Journal of Antimicrobial Chemotherapy最新文献

Background: Candida albicans can form polymicrobial biofilms with other microorganisms, such as Pseudomonas aeruginosa, at infection sites.

Objectives: As biofilms are highly resistant to antibiotics there is a need for new antibiofilm agents that have unique targets and modes of action.

Methods: In this study the antibiofilm effects of two quorum-sensing molecules (QSMs), farnesol and tyrosol, were investigated alone and in combination with antibiotics (aztreonam, colistin, tobramycin) and antifungals (fluconazole, amphotericin B, caspofungin), against single- and dual-species biofilms of C. albicans and P. aeruginosa in in vitro and in vivo systems.

Results: It was observed that QSMs alone, especially farnesol, showed at least a 1-log reduction against preformed single- and dual-species biofilms of C. albicans and P. aeruginosa. Combination of QSMs with colistin or fluconazole was found to be effective against both single- and dual-species biofilms in vitro. Increased survival was observed in C. elegans when treated with colistin or fluconazole in combination with QSMs, compared with no treatment. Additionally, the QSMs and colistin and farnesol combinations effectively inhibited biofilm formation by C. albicans and P. aeruginosa on bronchial epithelial cells, and reduced IL-1β expression in lung bronchial epithelial cells.

Conclusions: There is a need for effective treatments for bacterial-fungal biofilm infections and, to our knowledge, there have been no studies of QSMs and antimicrobial combinations against dual-species biofilms involving C. albicans and P. aeruginosa. Hence these findings will make a significant contribution to the literature.

Background: There are limited treatment options for prosthetic joint infections (PJI) due to multidrug-resistant Staphylococcus epidermidis (MDRSE). Fosfomycin (FOF) has gained attention as a potential therapy, but there is a paucity of information on the phenotypic and genotypic susceptibility amongst S. epidermidis, including MDRSE.

Objectives: To investigate phenotypical and genotypical susceptibility to FOF in S. epidermidis isolates prospectively collected from PJIs in Sweden.

Methods: MIC determination was performed using in-house agar dilution (AD) and a commercial AD panel. Genes and gene variants associated with FOF resistance were analysed.

Results: Multidrug resistance was common [74/89 (83%) isolates were MDRSE].FOF inhibited all isolates except one, which had an MIC > 256 mg/L. The commercial AD panel demonstrated good overall performance but tended to overestimate the MIC, resulting in 84% essential agreement with the gold standard. Genomic analysis with publically available tools for whole-genome sequencing (WGS) data suggested genotypic FOF resistance in all isolates, but in-depth analysis revealed that fosB, associated with FOF resistance, was only present in the phenotypically resistant isolate. No other genes or gene variants associated with FOF resistance were detected.

Conclusions: Phenotypic resistance to FOF and presence of fosB were rare in this collection, indicating FOF's potential as a treatment option for S. epidermidis. The commercial AD panel demonstrated high reproducibility, but EA with the reference method was less than optimal. Findings of genotypic FOF resistance using common tools for WGS data should be critically evaluated and appropriately verified with relevant fosB references for S. epidermidis.

Background: Preclinical murine infection models lack inter-laboratory uniformity, complicating result comparisons and data reproducibility. The European Innovative Medicines initiative-funded consortium (COMBINE) has developed a standardized murine neutropenic pneumonia protocol to address these concerns. While model methods have been standardized, a major obstacle to consistent results is the lack of available bacteria with defined viability and variability. Herein, we establish a diverse challenge set of Klebsiella pneumoniae and Pseudomonas aeruginosa suitable for use in the COMBINE protocol to further minimize experimental inconsistency and improve the interpretability of data generated among differing laboratories.

Materials and methods: Sixty-six K. pneumoniae and 65 P. aeruginosa were phenotypically profiled against tigecycline (K. pneumoniae only), levofloxacin, meropenem, cefiderocol and tobramycin. Fifty-nine isolates were introduced into the COMBINE model to assess the sufficiency of the starting bacterial inoculation, resultant baseline bacterial burden, achievement of ≥1 log10cfu/lung growth at 24 h, time to and percentage mortality. Forty-five isolates displaying desirable minimum inhibitory concentration profiles were subjected to replicate in vivo testing to assess target parameters.

Results: 83% of K. pneumoniae reached the prerequisite growth at 24 h using a starting bacterial burden ≥7 log10cfu/lung. P. aeruginosa isolates grew well in the model: 90% achieved the growth target with a starting bacterial burden of 6 log10cfu/lung. Mortality was negligible for K. pneumoniae but high for P. aeruginosa. Poor or inconsistent achievement of the 24 h growth target was seen in 11/59 isolates.

Conclusions: With this diverse cache of viable isolates established in the COMBINE pneumonia model, future translational studies can be undertaken to set efficacy benchmarks among laboratories.

Objectives: Therapeutic drug monitoring (TDM) is recommended for posaconazole to achieve target concentrations of ≥0.7 mg/L and ≥1.0 mg/L for prophylaxis and treatment of invasive fungal infection (IFI), respectively. However, target attainment is challenging with the oral suspension, particularly in children. Here, we describe our experience using crushed delayed-release tablet (DRT) in a paediatric cohort, with a focus on TDM.

Methods: We undertook a retrospective audit of crushed posaconazole DRT administration via enteral feeding tubes (EFTs) for patients aged ≤18 years over 18 months at The Royal Children's Hospital Melbourne who had at least one trough concentration measured at steady state. Details of patient demographics, posaconazole dosing, monitoring and adverse effects were recorded.

Results: Twelve patients with a median age of 9 years (range 2 to 14) received posaconazole DRT via EFT for prophylaxis (n = 8) or treatment (n = 4). All children achieved target concentration, with a median dose of 7 mg/kg/day (range 5 to 11) for prophylaxis and 13 mg/kg/day (range 9 to 20) for treatment. The median time to reach therapeutic levels was 7 days (range 5 to 14) for prophylaxis and 20 days (range 15 to 35) for treatment. One child had blockage of their EFT, which was attributed to posaconazole. No other adverse effects were observed.

Conclusions: Crushed posaconazole DRT administered via EFT may be used as a method of attaining therapeutic posaconazole concentrations in children for antifungal prophylaxis and treatment.

Objectives: We compared the effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide fumarate (BIC/FTC/TAF) and dolutegravir plus lamivudine (DTG + 3TC) in our cohort of treatment-naive people with HIV (PWH).

Methods: In a multicentre cohort of treatment-naive PWH starting a first-line regimen with either dolutegravir plus lamivudine or BIC/FTC/TAF, Kaplan-Meier survival analysis was used to estimate time to virological failure (VF) and time to treatment discontinuation (TD), whereas Cox regression was used to evaluate predictors of VF and TD. Changes in CD4+ cell count were assessed via non-parametric tests, and linear regression analyses were performed to explore predictors of CD4+ cell count changes.

Results: One hundred and seventy individuals were included: 66 started dolutegravir plus lamivudine (DTG group) and 104 started BIC/FTC/TAF (BIC group). During follow-up, we observed two VFs in the DTG group [1.7 per 100 person-years of follow-up (PYFU)] and two in the BIC group (1.7 per 100 PYFU). Estimated probability of remaining free from VF at Week 144 was 95.9% in the DTG group and 95.2% in the BIC group (log-rank P = 0.955). Four TDs were observed in the DTG group (3.4 per 100 PYFU) and 21 in the BIC group (17.6 per 100 PYFU). Estimated probability of maintaining the study regimen at Week 144 was 90.3% in the DTG group and 70.0% in the BIC group; individuals in the BIC group had a higher probability of TD (log-rank P = 0.003). In both groups, the CD4+ count improved significantly during follow-up.

Conclusions: Our study shows that both strategies are effective and safe, with few VFs and TDs due to tolerability issues.

Background: The increasing prevalence of carbapenem-resistant Enterobacteriaceae (CRE) infections among children represents a significant global concern, leading to elevated mortality rates. The aim of this study was to evaluate the risk factors, outcomes, 30-day mortality rates and contributing factors in children with CRE bloodstream infections (CRE-BSIs).

Methods: Data regarding demographic characteristics, treatment approaches and outcomes of hospitalized children aged 0-18 years diagnosed with CRE-BSIs between January 2018 and December 2022 were extracted from medical records. Mortality within 30 days of diagnosis and the predictive factors were analysed.

Results: A total of 114 children, with a median age of 11 months (range: 6-69.5), were included. All cases of CRE-BSIs were either healthcare associated or hospital acquired and presented with at least one underlying comorbidity. A previous history of CRE colonization or infection rate was 48.2% (55/114). Klebsiella pneumoniae 87.7% (100/114) was the most frequently isolated microorganism, with a 30-day mortality rate of 14% (16/114). Multivariate analysis identified paediatric intensive care unit admission, invasive mechanical ventilation, inotropic support and thrombocytopenia due to CRE-BSIs as the most discriminative predictors for 30-day mortality (P < 0.001). Central venous catheter (CVC) removal was associated with a reduced mortality rate (P = 0.012). High-dose prolonged infusion of MEM-based or polymyxin-based antibiotic combinations did not impact survival. Lower MEM MIC values were associated with improved survival.

Conclusions: The mortality rate of CRE-BSI is notably high in childhood. The use of antibiotic combination strategies did not demonstrate a significant impact on 30-day survival; however, the removal of CVCs was found to lower mortality rates.

Objectives: Escherichia coli producing metallo-β-lactamases with penicillin-binding protein 3 (PBP3) insertions have reduced susceptibility to aztreonam-avibactam and cefiderocol. Here, we analysed high-quality E. coli genomes for PBP3 insertions.

Methods: E. coli genomes (n = 167 518) were retrieved from EnteroBase with CheckM2 for quality control, fastANI for species confirmation, multi-locus sequencing typing for sequence type (ST) determination and AMRFinderPlus for resistance gene identification. For PBP3 insertion analysis, we used Prokka for predicting coding sequences, BLAST+ for comparing resulted protein sequences and SnpEff for annotating variants.

Results: Among the included 159 341 genomes, PBP3 insertions with 11 variants were found in 2.01% (n = 3198). The predominant variant is a duplication of 334-337 amino acids (aa) (94.75%, n = 3030), comprising YRIN (65.92%, n = 2108) and its single-aa-variant YRIK (28.83%, n = 922), followed by a similar PYRI duplication of 333-336 (4.16%, n = 133). The less common ones are a TIPY duplication of 331-334 (n = 24) and its single-aa-variant TVPY's duplication: TVVPY (n = 1), TVPYTVPY (n = 1) and TVPYPVPY (n = 1). Rare duplications include VGDR of 106-109 (n = 3), ANALNIPL of 114-121 (n = 3), AL of 567-568 (n = 1) and TG of 584-585 (n = 1). Insertion variants were detected across 62 countries on six continents, primarily in human samples, and associated with 85 STs, concentrated in high-risk clones ST410 (29.18%, n = 1923), ST167 (23.40%, n = 1740) and ST405 (10.56%, n = 1334), with 83.32% (n = 2218) encoding metallo-β-lactamase NDM.

Conclusions: Global spread of E. coli harbouring PBP3 insertion, often with NDM β-lactamase, high-risk ST410, ST167 and ST405 clones and various hosts, underscores the escalating antimicrobial resistance crisis and the urgency for a 'One Health' strategy.

Introduction: Antimicrobial resistance (AMR) is a global issue that needs addressing. While antibiotic stewardship has improved often by restricting antibiotic use, some antibiotics that are still sold legally over the counter (OTC), notably in sore throat medications. Recent findings suggest OTC antibiotics could trigger cross-resistance to antibiotics used in clinical treatments, whether systemic or topical. Here we investigated the impact of three antibiotics contained in OTC sore throat medicines on emerging AMR in vitro.

Methods: Bacterial pathogens were exposed to a bactericidal concentration of an aminoglycoside in the presence or absence of a during-use concentration of bacitracin, gramicidin or tyrothricin in a time-kill assay. Damage to the bacterial membrane was also investigated by measuring potassium leakage and membrane potential alteration post-OTC antibiotic exposure.

Results: Gramicidin (15 µg/mL) significantly decreased the bactericidal activity of amikacin, tobramycin or gentamicin in Acinetobacter baumannii. It also decreased gentamicin bactericidal activity in Enterobacter cloacae, Escherichia coli and Klebsiella pneumoniae, while tyrothricin decreased the aminoglycoside efficacy in E. cloacae and E. coli. Gramicidin significantly decreased bacterial membrane potential and caused significant potassium leakage.

Conclusion: Gramicidin and to some extent tyrothricin impacted aminoglycoside efficacy by affecting membrane potential, which is essential for aminoglycosides uptake. Thus, some OTC antibiotics can interfere with aminoglycoside activity, which could in turn affect treatment efficacy. Although the likelihood of OTC antibiotics and aminoglycosides being used at the same time might not be common, this research highlights one potential reason for OTC antibiotics' usage to result in treatment failure and their contribution to AMR development.

Antibacterial activity can be classified as either bactericidal or bacteriostatic, using methods such as the MBC/MIC ratio and time-kill curves. However, such categorization has proven challenging in clinical practice, as these definitions only apply under specific laboratory conditions, which may differ from clinical settings. Several factors, such as the specific bacteria or infectious medium, can affect the action of antibiotics, with many antibacterials exerting both activities. These definitions have also led to the belief that bactericidal antibacterials are superior to bacteriostatic, especially in more severe cases, such as endocarditis, neutropenia and bacteraemia. Additionally, current dogma dictates against the combination of bactericidal and bacteriostatic antibacterials in clinical practice, due to potential antagonism. This review aimed to assess the differences in antibacterial activity of bactericidal and bacteriostatic antibacterials based on in vitro and in vivo studies and examine their antagonistic or synergistic effects. Our findings show that specific bacteriostatic agents, such as linezolid and tigecycline, are clinically non-inferior to bactericidals in multiple infections, including pneumonia, intra-abdominal infections, and skin and soft tissue infections. Studies also support using several bacteriostatic agents as salvage therapies in severe infections, such as neutropenic fever and endocarditis. Additionally, not all combinations of bacteriostatic and bactericidal agents appear to be antagonistic, with many combinations, such as linezolid and rifampicin, already being used. The findings should be interpreted with caution, as most evidence is from observational studies and there is a need for randomized controlled trials to assess their effectiveness and combinations, especially within the context of rising antimicrobial resistance.