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PurposeIndividualising drug dosing using model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin has been proposed as an alternative to standard dosing to optimise antibiotic efficacy in critically ill patients. However, randomised clinical trials (RCT) on clinical outcomes have been lacking.MethodsThis multicentre RCT, including patients admitted to the intensive care unit (ICU) who were treated with antibiotics, was conducted in eight hospitals in the Netherlands. Patients were randomised to MIPD with dose and interval adjustments based on monitoring serum drug levels (therapeutic drug monitoring) combined with pharmacometric modelling of beta-lactam antibiotics and ciprofloxacin. The primary outcome was ICU length of stay (LOS). Secondary outcomes were ICU mortality, hospital mortality, 28-day mortality, 6-month mortality, delta sequential organ failure assessment (SOFA) score, adverse events and target attainment.ResultsIn total, 388 (MIPD n = 189; standard dosing n = 199) patients were analysed (median age 64 [IQR 55–71]). We found no significant differences in ICU LOS between MIPD compared to standard dosing (10 MIPD vs 8 standard dosing; IRR = 1.16; 95% CI 0.96–1.41; p = 0.13). There was no significant difference in target attainment before intervention at day 1 (T1) (55.6% MIPD vs 60.9% standard dosing; p = 0.24) or at day 3 (T3) (59.5% vs 60.4%; p = 0.84). There were no significant differences in other secondary outcomes.ConclusionsWe could not show a beneficial effect of MIPD of beta-lactam antibiotics and ciprofloxacin on ICU LOS in critically ill patients. Our data highlight the need to identify other approaches to dose optimisation.

In this Review, we explore natural product antibiotics that do more than simply inhibit an active site of an essential enzyme. We review these compounds to provide inspiration for the design of much-needed new antibacterial agents, and examine the complex mechanisms that have evolved to effectively target bacteria, including covalent binders, inhibitors of resistance, compounds that utilize self-promoted entry, those that evade resistance, prodrugs, target corrupters, inhibitors of ‘undruggable’ targets, compounds that form supramolecular complexes, and selective membrane-acting agents. These are exemplified by β-lactams that bind covalently to inhibit transpeptidases and β-lactamases, siderophore chimeras that hijack import mechanisms to smuggle antibiotics into the cell, compounds that are activated by bacterial enzymes to produce reactive molecules, and antibiotics such as aminoglycosides that corrupt, rather than merely inhibit, their targets. Some of these mechanisms are highly sophisticated, such as the preformed β-strands of darobactins that target the undruggable β-barrel chaperone BamA, or teixobactin, which binds to a precursor of peptidoglycan and then forms a supramolecular structure that damages the membrane, impeding the emergence of resistance. Many of the compounds exhibit more than one notable feature, such as resistance evasion and target corruption. Understanding the surprising complexity of the best antimicrobial compounds provides a roadmap for developing novel compounds to address the antimicrobial resistance crisis by mining for new natural products and inspiring us to design similarly sophisticated antibiotics. This Review examines the diverse strategies utilized by naturally occurring antibiotics and suggests how they have provided, and will in future provide, inspiration for the design of novel antibiotics.

Background Acute kidney injury is a common complication in critically ill patients, often coinciding with the need for antibiotic therapy. The dose of beta-lactam antibiotics is frequently adjusted and often reduced based on estimated Glomerular Filtration Rate. However, early dose reductions may lead to underdosing, especially during the critical first 48 h of infection treatment, when acute kidney injury may be transient and adequate antibiotic treatment is critical. While some reviews suggest delaying dose reductions improves clinical outcomes, evidence remains limited. This scoping review evaluates the current literature on beta-lactam dosing strategies in critically ill patients with acute kidney injury, focusing on pharmacological and clinical outcomes. Methods We conducted a systematic scoping review following PRISMA-ScR guidelines. We searched Medline, Embase, Web of Science, Cochrane CENTRAL, and Google Scholar from database inception through March 24, 2025. Two reviewers independently screened all articles and assessed study quality using ROB-2 and ROBINS-E tools. Eligible studies included critically ill adult patients with acute kidney injury, receiving beta-lactams, and reporting clinical or pharmacological outcomes. Data were extracted using a standardized template and categorized by pharmacological or clinical outcomes. Further stratification by antibiotic type or patient characteristics was not feasible. Results Out of the 1,436 screened articles, 11 studies involving 1,407 patients were included. The risk of bias was high in most studies. Most studies were observational; one was a randomized controlled trial. Seven studies reported beta-lactam plasma concentrations. Higher concentrations were generally observed in patients with acute kidney injury, even though dosages were oftentimes already reduced. One study associated early dose reductions with lower rates of neurotoxicity. One study reported higher rates of treatment failure with early dose reductions and three studies linked delayed dose reductions to reduced mortality. Conclusions Current evidence on beta-lactam dose reduction in critically ill patients with acute kidney injury is limited and of low quality. Delaying reductions may improve clinical outcomes, but further prospective studies are urgently needed. Trial registration The protocol for this scoping review was not prospectively registered.

Purpose Antibiotic de-escalation is promoted to limit prolonged exposure to broad-spectrum antibiotics, but proof that it prevents the emergence of resistance is lacking. We evaluated determinants of antibiotic de-escalation in an attempt to assess whether the latter is associated with a lower emergence of antimicrobial resistance. Methods Antibiotic treatments, starting with empirical beta-lactam prescriptions, were prospectively documented during 2013 and 2014 in a tertiary intensive care unit (ICU) and categorized as continuation, de-escalation or escalation of the empirical antimicrobial treatment. Determinants of the de-escalation or escalation treatments were identified by multivariate logistic regression; the continuation category was used as the reference group. Using systematically collected diagnostic and surveillance cultures, we estimated the cumulative incidence of antimicrobial resistance following de-escalation or continuation of therapy, with adjustment for ICU discharge and death as competing risks. Results Of 478 anti-pseudomonal antibiotic prescriptions, 42 (9 %) were classified as escalation of the antimicrobial treatment and 121 (25 %) were classified as de-escalation, mainly through replacement of the originally prescribed antibiotics with those having a narrower spectrum. In multivariate analysis, de-escalation was associated with the identification of etiologic pathogens ( p  < 0.001). The duration of the antibiotic course in the ICU in de-escalated versus continued prescriptions was 8 (range 6–10) versus 5 (range 4–7) days, respectively ( p  < 0.001). Mortality did not differ between patients in the de-escalation and continuation categories. The cumulative incidence estimates of the emergence of resistance to the initial beta-lactam antibiotic on day 14 were 30.6 and 23.5 % for de-escalation and continuation, respectively ( p  = 0.22). For the selection of multi-drug resistant pathogens, these values were 23.5 (de-escalation) and 18.6 % (continuation) respectively ( p  = 0.35). Conclusion The emergence of antibiotic-resistant bacteria after exposure to anti-pseudomonal beta-lactam antibiotics was not lower following de-escalation.

Background The role of antibiotics in the treatment of chronic obstructive pulmonary disease (COPD) exacerbations and their effectiveness in combination have not been clearly established. To determine whether using a combination of fluoroquinolones and beta-lactams improves the clinical and microbiological efficacy of antibiotics on day 20 of treatment, we conducted an open-label randomized trial based on clinical outcomes, microbiological clearance, spirometry tests, and signs of systemic inflammation in patients hospitalized with acute exacerbations of COPD. Methods We enrolled 139 subjects with COPD exacerbations, defined as acute worsening of respiratory symptoms leading to additional treatment. Patients were divided randomly into two groups: 79 patients using beta-lactam antibiotics alone and 60 using beta-lactam antibiotics plus fluoroquinolones. Clinical and microbiological responses, spirometry tests, symptom scores, and serum C-reactive protein (CRP) levels were evaluated. Results Clinical success, lung function, and symptoms were similar in patients with or without fluoroquinolone administration on days 10 and 20. Combination therapy was superior in terms of microbiological outcomes and reduction in serum CRP value. Although equivalent to monotherapy in terms of clinical success, the combination showed superiority in terms of microbiological success and a decrease in CRP. The combination therapy group had a higher microbiological success rate with gram-negative bacteria than the monotherapy group with Pseudomonas aeruginosa (100% vs. 33.3%, respectively) and Acinetobacter baumanii (100% vs. 20%, respectively) ( P  < 0.05). Conclusions Concomitant use of fluoroquinolone and beta-lactam antibiotics for bacterial infections during COPD exacerbations caused by gram-negative bacteria appear to be effective and should be applied in clinical practice.

Background The global spread of extended‐spectrum beta‐lactamase (ESBL)‐producing and carbapenem‐resistant Enterobacterales (CRE) poses a significant concern. Acquisition of antimicrobial resistance genes leads to resistance against several antibiotics, limiting treatment options. We aimed to study ESBL‐producing and CRE transmission in clinical settings. Methods From clinical samples, 227 ESBL‐producing and CRE isolates were obtained. The isolates were cultured on bacterial media and confirmed by VITEK 2. Antibiograms were tested against several antibiotics using VITEK 2. The acquired resistance genes were identified by PCR. Results Of the 227 clinical isolates, 145 (63.8%) were Klebsiella pneumoniae and 82 (36.1%) were Escherichia coli; 76 (33.4%) isolates were detected in urine, 57 (25.1%) in pus swabs, and 53 (23.3%) in blood samples. A total of 58 (70.7%) ESBL‐producing E. coli were resistant to beta‐lactams, except for carbapenems, and 17.2% were amikacin‐resistant; 29.2% of E. coli isolates were resistant to carbapenems. A total of 106 (73.1%) ESBL‐producing K. pneumoniae were resistant to all beta‐lactams, except for carbapenems, and 66.9% to ciprofloxacin; 38 (26.2%) K. pneumoniae were resistant to carbapenems. Colistin emerged as the most effective antibiotic against both bacterial types. Twelve (20.6%) E. coli isolates were positive for blaCTX‐M, 11 (18.9%) for blaTEM, and 8 (33.3%) for blaNDM. Forty‐six (52.3%) K. pneumoniae isolates had blaCTX‐M, 27 (18.6%) blaTEM, and 26 (68.4%) blaNDM. Conclusion This study found a high prevalence of drug‐resistant ESBL‐producing and CRE, highlighting the need for targeted antibiotic use to combat resistance. This study investigates the transmission of extended‐spectrum beta‐lactamase‐producing and carbapenem‐resistant Klebsiella pneumoniae and Escherichia coli. Widespread resistance among these pathogens underscores the need for a comprehensive analysis of antibiotic resistance patterns to mitigate resistance effectively.

The surge in antimicrobial resistance and the limited availability of new antimicrobial drugs has fueled the interest in optimizing antibiotic dosing. An ideal dosing regimen leads to maximal bacterial cell kill, whilst minimizing the risk of toxicity or antimicrobial resistance. For beta-lactam antibiotics specifically, PK/PD-based considerations have led to the widespread adoption of prolonged infusion. The rationale behind prolonged infusion is increasing the percentage of time the beta-lactam antibiotic concentration remains above the minimal inhibitory concentration (%fT>MIC). The ultimate goal of prolonged infusion of beta-lactam antibiotics is to improve the outcome of infectious diseases. However, merely increasing target attainment (or the %fT>MIC) is unlikely to lead to improved clinical outcome for several reasons. First, the PK/PD index and target are dynamic entities. Changing the PK (as is the case if prolonged instead of intermittent infusion is used) will result in different PK/PD targets and even PK/PD indices necessary to obtain the same level of bacterial cell kill. Second, the minimal inhibitory concentration is not a good denominator to describe either the emergence of resistance or toxicity. Therefore, we believe a different approach to antibiotic dosing is necessary. In this perspective, we introduce the concept of the maximum tolerable dose (MTD). This MTD is the highest dose of an antimicrobial drug deemed safe for the patient. The goal of the MTD is to maximize bacterial cell kill and minimize the risk of antimicrobial resistance and toxicity. Unfortunately, data about what beta-lactam antibiotic levels are associated with toxicity and how beta-lactam antibiotic toxicity should be measured are limited. This perspective is, therefore, a plea to invest in research aimed at deciphering the dose–response relationship between beta-lactam antibiotic drug concentrations and toxicity. In this regard, we provide a theoretical approach of how increasing uremic toxin concentrations could be used as a quantifiable marker of beta-lactam antibiotic toxicity.

Beta-lactam antibiotics have been a major climacteric in medicine for being the first bactericidal compound available for clinical use. They have continually been prescribed since their development in the 1940s, and their application has saved an immeasurable number of lives. With such immense use, the rise in antibiotic resistance has truncated the clinical efficacy of these compounds. Nevertheless, the synergism of combinational antibiotic therapy has allowed these drugs to burgeon once again. Here, the development of meropenem with vaborbactam—a recently FDA-approved beta-lactam combinational therapy—is reviewed in terms of structure rationale, activity gamut, pharmacodynamic/pharmacokinetic properties, and toxicity to provide insight into the future development of analogous therapies.

Streptococcus agalactiae is an important pathogen for tilapia meningitis. Most of the infected tilapia die rapidly in production, when the way to study the pathogenic mechanism of bacteria on host through chronic infection in laboratory is not comprehensive and accurate enough to elucidate the real pathogenic mechanism. The objective of this study was to investigate the mechanism of acute bacterial meningitis of tilapia caused by Streptococcus agalactiae (GBS), and provide a theoretical basis for its prevention and treatment. Duel RNA-seq, proteome analysis, histopathological analysis, plasma biochemical indexes, and blood routine examination were performed on tilapias infected with fish-derived GBS attenuated strain YM001 and its parental virulent strain HN016. The results showed that the contents of white blood cell (WBC), monocytes (MON), and neutrophil (NEU) were significantly lower in the HN016 group compared to that in the YM001 group (p < 0.05). Histopathological examination showed that there were partially lesions in the examined tissues of tilapia infected by HN016, while no obvious histopathological changes occurred in the YM001 group. The differential expressed genes (DEGs) and differential expressed proteins (DEPs) between YM001 and HN016 were mainly enriched in the beta-lactam resistance pathway (oppA1, oppA2, oppB, oppC, oppD, oppF, and mrcA). The DEGs DEPs between YM001-brain and HN016-brain were mainly enriched in the complement and coagulation cascades signaling pathway (C2a, c4b, c3b, c7, CD59, ITGB2, and ITGAX). The present study indicates that the interaction between phagocytes and GBS mediated by the activated complement system is the key to GBS inducing tilapia acute bacterial meningitis. The low survival ability caused by reduced β-lactam antibiotics resistance is one of the important reasons for why YM001 lost its pathogenicity to tilapia.

Background Acute generalized exanthematous pustulosis (AGEP) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions. These rare conditions differ in clinical presentation, pathological features, treatment and prognosis, but overlap has been described implying a challenging clinical management. Case presentation We describe a case of overlap between TEN and AGEP probably secondary to beta-lactams in a 77-year-old patient treated for a complicated cholangitis. We review the diagnosis and the management of these two conditions. The diagnosis of TEN was suggested by the initial clinical presentation with severe hemodynamic instability, skin detachment, positive Nikolsky sign and mucosal involvement. However, the skin biopsy as well as the rapid improvement of the skin lesions were discriminative for AGEP. This indicated an overlap presentation. Unfortunately, the patient refused allergy investigations in order to find the culprit drug. Medical photographs, proper physical examination and histopathological results are integrated. Conclusion Despite clinical features indicating a diagnosis of TEN, histopathology was conclusive for AGEP thus indicating a possible clinical-pathological overlap between the two conditions, a scarcely described situation in the medical literature. To our knowledge, this is one of the few cases that portrays a TEN–AGEP overlap probably secondary to Piperacillin Tazobactam. Understanding the immunological implications of these conditions can help us better distinguish and manage these severe reactions.