For the year 2018, sampling density was 10.2 samples per represented ICU bed; sampling density was higher for ICU from the south-west (12.2 per represented bed) compared with those from the east (9.3 per represented bed) (p = 0.002) .Supplementary Figures S2/S3 for eastern and south-western Switzerland separately).After removal of duplicates, we identified 34,887 tested pathogens. A majority of isolates  originated from eastern and 15,316 (44%) from south-western Switzerland. Resistance data by geographical region and year (2009 and 2018) are shown in S. aureus isolates , meticillin resistance decreased from 14% to 6% (p = 0.005) from 2009 to 2018. This effect was driven by a decline in hospital-associated MRSA (haMRSA) in south-western Switzerland from 18% to 2% (p < 0.001); the proportion of caMRSA was stable around 3% (p = 0.196). Among the 4,776 enterococcal isolates , GRE increased from 1% to 3% (p = 0.011), which was exclusively due to an increase in eastern Switzerland.Among the E. coli  and 4,052 K. pneumoniae  isolates. From 2008 to 2019, ESCR for E. coli increased from 7% to 15% (p < 0.001) and for K. pneumoniae from 5% to 11% (p = 0.002). Proportions and trends for ESCR were similar between the two geographical regions. The CRE showed an increase from 1% to 5%  and were more common in eastern Switzerland . In 2009, 16 of 17 CRE were Enterobacter spp., whereas in 2018, 77% (82/107) were Enterobacter spp., 11% (12/107) were K. pneumoniae, and 8% (9/107) were E. coli. Among 4,185 P. aeruginosa isolates , 27% were CRPA, with no change over time (p = 0.759). Isolates of the A. baumannii complex were rarely detected (n = 316); 37% of these isolates were CRAB, without temporal change (p = 0.495). Also for the 1,158 S. maltophilia isolates, of which 4% were TSRSM, no trend could be observed (p = 0.091).We identified 10,648 Supplementary Table S2). Temporal trends of these antibiotic groups, for quinolones and for the total antibiotic consumption are shown in Supplementary Figures S4/S5 stratified by geographical region). We observed an increase in total antibiotic consumption from 2009 (82.5 DDD/100 BD) to 2013 (97.4 DDD/100 BD), followed by a decrease until 2018 (78.3 DDD/100 BD). Segmented linear regression (performed post-hoc) confirmed these opposing trends (p = 0.044). Similar patterns were observed for the 'watch and reserve' group of antibiotics (WHO AWaRe classification) [Supplementary Table S3).Among 35 ICU from south-western and 23 from eastern Switzerland, penicillins, cephalosporins and carbapenems were the three antibiotic groups used the most. For 2018, they accounted for 68% (52.9 DDD/100 BD) of the total (78.3 DDD/100 BD) antibiotic consumption (for a detailed list see ication) , as wellFor CRE, institutional antibiotic consumption was significantly (but not very strongly) associated with carbapenem resistance in the mixed effects model (odds ratio (OR) per DDD: 1.01; 95% confidence interval (CI): 1.0–1.02; p = 0.004), as was the year of detection . For CRPA, the association with antibiotic consumption was not statistically significant . Interestingly, male sex was positively  and year of detection - although with very small effect - negatively  associated with CRPA. Older age and detection in urine were negatively associated with both CRE and CRPA. Neither geographical region nor university hospital status was predictive for CRE or CRPA .Considering only those ICU that provided data for at least 8 years between 2009 and 2018, we observed the same temporal trends regarding AMR  and antibiotic consumption  (data not shown).In this laboratory-based analysis of national surveillance data from Swiss ICU, we have shown that the occurrence of MRSA has been decreasing steadily, whereas resistant Gram-negative bacteria including ESCR-EC, ESCR-KP and – of particular concern – CRE have become more frequent between 2009 and 2018. The only modifiable factor associated with CRE was institutional antibiotic consumption. On a national level, antibiotic consumption peaked in 2013 and has since been declining. The strengths of this study were its large sample size, the representativeness of the database for the Swiss ICU setting and the robustness of temporal trends in sensitivity analyses.Enterobacterales in Swiss ICU over the last decade. These data are in line with trends described from other European countries, although the different observation periods overlap only partly with our analysis. In German ICU, ESCR-EC increased from 1.3% to 16.3% and imipenem-resistant K. pneumoniae from 0.4% to 1.6% between 2001 and 2015 [Enterobacterales increased by 73% between 2009 and 2013, with higher rates in ICU [E. coli being ESCR-EC in long-term care institutions [Our main finding was the emergence of resistance among s in ICU . In Itals in ICU . Resistaitutions ,20.Enterobacter spp. were the predominant species among our CRE. Carbapenem-resistance in Enterobacter spp. can be conferred either by de-repressed AmpC in combination with porin loss/modification or by carbapenemase production [Enterobacter spp. is usually observed after beta-lactam exposure, which is in accordance with our finding that institutional antibiotic consumption was associated - although not very strongly - with detection of CRE. However, we cannot exclude the possibility that the rise in carbapenem-resistant Enterobacter spp. may be due to dissemination of high-risk clones such as ST171 and ST78, which can also carry carbapenemase-encoding plasmids [K. pneumoniae and E. coli are increasing among CRE. Increased importation of CPE from high-risk countries or even acquisition in local hospitals could account for their spread, as CPE are considered to spread primarily through horizontal transmission in the healthcare setting [The emergence of CRE, associated with increased morbidity and mortality, is particularly worrying . Enteroboduction ,23. De-r setting ,25. For  setting . Also, n setting .P. aeruginosa isolates to be carbapenem-resistant. This figure is comparable to data from 36 ICU in the United States which showed 35% CRPA, mostly from the respiratory tract [We found 27% of ry tract . The assry tract . On the ry tract . On the ry tract .A favourable trend was observed regarding MRSA in Swiss ICU. The fact that the decline in MRSA was exclusively attributable to haMRSA (and not to caMRSA) has been observed in other countries and has partly been attributed to increased awareness and infection control interventions, including the Dutch search-and-destroy approach . MoleculGeographical differences have to be taken into account when explaining AMR trends in Switzerland. Historically, the south-western part of the country has been more affected by AMR than the east . HoweverAntibiotic consumption in Switzerland has traditionally been lower compared with other European countries . Our datE. coli among employees of a Swiss veterinary clinic, which was probably due to cross-transmission from hospitalised companion animals [Despite the decreased antibiotic use in intensive care, many antimicrobial stewardship activities are still lacking in a majority of Swiss hospitals . Given t animals .An important limitation of this study was the lack of information on day of patient admission to the ICU. Although we excluded screening samples from the analysis, part of our data reflect antibiotic susceptibilities of samples collected at the time of ICU admission. This means that some resistant pathogens in our dataset were in fact community-acquired and were not a consequence of high institutional antibiotic consumption. We also suppose that restriction to bacterial samples collected 48 h after ICU admission would have resulted in even higher resistance rates. Furthermore, we could not distinguish between pathogens representing true infection and those only colonising. Also, because of the institution-specific patient identifier, we cannot exclude the possibility of duplicate isolates for patients being admitted to more than one ICU in the same year. Another limitation was the lack of information on individual antibiotic treatment before admission. This prevented us from including antibiotic consumption as a patient level variable in our hierarchical model.Enterobacterales in Swiss ICU is increasing. The rise in carbapenem resistance calls for a multimodal approach to improve surveillance (including systematic screening of ICU patients and molecular typing of resistant isolates) and adherence to standard infection control measures. Although antibiotic consumption is decreasing, the observed association between total antibiotic consumption and the occurrence of CRE underscores the need for antimicrobial stewardship in the Swiss intensive care setting.Resistance among


Multidrug-resistant bacteria and antibiotic resistance genes can be monitored as indicators of contamination in several environments. Mangroves are among the most productive ecosystems, and although they can be resilient to the action of climate phenomena, their equilibrium can be affected by anthropogenic activities. Regarding the presence and persistence of multidrug-resistant bacteria in mangroves, it is common to think that this ecosystem can function as a reservoir, which can disperse the antibiotic resistance capacity to human pathogens, or serve as a filter to eliminate drug-resistant genes. The possible impact of anthropogenic activities carried out near mangroves is reviewed, including wastewater treatment, food production systems, leisure, and tourism. Adverse effects of antibiotic resistance genes or multidrug-resistant bacteria, considered as emerging contaminants, have not been reported yet in mangroves. On the contrary, mangrove ecosystems can be a natural way to eliminate antibiotics, antibiotic-resistant bacteria, and even antibiotic-resistant genes from the environment. Although mangroves’ role in decreasing antibiotics and antibiotic resistance genes from the environment is being proposed, the mechanisms by which these plants reduce these emerging contaminants have not been elucidated and need further studies. Additionally, further evaluation is needed on the effects of antibiotics and antibiotic-resistant bacteria in mangroves to generate an analysis of the human contribution to the degradation of this specific ecosystem as well as to define if these contaminants can be used as indicators of contamination in mangrove ecosystems. There are 152,000 kmorldwide , influenorldwide , and aidorldwide . Mangrovorldwide  and an iorldwide . Due to orldwide , while iorldwide . Regardlorldwide . Becauseorldwide ,12. As aorldwide .The main indicators used for conservation or perturbation in mangrove ecosystems are based on image analysis of the several plants present. The most recognized variable that indicates the condition of mangroves is the vegetation structure, which involves leaf area index, canopy height, and standing biomass . The fluEmerging contaminants (ECs) such as antibiotic residues and antibiotic-resistant bacteria (ARB) are critical problems that have been reported lately in many different environments. Although these contaminants are not new, their presence in several environments has increased along with the increment in industrialized areas and crowded communities . Their pToday, the effect of anthropogenic activities in mangroves is contradictory. While the presence of ARB and antibiotic resistance genes (ARGs) in mangroves from India was related to anthropogenic activities , in otheA total of 1250 papers were obtained from the three different databases, and 870 were discarded as irrelevant to mangroves as they focused on wetlands or other water bodies. From the remaining 380 papers, 276 were discarded since they were dealing with other emerging contaminants such as heavy metals, hormones, or isolate microorganisms with antibiotic production. From the last 104 papers, 14 were repeated articles, 6 focused on the detection of antibiotic-resistant bacteria in animals or mollusks, and 7 were unavailable. The last 77 documents between papers and book chapters were analyzed and used for this review . Since iThe era of antibiotic therapy has led to an increase in the concentration of these compounds in the environment. Even more, the efforts to develop novel antibiotics have also increased the diversity of chemical structures with antibiotic capacities. Because of the dispersal of antibiotics in the environment, there is an increase in ARB as well as ARGs . The com3 GCN·mL−1 effluents [−1 and 1018 GCN·d−1 [Wastewater is recognized as one of the most common distribution lines of ECs related to antibiotic resistance  since wastewater treatment plants (WWTPs) have shown high variability in their capacity of antibiotic reduction. Depending on the season, WWTP efficiencies can vary from 66–97% in winter to 17–66% in autumn, while ARB prevalence has increased in effluents (up to 2 logs), reaching a value of 80% of the total bacteria. Similarly, the ARG presence in effluents of WWTPs shows a considerable increment compared with values in influents . The disffluents . Moreove GCN·d−1 ,29.On the other hand, mobile genetic elements such as transposons, plasmids, and integrons are abundant in parts of the wastewater treatment process, including activated and sewage sludge . For theE. coli  in a close-by mangrove area. This correlation could be considered proof of the impact of the effluents from wastewater treatment systems on this type of ecosystem. Nonetheless, more information is necessary to evaluate the direct effect of wastewater treatment in the presence of ECs on mangrove ecosystems.Mangroves have been considered as “natural wastewater wetlands” present in coastlines and could act as active nutrient filters from runoff water from cities or human communities. Moreover, mangrove plants have been proposed since the 1990s as part of the secondary treatment system for municipal wastewater in China. The proposal considers the advantage of both oxygenic and anoxic conditions that these plants develop in their roots, allowing oxidation and reduction processes by microorganisms from the mangrove rhizosphere for the removal and transformation of pollutants . NeverthThe increasing demand for food supply due to continuous human population growth requires the establishment of intensive production systems, and one example is the modern aquaculture industry. In intensive aquaculture methods, bacterial fish diseases are common. Consequently, the use of antibiotics has increased, reaching in some countries, such as Chile, values of 0.5 kg of antibiotics for each kg of salmon produced . Due to Iris pseudacorus and Phragmites australis) with high-rate removal capacity of emerging contaminants such as enrofloxacin, sulfamethoxazole, and ARGs has been proposed as an alternative to recover water from aquaculture effluents [Several approaches have been proposed to eliminate antibiotics in effluents from the treatment of domestic and industrial wastewater ,46,47, iffluents .−1) were reported in sediments of mangroves near mariculture farms, but a positive correlation between ARG abundance and antibiotic concentration in this environment was only found for ciprofloxacin [Mangroves, considered natural wetlands, are of great importance for coastal aquaculture systems, since this ecosystem supplies environmental services such as nursery grounds and shelter for fish, crabs, and shrimp, the maintenance of biodiversity, and water conservation . These cfloxacin . From thThe upsurge of antibiotic resistance due to the use of antibiotics in veterinary therapies has increased the cost of cattle production, along with a concern for the effect that the use of antibiotics can have on human health . Since 9−1) used in veterinary medicine [It has been reported that microbial communities found in wastewater from livestock breeding have a significant effect on modifications of the resistome (defined as the set of host genes with non-redundant function in resistance ) identifmedicine . Extensimedicine . Moreovemedicine . On the medicine ,62. Althmedicine .2) emissions in the short and long term [2 sequestration from the atmosphere, known as blue carbon [2 emissions and a diversity of emerging contaminants such as antibiotics, which represent an accumulative risk for the health of the ecosystem [The effect of urbanization in the presence of ECs in mangroves is one of the less studied human activities. However, increased urbanization produces changes in land cover, biogeochemical processes, hydrological systems, biodiversity, and climate ,65. One ong term , which ie carbon . Neverthcosystem .Economic inversion in tourism has found a fertile area in countries with coastlines, especially with a warm climate and a large extension of sand beaches. The urbanization of these areas has allowed for an increase in the community’s income due to tourism . The att−1: 87.8—fluoroquinolones; 0.97—chloramphenicol) than sediments from mangrove areas  [mtrA, rpoB, rpoC, rpsL, ef-Tu, and parY) and the target alteration (as resistant mechanism) were significantly lower in mangrove sediment than in non-mangrove sediment [Phragmites australis were removed but were not found in the plant’s roots. The latter supports the idea of a more active microbial degradation process for the ECs presented in these environments, as has been suggested before [Although the presence of ECs in mangroves can be related to anthropogenic activities, there is no clear evidence that the contaminants present a negative impact on these ecosystems since it has also been reported that mangrove plants and their sediments reduce the presence of ARGs and ABs in sediments and water samples ,24. In Ghenicol) . On the sediment , where td before . AnotherEven so, when the ECs of interest are antibiotics, the role of plants has been described as vital for their removal . The comMangroves have been proposed as a solution for the decrease in EC concentration in coastal water bodies. The effects of these pollutants, including antibiotics presented in aquaculture effluents on mangrove plants, as well as the uptake mechanisms of plants to reduce these compounds, are not yet understood ,80. AddiAccording to PRISMA recommendations , we condThe importance of mangrove ecosystems includes all the services that they provide to human communities. The relation between environmental degradation and anthropogenic activities has been studied for several years. The monitoring of emerging contaminants, including antibiotics, ARGs, and ARB in environments, has been proposed to determine the direct human impact in several environments. Nevertheless, monitoring these contaminants in mangroves has been studied for a few human activities, such as aquaculture, while other activities such as tourism, urbanism, and livestock breeding are still poorly understood. Moreover, the few EC analyses of AB, ARGs, and ARB in mangroves have been directed to propose these ecosystems as a solution to mitigate the presence of these pollutants, instead of analyses that correlate the presence of these ECs to human activities developed in the mangrove’s vicinity. Even more, the effect of these ECs on the physiology and health of this ecosystem remains unknown. The present review shows the lack of information on the actual effect of anthropogenic activities related to mangrove areas on physiology and functionality. The development of more studies in this area could warrant an accurate analysis of the human contribution to the degradation or conservation of these ecosystems.


The relationship between prescribing habits and demographics was analyzed using stepwise logistic regression models. The implementation of the guidelines significantly improved the overall prescribing habits of ECPs (p < 0.001), especially for prophylactic antibiotic use before and after ortho-k lens wear (p < 0.001). Most ECPs who prescribed antibiotics properly displayed significantly better knowledge of correct antibiotic use, which in turn affected the compliance in their ortho-k patients (p < 0.001). The ECPs’ occupations , clinical setting (distributor fitting centers), and age (younger than 25 years) were risk factors for the misuse of antibiotics. Although the implementation of the antibiotic guidelines significantly improved overall prescribing habits, some practitioners’ prescribing behavior still needs improvement. A limitation of this study was that all questions were mandatory, requiring ECPs to recall information, and therefore was subjected to selection and recall bias.It has been previously reported that the improper prescribing of antibiotic eye drops is common among orthokeratology (ortho-k) practitioners. Guidelines have since been developed and disseminated to improve their understanding and implementation of antibiotic prescriptions. This study aimed to investigate the influence of these guidelines on the knowledge, attitude, and prescribing habits of ortho-k practitioners by means of a questionnaire, which was administered nationwide via an official online account to eye care practitioners (ECPs) involved in ortho-k lens fitting, 548 of whom completed the survey. Differences in characteristics before and after the dissemination of the guidelines and between the groups were explored using χ Orthokeratology (ortho-k) employs specially designed rigid gas-permeable contact lenses, worn overnight to correct myopic refractive error during the day through temporary molding of the cornea . The mecIn the last decade, ortho-k has become the most accessible and popular myopia control modality in China, with over 1.5 million users in 2016 . The numThe safety of overnight contact lens therapy is an important concern for ECPs, especially when this treatment targets children and juveniles. As overnight ortho-k is associated with reduced tear exchange and oxygen tension at the ocular surface, it is suggested that microorganisms build up during sleep and increase the likelihood of microbial keratitis (MK) . AlthougA recent survey used a questionnaire to explore the antibiotic (eye drops) prescribing habits of ECPs who fit ortho-k contact lenses in Mainland China. The results indicated that the misuse or improper use of antibiotic eye drops is common among ECPs . TherefoAs these guidelines were promulgated for six months, the purpose of this study was to investigate their effect on knowledge, attitude, and behavioral change in antibiotic use among ortho-k ECPs in China. Further issues identified from this survey may provide insights into a more efficient means of practitioner education, not only for ECPs, but also for other medical practitioners.Over 4000 subscribers of the IAOA official online account received the invitation to complete the questionnaire. A total of548 recipients completed and returned the questionnaire. The respondents were composed of ophthalmologists (20.9%), optometrists (65.5%), and others (13.6%). The details of the respondents are shown in p < 0.001) . A. Ap < 0.< 0.001) B [11]. Ap < 0.001). Additionally, for the question “avoid dispensing antibiotic eye drops to patients for emergency use ”, 75.3% of the respondents who used antibiotics properly “agreed” or “strongly agreed” with this statement, compared to 46.4% of their counterparts (p < 0.001).A total of 215 of the respondents (39.2%) used antibiotic eye drops properly in all three aspects surveyed. Their overall knowledge of antibiotic use was significantly better than their counterparts who misused antibiotics in at least one of the behavior-related questions. For example, for the question “antibiotic eye drops may be used prophylactically before or after commencement of ortho-k treatment to prevent corneal infection”, 90.6% of the respondents who used antibiotics properly “disagreed” or “strongly disagreed” with this statement, compared to 75.7% of their counterparts  of the respondents “agreed” or “strongly agreed” that the article and the guidelines were useful. A total of 99.1% of all the respondents “agreed” or “strongly agreed” that they were more careful when considering the use of antibiotics in ortho-k treatment after reading the guidelines. For the question “in what aspects did the article and the guidelines change my practice”, the greatest change in behavior was “in the treatment of corneal epithelium defects after ortho-k treatment” (43.4%), and the least change was “in wetting the fluorescein strip using antibiotic eye drops during ortho-k lens fitting” (26.8%) .p < 0.001).The most common misuse of antibiotic eye drops by the patients was “applying eye drops irregularly (period of use or frequency)” (49.8%), followed by “using when not indicated ” (24.6%) and “contaminating eye drops via contact of the bottle tip with the eyelashes” (11.9%) . The resp < 0.05). Compared to younger respondents (<25 years), older ECPs appeared to be more likely to use antibiotics correctly. Younger respondents (<25 years) were more likely to wet the fluorescein strip with antibiotic eye drops and to dispense antibiotics to patients for emergency use without giving clear written instructions (both p < 0.05). Compared to other clinical settings, ECPs in the distributor fitting centers were more likely to use antibiotics improperly, including wetting the fluorescein strip with antibiotic eye drops and dispensing antibiotics to patients for emergency use without giving clear written instructions (both p < 0.05). However, they were less likely to use antibiotics prophylactically before or after the commencement of ortho-k treatment (p < 0.05).Overall, occupation, age, and clinical setting all significantly affected the likelihood of respondents’ using antibiotics correctly . SignifiThis study found that, compared to the previous survey, before the development and dissemination of guidelines on the use of antibiotic eye drops, the overall behavior of the respondents had improved significantly since the implementation of the guidelines six months earlier, although the prescribing habits of some ECPs required further improvement.The greatest change occurred in the prophylactic use of antibiotics before or after ortho-k treatment, as evidenced by a higher proportion (84.5%) of respondents not using antibiotics prophylactically, as compared to the previous survey (67.6%), and also by a decreased number of antibiotic prescriptions in the preceding six months. The most common reasons for using prophylactic antibiotics among ECPs, as reflected by the current survey were: 1. to prevent infection in case of corneal injury during the early phase of ortho-k lens wear; 2. to reduce the discomfort of ortho-k lens wear; 3. to reduce ocular discharge during the early adaptation period of ortho-k; 4. to prevent infection in all sorts of contact lens wear. Since the eyes of healthy young ortho-k patients do not usually carry a heavy burden of microorganisms, there is no evidence that antibiotic eye drops can prevent contact lens-related MK. Notably, ortho-k-induced MK typically occurs five to 15 months after the commencement of lens wear , and is Surprisingly, the implementation of the guidelines barely had any effect on the ECPs’ habits of prescribing antibiotics to ortho-k patients for use at their own discretion during emergencies. A total of 36.1% of the respondents did not give clear written instructions when dispensing antibiotics to patients. The respondent’s occupation , the ECP’s age (most frequent in those <25 years), and clinical setting (most frequent in distributor fitting centers) were identified as risk factors for this behavior. The most common reasons include: 1. patients live far away or overseas, and it is inconvenient to come to the clinic during an emergency; 2. patients have a heavy academic burden and are not compliant with routine follow-up visits; 3. patients may suffer seasonal allergic conjunctivitis and may need antibiotics “just in case”; 4. patients ask for antibiotics. It is evidenced by our study that the most common misuse of antibiotics among ortho-k patients is to use them irregularly  (49.8%) and to use them when not indicated  (24.6%). While it can be argued that medical resources are unevenly distributed across different regions in China and that patients may not have access to their ECP during an emergency, it is doubtful that dispensing antibiotics to patients is justified or ethical. An emergency contact number should be provided to patients along with clear instructions as to when to call . For patOne of the disturbing behaviors that still needs urgent attention is the use of antibiotic eye drops to wet fluorescein strips during ortho-k lens fitting. It is worrisome that no change has been observed in the proportion of ECPs conducting this practice since the administration of the guidelines, although significantly fewer respondents reported that they “always” or “often” use antibiotic eye drops to wet fluorescein strips (9.0%), as compared to the previous survey (27.7%). In concordance with this finding is that the fewest respondents reported a change in this behavior when responding to the question “In what aspects did the article and the guidelines change your practice”. The respondent’s occupation , the ECP’s age (most frequent in <25 years) and clinical setting (most frequent in distributor fitting centers) were the risk factors identified for this behavior. The most common reasons for this behavior are that: 1. antibiotic eye drops are easily accessible in the clinic; 2. no other solutions, such as saline solutions, are available in the clinic; 3. antibiotic eye drops may decrease the irritation and prevent infection during ortho-k lens fitting. These results indicated that the clinical setting plays a major role in the regulation of antibiotic use in ortho-k lens fitting. Hospitals and clinics should restrict the use of antibiotics, provide ortho-k ECPs with antibiotic stewardship programs , and, most importantly, provide non-preserved saline solution instead of antibiotic eye drops to wet fluorescein strips during ortho-k lens fitting. Trial lens disinfection should also be emphasized in clinical settings to address ECPs’ concerns about cross-infection among ortho-k patients.Generally, the overall attitude towards proper antibiotic use was positive. Therefore, the misuse of antibiotics by some respondents cannot be solely attributable to their indifference to the guidelines. The guidelines have been distributed on various online platforms and read by ECPs over 5000 times. Since the correlation between knowledge and behavior was found to be strong in this study, we are tempted to conclude that the efficiency of education mainly through online social media was insufficient. Reinforcement of guidelines in off-line conferences and continuing education programs are also suggested. Interestingly, it was noted that the respondents who used antibiotics properly reported fewer of their patients misusing antibiotics than the ECPs who did not. This finding indicated that ECPs’ knowledge about antibiotics might impact their behavior, which in turn influences their patients’ compliance with antibiotic use.One important issue identified in the current study that needs urgent attention is that the overall antibiotic misuse is most common among professionals other than ophthalmologists and optometrists, i.e., nurses and opticians. They are less likely to receive full-term medical training or optometric education, not to mention fitting specialty contact lenses such as ortho-k. Therefore, not only should the guidelines on antibiotic use be delivered to them in a timely manner, but regulations should also be reinforced to limit their prescription of this specialized therapy.One of the limitations of this study was that the two surveys were not conducted on the same cohort, since the first one was performed anonymously . TherefoDo you prescribe prophylactic antibiotic eye drops before or after fitting ortho-k?Do you dispense antibiotic eye drops to patients for emergency use (at patients’ discretion)?Do you use antibiotic eye drops to wet fluorescein strips during ortho-k lens fitting?A questionnaire see , comprisDo not use prophylactic antibiotic eye drops before or after fitting ortho-k lenses;Do not dispense antibiotic eye drops to patients for emergency use ;Do not use antibiotic eye drops to wet fluorescein strips during ortho-k lens fitting.To further determine which group of ECPs was more likely to misuse or overuse antibiotics, and whether the circulated guidelines had had any effect on the habitual use of antibiotics by ECPs, options for the above-mentioned questions were categorized based on the definitions of proper use of antibiotics below:The questionnaires were distributed through the official online account of the International Academy of Orthokeratology Asia (IAOA), which has over 4000 members listed as ortho-k practitioners throughout China. The survey was conducted over June and July 2020. The inclusion criteria comprised ECPs, including ophthalmologists, optometrists, and other professionals, such as nurses and opticians, who had been involved in ortho-k lens fitting and patient care. 2 tests. Using the definition of proper antibiotic use, ECPs were further divided into groups, and the differences between the groups were tested using χ2 tests for categorical variables. Stepwise logistic regression models were used to assess the relationship between prescribing habits and demographics. Two-sided values of p < 0.05 were deemed statistically significant. All statistical analyses were performed using software R (version 4.0.5).Data concerning prescribing habits (16 questions) and demographics of the ECPs (five questions) were expressed as percentages. Data of the three key prescribing habits were compared to those of the previous study using χThe current study revealed that the overall behavior of the ortho-k ECPs significantly improved after the nationwide implementation of guidelines on antibiotic use, although some ECPs’ prescribing habits require further improvement. Since the ECPs’ behavior was significantly affected by their knowledge, the effective delivery of education is the key to success: it should not only be delivered online, but also off-line to enhance its efficacy. Clinical settings, such as hospitals and clinics, can also play an important role by providing ECPs with non-preserved saline solution to replace antibiotic eye drops in ortho-k lens fitting, and by introducing an antibiotic stewardship program, especially for younger ECPs. Rigorous clinical governance measures, particularly at the distributor fitting centers, are strongly recommended with regard to ortho-k practice and antibiotic use.


In the acute care setting, urinary tract infections (UTIs) may be over diagnosed in up to 40% of cases. In most scenarios, asymptomatic bacteriuria (ASB) is not an indication for antibiotic therapy; inappropriate therapy is associated with a higher incidence of antibiotic-resistant bacteria and adverse drug reactions. Limiting inappropriate collection of urine cultures may decrease unnecessary treatment of ASB. The objective of this study is to assess the impact of a urine culture best practice advisory (BPA) on collection of unnecessary urine cultures. This retrospective, observational, single-center study included adult inpatients with an order for urinalysis/urine culture. Those who were pregnant, had a concomitant infection other than UTI and/or were taking antimicrobials for a non-UTI indication, and were undergoing urological procedures were excluded. Duplicate urine culture collections and/or admissions were excluded. Incorporation of a BPA into computerized provider order entry, allowing providers to assess need and document indication for urine culture collection, was implemented on July 2019. The following clinical outcomes were assessed: number of unnecessary urine cultures collected, number of antibiotic treatments, and antibiotic-associated adverse reactions. Two hundred met criteria for inclusion; 96 in the pre-BPA group (Aug – Oct 2018) and 104 in the post-BPA group (Aug – Oct 2019). Seventy-four (37%) were male and the mean age was 64 and 70 years (p=0.249), respectively. The Charlson Comorbidity Index (CCI) was similar between groups  and majority were admitted to a general medical ward (94.5%). Seventy patients (72.9%) in the pre-BPA group and 47 (51.6%) in the post-BPA group had inappropriately ordered urinalysis/urine cultures . Of these patients, 15 (21.4%) and 9 (19.1%) from the pre- and post-BPA groups, respectively, were treated (p=0.077). Among those treated, only two adverse drug reactions were reported. Implementation of a BPA significantly reduced the number of inappropriate urinalysis/urine culture orders. There was a trend towards decreased antibiotic use for ASB. Future studies are warranted to assess sustainability of these results. All Authors: No reported disclosures