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The article presents a case study of a 6-year-old girl experiencing recurrent Kawasaki disease (KD) accompanied by Kawasaki disease shock syndrome (KDSS). Topics discussed include the challenges in diagnosing KDSS, the elevated inflammatory markers indicating severity, and the management strategies implemented, including the use of intravenous immunoglobulin (IVIG) and antiplatelet therapy.

Background The treatment of carbapenem-resistant Acinetobacter baumannii / calcoaceticus complex (CRAB) presents significant treatment challenges. Methods We report the case of a 42-year-old woman with CRAB meningitis who experienced persistently positive cerebrospinal fluid (CSF) cultures for 13 days despite treatment with high-dose ampicillin-sulbactam and cefiderocol. On day 13, she was transitioned to sulbactam-durlobactam and meropenem; 4 subsequent CSF cultures remained negative. After 14 days of sulbactam-durlobactam, she was cured of infection. Whole genome sequencing investigations identified putative mechanisms that contributed to the reduced cefiderocol susceptibility observed during cefiderocol therapy. Blood and CSF samples were collected pre-dose and 3-hours post initiation of a sulbactam-durlobactam infusion. Results The CRAB isolate belonged to sequence type 2. An acquired bla OXA-23 and an intrinsic bla OXA-51-like (ie, bla OXA-66) carbapenemase gene were identified. The paradoxical effect (ie, no growth at lower cefiderocol dilutions but growth at higher dilutions) was observed by broth microdilution after 8 days of cefiderocol exposure but not by disk diffusion. Potential markers of resistance to cefiderocol included mutations in the start codon of piuA and piuC iron transport genes and an A515V substitution in PBP3, the primary target of cefiderocol. Sulbactam and durlobactam were detected in CSF at both timepoints, indicating CSF penetration. Conclusions This case describes successful treatment of refractory CRAB meningitis with the administration of sulbactam-durlobactam and meropenem and highlights the need to be cognizant of the paradoxical effect that can be observed with broth microdilution testing of CRAB isolates with cefiderocol. [ABSTRACT FROM AUTHOR]

Objectives Pharmacodynamic parameters evaluated under conditions that simulate an infection site volume and microbial load might reveal hidden risks of resistance selection and subsequent treatment failure. The study aimed to investigate the predictive potential of MICs determined at various conditions on the antimicrobial effect and emergence of resistance. Methods We assessed meropenem MICs (microdilution: 0.2 mL, 5 × 105 cfu/mL; macrodilution: 2 mL, 5 × 105 cfu/mL), MICHVs (220 mL, 5 × 105 cfu/mL), MICHIs (0.2 mL, 5 × 107 cfu/mL) and MICHVIs (220 mL, 5 × 107 cfu/mL) for five Klebsiella pneumoniae strains and analysed these values alongside the results of experiments in a dynamic in vitro model. A clinically relevant meropenem dosing regimen was simulated and the starting bacterial inocula were 106 and 108 cfu/mL. Results The effectiveness of meropenem agreed with MICHVs for the 106 cfu/mL inoculum and with MICHIs or MICHVIs for the 108 cfu/mL inoculum. Strains characterized as resistant according to these values grew during meropenem exposure, and resistant mutants were selected. Conclusions Our results suggest that MICHV-based parameters may be suitable for predicting antibacterial effects and the risk of resistance development when the inoculum is 106 cfu/mL, while MICHI- or MICHVI-based parameters are suitable for these purposes when the inoculum is 108 cfu/mL. Also, the correlation between resistance selection and the MICHI-based parameter was as high as one that corresponds with a mutant prevention concentration (MPC)-based parameter; this suggests that the MPC can be replaced by the more easily determined alternative parameter MICHI. [ABSTRACT FROM AUTHOR]

Background Meropenem, a β-lactam antibiotic commonly prescribed for severe infections, poses dosing challenges in critically ill patients due to highly variable pharmacokinetics. Objectives We sought to develop a population pharmacokinetic model of meropenem for critically ill paediatric and young adult patients. Patients and methods Paediatric intensive care unit patients receiving meropenem 20–40 mg/kg every 8 h as a 30 min infusion were prospectively followed for clinical data collection and scavenged opportunistic plasma sampling. Nonlinear mixed effects modelling was conducted using Monolix®. Monte Carlo simulations were performed to provide dosing recommendations against susceptible pathogens (MIC ≤ 2 mg/L). Results Data from 48 patients, aged 1 month to 30 years, with 296 samples, were described using a two-compartment model with first-order elimination. Allometric body weight scaling accounted for body size differences. Creatinine clearance and percentage of fluid balance were identified as covariates on clearance and central volume of distribution, respectively. A maturation function for renal clearance was included. Monte Carlo simulations suggested that for a target of 40% f T > MIC, the most effective dosing regimen is 20 mg/kg every 8 h with a 3 h infusion. If higher PD targets are considered, only continuous infusion regimens ensure target attainment against susceptible pathogens, ranging from 60 mg/kg/day to 120 mg/kg/day. Conclusions We successfully developed a population pharmacokinetic model of meropenem using real-world data from critically ill paediatric and young adult patients with an opportunistic sampling strategy and provided dosing recommendations based on the patients' renal function and fluid status. [ABSTRACT FROM AUTHOR]

Objectives We aimed to compare the stability of the newly developed β-lactams (cefiderocol) and β-lactam/β-lactamase inhibitor combinations (ceftazidime/avibactam, ceftolozane/tazobactam, aztreonam/avibactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/nacubactam and meropenem/xeruborbactam) against the most clinically relevant mechanisms of mutational and transferable β-lactam resistance in Pseudomonas aeruginosa. Methods We screened a collection of 61 P. aeruginosa PAO1 derivatives. Eighteen isolates displayed the most relevant mechanisms of mutational resistance to β-lactams. The other 43 constructs expressed transferable β-lactamases from genes cloned in pUCP-24. MICs were determined by reference broth microdilution. Results Cefiderocol and imipenem/relebactam exhibited excellent in vitro activity against all of the mutational resistance mechanisms studied. Aztreonam/avibactam, cefepime/taniborbactam, cefepime/zidebactam, meropenem/vaborbactam, meropenem/nacubactam and meropenem/xeruborbactam proved to be more vulnerable to mutational events, especially to overexpression of efflux operons. The agents exhibiting the widest spectrum of activity against transferable β-lactamases were aztreonam/avibactam and cefepime/zidebactam, followed by cefepime/taniborbactam, cefiderocol, meropenem/xeruborbactam and meropenem/nacubactam. However, some MBLs, particularly NDM enzymes, may affect their activity. Combined production of certain enzymes (e.g. NDM-1) with increased MexAB-OprM-mediated efflux and OprD deficiency results in resistance to almost all agents tested, including last options such as aztreonam/avibactam and cefiderocol. Conclusions Cefiderocol and new β-lactam/β-lactamase inhibitor combinations show promising and complementary in vitro activity against mutational and transferable P. aeruginosa β-lactam resistance. However, the combined effects of efflux pumps, OprD deficiency and efficient β-lactamases could still result in the loss of all therapeutic options. Resistance surveillance, judicious use of new agents and continued drug development efforts are encouraged. [ABSTRACT FROM AUTHOR]

Objective To analyse the biliary pharmacokinetics/pharmacodynamics (PK/PD) of continuous infusion (CI) meropenem-vaborbactam (MEM-VBM) in a case series of orthotopic liver transplant (OLT) recipients being treated for Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) related biliary tract infections (BTIs) or as preemptive therapy of KPC-Kp rectal colonization. Methods Critical OLT recipients receiving CI MEM-VBM (2 g/2 g q8h over 8 h) because of KPC-Kp related BTIs or as preemptive therapy of KPC-Kp rectal colonization, having Kehr's tube positioned and undergoing simultaneous therapeutic drug monitoring of MEM and VBM in plasma and bile were retrospectively assessed. Bile-to-plasma ratio of free steady-state concentrations (f Css) of MEM and VBM was used for assessing biliary penetration. Optimal joint MEM-VBM PK/PD target attainment was defined as MEM f Css/MIC ratio >4 coupled with VBM free area under time–concentration curve (f AUC)/threshold concentration (CT) ratio >24. Results Overall, four critical OLT recipients were included. Median bile-to-plasma ratio was 0.32 for MEM (range 0.21–0.79) and 0.40 for VBM (range 0.20–0.77). Biliary MEM-VBM joint PK/PD target attainment was optimal in 3/4 OLT recipients and quasi-optimal in the other one. Conclusions The 1:1 proportion between MEM and VBM concentrations was maintained unchanged in the bile, allowing us to assume that the efficacy of MEM-VBM may be appropriate even in the treatment of BTIs. CI administration was an effective strategy for attaining aggressive biliary joint PK/PD targets against pathogens with an MIC up to 2 mg/L. [ABSTRACT FROM AUTHOR]

Background Antibiotic overuse leads to the emergence of antibiotic resistance that threatens immunocompromised cancer patients. Infections caused by MDR Gram-negative pathogens are difficult to treat and associated with high mortality. Hence, empirical therapy with standard-of-care (SOC) antibiotics could be suboptimal in these vulnerable patients. New antibiotics covering potential resistant pathogens may be considered. Methods We conducted a randomized non-inferiority study comparing safety and efficacy of imipenem/cilastatin/relebactam (IPM/REL), a β-lactam/β-lactamase inhibitor combination, with SOC antibiotics (cefepime, piperacillin/tazobactam or meropenem) in cancer patients with febrile neutropenia. Patients received at least 48 h of IV antibiotics and were assessed at end-of-IV (EOIV) therapy, test of cure (TOC; Days 21–28), and late follow-up (LFU; Days 35–42). Results A total of 100 patients were enrolled (49 IPM/REL and 50 SOC). Demographics and rates of documented microbiological infections were similar in both groups. In the SOC arm, 86% of antibiotics consisted of cefepime. Patients on IPM/REL had a higher favourable clinical response at EOIV than those on SOC (90% versus 74%; P  = 0.042); however, responses were similar at TOC and LFU. Microbiological eradication was comparable at all three timepoints. Study drug-related adverse events and adverse events leading to drug discontinuation were similar in both groups, with no study drug-related mortality. Conclusions Our results suggest that compared with SOC antibiotics, predominantly cefepime, IPM/REL for empirical coverage of febrile neutropenia in cancer patients is generally safe and could be associated with a better clinical outcome at EOIV. The current SOC consisting mainly of agents that do not cover for ESBL-producing and carbapenem-resistant Enterobacterales bacteria should be reconsidered. [ABSTRACT FROM AUTHOR]

Aims: Meropenem/vaborbactam combination is approved in adults by FDA and EMA for complicated urinary tract infections and by EMA also for other Gram‐negative infections. We aimed to characterise the pharmacokinetics of both moieties in an ongoing study in children and use a model‐based approach to inform adequate dosing regimens in paediatric patients. Methods: Over 4196 blood samples of meropenem and vaborbactam (n = 414 subjects) in adults, together with 114 blood samples (n = 39) in paediatric patients aged 3 months to 18 years were available for this analysis. Data were analysed using a population with prior information from a pharmacokinetic model in adults to inform parameter estimation in children. Simulations were performed to assess the suitability of different dosing regimens to achieve adequate probability of target attainment (PTA). Results: Meropenem/vaborbactam PK was described with two‐compartment models with first‐order elimination. Body weight and CLcr were significant covariates on the disposition of both drugs. A maturation function was evaluated to explore changes in clearance in neonates. PTA ≥90% was derived for children aged ≥3 months after 3.5‐h IV infusion of 40 mg/kg Q8h of both meropenem and vaborbactam and 2 g/2 g for those ≥50 kg. Extrapolation of disposition parameters suggest that adequate PTA is achieved after a 3.5‐h IV infusion of 20 mg/kg for neonates and infants (3 months). Conclusions: An integrated analysis of adult and paediatric data allowed accurate description of sparsely sampled meropenem/vaborbactam PK in paediatric patients and provided recommendations for the dosing in neonates and infants (3 months). [ABSTRACT FROM AUTHOR]

The article focuses on a 5-month-old infant with a rapidly expanding rash and fever, initially misdiagnosed as cellulitis, but later identified as a potential spider bite. Topics include her clinical presentation and progression of symptoms, the initial treatment with antibiotics, and the findings of the blackish skin lesion with expanding erythema and subsequent evaluation in the emergency department.

Context.--Carbapenem-resistant Enterobacterales are disseminated worldwide and associated with infections with high rates of morbidity and mortality. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a useful tool for identification of pathogens directly from blood cultures in clinical microbiology laboratories. Furthermore, it has been applied for the detection of carba-penemase production, by evaluating carbapenem hydrolysis. Objective.--To determine meropenem hydrolysis to detect carbapenemase production directly from positive blood cultures, using logRQ to establish a quantitative measure of hydrolysis. Design.--We evaluated 100 Enterobacterales from positive blood cultures, with 81 carrying a carbapenemase gene (blaKPC, blaGES, blaNDM-1, blaIMP, blaVIM, and blaOXA-48-like), as determined by real-time multiplex polymerase chain reaction with high-resolution melting (HRM-qPCR). Bacterial proteins extracted from positive blood culture bottles were incubated in a meropenem solution (2-4 hours) followed by centrifugation for MALDI-TOF MS analysis. The intensity of peaks of the hydrolyzed and nonhydrolyzed forms were used to calculate the logRQ value. Results.--Overall, sensitivity was 86.8% and specificity, 89.5%. Of note, sensitivity varied depending on enzyme type. For blaKPC-positive isolates, sensitivity was 97.9%, while it reduced significantly for blaNDM-1 and blaOXA-48-like isolates: 62.5% (10 of 16) and 66.7% (6 of 9), respectively. Indeed, logRQ was higher in blaKPC-positive isolates (0.371.97) than in blaNDM-1 (-1.37 to 0.83) and blaOXA-48-like isolates (-1.08 to 1.79). Conclusions.--This is an inexpensive and rapid test to identify carbapenemase activity directly from blood culture bottles, which contributes to early adequate antimicrobial therapy and implementation of infection control measures. [ABSTRACT FROM AUTHOR]

In this study, we evaluated the performance of the EUCAST RAST method on a collection of 154 clinical strains of P. aeruginosa, including strains resistant to ceftazidime and carbapenems. While the test is convenient for routine laboratories, we observed significant rates of VME (ranging from 0.0 to 15.0%) and ME (ranging from 1.3 to 16.3%) after 6 h, particularly for key antibiotics such as ceftazidime, piperacillin/tazobactam, and meropenem. Extending the incubation time to 8 h may improve results (CA ranging from 87.2 to 99%), but caution is required in interpretation due to persistence of VME (ranging from 0.0 to 15.6%) and ME (ranging from 0.0 to 11.7%). [ABSTRACT FROM AUTHOR]

Meropenem is commonly used against Pseudomonas aeruginosa. Traditionally, the time unbound antibiotic concentration exceeds the MIC (f T > MIC) is used to select carbapenem regimens. We aimed to characterize the effects of different baseline resistance mechanisms on bacterial killing and resistance emergence; evaluate whether f T > MIC can predict these effects; and, develop a novel Quantitative and Systems Pharmacology (QSP) model to describe the effects of baseline resistance mechanisms on the time-course of bacterial response. Seven isogenic P. aeruginosa strains with a range of resistance mechanisms and MICs were used in 10-day hollow-fiber infection model studies. Meropenem pharmacokinetic profiles were simulated for various regimens (t 1/2,meropenem = 1.5 h). All viable counts on drug-free, 3 × MIC, and 5 × MIC meropenem-containing agar across all strains, five regimens, and control (n = 90 profiles) were simultaneously subjected to QSP modeling. Whole genome sequencing was completed for total population samples and emergent resistant colonies at 239 h. Regimens achieving ≥98% f T >1 × MIC suppressed resistance emergence of the mexR knockout strain. Even 100% f T >5 × MIC failed to achieve this against the strain with OprD loss and the ampD and mexR double-knockout strain. Baseline resistance mechanisms affected bacterial outcomes, even for strains with the same MIC. Genomic analysis revealed that pre-existing resistant subpopulations drove resistance emergence. During meropenem exposure, mutations in mexR were selected in strains with baseline oprD mutations, and vice versa , confirming these as major mechanisms of resistance emergence. Secondary mutations occurred in lysS or argS , coding for lysyl and arginyl tRNA synthetases, respectively. The QSP model well-characterized all bacterial outcomes of the seven strains simultaneously, which f T > MIC could not. [Display omitted] [ABSTRACT FROM AUTHOR]

We aimed to assess the accuracy of BD Phoenix for determining carbapenem susceptibility because we observed a decline in carbapenem susceptibility rate from the biannual cumulative data, after we transitioned to the BD Phoenix form Vitek 2 system. Between October 2021 and May 2022, we collected 82 non-duplicated Enterobacterales showing non-susceptible to at least one of the three carbapenems by BD Phoenix. We performed the broth microdilution (BMD) and disk diffusion (DD) according to the CLSI guideline. Compared to BMD, the categorical agreements for ertapenem (ERT), imipenem (IPM) and meropenem (MEPM) was 58.8%, 56.8% and 91.5% for BD Phoenix and it was 85.4%, 89.0%, and 97.6%, respectively, for DD (p value; 0.0001 for ERT and IPM , p value; 0.17 for MEPM). The major errors/minor errors for ERT, IPM, and MEPM were 14.0%/31.7%, 2.94%/40.7%, and 2.56%/6.10%, respectively for BD Phoenix, compared to 0%/14.6%, 0%/9.8%, and 0%/2.5%, for DD. While errors in the BD Phoenix showed tendency towards resistance, those in DD displayed no tendency towards either resistance or susceptibility. With DD, 21 out of the 27 isolates showing susceptible/intermediate/susceptible pattern (ERT/IPM/MEPM) and 13 out of the 16 isolates showing intermediate/susceptible/susceptible pattern (ERT/IPM/MEPM), were correctly categorized by DD. However, for 22 isolates showing resistant/susceptible/susceptible pattern (ERT/IPM/MEPM), only 13 isolates were correctly categorized by DD. In conclusion, to mitigate the risk of overcalling carbapenem non-susceptibility with BD Phoenix, it will be helpful to perform a complementary test using DD and to provide comments on the DD results to clinicians. [ABSTRACT FROM AUTHOR]

Background: Intravascular stent infections are often associated with high risks of morbidity and mortality. We report here a case of a patient with an arterial stent and recurrent Pseudomonas septicaemias successfully treated with phage–meropenem combination therapy. Methods: A 75-year-old female with arteriosclerosis and comorbidities went through a femoropopliteal bypass with prosthesis in the right inguinal area. After the bypass, she developed a recurring Pseudomonas aeruginosa infection and also neutropenia during different antibiotics. A rapidly growing pseudoaneurysm in the right inguinal area led to an emergency intra-arterial stent placement during blood stream infection, later suspected to host a P. aeruginosa biofilm. Removing the stent was deemed precarious, and phage therapy was considered as a compassionate treatment option. A three-phage cocktail infecting the P. aeruginosa strain was prepared and administered intravenously together with meropenem for two weeks, after which, a ten-month follow-up was carried out. Results: No adverse reactions occurred during the phage therapy treatment, while infection markers were normalized. In addition, recovery was seen in a PET-CT scan. During the 10-month follow-up, no further P. aeruginosa septicaemias occurred. Conclusions: Phage–meropenem combination therapy was thus found safe and effective in the treatment of recurrent Pseudomonas septicaemia in a patient with an arterial stent. [ABSTRACT FROM AUTHOR]

Purpose: Very low birth weight (VLBW) infants are at a risk of spontaneous focal intestinal perforation (FIP). Treatment includes supportive care, antibiotics, and drainage with/without surgery. Broad-spectrum antibiotic agents like carbapenems are applied frequently, although their use is not well-supported by the limited evidence of causal pathogens. We hypothesize that the use of carbapenems may not be necessary in VLBW infants with FIP. Our primary objective was to evaluate the antimicrobial use in VLBW infants with FIP in a cohort of the German Neonatal Network (GNN). The secondary objective was to characterize a subset in detail as a benchmark for future targets of stewardship. Methods: Data on VLBW infants with FIP was collected prospectively within the GNN, a collaboration of 68 neonatal intensive care units (NICU). With regards to the primary objective, patient characteristics and antimicrobial treatment were extracted from the predefined GNN database. To address our secondary objective, an additional on-site assessment of laboratory and microbiological culture results were performed. Results: In the GNN cohort, 613/21,646 enrolled infants (2.8%) developed FIP requiring surgery. They were frequently treated with carbapenems (500/613 (81.6%)) and vancomycin (497/613 (81.1%)). In a subset of 124 VLBW infants, 77 (72.6%) had proof of gram-positive bacteria in the abdominal cavity, coagulase-negative staphylococci (CoNS) predominantly. Despite the low prevalence of gram-negative bacteria (n = 6 (4.8%)), the combination of meropenem and vancomycin was prescribed most frequently (n = 96 (78.0%)). Conclusion: The use of carbapenems as broad-spectrum antimicrobials agents might not be justified in most VLBW infants with FIP. Knowledge on the development of the neonatal gut microbiota, local resistance patterns and individual microbiological findings should be taken into consideration when implementing antimicrobial stewardship programs (ASPs). [ABSTRACT FROM AUTHOR]

Background Septic melioidosis is associated with high mortality in resource-limited settings. The current study aims to find 28-d all-cause mortality predictors within 24 h of admission in melioidosis patients presenting to an emergency department. Methods This retrospective cohort study (2018–2022) included melioidosis patients divided into two groups based on their primary outcomes (28-d mortality). All the clinically relevant factors significant in univariate analysis were selected for binary logistic regression analysis. Those factors significant in logistic regression analysis were considered independent predictors of mortality. Results Of the 53 patients with melioidosis, the 28-d mortality of melioidosis patients admitted to the emergency department was 51% (n=27). Respiratory involvement, renal dysfunction, haemodynamic instability, elevated aspartate transaminase, elevated activated partial thromboplastin time, elevated CRP, elevated procalcitonin, decreased albumin, decreased absolute neutrophil count, decreased absolute lymphocyte count and use of piperacillin-tazobactam or azithromycin were significant predictors of mortality on univariate analysis. Vasopressor requirement (p=0.03) and low serum albumin level (0.041) at presentation were independent predictors of mortality. Conclusion Vasopressor requirement and low albumin levels at presentation in the emergency department are independent predictors of mortality. There is a need to create awareness among primary care physicians to enable early diagnosis and prompt initiation of treatment. [ABSTRACT FROM AUTHOR]

Stenotrophomonas maltophilia causes challenging infections in immunocompromised patients, exhibiting increasing resistance to multiple antimicrobials and possessing various virulence genes, including emerging resistance to trimethoprim‐sulfamethoxazole. A total of 80 clinical isolates of S. maltophilia were collected from multiple hospitals in Tehran, Iran. This study conducted an analysis of antibiotic susceptibility by disc diffusion method and E‐test assay, resistance and virulence gene frequencies were examined by PCR‐sequencing, and multilocus sequencing typing (MLST) was performed for strain typing. Across the tested isolates, we observed notably high resistance rates for imipenem 80 (100%), meropenem 78(97.5%), and ceftazidime 72 (90%), while trimethoprim‐sulfamethoxazole (SXT) showed a lower resistance rate of 2 (2.5%). Minocycline and levofloxacin demonstrated the highest susceptibility rates, with 70 (87.5%) and 80 (100%), respectively. The prevalence of antibiotic resistance genes blaL1, and blaL2 was 71 (88.75%) and 76 (95%), respectively. Additionally, the PCR analysis revealed that the frequency of virulence genes (fliC, virB, papD, pilU, hlyIII, stmPr1, and stmPr2) was 78 (97.5%), 77 (96.25%), 58 (72.5%), 77 (96.2%), 76 (95%), 31 (38.75%), and 80 (100%), respectively. Resistance to SXT isolate belong to the sequence type (ST15) and exhibits allelic profiles of (10, 29, 21, 21, 32, 32, and 10). The data obtained from our investigation have indicated that SXT remains an efficacious antibiotic and also highlighted the importance of effective management, identification of resistant isolates, and typing methods to address the global prevalence of antibiotic resistance in S. maltophilia. [ABSTRACT FROM AUTHOR]

The emission of glyphosate and antibiotic residues from human activities threatens the diversity and functioning of the microbial community. This study examines the impact of a glyphosate-based herbicide (GBH) and common antibiotics on Gram-negative bacteria within the ESKAPEE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. and Escherichia coli). Ten strains, including type and multidrug-resistant strains for each species were analysed and eight antibiotics (cefotaxime, meropenem, aztreonam, ciprofloxacin, gentamicin, tigecycline, sulfamethoxazole-trimethoprim, and colistin) were combined with the GBH. While most combinations yielded additive or indifferent effects in 70 associations, antagonistic effects were observed with ciprofloxacin and gentamicin in five strains. GBH notably decreased the minimum inhibitory concentration of colistin in eight strains and displayed synergistic activity with meropenem against metallo-β-lactamase (MBL)-producing strains. Investigation into the effect of GBH properties on outer membrane permeability involved exposing strains to a combination of this GBH and vancomycin. Results indicated that GBH rendered strains sensitive to vancomycin, which is typically ineffective against Gram-negative bacteria. Furthermore, we examined the impact of GBH in combination with three carbapenem agents on 14 strains exhibiting varying carbapenem-resistance mechanisms to assess its effect on carbapenemase activity. The GBH efficiently inhibited MBL activity, demonstrating similar effects to EDTA (ethylenediaminetetraacetic acid). Chelating effect of GBH may have multifaceted impacts on bacterial cells, potentially by increasing outer membrane permeability and inactivating metalloenzyme activity. [ABSTRACT FROM AUTHOR]

Objectives: In this retrospective observational study, the aim is to establish how the implementation of the use of antimicrobial stewardship programs at the hospital and intensive care unit level in a Sucre Clinic in Sincelejo has had a significant impact on the improvement of the rational use of antibiotics, due to the alarming situation of increasing antibiotic resistance. Materials and methods: The methodology used was to analyze the Excel database of the Clinic in such a way as to compare the data from 2017, the period prior to the implementation of the antimicrobial stewardship program (ASP), with the subsequent evolution between the years 2018 and 2022, in relation to the institutional records of four antibiotics—ceftriaxone3, ciprofloxacin4, meropenem5, and vancomycin6, measured in defined daily dose (DDD). Results: According to the defined daily dose values obtained for the four antibiotics, a reduction in the defined daily dose was identified in the post-implementation period. On the other hand, considering the DDD reported by the World Health Organization for each of the antibiotics, significant differences were verified in comparison with those obtained in the clinic in the hospitalization and intensive care unit services. Conclusions: In conclusion, in the clinic, a reduction in the defined daily dose was verified in the period after the implementation of the antimicrobial stewardship program compared to the previous period, both in the hospitalization and intensive care unit, as well as having a mild-to-large effect with Cohen's D. [ABSTRACT FROM AUTHOR]

Thyroid storm is a rare but life-threatening condition mainly triggered by infection and abrupt discontinuation of antithyroid drug therapy for Graves' disease. Pancytopenia is a rare adverse reaction to antithyroid drugs. We present a 13-year-old girl with thyroid storm and pancytopenia with symptoms similar to those of methimazole-induced pancytopenia. Although in this context the use of methimazole is still under debate, due to multiple normal complete blood counts (CBC) monitored during fever, sepsis-induced pancytopenia with thyroid storm was considered, and methimazole treatment combined with methylprednisolone and meropenem was able to resolve both pancytopenia and thyroid storm. During the period of infection and antithyroid drug therapy, close monitoring of CBC may help differentiate the aetiology of pancytopenia. This is the first paediatric case report that outlines the use of methimazole in the management of thyroid storm with pancytopenia. [ABSTRACT FROM AUTHOR]

Objectives The measurement of VOCs release in the headspace of a bacterial culture represents a new approach to rapidly assess antimicrobial susceptibility. Herein, we evaluated the diagnostic performance of the VITEK® REVEAL™ system directly from a collection of Gram-negative positive blood cultures. Materials and methods One hundred and twenty-eight positive blood cultures were included in the analysis (Enterobacterales, n  = 95; Pseudomonas aeruginosa , n  = 21; Acinetobacter baumannii complex, n  = 12). Samples were processed using VITEK® REVEAL™ according to the manufacturer's recommendations, and MICs of 22 antimicrobials were compared with those obtained using reference methods. Categorical agreement (CA), essential agreement (EA) and categorical errors were calculated. Results Overall, 2220 strain/antibiotic pair combinations were analysed. Of these, most were classified as resistant by reference antimicrobial susceptibility testing (1091/2220; 48.7%). The overall CA and EA were 97.6% and 97.7%, respectively. CA ranged from 97.5% in Enterobacterales to 97.9% in both P. aeruginosa and A. baumannii complex. The overall number of categorical discrepancies were: 18 very major errors (1.6%), 13 major errors (1.2%) and 22 minor errors (2.4%). EA ranged from 95.2% in P. aeruginosa to 98.1% in Enterobacterales. Screening test for ESBL phenotype was positive, indeterminate and negative in 13.7%, 32.6% and 27.4% of Enterobacterales isolates tested by both VITEK® REVEAL™ and the reference method, showing 100% CA. Conclusions VITEK® REVEAL™ represents a reliable tool to obtain antimicrobial susceptibility results of the main Gram-negative species directly from positive blood cultures with time to results of less than 8 h. [ABSTRACT FROM AUTHOR]

Background Sulbactam dosing for Acinetobacter baumannii infections has not been standardized due to limited available pharmacokinetics/pharmacodynamics (PK/PD) data. Herein, we report a comprehensive PK/PD analysis of ampicillin-sulbactam against A. baumannii pneumonia. Methods Twenty-one A. baumannii clinical isolates were tested in the neutropenic murine pneumonia model. For dose-ranging studies, groups of mice were administered escalating doses of ampicillin-sulbactam. Changes in log10cfu/lungs relative to 0 h were assessed. Dose-fractionation studies were performed. Estimates of the percentage of of time during which the unbound plasma sulbactam concentrations exceeded the MIC (% f T > MIC) required for different efficacy endpoints were calculated. The probabilities of target attainment (PTA) for the 1-log kill plasma targets were estimated following clinically utilized sulbactam regimens. Results Dose-fractionation studies demonstrated time-dependent kill. Isolates resistant to both sulbactam and meropenem required three times the exposures to achieve 1-log kill; median [IQR] % f T > MIC of 60.37% [51.6–66.8] compared with other phenotypes (21.17 [16.0–32.9] % f T > MIC). Sulbactam standard dose (1 g q6h, 0.5 h infusion) provided >90% PTA up to MIC of 4 mg/L. Sulbactam 3 g q8h, 4 h inf provided greater PTA for isolates with sulbactam-intermediate susceptibility (8 mg/L, 100% versus 86% following the standard dose). Despite the higher exposure following 3 g q8h, 4 h inf, PTA was ≤57% among sulbactam-resistant/meropenem-resistant isolates. Conclusion Sulbactam standard dose is a valuable regimen across sulbactam-susceptible isolates while the high-dose extended-infusion provides additional benefit against sulbactam-intermediate isolates. Given that most of the sulbactam-resistant A. baumannii isolates are meropenem-resistant, high-dose prolonged-infusion regimens are not expected to be effective as monotherapy against infections due to these isolates. [ABSTRACT FROM AUTHOR]

Background β-lactam antibiotics, which inhibit penicillin-binding protein 3 (PBP3) that is required for cell division, play a key role in treating P. aeruginosa infections. Some sequence variations in PBP3 have been associated with β-lactam resistance but the effects of variations on antibiotic susceptibility and on cell division have not been quantified. Antibiotic efflux can also reduce susceptibility. Objectives To quantify the effects of PBP3 variations on β-lactam susceptibility and cell morphology in P. aeruginosa. Methods Nineteen PBP3 variants were expressed from a plasmid in the reference strain P. aeruginosa PAO1 and genome engineering was used to construct five mutants expressing PBP3 variants from the chromosome. The effects of the variations on β-lactam minimum inhibitory concentration (MIC) and cell morphology were measured. Results Some PBP3 variations reduced susceptibility to a variety of β-lactam antibiotics including meropenem, ceftazidime, cefepime and ticarcillin with different variations affecting different antibiotics. None of the tested variations reduced susceptibility to imipenem or piperacillin. Antibiotic susceptibility was further reduced when PBP3 variants were expressed in mutant bacteria overexpressing the MexAB-OprM efflux pump, with some variations conferring clinical levels of resistance. Some PBP3 variations, and sub-MIC levels of β-lactams, reduced bacterial growth rates and inhibited cell division, causing elongated cells. Conclusions PBP3 variations in P. aeruginosa can increase the MIC of multiple β-lactam antibiotics, although not imipenem or piperacillin. PBP3 variations, or the presence of sub-lethal levels of β-lactams, result in elongated cells indicating that variations reduce the activity of PBP3 and may reduce bacterial fitness. [ABSTRACT FROM AUTHOR]

Background Fosfomycin is gaining increasing attention for its activity against MDR or XDR pathogens. Currently, IV fosfomycin is a potential option for treating various infections, including urinary tract infections, pneumonia and skin infections when first-line treatments fail. Objectives To evaluate the demographic, clinical, microbiological and treatment modality of children received IV fosfomycin to treat infections caused by MDR pathogens since there are few data on the use of fosfomycin in children. Methods This study was conducted retrospectively with patients under 18 years of age who were treated with IV fosfomycin for at least 72 h due to infections caused by MDR pathogens between January 2019 and October 2023 at Marmara University Pendik Training and Research Hospital, İstanbul, Türkiye. Data on demographic and clinical features, microbiological findings, treatment modalities and side effects were evaluated. Results Twenty-five children, for a total of 32 cases of infection episodes, with a mean age of 11.4 ±   3.92 years who received IV fosfomycin were included. The most frequent comorbidity was chronic pulmonary diseases, and the most common infection needed for IV fosfomycin was MDR Pseudomonas aeruginosa pneumonia. In all cases, fosfomycin was administered in combination with other antibiotics, mainly meropenem–colistin (68.7%) or meropenem (15.6%). Twenty-two (71.9%) cases had favourable clinical responses at the end of therapy. Conclusions Our results suggest that IV fosfomycin may be an effective treatment option for MDR pathogens in the paediatric population. Nevertheless, careful stewardship is necessary to maintain efficacy and reduce antimicrobial resistance selection risk. [ABSTRACT FROM AUTHOR]

• A PBPK model of meropenem for critically ill patients was established. • The % f T>MIC values varied greatly in different two-step infusion (TIT) strategies. • The TIT did not improve the PK/PD target attainment rate of meropenem. • Intermittent infusion was appropriate at MICs of ≤1 mg/L. • Prolonged infusion was recommended at MICs of 2–8 mg/L. The optimal method for administering meropenem remains controversial. This study was conducted to explore the optimal two-step infusion strategy (TIT), and to investigate whether TIT is superior to intermittent infusion therapy (IIT) and prolonged infusion therapy (PIT). A physiologically based pharmacokinetics model for critically ill patients was established and evaluated. The validated model was utilized to evaluate the pharmacokinetics/pharmacodynamics (PK/PD) target attainment of meropenem. The PK/PD target attainment of different TITs varied greatly, and the total infusion duration and the first-step dose greatly affected these values. The optimal TIT was 0.25 g (30 min) + 0.75 g (150 min) at MICs of ≤2 mg/L, and 0.25 g (45 min) + 0.75 g (255 min) at MICs of 4–8 mg/L. The PK/PD target attainment of optimal TIT, PIT, and IIT were 100 % at MICs of ≤1 mg/L. When MIC increased to 2–8 mg/L, the PK/PD target attainment of optimal TIT was similar to that of PIT and higher than IIT. In conclusion, TIT did not significantly improve the PK/PD target attainment of meropenem compared with PIT. IIT is adequate at MICs of ≤1 mg/L, and PIT may be the optimal meropenem infusion method in critically ill patients with MICs of 2–8 mg/L. [ABSTRACT FROM AUTHOR]

Background: Piperacillin/tazobactam may be associated with less favourable outcomes than carbapenems in patients with severe bacterial infections, but the certainty of evidence is low. Methods: The Empirical Meropenem versus Piperacillin/Tazobactam for Adult Patients with Sepsis (EMPRESS) trial is an investigator‐initiated, international, parallel‐group, randomised, open‐label, adaptive clinical trial with an integrated feasibility phase. We will randomise adult, critically ill patients with sepsis to empirical treatment with meropenem or piperacillin/tazobactam for up to 30 days. The primary outcome is 30‐day all‐cause mortality. The secondary outcomes are serious adverse reactions within 30 days; isolation precautions due to resistant bacteria within 30 days; days alive without life support and days alive and out of hospital within 30 and 90 days; 90‐ and 180‐day all‐cause mortality and 180‐day health‐related quality of life. EMPRESS will use Bayesian statistical models with weak to somewhat sceptical neutral priors. Adaptive analyses will be conducted after follow‐up of the primary outcome for the first 400 participants concludes and after every 300 subsequent participants, with adaptive stopping for superiority/inferiority and practical equivalence (absolute risk difference <2.5%‐points) and response‐adaptive randomisation. The expected sample sizes in scenarios with no, small or large differences are 5189, 5859 and 2570 participants, with maximum 14,000 participants and ≥99% probability of conclusiveness across all scenarios. Conclusions: EMPRESS will compare the effects of empirical meropenem against piperacillin/tazobactam in adult, critically ill patients with sepsis. Due to the pragmatic, adaptive design with high probability of conclusiveness, the trial results are expected to directly inform clinical practice. [ABSTRACT FROM AUTHOR]

Carbapenemases, classified as bacterial enzymes, have the ability to hydrolyze carbapenems – important broad-spectrum antibiotics. This work attempts to summarize the information on the diversity of Guiana Extended-Spectrum (GES) subgroup of carbapenemases, and highlights the serious threat posed by infections caused by bacteria capable of producing these enzymes. The structure, functional characteristics, classification of different types of GES carbapenemases and diagnostic methods are discussed in detail. There are 59 GES-type carbapenemases, which have different amino acid sequences of the protein chains as well as activity against various antibiotics. Currently, bacterial strains with antibiotic resistance of the GES type are treated with: cefiderocil belonging to the cephalosporins, eravacycline belonging to the tetracyclines, lefamulin belonging to the pleuromutulins, colistin, fosfomycin, nitrofurantoin, tobramycin, amikacin, imipenem with relebactam, meropenem with waborbactam, ceftazidime with avibactam and plazomycin. In addition, the following drugs are under study: durlobactam with sulbactam, taniborbactam and cefepime with enmetazobactam This paper aims to summarize the current knowledge on GES-type carbapenemases, their diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate literature from a 12-year period (2010–2021) on the antimicrobial resistance profile of Pseudomonas aeruginosa from the Arabian Gulf countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates). Methods: An electronic literature search was conducted for articles on antimicrobial resistance in P. aeruginosa and associated phenotypes, covering the period of 1st January 2010 to 1st December 2021. Results: Antimicrobial resistance in the Arabian Gulf was highest to meropenem (10.3–45.7%) and lowest to colistin (0.0–0.8%), among the agents tested. Annual data showed that ceftazidime resistance (Kuwait), piperacillin-tazobactam non-susceptibility (Qatar), and aztreonam, imipenem, and meropenem resistance (Saudi Arabia) increased by 12–17%. Multiple mechanisms of carbapenem resistance were identified and multiple clones were detected, including high-risk clones such as ST235. The most common carbapenemases detected were the VIM-type metallo-β-lactamases. Conclusions: Among P. aeruginosa in the Arabian Gulf countries, resistance to meropenem was higher than to the other agents tested, and meropenem resistance increased in Saudi Arabia during the study period. Resistance to colistin, a classic antibiotic used to treat Pseudomonas spp. infections, remained low. The VIM-type β-lactamase genes were dominant. We recommend local and regional antimicrobial resistance surveillance programs to detect the emergence of resistance genes and to monitor antimicrobial resistance trends in P. aeruginosa. [ABSTRACT FROM AUTHOR]

Background: Childhood urinary tract infections (UTIs) are among the most prevalent diseases. In recent years, the overuse of common antibiotics has increased antibiotic resistance among urinary tract pathogens worldwide, with changes in the pattern of microbial resistance varying by geographical area and time. Objectives: This study aims to investigate the pattern of microbial resistance of UTI pathogens in pediatric patients. Methods: In this cross-sectional study, children aged < 13 years with UTI and positive urine cultures, who were admitted to Bahrami Hospital in Tehran, Iran, between 2015 and 2019, were evaluated. The pathogens' frequency, their antimicrobial resistance, and clinical and demographic information were extracted from the patients' files. Statistical relationships between clinical and demographic data and antibiotic resistance were analyzed using appropriate statistical tests. Results: The files of 202 patients were evaluated. The majority of patients were female (79.2%). UTI was more common among the 12 - 60 months age group (36.3%) in females and the 1 - 12 months age group (50%) in males. The most common UTI pathogen was Escherichia coli (85.1%). The lowest rates of microbial resistance were related to Meropenem (0% resistance), Gentamicin (9.2%), and Amikacin (10.8%). Conversely, the highest resistance rates were observed for Cotrimoxazole (74.6%), Ampicillin (74.5%), and Cephalothin (64.9%). Conclusions: UTI is more common in females aged 1 to 60 months. E. coli is the most common cause of UTI. Microbial resistance to antibiotics used for empirical treatment, such as ceftriaxone, is high and changes over time. It is recommended to use alternative antibiotics and avoid the inappropriate administration of antibiotics. [ABSTRACT FROM AUTHOR]

This study aimed to develop a population pharmacokinetic (PK) model for meropenem in healthy adults and explore optimal dosing regimens for patients with normal renal function. PK samples were obtained from 12 healthy participants, which were analyzed using noncompartmental analysis and nonlinear mixed-effect modeling. The PK profiles of meropenem were characterized using a two-compartment model, and serum creatinine level was identified as a significant covariate affecting total clearance. Monte Carlo simulations were conducted using this model to inform dosing recommendations. The target index for meropenem efficacy was defined as the cumulative percentage over 24 h during which free (f) drug concentration exceeded the minimum inhibitory concentration (MIC) under steady state conditions (fT>MIC). These simulations indicated that the current dosage regimen of 1 g for 30 min infusions every 8 h achieved a 90% probability of target attainment (PTA) for 40%fT>MIC when the MIC was <2 mg/L. However, to achieve more stringent therapeutic targets, such as a 90%PTA for 100%fT>MIC or a 90%PTA for 100%fT>4MIC, higher doses administered as 3 h extended infusions or as continuous infusions may be necessary. These results highlight the need for model-informed precision dosing to enhance the efficacy of meropenem therapy across various MIC levels and therapeutic targets. [ABSTRACT FROM AUTHOR]

Meropenem is a broad-spectrum antibiotic used for the treatment of multi-drug-resistant infections. Due to its pharmacokinetic profile, meropenem's activity is optimized by maintaining a specific time the serum concentration remains above the minimum inhibitory concentration (MIC) via extended infusion (EI), continuous infusion, or intermittent infusion dosing strategies. The available literature varies regarding the superiority of these dosing strategies. This study's primary objective was to determine the difference in time to clinical stabilization between intravenous push (IVP) and EI administration. We performed a retrospective pilot cohort study of 100 critically ill patients who received meropenem by IVP (n = 50) or EI (n = 50) during their intensive care unit (ICU) admission. There was no statistically significant difference in the overall achievement of clinical stabilization between IVP and EI (48% vs. 44%, p = 0.17). However, the median time to clinical stability was shorter for the EI group (20.4 vs. 66.2 h, p = 0.01). EI administration was associated with shorter hospital (13 vs. 17 days; p = 0.05) and ICU (6 vs. 9 days; p = 0.02) lengths of stay. Although we did not find a statistically significant difference in the overall time to clinical stabilization, the results of this pilot study suggest that EI administration may produce quicker clinical resolutions than IVP. [ABSTRACT FROM AUTHOR]

Background: Due to its distinct vascular tropism, Campylobacter fetus is recognized as a significant cause of severe systemic infections, especially in immunocompromised individuals, while it is rarely reported as a cause of gastrointestinal infections. Methods: A rare case of mycotic abdominal aortic aneurysm associated with Campylobacter fetus detected on the aneurysm wall itself was described. Results: A 68-year-old male was admitted to the hospital due to severe abdominal pain. The patient was afebrile, hemodynamically stable with elevated C-reactive protein levels. A physical examination revealed a palpable, pulsatile, tender mass located in the periumbilical region. Ultrasonography and multi-slice computer tomography angiography (MSCTA) identified an infrarenal abdominal aortic aneurysm with a maximum diameter of 6.5 cm, showing suspicious signs of dissection. Aneurysmectomy with Dacron tube graft interposition was performed. Although the blood cultures remained negative, the culture of the aneurysmal wall grew Campylobacter fetus, enabling early diagnosis and targeted antibiotic therapy. The patient was treated with meropenem for two weeks, followed by amoxicillin-clavulanate for another two weeks after hospital discharge. Conclusions: Campylobacter fetus associated with abdominal aortic aneurysms represents a life-threatening condition, posing a significant challenge in vascular surgery. Due to the lack of clear guidelines on antibiotic susceptibility testing and the treatment of infections associated with this pathogen, enhanced surveillance of Campylobacter fetus is necessary in both human and veterinary medicine. [ABSTRACT FROM AUTHOR]