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Background: Antimicrobial stewardship (AMS) programmes in hospitals support optimal antimicrobial use by utilizing strategies such as restriction policies and education. Several systematic reviews on digital interventions supporting AMS have been conducted but they have focused on specific interventions and outcomes.Objectives: To provide a systematic overview and synthesis of evidence on the effectiveness of digital interventions to improve antimicrobial prescribing and monitoring in hospitals.Methods: Multiple databases were searched from 2010 onwards. Review papers were eligible if they included studies that examined the effectiveness of AMS digital interventions in an inpatient hospital setting. Papers were excluded if they were not systematic reviews, were limited to a paediatric setting, or were not in English.Results: Eight systematic reviews were included for data extraction. A large number of digital interventions were evaluated, with a strong focus on clinical decision support. Due to the heterogeneity of the interventions and outcome measures, a meta-analysis could not be performed. The majority of reviews reported that digital interventions reduced antimicrobial use and improved antimicrobial appropriateness. The impact of digital interventions on clinical outcomes was inconsistent.Conclusions: Digital interventions reduce antimicrobial use and improve antimicrobial appropriateness in hospitals, but no firm conclusions can be drawn about the degree to which different types of digital interventions achieve these outcomes. Evaluation of sociotechnical aspects of digital intervention implementation is limited, despite the critical role that user acceptance, uptake and feasibility play in ensuring improvements in AMS are achieved with digital health. [ABSTRACT FROM AUTHOR]

Introduction Inappropriate antibiotic use contributes to antimicrobial resistance. High-income countries have high rates of antibiotic use, with a prevalence of health inequalities amongst populations. Objectives To understand the influence of factors commonly known to be associated with health inequalities on antibiotic use in high-income countries. Methods Factors commonly known to be associated with health inequalities were defined as protected characteristics under UK's Equality Act (age, disability, gender reassignment, marriage and civil partnership, pregnancy and maternity, race/ethnicity, religion or belief, sex, sexual orientation), socioeconomic characteristics (income, insurance, employment status, deprivation, education), geography (urban versus rural, region) and vulnerable groups. The study followed PRISMA-ScR and, PRISMA-E statements. Results Fifty-eight of 402 identified studies met inclusion criteria. Fifty of those papers (86%) included one or more protected characteristics, 37 (64%) socioeconomic characteristics, 21 (36%) geography and 6 (10%) vulnerable groups. Adults in older age groups, especially those in residential care, had the highest antibiotic use. The influence of race or ethnicity and antibiotic use was particular to country context. Areas of high deprivation had higher antibiotic use compared with areas of no or low deprivation, and geographical variation existed within countries. When faced with health system barriers, migrants relied on alternative routes of antibiotic supply other than prescription. Recommendations for future research To investigate how factors and wider social determinants of health interplay and impact antibiotic use, using frameworks/approaches to reduce health inequalities such as England's Core20PLUS approach. Antimicrobial stewardship initiatives should equip healthcare professionals to review patients at the highest risk of antibiotic use. [ABSTRACT FROM AUTHOR]

Objectives Artemisinin-resistant Plasmodium falciparum malaria is currently spreading globally, including in Africa. Artemisinin resistance also leads to resistance to partner drugs used in artemisinin-based combination therapies. Sequencing of kelch13 , which is associated with artemisinin resistance, culture-based partner drug susceptibility tests, and ELISA-based growth measurement are conventionally used to monitor resistance; however, their application is challenging in resource-limited settings. Methods An experimental package for field studies with minimum human/material requirements was developed. Results First, qPCR-based SNP assay was applied in artemisinin resistance screening, which can detect mutations within 1 h and facilitate sample selection for subsequent processes. It had 100% sensitivity and specificity compared with DNA sequencing in the detection of the two common artemisinin resistance mutations in Uganda, C469Y and A675V. Moreover, in the partner drug susceptibility test, the cultured samples were dry-preserved on a 96-well filter paper plate and shipped to the central laboratory. Parasite growth was measured by ELISA using redissolved samples. It well reproduced the results of direct ELISA, reducing significant workload in the field (Pearson correlation coefficient: 0.984; 95% CI: 0.975–0.990). Conclusions Large-scale and sustainable monitoring is required urgently to track rapidly spreading drug-resistant malaria. In malaria-endemic areas, where research resources are often limited, simplicity and feasibility of the procedure is especially important. Our approach combines a qPCR-based rapid test, which is also applicable to point-of-care diagnosis of artemisinin resistance and centralized analysis of ex vivo culture. The approach could improve efficiency of field experiments and accelerate global drug resistance surveillance. [ABSTRACT FROM AUTHOR]

Management of invasive mould infections (IMIs) is challenging in Asia, as awareness among medical practitioners can be low and resources are limited. Timely diagnosis and appropriate treatment of IMIs can mitigate the impact on morbidity and mortality, but diagnostic methods, as well as access to preferred antifungal medications, may vary throughout the region. Knowledge of local epidemiology and accurate diagnosis and identification of causal pathogens would facilitate optimal treatment but data in Asia are lacking. To address these unmet needs in the management of IMIs, this paper is a call for urgent action in the following areas: improving awareness of the threat of IMIs; providing education to frontline clinicians across a broad range of specialties on 'red flags' for suspicion of IMIs; prioritizing cost-effective rapid diagnostic testing; improving access to preferred antifungal medications; and closing the gaps in local epidemiological data on IMIs to inform local treatment guidelines. [ABSTRACT FROM AUTHOR]

Background: In daily hospital practice, antibiotic therapy is commonly prescribed for longer than recommended in guidelines. Understanding the key drivers of prescribing behaviour is crucial to generate meaningful interventions to bridge this evidence-to-practice gap.Objectives: To identify behavioural determinants that might prevent or enable improvements in duration of antibiotic therapy in daily practice.Methods: We systematically searched PubMed, Embase, PsycINFO and Web of Science for relevant studies that were published between January 2000 and August 2021. All qualitative, quantitative and mixed-method studies in adults in a hospital setting that reported determinants of antibiotic therapy duration were included.Results: Twenty-two papers were included in this review. A first set of studies provided 82 behavioural determinants that shape how health professionals make decisions about duration; most of these were related to individual health professionals' knowledge, skills and cognitions, and to professionals' interactions. A second set of studies provided 17 determinants that point to differences in duration regarding various pathogens, diseases, or patient, professional or hospital department characteristics, but do not explain why or how these differences occur.Conclusions: Limited literature is available describing a wide range of determinants that influence duration of antibiotic therapy in daily practice. This review provides a stepping stone for the development of stewardship interventions to optimize antibiotic therapy duration, but more research is warranted. Stewardship teams must develop complex improvement interventions to address the wide variety of behavioural determinants, adapted to the specific pathogen, disease, patient, professional and/or hospital department involved. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic saw unprecedented resources and funds driven into research for the development, and subsequent rapid distribution, of vaccines, diagnostics and directly acting antivirals (DAAs). DAAs have undeniably prevented progression and life-threatening conditions in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, there are concerns of antimicrobial resistance (AMR), antiviral resistance specifically, for DAAs. To preserve activity of DAAs for COVID-19 therapy, as well as detect possible mutations conferring resistance, antimicrobial stewardship and surveillance were rapidly implemented in England. This paper expands on the ubiquitous ongoing public health activities carried out in England, including epidemiologic, virologic and genomic surveillance, to support the stewardship of DAAs and assess the deployment, safety, effectiveness and resistance potential of these novel and repurposed therapeutics. [ABSTRACT FROM AUTHOR]

With a WHO-estimated excess mortality burden of 14.9 million over the course of 2020 and 2021, the COVID-19 pandemic has had a major human impact so far. It has also affected a range of disciplines, systems and practices from mathematical modelling to behavioural sciences, pharmaceutical development to health system management. This article explores these developments and, to set the scene, this paper summarizes the global epidemiology of COVID-19 from January 2020 to June 2021 and considers some potential drivers of variation. [ABSTRACT FROM AUTHOR]

One of the major challenges for tackling antimicrobial resistance (AMR) is understanding the true burden of resistance and its impact on human health, particularly in locations where surveillance is minimal and data are sparse. The Global Research on AntiMicrobial resistance (GRAM) Project was launched to address these gaps. The scale of the challenge was considerable, but after 4 years of developing a stringent methodological approach and collecting/analysing data from many different sources, the capstone GRAM paper was published in January 2022. This article discusses the key findings and reviews the challenges in scaling-up AMR surveillance systems in a One Health framework. The GRAM Project represents a critical first-step in obtaining the accurate data that are needed to correctly target actions to control AMR. [ABSTRACT FROM AUTHOR]

Background Antimicrobial resistance (AMR) is one of the biggest threats to global public health. Selection of resistant bacteria is driven by inappropriate use of antibiotics, amongst other factors. COVID-19 may have exacerbated AMR due to unnecessary antibiotic prescribing. Country-level knowledge is needed to understand options for action. Objectives To review AMR in Kuwait and initiatives underway addressing it. Identifying any areas where more information is required will provide a call to action to minimize any further rise in AMR within Kuwait and to improve patient outcomes. Methods National initiatives to address AMR, antibiotic use and prescribing, and availability of susceptibility data, particularly for the key community-acquired respiratory tract infection (CA-RTI) pathogens Streptococcus pneumoniae and Haemophilus influenzae , were identified. National and international antibiotic prescribing guidelines commonly used locally for specific CA-RTIs (community-acquired pneumonia, acute otitis media and acute bacterial rhinosinusitis) were also reviewed, plus local antibiotic availability. Insights from a clinician in Kuwait were sought to contextualize this information. Conclusions In Kuwait there have been some initiatives addressing AMR such as annual campaigns for proper use of antibiotics. Antibiotic use is high but there appears to be a low understanding in the general public about their appropriate use. However, there is legislation in place prohibiting over-the-counter purchase of antibiotics. Only international guidelines for CA-RTIs are used. A more standardized inclusive approach in developing local guidelines, using up-to-date surveillance data of isolates from community-acquired infections in Kuwait, could make management guideline use more locally relevant for clinicians. This would pave the way for a higher level of appropriate antibiotic prescribing and improved adherence. This would, in turn, potentially limit AMR development and improve clinical patient outcomes. [ABSTRACT FROM AUTHOR]

Background Antimicrobial resistance (AMR) is one of the biggest threats to global public health. Selection of resistant bacteria is driven by inappropriate use of antibiotics, amongst other factors. COVID-19 may have exacerbated AMR due to unnecessary antibiotic prescribing. Country-level knowledge is needed to understand options for action. Objectives To review AMR in Saudi Arabia and initiatives addressing it. Identifying areas where more information is required will provide a call to action to minimize a further rise in AMR within Saudi Arabia and improve patient outcomes. Methods National AMR initiatives, antibiotic use and prescribing, and availability of susceptibility data, particularly for the key community-acquired respiratory tract infection (CA-RTI) pathogens Streptococcus pneumoniae and Haemophilus influenzae , were identified. National and international antibiotic prescribing guidelines commonly used locally for specific CA-RTIs (community-acquired pneumonia, acute otitis media and acute bacterial rhinosinusitis) were also reviewed, plus local antibiotic availability. Insights from a clinician in Saudi Arabia were sought to contextualize this information. Conclusions Various initiatives are underway in Saudi Arabia, including a National Action Plan for AMR, which was published in 2017. However, AMR is rising and knowledge about appropriate antibiotic use seems to be lacking among physicians and the general public. Various international guidelines are utilized by clinicians in Saudi Arabia, but a more standardized inclusive approach in developing local guidelines, using up-to-date surveillance data of isolates from community-acquired infections in Saudi Arabia could make management guideline use more locally relevant for clinicians. This would pave the way for a higher level of appropriate antibiotic prescribing and improved adherence. This would, in turn, potentially limit AMR development and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background Antimicrobial reistance (AMR) is one of the biggest threats to global public health. Selection of resistant bacteria is driven by inappropriate use of antibiotics, amongst other factors. COVID-19 may have exacerbated AMR due to unnecessary antibiotic prescribing. Country-level knowledge is needed to understand options for action. Objectives To review AMR in Russia and any initiatives addressing it. Identifying any areas where more information is required will provide a call to action to minimize any further rise in AMR within Russia and to improve patient outcomes. Methods National AMR initiatives, antibiotic use and prescribing, and availability of susceptibility data, in particular for the key community-acquired respiratory tract infection (CA-RTI) pathogens Streptococcus pneumoniae and Haemophilus influenzae , were identified. National and international antibiotic prescribing guidelines commonly used locally for specific CA-RTIs (community-acquired pneumonia, acute otitis media and acute bacterial rhinosinusitis) were also reviewed, plus local antibiotic availability. Insights from both a local clinician and a local clinical microbiologist were sought to contextualize this information. Conclusions Russia launched a national strategy in 2017 to prevent the spread of AMR and the WHO reports that as of 2020–21, it is being implemented and actively monitored. Reports suggest outpatient antibiotic use of antibiotics is high and that non-prescription access and self-medication are very common. Antibiotic susceptibility studies in Russia include PeHASus, a multicentre epidemiological study focusing on susceptibilities of community-acquired respiratory pathogens and international studies such as Survey of Antibiotic Resistance (SOAR), Antimicrobial Testing Leadership and Surveillance (ATLAS) and SENTRY Antimicrobial Surveillance Program. International guidelines are used to support the development of local guidelines in Russia, and for the common CA-RTIs Russian clinicians use of several country-specific local antibiotic prescribing guidelines. A standardized inclusive approach in developing local guidelines, using up-to-date surveillance data of isolates from community-acquired infections in Russia, could make guideline use more locally relevant for clinicians. This would pave the way for a higher level of appropriate antibiotic prescribing and improved adherence. This would, in turn, potentially limit AMR development and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background Antimicrobial resistance (AMR) is one of the biggest threats to global public health. Selection of resistant bacteria is driven by inappropriate use of antibiotics, amongst other factors. COVID-19 may have exacerbated AMR due to unnecessary antibiotic prescribing. Country-level knowledge is needed to understand options for action. Objectives To review AMR in Mexico and initiatives addressing it. Identifying any areas where more information is required will provide a call to action to minimize any further rises in AMR and to improve patient outcomes. Methods National AMR initiatives in Mexico, antibiotic use and prescribing, and availability of susceptibility data, particularly the key community-acquired respiratory tract infection (CA-RTI) pathogens Streptococcus pneumoniae and Haemophilus influenzae , were identified. National and international antibiotic prescribing guidelines commonly used in Mexico for specific CA-RTIs (community-acquired pneumonia, acute otitis media and acute bacterial rhinosinusitis) were also reviewed, along with local antibiotic availability. Insights from a local clinician were sought to contextualize this information. Conclusions The Mexican national AMR strategy was published in 2018. This comprised similar objectives to the Global Action Plan from the World Health Assembly (2015) and was compulsory, requiring full compliance from members of the National Health System. Historically, antibiotic consumption in Mexico has been high, however, between 2000 and 2015, consumption fell, in sharp contrast to the majority of countries. Mexico lacks a national surveillance network for AMR, however there are several ongoing global surveillance studies providing local antibiotic susceptibility data. International and local antibiotic prescribing guidelines for CA-RTIs are used. A more standardized inclusive approach in developing local guidelines, using up-to-date local surveillance data of isolates from community-acquired infections, could make guideline use more locally relevant. This would pave the way for a higher level of appropriate antibiotic prescribing and improved adherence. This would, in turn, potentially limit AMR development in Mexico and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background Antimicrobial resistance (AMR) is one of the biggest threats to global public health. Selection of resistant bacteria is driven by inappropriate use of antibiotics, amongst other factors. COVID-19 may have exacerbated AMR due to unnecessary antibiotic prescribing. Country-level knowledge is needed to understand options for action. Objectives To review the situation with respect to AMR in Brazil and initiatives addressing it. Identifying areas where more information is required will provide a call to action to minimize any further rises in AMR within Brazil and to improve patient outcomes. Methods National initiatives to address AMR, antibiotic use and prescribing in Brazil, and availability of susceptibility data, particularly for the key community-acquired respiratory tract infections (CA-RTI) pathogens Streptococcus pneumoniae and Haemophilus influenzae , were identified. National and international antibiotic prescribing guidelines for CA-RTIs (community-acquired pneumonia, acute otitis media and acute bacterial rhinosinusitis) commonly used locally were also reviewed, along with local antibiotic availability. Conclusions In Brazil there have been some initiatives addressing AMR such as the National Action Plan for AMR, established in 2018. Antibiotic consumption in Brazil is high but a ban on over-the-counter sales of antibiotics has led to a decrease in consumption. Local antibiotic susceptibility testing needs to be increased and the Survey of Antibiotic Resistance (SOAR) study in Brazil will provide useful data for pathogens causing CA-RTIs. A more standardized inclusive approach in developing local guidelines, using up-to-date surveillance data of isolates from community-acquired infections in Brazil, could make guideline use more locally relevant for clinicians. This would pave the way for a higher level of appropriate antibiotic prescribing and improved adherence. This would, in turn, potentially limit AMR development and improve clinical outcomes for patients. [ABSTRACT FROM AUTHOR]

Su I et al. i propose that more severely ill patients receive less antibiotic treatment because they may have shorter hospitals stays. Impact of introducing procalcitonin testing on antibiotic usage in acute NHS hospitals during the first wave of COVID-19 in the UK: a controlled interrupted time series analysis of organization-level data - authors' response We thank Dr Su and colleagues for their interest in our paper with reference to their pre-pandemic study.[1] We agree that procalcitonin (PCT) has the potential to improve the accuracy of both decisions to start and to de-escalate antibiotic treatment. [Extracted from the article]

Third, it is recommended to perform both intention-to-treat (ITT) and per-protocol (PP) analyses for non-inferiority trials.[2] This article did not provide either of the two. We read with interest the article by Zhao I et al i .[1] in which they present the results of a Phase III non-inferiority trial comparing the effectiveness and safety of the new drug contezolid with linezolid for complicated skin and soft tissue infections (cSSTIs). [Extracted from the article]

We thank Drs Sulis, Pai and Gandra for their interest in our paper and their knowledgeable comments.[1] We agree with the authors that the global decrease in antibiotic consumption during the COVID-19 pandemic is only suggestive of continued antimicrobial resistance (AMR) efforts. Country-level variations in antibiotic consumption are expected as we displayed in our analysis (Figure 4 and Table S3).[2] Our analysis presented aggregated data on total antimicrobial consumption worldwide and in developing and developed countries. The decrease in azithromycin consumption in developed countries follows the overall decrease in total antibiotic consumption during this period and could be due to dissemination of evidence recommending against the use of azithromycin for COVID-19 treatment. [Extracted from the article]

Conventional laboratory agar media provide an iron-limited environment for bacterial growth. We thank Longshaw I et al. i for catching a critical misstatement in our paper's supplementary material - iron-limited, cation-adjusted Mueller-Hinton, rather than standard Mueller-Hinton broth, was indeed used to grow the isolates per CLSI methodology and then plated on standard Mueller-Hinton agar for the population analysis profile (PAP).[2] Despite iron being present in Mueller-Hinton agar, this iron is not thought to be free and bacteria have previously been shown to have a phenotype consistent with iron limitation on standard agar.[3],[4] Furthermore, we follow CLSI guidelines for cefiderocol susceptibility testing on solid medium. We appreciate the inquiry from Longshaw I et al. i with regards to our case report entitled 'Bacteraemia with an MBL-producing I Klebsiella pneumoniae i : treatment and the potential role of cefiderocol heteroresistance'.[1] We agree, as stated in our original report, that it is unclear whether the patient was re-infected with the same I Klebsiella i isolate adherent to a retained indwelling catheter or potentially from a lack of complete bacterial killing due to cefiderocol heteroresistance. [Extracted from the article]

Echinocandins are the preferred initial therapy for I Candida parapsilosis i infections.[1] While mutations in I fks1p i hotspot (HS) regions have been identified to confer echinocandin resistance in other I Candida i species, such as I Candida albicans i and I Candida glabrata i ,[2] there have been few data documenting mechanisms of echinocandin resistance in I C. parapsilosis. i A recently published paper by Arastehfar I et al i .[3] identified a novel mutation (R658G) in HS1 of I fks1p i in four micafungin-resistant I C. parapsilosis i isolates. Genetically related micafungin-resistant Candida parapsilosis blood isolates harbouring novel mutation R658G in hotspot 1 of Fks1p: a new challenge?. [Extracted from the article]

We believe that our analyses of ICONA cohort data, which focused specifically on the association between sex and response to DTG-containing regimens, cannot be directly compared to those of the Ciccullo study. We do not know how the reasons for discontinuation were collected by the Ciccullo cohort; in particular, it is unclear whether discontinuations due to simplification were counted as events in the analysis with outcome treatment failure. Long-term outcome of dolutegravir-containing regimens according to sex: data from the ICONA Study-authors' response. [Extracted from the article]

The patient was diagnosed with a second recurrence of CDI and was treated with a 14 day course of enteral vancomycin and a concurrent 10 day course of enteral metronidazole, with plans for a slow vancomycin taper. I Clostridioides difficile i infection (CDI) is a common hospital-acquired infection and an increasingly frequent cause of morbidity and mortality among hospitalized patients. The patient continued to have between two and four loose bowel movements a day and two I C. difficile i toxin assays performed on treatment Day 5 and post-treatment Day 1 were negative. [Extracted from the article]

Objectives Pre-existing rilpivirine resistance-associated mutations (RVP-RAMs) have been found to predict HIV-1 virological failure in those switching to long-acting injectable cabotegravir/rilpivirine. We here evaluated the prevalence of archived RPV-RAMs in a cohort of people living with HIV (PWH). Methods We analysed near full-length HIV-1 pol sequences from proviral DNA for the presence of RPV-RAMs, which were defined according to the 2022 IAS–USA drug resistance mutation list and Stanford HIV drug resistance database. Results RPV-RAMs were identified in 757/5805 sequences, giving a prevalence of 13.0% (95% CI 12%–13.9%). Amongst the ART-naive group, 137/1281 (10.7%, 95% CI 9.1%–12.5%) had at least one RPV-RAM. Of the 4524 PWH with viral suppression on ART (VL <400 copies/mL), 620 (13.7%, 95% CI 12.7%–14.7%) had at least one RPV-RAM. E138A was the most prevalent RPV-RAM in the ART-naive group (7.9%) and the ART-suppressed group (9.3%). The rest of the mutations observed (L100I, K101E, E138G, E138K, E138Q, Y181C, H221Y, M230L, A98G, V179D, G190A, G190E and M230I) were below a prevalence of 1%. Conclusions RPV-RAMs were present in 10.7% of ART-naive and 13.7% of ART-suppressed PWH in Botswana. The most common RPV-RAM in both groups was E138A. Since individuals with the E138A mutation may be more likely to fail cabotegravir/rilpivirine, monitoring RPV-RAMs will be crucial for effective cabotegravir/rilpivirine implementation in this setting. [ABSTRACT FROM AUTHOR]

Critically ill patients have increased variability in beta-lactam antibiotic (beta-lactam) exposure due to alterations in their volume of distribution and elimination. Therapeutic drug monitoring (TDM) of beta-lactams, as a dose optimization and individualization tool, has been recommended to overcome this variability in exposure. Despite its potential benefit, only a few centres worldwide perform beta-lactam TDM. An important reason for the low uptake is that the evidence for clinical benefits of beta-lactam TDM is not well established. TDM also requires the availability of specific infrastructure, knowledge and expertise. Observational studies and systematic reviews have demonstrated that TDM leads to an improvement in achieving target concentrations, a reduction in potentially toxic concentrations and improvement of clinical and microbiological outcomes. However, a small number of randomized controlled trials have not shown a mortality benefit. Opportunities for improved study design are apparent, as existing studies are limited by their inclusion of heterogeneous patient populations, including patients that may not even have infection, small sample size, variability in the types of beta-lactams included, infections caused by highly susceptible bacteria, and varied sampling, analytical and dosing algorithm methods. Here we review the fundamentals of beta-lactam TDM in critically ill patients, the existing clinical evidence and the practical aspects involved in beta-lactam TDM implementation. [ABSTRACT FROM AUTHOR]

Objectives To investigate complication rates of acute sinusitis in general practice, and whether antibiotic prescribing had an impact on complication rate. Methods All adult patients diagnosed with sinusitis in Norwegian general practice between 1 July 2012 and 30 June 2019 were included. GP consultation data from the Norwegian Control and Payment for Health Reimbursements Database were linked with antibiotic prescriptions (Norwegian Prescription Database) and hospital admissions (Norwegian Patient Registry). Main outcomes were sinusitis-related hospitalizations and severe complications within 30 days. Logistic regression was used to estimate associations between antibiotic prescriptions, prespecified risk factors, individual GP prescribing quintile, and outcomes. Results A total of 711 069 episodes of acute sinusitis in 415 781 patients were identified. During the study period, both annual episode rate (from 30.2 to 21.2 per 1000 inhabitants) and antibiotic prescription rate (63.3% to 46.5%; P  < 0.001) decreased. Yearly hospitalization rate was stable at 10.0 cases per 10 000 sinusitis episodes and the corresponding rate of severe complications was 3.2, with no yearly change (P  = 0.765). Antibiotic prescribing was associated with increased risk of hospitalization [adjusted OR 1.8 (95% CI 1.5–2.1)] but not with severe complications. Individual GP prescribing quintile was not associated with any of the outcomes, whereas risk factors such as previous drug abuse, or head injury, skull surgery or malformations, and being immunocompromised were significantly associated with increased risk of both outcomes. Conclusions Severe complications of acute sinusitis were rare and no protective effect of high prescribing practice among GPs was found. Recommendations to further reduce antibiotic prescribing are generally encouraged, except for high-risk groups. [ABSTRACT FROM AUTHOR]

Background Imipenem/funobactam (formerly XNW4107) is a novel β-lactam/β-lactamase inhibitor with activity against MDR Acinetobacter baumannii , Pseudomonas aeruginosa and Enterobacterales strains. Using a neutropenic murine thigh infection model, we aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) index, relative to funobactam exposure, that correlated most closely with the in vivo efficacy of imipenem/funobactam combination and the magnitude of index required for efficacy against serine carbapenemase-producing clinical strains. Methods Dose-fractionation was conducted against three strains. Imipenem human-simulated regimen (HSR, 500 mg q6h 1 h infusion) efficacy in combination with escalating funobactam exposures against seven A. baumannii , four P. aeruginosa and four Klebsiella pneumoniae (imipenem/funobactam MICs 0.25–16 mg/L) was assessed as 24 h change in log10cfu/thigh. Results Increased funobactam fractionation enhanced efficacy, indicating time-dependent killing. Changes in log10cfu/thigh versus % f T > MIC were poorly predictive of efficacy; bactericidal activity was observed at % f T > MIC = 0%. Across different threshold plasma funobactam concentrations (C Ts), % f T >  C T(1 mg/L) had the highest correlation with efficacy. Normalizing the % f T >  C T = 1 mg/L index to the respective isolate imipenem/funobactam MIC ([% f T >  C T]/MIC) allowed integration of the isolate's susceptibility, which further enhanced the correlation. Median (% f T >  C T[1 mg/L])/MIC values associated with 1-log reductions were 9.82 and 9.90 for A. baumannii and P. aeruginosa, respectively. Median (% f T >  C T[1 mg/L])/MIC associated with stasis was 55.73 for K. pneumoniae. Imipenem/funobactam 500/250 mg q6h 1 h infusion HSR produced >1-log kill against 6/7 A. baumannii , 4/4 P. aeruginosa and stasis against 4/4 K. pneumoniae. Conclusions Imipenem/funobactam showed potent in vivo efficacy against serine carbapenemase-producers. The novel PK/PD index (% f T >  C T)/MIC appeared to best describe in vivo activity. [ABSTRACT FROM AUTHOR]

Objectives Resistance genes can be genetically transmitted and exchanged between commensal and pathogenic bacterial species, and in different compartments including the environment, or human and animal guts (One Health concept). The aim of our study was to evaluate whether subdosages of antibiotics administered in veterinary medicine could enhance plasmid transfer and, consequently, resistance gene exchange in gut microbiota. Methods Conjugation frequencies were determined with Escherichia coli strains carrying IncL- (bla OXA-48) or IncI1-type (bla CTX-M-1) plasmids subjected to a series of subinhibitory concentrations of antibiotics used in veterinary medicine, namely amoxicillin, ceftiofur, apramycin, neomycin, enrofloxacin, colistin, erythromycin, florfenicol, lincomycin, oxytetracycline, sulfamethazine, tiamulin and the ionophore narasin. Treatments with subinhibitory dosages were performed with and without supplementation with the antioxidant edaravone, known as a mitigator of the inducibility effect of several antibiotics on plasmid conjugation frequency (PCF). Expression of SOS-response associated genes and fluorescence-based reactive oxygen species (ROS) detection assays were performed to evaluate the stress oxidative response. Results Increased PCFs were observed for both strains when treating with florfenicol and oxytetracycline. Increased expression of the SOS-associated recA gene also occurred concomitantly, as well as increased ROS production. Addition of edaravone to the treatments reduced their PCF and also showed a decreasing effect on SOS and ROS responses for both plasmid scaffolds. Conclusions We showed here that some antibiotics used in veterinary medicine may induce transfer of plasmid-encoded resistance and therefore may contribute to the worldwide spread of antibiotic resistance genes. [ABSTRACT FROM AUTHOR]

Objectives To analyse the influence of antibiotic consumption on healthcare-associated healthcare onset (HAHO) Clostridioides difficile infection (CDI) in a German university hospital setting. Methods Monthly ward-level antibiotic consumption measured in DDD/100 patient days (pd) and CDI surveillance data from five university hospitals in the period 2017 through 2019 were analysed. Uni- and multivariable analyses were performed with generalized estimating equation models. Results A total of 225 wards with 7347 surveillance months and 4 036 602 pd participated. With 1184 HAHO-CDI cases, there was a median incidence density of 0.17/1000 pd (IQR 0.03–0.43) across all specialties, with substantial differences among specialties. Haematology-oncology wards showed the highest median incidence density (0.67/1000 pd, IQR 0.44–1.01), followed by medical ICUs (0.45/1000 pd, IQR 0.27–0.73) and medical general wards (0.32/1000 pd, IQR 0.18–0.53). Multivariable analysis revealed carbapenem (mostly meropenem) consumption to be the only antibiotic class associated with increased HAHO-CDI incidence density. Each carbapenem DDD/100 pd administered increased the HAHO-CDI incidence density by 1.3% [incidence rate ratio (IRR) 1.013; 95% CI 1.006–1.019]. Specialty-specific analyses showed this influence only to be valid for haematological-oncological wards. Overall, factors like ward specialty (e.g. haematology-oncology ward IRR 2.961, 95% CI 2.203–3.980) or other CDI cases on ward had a stronger influence on HAHO-CDI incidence density (e.g. community-associated CDI or unknown association case in same month IRR 1.476, 95% CI 1.242–1.755) than antibiotic consumption. Conclusions In the German university hospital setting, monthly ward-level carbapenem consumption seems to increase the HAHO-CDI incidence density predominantly on haematological-oncological wards. Furthermore, other patient-specific factors seem to be equally important to control HAHO-CDI. [ABSTRACT FROM AUTHOR]

Objectives To use a pre-clinical pharmacokinetic infection model to assess the antibacterial effect of ceftolozane/tazobactam alone or in combination with fosfomycin or tobramycin against Pseudomonas aeruginosa strains with MICs at or higher than the clinical breakpoint (MIC ≥ 4 mg/L). Methods An in vitro model was used to assess changes in bacterial load and population profiles after exposure to mean human serum concentrations of ceftolozane/tazobactam associated with doses of 2 g/1 g q8h, fosfomycin concentrations associated with doses of 8 g q8h or tobramycin at doses of 7 mg/kg q24 h over 168 h. Results Simulations of ceftolozane/tazobactam at 2 g/1 g q8h alone produced 3.5–4.5 log reductions in count by 6 h post drug exposure for strains with MIC ≤32 mg/L. The antibacterial effect over the first 24 h was related to ceftolozane/tazobactam MIC. There was subsequent regrowth with most strains to bacterial densities of >106 CFU/mL. Addition of either fosfomycin or tobramycin resulted in suppression of regrowth and in the case of tobramycin more rapid initial bacterial killing up to 6 h. These effects could not be related to either fosfomycin or tobramycin MICs. Changes in population profiles were noted with ceftolozane/tazobactam alone often after 96 h exposure but such changes were suppressed by fosfomycin and almost abolished by the addition of tobramycin. Conclusions The addition of either fosfomycin or tobramycin to ceftolozane/tazobactam at simulated human clinically observed concentrations reduced P. aeruginosa bacterial loads and the risk of resistance to ceftolozane/tazobactam when strains had ceftolozane/tazobactam MIC values at or above the clinical breakpoint. [ABSTRACT FROM AUTHOR]

Background Carbapenem-resistant Enterobacterales (CRE) are a public health concern. Among these isolates, there are reports of isolates that test as cefepime susceptible or susceptible-dose dependent (SDD) in vitro despite presence of a carbapenemase. This study aimed to evaluate the pharmacokinetic/pharmacodynamic profile of cefepime against carbapenemase-producing (CP-CRE) and non-producing (non-CP-CRE) isolates with a range of cefepime MICs. Methods Reference broth microdilution and modified carbapenem inactivation method (mCIM) were performed on genotypically characterized clinical CRE isolates. Ultimately, CP-CRE (n  = 21; bla KPC) and non-CP-CRE (n  = 19) isolates with a distribution of cefepime MICs (≤0.5 to >256 mg/L) were utilized in the murine thigh infection model. Mice were treated with cefepime human-simulated regimens (HSRs) representative of a standard dose (1 g q12h 0.5 h infusion) or the SDD dose (2 g q8h 0.5 h infusion). Efficacy was assessed as the change in bacterial growth at 24 h compared with 0 h control, where ≥1 log bacterial reduction is considered translational value for clinical efficacy. Results Among both cohorts of CRE isolates, i.e. CP-CRE and non-CP-CRE, that tested as SDD to cefepime in vitro , 1 log bacterial reduction was not attainable with cefepime. Further blunting of cefepime efficacy was observed among CP-CRE isolates compared with non-CP-CRE across both susceptible and SDD categories. Conclusions Data indicate to avoid cefepime for the treatment of serious infections caused by CRE isolates that test as cefepime susceptible or SDD. Data also provide evidence that isolates with the same antibiotic MIC may have different pharmacokinetic/pharmacodynamic profiles due to their antimicrobial resistance mechanism. [ABSTRACT FROM AUTHOR]

Background Pharmacokinetic (PK) data underlying paediatric penicillin dosing remain limited, especially in critical care. Objectives The primary objective of the Neonatal and Paediatric Pharmacokinetics of Antimicrobials study (NAPPA) was to characterize PK profiles of commonly used penicillins using data obtained during routine care, to further understanding of PK variability and inform future evidence-based dosing. Methods NAPPA was a multicentre study of amoxicillin, co-amoxiclav, benzylpenicillin, flucloxacillin and piperacillin/tazobactam. Patients were recruited with informed consent. Antibiotic dosing followed standard of care. PK samples were obtained opportunistically or at optimal times, frozen and analysed using UPLC with tandem MS. Pharmacometric analysis was undertaken using NONMEM software (v7.3). Model-based simulations (n  = 10 000) tested PTA with British National Formulary for Children (BNFC) and WHO dosing. The study had ethical approval. Results For the combined IV PK model, 963 PK samples from 370 participants were analysed simultaneously incorporating amoxicillin, benzylpenicillin, flucloxacillin and piperacillin data. BNFC high-dose regimen simulations gave these PTA results (median fT >MIC at breakpoints of specified pathogens): amoxicillin 100% (Streptococcus pneumoniae); benzylpenicillin 100% (Group B Streptococcus); flucloxacillin 48% (MSSA); and piperacillin 100% (Pseudomonas aeruginosa). Oral population PK models for flucloxacillin and amoxicillin enabled estimation of first-order absorption rate constants (1.16 h−1 and 1.3 h−1) and bioavailability terms (62.7% and 58.7%, respectively). Conclusions NAPPA represents, to our knowledge, the largest prospective combined paediatric penicillin PK study undertaken to date, and the first paediatric flucloxacillin oral PK model. The PTA results provide evidence supportive of BNFC high-dose IV regimens for amoxicillin, benzylpenicillin and piperacillin. [ABSTRACT FROM AUTHOR]

In recent years, publications and debate have emerged in the scientific literature that have linked the use of ionophore coccidiostats, which are themselves not medically important and not related to any therapeutic antibiotics used in human and animal medicine, to resistance development to medically important antibiotics in Enterococcus faecium and Enterococcus faecalis , isolated from broilers and broiler meat. This has been based on the discovery of genes, now named NarAB, that appear to result in elevated MICs of the ionophores narasin, salinomycin and maduramycin and that these are linked to genes responsible for resistance to antibiotics that may be clinically relevant in human medicine. This article will seek to review the most significant publications in this regard and will also examine national antimicrobial resistance surveillance programmes in Norway, Sweden, Denmark and the Netherlands, in order to further evaluate this concern. The conclusion of the review is that the risk that enterococci may pass from broilers to humans and that antimicrobial resistance gene transfer may occur is negligible, remains unquantified and is highly unlikely to be of significance to human health. Indeed, to date no human nosocomial infections have been linked to poultry sources. Concurrently a review of the possible impact of a policy that limits access for poultry farmers and poultry veterinarians to ionophore coccidiostats in broilers indicates predictable negative consequences with regard to antibiotic resistance of significance to animal welfare and to human health. [ABSTRACT FROM AUTHOR]

Background The use of oral antimicrobial agents in patients with short bowel syndrome (SBS) is challenging due to the changes in gastrointestinal anatomy that may result in diminished absorption and altered drug bioavailability. Prospective studies evaluating bioavailability of antimicrobial agents after oral administration in SBS patients are lacking. Objectives To determine the bioavailability of orally administered antimicrobial agents commonly used for treatment in SBS patients to guide clinical decision making when faced with infections. Methods We performed an explorative, clinical study investigating the pharmacokinetics (PK) of clindamycin, ciprofloxacin, flucloxacillin and fluconazole in SBS patients with intestinal failure. Participants received a combination of two antimicrobial agents simultaneously. To determine the oral bioavailability, participants received a single oral and IV dose of both agents on two occasions, after which they underwent intensive PK sampling on six predefined time points up to 12 hours after administration. Primary outcome was the oral bioavailability of these antimicrobial agents. Secondary outcomes were intravenous PK characteristics following non-compartmental analysis. Results Eighteen SBS patients were included: the mean (SD) age was 59 (17) years and 61% of participants were female. The median observed (IQR) bioavailability of ciprofloxacin, clindamycin, flucloxacillin and fluconazole were 36% (24–50), 93% (56–106), 50% (32–76) and 98% (61–107), respectively. Conclusion The bioavailability of selected antimicrobial agents in certain patients with SBS appeared to be better than expected, providing a feasible treatment option. Due to the large observed differences between patients, therapeutic drug monitoring should be part of the treatment to safeguard adequate exposure in all patients. Trial registration Registered in the Dutch Trial Register (NL7796) and EudraCT number 2019-002587-28 [ABSTRACT FROM AUTHOR]

Background Fidaxomicin is a first-line treatment for Clostridioides difficile infections (CDIs). Fidaxomicin resistance has rarely been reported in this urgent antimicrobial resistance threat as defined by the CDC. Objectives To report a case of fidaxomicin-resistant C. difficile isolation in a patient treated by fidaxomicin, characterize the genetic determinant for resistance and the consequences on pathophysiological traits, and review the literature. Patient and methods A 38-year-old male patient with several risk factors for CDI experienced three episodes of hospital-acquired CDI and received fidaxomicin for the first episode. The successive isolates were subjected to phenotypic characterization (antimicrobial susceptibility, growth, sporulation ability and toxin production) and WGS analysis to evaluate clonality and modifications associated with resistance. Results Resistance to fidaxomicin arose in isolates from the recurrences of CDI (MIC: 16 mg/L). WGS analysis showed a close genetic link between strains suggestive of relapses in this patient. A T3428G mutation in the rpoB gene might be associated with fidaxomicin resistance. The resistance was associated with defects in growth, sporulation and production of toxins. A review of the literature found only three previous fidaxomicin-resistant C. difficile clinical strains. Conclusions Although rarely reported, resistance to fidaxomicin may quickly emerge in vivo after a single course of treatment. This observation supports the need for prospective surveillance of the susceptibility of C. difficile to treatment antibiotics. However, the clinical relevance of fidaxomicin resistance still needs to be elucidated, particularly due to its apparent rareness and associated fitness cost. [ABSTRACT FROM AUTHOR]

Aminopenicillins have been widely used for decades for the treatment of various infections in animals and humans in European countries. Following this extensive use, acquired resistance has emerged among human and animal pathogens and commensal bacteria. Aminopenicillins are important first-line treatment options in both humans and animals, but are also among limited therapies for infections with enterococci and Listeria spp. in humans in some settings. Therefore, there is a need to assess the impact of the use of these antimicrobials in animals on public and animal health. The most important mechanisms of resistance to aminopenicillins are the β-lactamase enzymes. Similar resistance genes have been detected in bacteria of human and animal origin, and molecular studies suggest that transmission of resistant bacteria or resistance genes occurs between animals and humans. Due to the complexity of epidemiology and the near ubiquity of many aminopenicillin resistance determinants, the direction of transfer is difficult to ascertain, except for major zoonotic pathogens. It is therefore challenging to estimate to what extent the use of aminopenicillins in animals could create negative health consequences to humans at the population level. Based on the extent of use of aminopenicillins in humans, it seems probable that the major resistance selection pressure in human pathogens in European countries is due to human consumption. It is evident that veterinary use of these antimicrobials increases the selection pressure towards resistance in animals and loss of efficacy will at minimum jeopardize animal health and welfare. [ABSTRACT FROM AUTHOR]

Background Linezolid-induced thrombocytopenia is the main factor restricting the clinical application of linezolid. Objectives To investigate the relationship between PNU-14230 concentration and linezolid-induced thrombocytopenia and further develop and validate a risk model for predicting linezolid-induced thrombocytopenia. Methods A regression model was constructed to predict the occurrence of linezolid-induced thrombocytopenia, and further externally validated. The predictive performance was evaluated by receiver operating characteristic curve and Hosmer–Lemeshow test. Linezolid C min and PNU-142300 concentrations were compared for different kidney function groups. The Kaplan–Meier method was used to estimate the difference in cumulative incidence of linezolid-induced thrombocytopenia among different kidney function patients. Results In the derivation (n = 221) and validation (n = 158) cohorts, 28.5% and 24.1% of critically ill patients developed linezolid-induced thrombocytopenia. Logistic regression analysis indicated that the independent risk factors were linezolid C min, PNU-142300 concentration, baseline platelet count, renal insufficiency (RI) and continuous venovenous haemofiltration (CVVH). The AUC for the risk model was 0.901, and the model was good (P  = 0.633). The model also showed good discrimination (AUC 0.870) and calibration (P  = 0.282) in the external validation cohort. Compared with normal kidney function patients, patients with RI and CVVH had higher linezolid C min and PNU-142300 concentrations (P < 0.001) and higher cumulative incidence of linezolid-induced thrombocytopenia (P < 0.001). Conclusions PNU142300 concentration, as well as linezolid C min, might identify patients at risk of linezolid-induced thrombocytopenia. The risk prediction model had good predictive performance for linezolid-induced thrombocytopenia development. Concentrations of linezolid and PNU-142300 accumulated in patients with RI and CVVH. [ABSTRACT FROM AUTHOR]

Background The use of dolutegravir/lamivudine is based on solid clinical trials; however, real-world data remain limited. Objectives To provide data on the clinical use and effectiveness of dolutegravir/lamivudine in persons with HIV in a real-world scenario. Patients and methods Retrospective, single-centre and observational study. We included all adults starting dolutegravir/lamivudine since November 2014. We reported all demographic, virological and immunological variables at baseline and assessed effectiveness [on treatment (OT), modified ITT (mITT) and ITT in those persons who reached 6 and 12 month follow-ups (M6 and M12). Results Of the 1058 persons, 9 were treatment-naive; the final analysis included 1049 treatment-experienced people with HIV. Median (IQR) follow-up was 1 (0.3–1.6) years, with 81% and 63% persons reaching M6 and M12, respectively. The longest use of dolutegravir/lamivudine was 7.4 years. Per OT, mITT and ITT, HIV-RNA < 50 copies/mL was 97%, 92% and 81% (M6) and 98%, 90% and 80% (M12), respectively. Females [adjusted risk ratio, aRR (95% CI): 1.69 (1.19–2.40)]; immediate, previous PI-based regimen [aRR (95% CI): 1.67 (1.09–2.56)]; and viral load (VL) ≥ 50 copies/mL at dolutegravir/lamivudine initiation [aRR (95% CI): 3.36 (2.32–4.88)] were independently associated with lack of effectiveness at M12; other demographic, immunological and virological variables like previous M184V/I substitutions or virological failure, were unrelated. Of the total, 944 (90%) continued dolutegravir/lamivudine. The most frequent known reason for discontinuation was toxicity [48 (46%) cases]. Conclusions In our real-world experience, virological suppression rates were high for treatment-experienced persons on dolutegravir/lamivudine; however, we identified subgroups with a higher risk of lack of effectiveness at M12, who may benefit from closer follow-ups. [ABSTRACT FROM AUTHOR]

Introduction A lower adherence rate (percentage of individuals taking drugs as prescribed) to ART may increase the risk of emergence and transmission of HIV drug resistance, decrease treatment efficacy, and increase mortality rate. Exploring the impact of ART adherence on the transmission of drug resistance could provide insights in controlling the HIV epidemic. Methods We proposed a dynamic transmission model incorporating the CD4 cell count-dependent rates of diagnosis, treatment and adherence with transmitted drug resistance (TDR) and acquired drug resistance. This model was calibrated and validated by 2008–2018 HIV/AIDS surveillance data and prevalence of TDR among newly diagnosed treatment-naive individuals from Guangxi, China, respectively. We aimed to identify the impact of adherence on drug resistance and deaths during expanding ART. Results In the base case (ART at 90% adherence and 79% coverage), we projected the cumulative total new infections, new drug-resistant infections, and HIV-related deaths between 2022 and 2050 would be 420 539, 34 751 and 321 671. Increasing coverage to 95% would reduce the above total new infections (deaths) by 18.85% (15.75%). Reducing adherence to below 57.08% (40.84%) would offset these benefits of increasing coverage to 95% in reducing infections (deaths). Every 10% decrease in adherence would need 5.07% (3.62%) increase in coverage to avoid an increase in infections (deaths). Increasing coverage to 95% with 90% (80%) adherence would increase the above drug-resistant infections by 11.66% (32.98%). Conclusions A decrease in adherence might offset the benefits of ART expansion and exacerbate the transmission of drug resistance. Ensuring treated patients' adherence might be as important as expanding ART to untreated individuals. [ABSTRACT FROM AUTHOR]

Background Stenotrophomonas maltophilia is ubiquitous in the environment and is an important MDR opportunistic pathogen. Oxidative stress is an inevitable challenge to an aerobic bacterium. Accordingly, S. maltophilia has many capabilities to face variable oxidative stress. Some of the oxidative stress alleviation systems cross-protect bacteria from antibiotics. In our recent RNA-sequencing transcriptome analysis, we documented the increased expression of a three-gene cluster, yceA-cybB-yceB , in the presence of hydrogen peroxide (H2O2). The YceI-like, cytochrome b561 and YceI-like proteins encoded by yceA , cybB and yceB are located in the cytoplasm, inner membrane and periplasm, respectively. Objectives To characterize the role of the yceA-cybB-yceB operon of S. maltophilia in oxidative stress tolerance, swimming motility and antibiotic susceptibility. Methods The presence of the yceA-cybB-yceB operon was verified by RT–PCR. The functions of this operon were revealed by in-frame deletion mutant construction and complementation assay. Expression of the yceA-cybB-yceB operon was assessed by quantitative RT–PCR. Results The yceA , cybB and yceB genes form an operon. Loss of function of the yceA-cybB-yceB operon compromised menadione tolerance, enhanced swimming motility and increased susceptibility to fluoroquinolone and β-lactam antibiotics. The expression of the yceA-cybB-yceB operon was up-regulated by oxidative stress, such as H2O2 and superoxide, and not impacted by antibiotics, such as fluoroquinolone and β-lactams. Conclusions The evidence strongly supports the view that the physiological function of the yceA-cybB-yceB operon is to alleviate oxidative stress. The operon provides an additional example that oxidative stress alleviation systems can cross-protect S. maltophilia from antibiotics. [ABSTRACT FROM AUTHOR]

The effects of postnatal age (PNA) and serum creatinine concentration were also tested on the basis of the equations from the previous study.[2] HT ht HT ht HT ht where TSCr is a typical value of serum creatinine for a specific PMA, I MSCr i is measured serum creatinine and I PNA i SB 50 sb is the PNA when clearance has reached 50% of a typical adult's clearance. We thank Dr Standing for his comments on our recently published study[1] on population pharmacokinetics and dosing optimization of mezlocillin in neonates and young infants. [Extracted from the article]

Drug monitoring may be mandatory for properly managing the duration of the optimal treatment.[5] We agree that the number of previous PJI episodes are a key determinant of treatment outcome and we would like to thank Courjon I et al. i for pointing this out. The treatment duration was based on the treatment algorithm from Li I et al. i with a minimum total treatment of 12 weeks in the standard of care (SoC) and the DAL group.[4] The patients were treated with DAL by two different regimens: a first dose of 1500 mg on day 1 and a second dose of either 1500 mg (regimen-1) or 1000 mg (regimen-2) on day 8. DAL dosage or its combination with other antimicrobial agents and its real-life use for the treatment of Gram-positive prosthetic joint infections (PJIs) is not established.[1] Nevertheless, DAL treatment allows earlier discharge, reducing hospital stay, and seems to be safe, efficient and cost saving.[2],[3] Currently, long-term oral antibiotic treatment is required for the treatment of PJI.[4] However, DAL maybe an attractive alternative. [Extracted from the article]

Objectives Immunocompromised patients have an increased risk of severe or prolonged COVID-19. Currently available drugs are registered to treat COVID-19 during the first 5 to 7 days after symptom onset. Data on the effectivity in immunocompromised patients with chronic non-resolving COVID-19 are urgently needed. Here, we report the outcome of patients treated with nirmatrelvir/ritonavir together with high-titer convalescent plasma (CP) in six immunocompromised patients with non-resolving COVID-19. Methods Immunocompromised patients with persisting COVID-19 (positive PCR with Ct values <30 for ≥20 days) received off-label therapy with nirmatrelvir/ritonavir. It was combined with CP containing BA.5 neutralizing titers of ≥1/640 whenever available. Follow-up was done by PCR and sequencing on nasopharyngeal swabs on a weekly basis until viral genome was undetectable consecutively. Results Five immunocompromised patients were treated with high-titer CP and 5 days of nirmatrelvir/ritonavir. One patient received nirmatrelvir/ritonavir monotherapy. Median duration of SARS-CoV-2 PCR positivity was 70 (range 20–231) days before nirmatrelvir/ritonavir treatment. In four patients receiving combination therapy, no viral genome of SARS-CoV-2 was detected on day 7 and 14 after treatment while the patient receiving nirmatrelvir/ritonavir monotherapy, the day 7 Ct value increased to 34 and viral genome was undetectable thereafter. Treatment was unsuccessful in one patient. In this patient, sequencing after nirmatrelvir/ritonavir treatment did not show protease gene mutations. Conclusions In immunocompromised patients with non-resolving COVID-19, the combination of nirmatrelvir/ritonavir and CP may be an effective treatment. Larger prospective studies are needed to confirm these preliminary results and should compare different treatment durations. [ABSTRACT FROM AUTHOR]

Invasive candidiasis (IC) is a serious infection caused by several Candida species, and the most common fungal disease in hospitals in high-income countries. Despite overall improvements in health systems and ICU care in the last few decades, as well as the development of different antifungals and microbiological techniques, mortality rates in IC have not substantially improved. The aim of this review is to summarize the main issues underlying the management of adults affected by IC, focusing on specific forms of the infection: IC developed by ICU patients, IC observed in haematological patients, breakthrough candidaemia, sanctuary site candidiasis, intra-abdominal infections and other challenging infections. Several key challenges need to be tackled to improve the clinical management and outcomes of IC patients. These include the lack of global epidemiological data for IC, the limitations of the diagnostic tests and risk scoring tools currently available, the absence of standardized effectiveness outcomes and long-term data for IC, the timing for the initiation of antifungal therapy and the limited recommendations on the optimal step-down therapy from echinocandins to azoles or the total duration of therapy. The availability of new compounds may overcome some of the challenges identified and increase the existing options for management of chronic Candida infections and ambulant patient treatments. However, early identification of patients that require antifungal therapy and treatment of sanctuary site infections remain a challenge and will require further innovations. [ABSTRACT FROM AUTHOR]

Background Cefepime and aztreonam are highly efficacious against H. influenzae , and resistant strains are rare. In this study, we isolated cefepime- and aztreonam-nonsusceptible H. influenzae strains and addressed the molecular basis of their resistance to cefepime and aztreonam. Methods Two hundred and 28 specimens containing H. influenzae were screened, of which 32 isolates were enrolled and applied to antimicrobial susceptibility testing and whole-genome sequencing. Genetic variations that were detected in all nonsusceptible isolates with statistical significance by Fisher's exact tests were identified as cefepime or aztreonam nonsusceptibility related. Functional complementation assays were conducted to assess the in vitro effects of proteins with sequence substitutions on drug susceptibility. Results Three H. influenzae isolates were nonsusceptible to cefepime, one of which was also nonsusceptible to aztreonam. Genes encoding TEM, SHV and CTX-M extended-spectrum β-lactamases were not detected in the cefepime- and aztreonam-nonsusceptible isolates. Five genetic variations in four genes and 10 genetic variations in five genes were associated with cefepime and aztreonam nonsusceptibility, respectively. Phylogenetic analyses revealed that changes in FtsI were correlated strongly with the MIC of cefepime and moderately with aztreonam. FtsI Thr532Ser-Tyr557His cosubstitution linked to cefepime nonsusceptibility and Asn305Lys-Ser385Asn-Glu416Asp cosubstitution to aztreonam nonsusceptibility. Functional complementation assays revealed that these cosubstitutions increased MICs of cefepime and aztreonam in susceptible H. influenzae isolates, respectively. Conclusions Genetic variations relevant to resistant phenotypes of cefepime and aztreonam nonsusceptibility in H. influenzae were identified. Moreover, the effects of FtsI cosubstitutions on increasing MICs of cefepime and aztreonam in H. influenzae were demonstrated. [ABSTRACT FROM AUTHOR]

Introduction A large proportion of the burden of infections with antibiotic-resistant bacteria is linked to community-associated infections. This suggests that interventions set in community settings are needed. Currently there is a gap in understanding the potential of such interventions across all geographies. This systematic review aimed to synthesize the evidence on the value of community-based behaviour change interventions to improve antibiotic use. These are any interventions or innovations to services intended to stimulate behaviour changes among the public towards correct antibiotic use, delivered in a community setting and online. Methods Systematic searches of studies published after 2001 were performed in several databases. Of 14 319 articles identified, 73 articles comprising quantitative, qualitative and mixed-methods studies met the inclusion criteria. Results Findings showed positive emerging evidence of the benefits of community-based behaviour change interventions to improve antibiotic use, with multifaceted interventions offering the highest benefit. Interventions that combine educational aspects with persuasion may be more effective than solely educational interventions. The review uncovered difficulties in assessing this type of research and highlights the need for standardized approaches in study design and outcomes measurements. There is emerging, but limited, indication on these interventions' cost-effectiveness. Conclusions Policy makers should consider the potential of community-based behaviour change interventions to tackle antimicrobial resistance (AMR), complementing the clinical-based approaches. In addition to the direct AMR benefits, these could serve also as a means of (re)building trust, due to their inclusive participation leading to greater public ownership and use of community channels. [ABSTRACT FROM AUTHOR]

Objectives To assess the effectiveness and tolerability of dolutegravir (DTG)/lamivudine (3TC) among treatment-naive and virologically suppressed treatment-experienced individuals in the multicentre cohort of the Spanish HIV/AIDS Research Network (CoRIS) during the years 2018–2021. Methods We used multivariable regression models to compare viral suppression (VS) [HIV RNA viral load (VL) <50 copies/mL] and the change in CD4 cell counts at 24 and 48 (±12) weeks after initiation with dolutegravir/lamivudine or other first-line ART regimens. Results We included 2160 treatment-naive subjects, among whom 401 (18.6%) started with dolutegravir/lamivudine. The remaining subjects started bictegravir (BIC)/emtricitabine (FTC)/tenofovir alafenamide (TAF) (n  = 949, 43.9%), DTG + FTC/tenofovir disoproxil fumarate (TDF) (n  = 282, 13.1%), DTG/3TC/abacavir (ABC) (n  = 255, 11.8%), darunavir (DRV)/cobicistat(COBI)/FTC/TAF (n  = 147, 6.8%) and elvitegravir (EVG)/COBI/FTC/TAF (n  = 126, 5.8%). At 24 and 48 weeks after starting dolutegravir/lamivudine, 91.4% and 93.8% of the subjects, respectively, achieved VS. The probability of achieving VS with dolutegravir/lamivudine was not significantly different compared with any other regimen at 24 or 48 weeks, with the exception of a lower chance of achieving VS at 24 weeks for DRV/COBI/FTC/TAF (adjusted OR: 0.47; 95% CI: 0.30–0.74) compared with dolutegravir/lamivudine. For the analysis of treatment-experienced virally suppressed subjects we included 1456 individuals who switched to dolutegravir/lamivudine, among whom 97.4% and 95.5% maintained VS at 24 and 48 weeks, respectively. During the first 48 weeks after dolutegravir/lamivudine initiation, 1.0% of treatment-naive and 1.5% of treatment-experienced subjects discontinued dolutegravir/lamivudine due to an adverse event. Conclusions In this large multicentre cohort, effectiveness and tolerability of dolutegravir/lamivudine were high among treatment-naive and treatment-experienced subjects. [ABSTRACT FROM AUTHOR]

Objectives We aimed to describe the clinical outcomes and duration of viral shedding in high-risk patients with haematological malignancies hospitalized with COVID-19 during Omicron variant predominance who received early treatment with antivirals. Methods We conducted a prospective observational study on high-risk haematological patients admitted in our hospital between December 2021 and March 2022. We performed detection techniques on viral subgenomic mRNAs until negative results were obtained to document active, prolonged viral replication. Results This analysis included 60 consecutive adults with high-risk haematological malignancies and COVID-19. All of these patients underwent early treatment with remdesivir. Thirty-two (53%) patients received combined antiviral strategies, with sotrovimab or hyperimmune plasma being added to remdesivir. The median length of viral replication—as measured by real-time RT-PCR and/or subgenomic RNA detection—was 20 (IQR 14–28) days. Prolonged viral replication (6 weeks after diagnosis) was documented in six (10%) patients. Only two patients had prolonged infection for more than 2 months. Overall mortality was 5%, whereas COVID-19-related mortality was 0%. Conclusions Current outcomes of high-risk patients with haematological malignancies hospitalized with COVID-19 during Omicron variant predminance are good with the use of early antiviral strategies. Persistent viral shedding is uncommon. [ABSTRACT FROM AUTHOR]

Background This work aims to evaluate integrase resistance and its predictors in HIV-1 infected combined antiretroviral therapy (cART) experienced individuals failing a dolutegravir-based regimen. Methods Major resistance mutations (MRM) and genotypic susceptibility score (GSS) of dolutegravir companion drugs were evaluated on plasma genotypic resistance test (GRT) performed at dolutegravir failure. Logistic regression was used to evaluate factors associated to the risk of integrase strand-transfer inhibitors (INSTI)-resistance at dolutegravir failure. Results We retrospectively analysed 467 individuals. At failure GRT, individuals had been under dolutegravir for a median (IQR) time of 11 (5–20) months; around half of them had never been exposed to INSTI (52%) and 10.7% were at first-line regimen. Fifty-eight (12.4%) individuals showed ≥1 INSTI MRM. Among them, people INSTI-exposed showed significantly higher prevalence of INSTI resistance compared to those who were INSTI naïve [46 (21.2%) versus 9 (3.9%), P  < 0.001]. N155H was the most prevalent MRM (5.4%), followed by G140S (4.5%) and Q148H (4.3%). These MRM were more probably present in INSTI-experienced individuals compared to those INSTI naïve. Despite failure, 89.5% of individuals harboured viral strains fully susceptible to dolutegravir and bictegravir and 85.0% to all INSTI. No INSTI exposure before receiving dolutegravir [OR: 0.35 (0.16–0.78), P  < 0.010] and a GSS for companion drugs ≥2 (OR: 0.09 [0.04–0.23], P  < 0.001) were negatively associated with INSTI resistance at failure. Conclusions In a large set of individuals failing dolutegravir in real-life, INSTI resistance was low and mainly related to previous first-generation INSTI exposure. Surveillance of integrase resistance remains crucial to preserve efficacy of INSTI class in the future. [ABSTRACT FROM AUTHOR]

Background Detailed information is needed on the dynamic pattern of antimicrobial resistance (AMR) in Neisseria gonorrhoeae in Latin America and the Caribbean (LAC). Objectives To conduct a systematic review of AMR in N. gonorrhoeae in LAC. Methods Electronic searches without language restrictions were conducted in PubMed, Embase, Cochrane Library, EconLIT, Cumulative Index of Nursing and Allied Health Literature, Centre for Reviews and Dissemination, and Latin American and Caribbean Literature in Health Sciences. Studies were eligible if published between 1 January 2011 and 13 February 2021, conducted in any LAC country (regardless of age, sex and population) and measured frequency and/or patterns of AMR to any antimicrobial in N. gonorrhoeae. The WHO Global Gonococcal Antimicrobial Surveillance Programme (WHO-GASP) for LAC countries and Latin American AMR Surveillance Network databases were searched. AMR study quality was evaluated according to WHO recommendations. Results AMR data for 38, 417 isolates collected in 1990–2018 were included from 31 publications, reporting data from Argentina, Brazil, Colombia, Peru, Uruguay, Venezuela and WHO-GASP. Resistance to extended-spectrum cephalosporins was infrequent (0.09%–8.5%). Resistance to azithromycin was up to 32% in the published studies and up to 61% in WHO-GASP. Resistance to penicillin, tetracycline and ciprofloxacin was high (17.6%–98%, 20.7%–90% and 5.9%–89%, respectively). Resistance to gentamicin was not reported, and resistance to spectinomycin was reported in one study. Conclusions This review provides data on resistance to azithromycin, potentially important given its use as first-line empirical treatment, and indicates the need for improved surveillance of gonococcal AMR in LAC. Trial registration: Registered in PROSPERO, CRD42021253342. [ABSTRACT FROM AUTHOR]

Objectives To investigate the lineages and genomic antimicrobial resistance (AMR) determinants of the 10 most common pneumococcal serotypes identified in Canada during the five most recent years of the SAVE study, in the context of the 10-year post-PCV13 period in Canada. Methods The 10 most common invasive Streptococcus pneumoniae serotypes collected by the SAVE study from 2016 to 2020 were 3, 22F, 9N, 8, 4, 12F, 19A, 33F, 23A and 15A. A random sample comprising ∼5% of each of these serotypes collected during each year of the full SAVE study (2011–2020) were selected for whole-genome sequencing (WGS) using the Illumina NextSeq platform. Phylogenomic analysis was performed using the SNVPhyl pipeline. WGS data were used to identify virulence genes of interest, sequence types, global pneumococcal sequence clusters (GPSC) and AMR determinants. Results Of the 10 serotypes analysed in this study, six increased significantly in prevalence from 2011 to 2020: 3, 4, 8, 9N, 23A and 33F (P  ≤ 0.0201). Serotypes 12F and 15A remained stable in prevalence over time, while serotype 19A decreased in prevalence (P  < 0.0001). The investigated serotypes represented four of the most prevalent international lineages causing non-vaccine serotype pneumococcal disease in the PCV13 era: GPSC3 (serotypes 8/33F), GPSC19 (22F), GPSC5 (23A) and GPSC26 (12F). Of these lineages, GPSC5 isolates were found to consistently possess the most AMR determinants. Commonly collected vaccine serotypes 3 and 4 were associated with GPSC12 and GPSC27, respectively. However, a more recently collected lineage of serotype 4 (GPSC192) was highly clonal and possessed AMR determinants. Conclusions Continued genomic surveillance of S. pneumoniae in Canada is essential to monitor for the appearance of new and evolving lineages, including antimicrobial-resistant GPSC5 and GPSC162. [ABSTRACT FROM AUTHOR]