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The Journal of Antimicrobial Chemotherapy
Academic Press for the British Society for Antimicrobial Chemotherapy
The Journal of Antimicrobial Chemotherapy

Academic Press for the British Society for Antimicrobial Chemotherapy

0305-7453

The Journal of Antimicrobial Chemotherapy/Journal The Journal of Antimicrobial Chemotherapy
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    Linezolid versus omadacycline in diabetic soft tissue infections: a signal of different adjunctive immunological properties?

    Sakoulas, George
    3页
    查看更多>>摘要：Recent understanding of antimicrobial chemotherapy has expanded to appreciate significant impacts on the host-pathogen relationship by antibiotics. Omadacycline statistically outperformed linezolid in treating acute bacterial skin and skin structure infections in patients with diabetes mellitus in a recent post-hoc analysis of the OASIS-1 and OASIS-2 clinical trials. This difference may speak directly or indirectly to neutrophil dysfunction in diabetes. Neutrophil dysfunction increases the likelihood of Gram-negative bacterial infection, whereby diabetics may benefit from the broader spectrum of omadacycline compared with linezolid. Indirectly, oxazolidinones like linezolid have been shown to be dependent on neutrophil function, potentially compromising the potency of this drug class in diabetics. Finally, tetracyclines like omadacycline have collateral anti-inflammatory properties that have not been seen in other antibiotic drug classes. These differences may impact clinical outcomes in the treatment of infections that are not predicted by their antimicrobial activities alone, as measured in standard susceptibility testing assays.
      原文链接:
    • NSTL
    • Oxford Univ Press

    BSAC Vanguard Series: Why culture matters to tackle antibiotic resistance

    Charani, Esmita
    2页
    查看更多>>摘要：Research has demonstrated that antibiotic prescribing and use are social processes. Despite the availability of guidelines and policies for optimized use, many challenges remain. Whilst much of the research in antimicrobial resistance is focused on new drugs, the socio-cultural and socio-economic drivers for infections and antibiotic use are also important considerations. Context-specific solutions that are co-developed with end users are needed if we are to optimize the use of existing and new antibiotics. The threat of antimicrobial resistance is not subject to geographical boundaries, and to truly be effective, interventions need to have the potential to be scaled to different settings. The inequities in funding, knowledge generation, ownership and transfer between the global North and South must be acknowledged and eradicated. Striking a balance in funding and equity requires in-country capacity building for: (i) delivering sustainable research; (ii) assuring equitable representation in research outputs; and (iii) supporting career progression of researchers through further funding, to support the generation of Locally owned knowledge that contributes to optimized healthcare systems and translation into clinical practice.
      原文链接:
    • NSTL
    • Oxford Univ Press

    Antifungal use in children with acute leukaemia: state of current evidence and directions for future research

    Yeoh, Daniel K.Haeusler, Gabrielle M.McMullan, Brendan J.Butters, Coen...
    17页
    查看更多>>摘要：Invasive fungal disease (IFD) remains a common and serious complication in children treated for leukaemia. Antifungal prescription in children with leukaemia presents unique challenges, particularly due to variation in IFD risk between and within leukaemia treatment protocols, drug toxicities and interactions between antifungals and chemotherapeutic agents. With recent advances in the understanding of IFD epidemiology and large clinical trials in adults assessing antifungals for IFD treatment and prophylaxis, together with paediatric clinical and pharmacokinetic studies, there is a growing body of data to inform optimal antifungal use in children. A panel of infectious diseases and haematology-oncology clinicians with expertise in IFD management compiled a list of 10 key clinical questions following development of the 2021 Australia and New Zealand Mycology Antifungal Consensus Guidelines. A focused literature review was conducted to explore available evidence and identify gaps in knowledge to direct future research. With the changing epidemiology of IFD globally, the ongoing evolution of paediatric leukaemia treatment and the increasing availability of novel antifungal agents, advocacy for paediatric clinical studies will remain vital to optimize IFD prevention and treatment in children with leukaemia.
      原文链接:
    • NSTL
    • Oxford Univ Press

    Contemporary and emerging pharmacotherapeutic agents for the treatment of Lassa viral haemorrhagic fever disease

    Joseph, Adejoke AdijatFasipe, Olumuyiwa JohnJoseph, Oluyemi AdesojiOlatunji, Olalekan Aliu...
    7页
    查看更多>>摘要：This review was designed to discuss the emerging and current pharmacotherapeutic agents for the treatment of Lassa viral haemorrhagic fever disease (LVHFD), also known as Lassa fever (LF). Original peer-reviewed articles that investigated LF were identified using the Medline Entrez-PubMed search. Information was also sourced from printed textbooks and reports by recognized health professional bodies such as the WHO, CDC, the Nigerian Federal Ministry of Health and the United Nations Children's Fund (UNICEF). A total of 103 articles were reviewed and 78 were found to contain information relevant to the study. LF remains an endemic disease of public health concern in the West Africa region, and in the rest of the world as cases have been imported into non-endemic regions as well. Currently, there are no approved vaccines or therapeutics for the treatment of Lassa mammarenavirus (LASV) infection. There are, however, off-label therapeutics being used (ribavirin and convalescent plasma) whose efficacy is suboptimal. Research is still ongoing on possible therapeutic options and drug repurposing of therapeutic agents currently in use for other clinical conditions. Considered therapeutic options include favipiravir, taribavirin, Arevirumab-3 and experimental drugs such as losmapimod, adamantyl diphenyl piperazine 3.3, Arbidol (umifenovir) and decanoyl-RRLL-chloromethyl ketone (dec-RRLL-CMK). Current treatments for LF are limited, hence the institution of mitigating measures to prevent infection is of utmost importance and should be prioritized, especially in endemic regions. Heightened searches for other therapeutic options with greater efficacy and lower toxicity are still ongoing, as well as for vaccines as the absence of these classifies the disease as a priority disease of high public health impact.
      原文链接:
    • NSTL
    • Oxford Univ Press

    A systematic review of the effect of therapeutic drug monitoring on patient health outcomes during treatment with penicillins

    Luxton, TimothyKing, NatalieWalti, ChristophJeuken, Lars...
    10页
    查看更多>>摘要：Background Dosing regimens guided by therapeutic drug monitoring (TDM) may be able to improve penicillin exposure in patients, which could result in improved patient health outcomes. Objectives This systematic review aims to describe the impact penicillin TDM has on health outcomes, including antimicrobial resistance (AMR). Methods Studies measuring penicillins in patient samples that adjusted regimens according to the result, and reported health outcomes were selected. Study bias was assessed according to study type. Included study characteristics were tabulated and described by narrative synthesis. Results Three randomized controlled trials (RCTs), 16 cohort studies, and 9 case studies were included. No RCTs showed statistically significant improvements in health outcomes. Five cohort studies showed improvement in at least one health outcome associated with target attainment. However, there was a high risk of bias in all studies for health outcomes. One study assessed the impact of penicillin TDM on AMR and found that improved target attainment was associated with suppression of resistance. No studies found a detrimental effect of penicillin TDM. Conclusions There is little evidence to suggest that TDM improves health outcomes, however neither health outcomes nor impact on AMR were adequately addressed. Variations in TDM implementation meant that a meta-analysis was not suitable. Penicillin TDM needs standardization, however there is currently no clear evidence of optimal conditions. Suitably powered studies are required to resolve the ambiguity surrounding the impact of TDM on clinical outcomes, including AMR. Further, standardized protocols and concentration targets need to be identified for TDM to be implemented successfully.
      原文链接:
    • NSTL
    • Oxford Univ Press

    Genomic analysis of CTX-M-115 and OXA-23/-72 co-producing Acinetobacter baumannii, and their potential to spread resistance genes by natural transformation

    Vuillemenot, Jean-BaptisteBour, MaximeBeyrouthy, RachaBonnet, Richard...
    11页
    查看更多>>摘要：Objectives To characterize Acinetobacter baumannii strains co-producing the ESBL CTX-M-115 and carbapenem-hydrolysing class D beta-lactamases (CHDLs), and to assess the potential diffusion of their resistance genes by horizontal transfer. Methods Nineteen CTX-M-115/CHDL-positive A. baumannii were collected between 2015 and 2019 from patients hospitalized in France. Their whole-genome sequences were determined on Illumina and Oxford Nanopore platforms and were compared through core-genome MLST (cgMLST) and SNP analyses. Transferability of resistance genes was investigated by natural transformation assays. Results Eighteen strains were found to harbour CHDL OXA-72, and another one CHDL OXA-23, in addition to CTX-M-115, narrow-spectrum beta-lactamases and aminoglycoside resistance determinants including ArmA. cgMLST typing, as well as Oxford Scheme ST and K locus typing, confirmed that 17 out of the 18 CTX-M-115/OXA-72 isolates belonged to new subclades within clonal complex 78 (CC78). The chromosomal region carrying the bla(CTX-M-115) gene appeared to vary greatly both in gene content and in length (from 20 to 79 kb) among the strains, likely because of IS26-mediated DNA rearrangements. The bla(OXA-72) gene was localized on closely related plasmids showing structural variations that occurred between pdif sites. Transfer of all the beta-lactamase genes, as well as aminoglycoside resistance determinants to a drug-susceptible A. baumannii recipient, was easily obtained in vitro by natural transformation. Conclusions This work highlights the propensity of CC78 isolates to collect multiple antibiotic resistance genes, to rearrange and to pass them to other A. baumannii strains via natural transformation. This process, along with mobile genetic elements, likely contributes to the considerable genomic plasticity of clinical strains, and to the diversity of molecular mechanisms sustaining their multidrug resistance.
      原文链接:
    • NSTL
    • Oxford Univ Press

    A novel Bacteroides metallo-beta-lactamase (MBL) and its gene (crxA) in Bacteroides xylanisolvens revealed by genomic sequencing and functional analysis

    Soki, JozsefLang, UweSchumacher, UlrikeNagy, Istvan...
    4页
    查看更多>>摘要：Objectives We sought to characterize the carbapenem resistance mechanism of Bacteroides xylanisolvens 14880, an imipenem-resistant strain from Germany, and assess its prevalence. Methods Antimicrobial susceptibilities were determined using agar dilution or Etest methodology and specific imipenemase activity was detected. The genomic sequence of B. xylanisolvens 14880 was determined and analysed for antibiotic resistance genes and genomic islands. We also used gene transfer to a carbapenem susceptible host, along with 5 '-RACE, conventional PCR with capillary sequencing and RT-PCR-based screening. Results B. xylanisolvens 14880 displayed resistance to carbapenems and produced high specific imipenemase activity. Its genomic sequence was 6.1 Mbp and a class B1 beta-lactamase gene (termed crxA) was detected in it. crxA was carried on a putative genomic island with insertion sequence (IS) elements and a putative GNAT (Gcn5-like acetyltransferase) toxin gene. Promoter localization by 5 '-RACE and gene targeting to an imipenem-susceptible Bacteroides host indicated that it is activated by an IS1380-like IS element and it can confer carbapenem resistance. The PCR screening of Bacteroides strains showed that crxA was specific to B. xylanisolvens with a carriage rate of 16.7%. Conclusions B. xylanisolvens strains can harbour a carbapenem resistance gene, which has many similarities to the 'cfiA system': metallo-beta-lactamase (MBL), IS element activation, carriage of a GNAT toxin gene, specific for a unique Bacteroides species with a significant prevalence.
      原文链接:
    • NSTL
    • Oxford Univ Press

    Telithromycin resistance in Campylobacter mediated by 23S rRNA A2075G mutation and erm(B)

    Liu, PengQin, XiaoxiaCao, TingtingYang, Yuying...
    4页
    查看更多>>摘要：Objectives Recently, epidemiological research has shown an unusually high prevalence of telithromycin-resistant Campylobacter. This study was designed to investigate the potential resistance mechanism of telithromycin resistance in Campylobacter. Methods A total of 122 Campylobacter isolates of chicken origin collected in 2019 from three regions of China were tested for susceptibility to telithromycin. The potential mechanism of resistance to telithromycin in Campylobacter was revealed through WGS analysis and natural transformation. Results In this study, 51.3% (61/119) of Campylobacter coli and 100.0% (3/3) of Campylobacter jejuni were resistant to telithromycin. erm(B) or A2075G mutation in 23S rRNA (23S_A2075G) was identified in the telithromycin-resistant C. coli. Cloning of the erm(B) or 23S_A2075G into C. jejuni NCTC 11168 resulted in a 256-fold increase in the MIC of telithromycin. MLST results indicated that various STs were involved in the dissemination of 23S_A2075G and erm(B). Phylogenetic analysis showed that the C. coli isolates with 23S_A2075G and erm(B) from chickens and humans were closely related. Conclusions 23S_A2075G and erm(B), which have been widely spread in different genotypes of C. coli isolated from animals and humans, could mediate high levels of resistance to telithromycin in C. coli. C. coli containing 23S_A2075G or erm(B) are clonally related and have the potential to spread zoonotic diseases.
      原文链接:
    • NSTL
    • Oxford Univ Press

    Multiple secondary outbreaks of NDM-producing Enterobacter hormaechei in the context of endemic NDM-producing Klebsiella pneumoniae

    Izdebski, R.Biedrzycka, M.Urbanowicz, P.Papierowska-Kozdoj, W....
    9页
    查看更多>>摘要：Background Consecutive Polish regions have become endemic for NDM-1-producing Klebsiella pneumoniae ST11, followed by K. pneumoniae ST147. Since 2017 a significant increase in NDM-positive Enterobacter hormaechei cases has been observed. Objectives To investigate the origin and character of this increase in NDM-positive E. hormaechei. Methods The analysis included 160 NDM-producing Enterobacter cloacae complex isolates, recovered in 2015-20 in 37 centres of 9/16 regions. These were typed by PFGE and MLST, and screened by PCR-mapping for NDM-1-encoding Tn125-like elements. Forty-four isolates were sequenced by MiSeq. Species identification was based on whole-genome average nucleotide identity; clonality and phylogeny were inferred by SNP approaches. The structural plasmid analysis was done for 12 isolates sequenced by MinION. Results The isolates belonged to 11 STs, predominantly ST89 (65.6%), followed by ST146 (15.6%), ST198 (7.5%) and ST1303 (3.7%), representing different E. hormaechei subspecies. Most of the isolates contained the Tn125A variant of the K. pneumoniae ST11 lineage, and several had Tn125F of the ST147. Individual E. hormaechei genotypes represented various epidemiological situations, from sporadic cases to single-hospital, city and regional outbreaks, including one caused by ST89 organisms with 82 cases in 17 centres. Acquisitions of the Tn125A/Tn125F determinants by the E. hormaechei strains occurred around 10 times and were plasmid-mediated, with a significant plasmid rearrangement in case of Tn125F. Conclusions The increase in E. hormaechei NDM-1 cases in Poland is a consequence of the uncontrolled spread of NDM-1-producing K. pneumoniae genotypes. Several E. hormaechei lineages have acquired NDM-encoding plasmids in different locales which started 'secondary' progressive outbreaks.
      原文链接:
    • NSTL
    • Oxford Univ Press

    Dynamic evolution of imipenem/relebactam resistance in a KPC-producing Klebsiella pneumoniae from a single patient during ceftazidime/avibactam-based treatments

    Gaibani, PaoloBovo, FedericaBussini, LindaLazzarotto, Tiziana...
    8页
    查看更多>>摘要：Objectives The novel carbapenem/beta-lactamase inhibitor combination imipenem/cilastatin/relebactam has been developed for the treatment of infections due to carbapenemase-producing Enterobacteriaceae (CPE). Herein, we describe the in vivo evolution of imipenem/cilastatin/relebactam resistance in longitudinal intra-patient Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) strains isolated from a patient following ceftazidime/avibactam-based treatments. Methods WGS analysis was performed on KPC-Kp strains isolated at different times and during antimicrobial treatments from the same patient. Genome assemblies were performed using a hybrid approach using Illumina iSeq 100 and Minion Oxford Nanopore platforms. Subpopulation analysis and allele frequency determination was performed by mapping Illumina reads to bla(KPC). Results During antimicrobial treatment, resistance to ceftazidime/avibactam was observed following 16 days of antimicrobial therapy. WGS results showed that all KPC-Kp exhibited a low SNP rate of divergence, belonged to ST512 and shared similar antimicrobial resistance and porin gene patterns. Genetic analysis demonstrated that the first ceftazidime/avibactam-resistant KPC-Kp strain harboured a bla(KPC-53) gene in a Tn4401 transposon moved from IncFII(K) to a 43 kb IncX3 plasmid, while a imipenem/cilastatin/relebactam-resistant strain exhibited two copies of the Tn4401 transposon in IncFII(K) and IncX3 plasmids, resulting in an increased bla(KPC) copy number. Of note, frequency analysis demonstrated that imipenem/cilastatin/relebactam-resistant KPC-Kp consisted of mixed subpopulations harbouring bla(KPC-40) and bla(KPC-53) alleles. Conclusions Our results show the in vivo evolution of genetic rearrangement conferring resistance to imipenem/relebactam in a patient with KPC-Kp infection and treated with different ceftazidime/avibactam-based treatments. The rapid development of mutations and the high adaptability of its genome highlight the potential threat of KPC-Kp.
      原文链接:
    • NSTL
    • Oxford Univ Press