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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 Prolonged infusion (extended [EI, 2–4 h] or continuous [CI, 24 h] extended) of beta-lactam antibiotics is considered to have advantages for patients with severe infection compared with intermittent bolus (IB). However, the choice of EI and CI is unclear due to the lack of direct comparison. We aimed to compare the EI and CI of beta-lactams in patients with severe infections using a network meta-analysis method. Methods We systematically searched PubMed, Embase, Web of Science, Cochrane Library, CNKI, Wanfang Database, and Weipu Database for randomized controlled trials (RCTs) comparing EI, CI, or IB with beta-lactams in adults with severe infections. The primary outcome was all-cause mortality. A frequentist network meta-analysis with a random-effects model was performed. Risk of bias was assessed using the Cochrane RoB 2 tool. Findings Thirty-five RCTs (10,627 patients) were included. Risk of bias was moderate to high in most studies. For mortality, EI ranked highest (SUCRA 74.20%) with numerically lower rates versus IB (EI: OR 0.80, 95% CI 0.55–1.17; CI: OR 0.86, 95% CI 0.62–1.02). Both EI and CI significantly improved clinical cure rates versus IB (EI: OR 1.58, 95% CI 1.13–2.23; CI: OR 1.35, 95% CI 1.05–1.85), and EI ranked first (SUCRA 87.72%). For microbiological success, CI ranked highest (SUCRA 83.03%), followed by EI (SUCRA 42.98%) and IB (SUCRA 23.99%), but no significant difference was found. For hospital stay, EI was associated with a reduction of borderline statistical significance (MD -3.49 days, 95% CI -6.79 – -0.08), whereas CI did not show a significant reduction (MD 1.11 days, 95% CI -1.24 – 3.63), and EI ranked best (SUCRA 98.09%). No significant adverse event differences were observed. Subgroup analyses showed variable treatment rankings across categories, with no statistically significant subgroup effects. Conclusion In patients with severe infections, both EI and CI improved clinical cure versus IB, whereas mortality did not differ significantly. Indirect evidence suggests EI may be more effective than CI in most outcomes except microbiological response. EI trended to shorten hospital stay but the difference was of borderline significance. Considering its practical feasibility, EI appears to be a favorable option based on current evidence. However, this finding is based on indirect evidence and requires confirmation in head-to-head trials. Registration PROSPERO CRD420251242437

Background Enzymatic degradation mediated by beta-lactamases constitutes one of the primary mechanisms of resistance to beta-lactam antibiotics in gram-negative bacteria. This enzyme family comprises four molecular classes, categorized into serine beta-lactamases (Classes A, C, and D) and zinc-dependent metallo-beta-lactamases (Class B). Gram-negative bacteria producing beta-lactamase are of significant concern, particularly due to their prevalence in nosocomial infections. A comprehensive understanding of the evolution and dissemination of this enzyme family is essential for effective control of these pathogens. In this study, we conducted the prospecting, phylogenetic analysis, and in silico analysis of beta-lactamases and homologous proteins identified in 1827 bacterial genomes with phenotypic data on beta-lactam resistance. These genomes were distributed among Klebsiella pneumoniae (45%), Acinetobacter baumannii (31%), Pseudomonas aeruginosa (14%), Escherichia coli (6%), and Enterobacter spp. (4%). Using an HMM profile and searching for conserved domains, we mined 2514, 8733, 5424, and 2957 proteins for molecular classes A, B, C, and D, respectively. This set of proteins encompasses canonical subfamilies of beta-lactamases as well as hypothetical proteins and other functional groups. Canonical beta-lactamases were found to be phylogenetically distant from hypothetical proteins, which, in turn, are closer to other representatives of the penicillin-binding-protein (PBP-like) and metallo-beta-lactamase (MBL) families. The catalytic amino acid residues characteristic of beta-lactamases were identified from the sequence alignment and revealed that motifs are less conserved in homologous groups than in beta-lactamases. After comparing the frequency of protein groups in genomes of resistant strains with those of sensitive ones applying Fisher’s exact test and relative risk, it was observed that some groups of homologous proteins to classes B and C are more common in the genomes of resistant strains, particularly to carbapenems. We identified the beta-lactamase-like domain widely distributed in gram-negative species of the ESKAPEE group, which highlights its importance in the context of beta-lactam resistance. Some hypothetical homologous proteins have been shown to potentially possess promiscuous activity against beta-lactam antibiotics, however, they do not appear to expressly determine the resistance phenotype. The selective pressure due to the widespread use of antibiotics may favor the optimization of these functions for specialized resistance enzymes.

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.

Antimicrobial resistance is a growing global concern that compromises the efficacy of antibiotics, particularly due to the misuse and overuse of these agents. Beta-lactam antibiotics, widely used for their broad-spectrum activity, are increasingly threatened by bacterial resistance mechanisms. Recent studies showed that resistant Gram-negative bacteria cause many hospital infections, which makes the search for new treatments very urgent. This review explores recent advancements in the development of novel beta-lactam antibiotics, including new drug combinations and structural modifications designed to overcome beta-lactamase degradation and effectively target mutated penicillin-binding proteins (PBPs). One of the main resistance mechanisms in Gram-negative bacteria is the production of beta-lactamases, which break the beta-lactam ring and stop the drug from working. New ideas include adding more than one beta-lactam ring in the drug, combining with strong beta-lactamase inhibitors, and making hybrid structures. These strategies have shown promising results in preclinical evaluations. Novel beta-lactam antibiotics demonstrate significant potential in combating resistant bacterial strains. Future directions should emphasize large-scale in vivo validation, the incorporation of novel β-lactamase inhibitors, and the development of advanced drug delivery systems. Integration of these strategies may enhance the clinical applicability of β-lactams and provide sustainable solutions to address the global burden of antimicrobial resistance.

Background Standard dosing regimens of meropenem and piperacillin-tazobactam frequently fail to achieve targeted plasma concentrations in critically ill patients. Extended or continuous regimens are often used to improve target attainment. Although prompt antibiotic initiation is a major determinant of survival, few studies have reported systemic concentrations early after treatment initiation. No prior study has reported concentrations immediately after the loading dose and first extended infusion. This study aimed to evaluate plasma target attainment during the first dosing interval with an extended infusion regimen in a general intensive care unit (ICU). Methods Adult ICU patients were prospectively included in conjunction with the first administration of meropenem or piperacillin-tazobactam. Treatment was initiated with a 0.5 h loading dose immediately followed by a 3 h extended infusion; typically 4 + 4 g piperacillin or 1(− 2)g + 1(− 2)g meropenem, in line with the local ICU protocol. Patients requiring renal replacement therapy were excluded. Plasma concentrations were measured post-loading dose (C max ), near the end of the first extended infusion, and at the end of the first dosing interval (C min ). Samples were analyzed using validated tandem mass spectrometry (UHPLC-MS/MS) methods. The primary endpoint was the proportion of patients achieving 100% time above minimum inhibitory concentrations ( f T > MIC) during the first dosing interval. This was evaluated using observed C min above 2 mg/L (meropenem) and 20 mg/L (piperacillin). Additionally, published pharmacokinetic models were applied to the observed data for %fT > MIC estimation, using an a posteriori Bayesian approach. Results We included 65 meropenem and 142 piperacillin measurements from 22 and 48 patients, respectively. Many patients (45% meropenem, 38% piperacillin) failed to reach 100% f T > MIC with the standard regimens used. Target non-attainment was associated with high estimated glomerular filtration rates (eGFR) and suspected augmented renal clearance (ARC). All meropenem patients that failed to reach target had eGFR > 90 mL/min/1.73 m 2 , as did 76% of corresponding piperacillin patients. Patients with suspected ARC frequently exhibited a tenfold or greater peak-to-trough decline (C min /C max  < 0.1). Conclusions Despite aggressive dosing, plasma concentrations often fail to reach 100% f T > MIC during the first dosing interval. Alternative regimens and early plasma concentration measurements followed by adaptive dose adjustments should be considered to improve target attainment.

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.

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.