Psychiatric admissions in young people after expiration of criminal justice supervision in Australia: a retrospective data linkage study.

BACKGROUND: Mental health services are available for young people involved with the criminal justice system. However, they have unmet mental health needs after the expiration of criminal justice supervision. OBJECTIVE: To determine the incidence rate and identify predictors of psychiatric hospitalisations within 24 months after the expiration of criminal justice supervision among young people involved with the New South Wales (NSW) criminal justice system. METHODS: Retrospective data from 1556 individuals aged 14-22 years who participated in four surveys of justice-involved young people in NSW were harmonised and linked to four NSW data collections. We calculated the incidence rates of psychiatric hospitalisations within 24 months postsupervision and identified predictors of these hospitalisations using a competing risks regression analysis. RESULTS: Within 24 months postsupervision, 11.4% had a psychiatric hospitalisation compared with 3.5% during supervision. 20.7% of those admitted had a known history of mental illness and engaged with community-based and outpatient mental health services postsupervision. Predictors of psychiatric hospitalisations were: female sex (adjusted subdistribution HR (asHR) 1.84, 95% CI 1.24 to 2.73); previous incarceration (highest asHR for ≥4 episodes 1.67, 95% CI 1.01 to 2.78); head injury (asHR 1.63, 95% CI 1.20 to 2.21); personality disorder (asHR 3.66, 95% CI 2.06 to 6.48) and alcohol and substance use disorder (asHR 1.89, 95% CI 1.29 to 2.77). CONCLUSION: Justice-involved youth have higher rates of psychiatric admissions after criminal justice supervision. Engagement with mental health services postsupervision is important in addressing emerging or persisting mental health needs.

Who gets diverted into treatment? a study of defendants with psychosis.

The current study aimed to advance our understanding of the factors that influence mental health diversion in Local Courts in New South Wales, Australia. Logistic regression was used to systematically identify the factors that are correlated with diversion in a cohort of individuals (N = 7283) diagnosed with psychosis. Those with a substance-induced psychotic disorder were less likely to be diverted than those with an affective psychosis or schizophrenia, after adjusting for age, gender, Indigenous status, offence seriousness, violence and criminal history. Unexpectedly, those with psychotic disorders committing violent or serious offences were more likely to be diverted than those committing non-violent, less serious offences. Legal representation should be provided to all individuals with serious mental illnesses facing criminal charges. The State-wide Community and Court Liaison Service should be expanded to more Local Courts. Further research is required into why Aboriginal defendants with a psychotic illness are less likely to be diverted.

Ribosomal protein L24 mediates mammalian microRNA processing in an evolutionarily conserved manner.

To investigate the mechanism(s) underlying the expression of primate-specific microRNAs (miRs), we sought DNA regulatory elements and proteins mediating expression of the primate-specific hsa-miR-608 (miR-608), which is located in the SEMA4G gene and facilitates the cholinergic blockade of inflammation by targeting acetylcholinesterase mRNA. 'Humanized' mice carrying pre-miR-608 flanked by 250 bases of endogenous sequences inserted into the murine Sema4g gene successfully expressed miR-608. Moreover, by flanking miR-608 by shortened fragments of its human genome region we identified an active independent promoter within the 150 nucleotides 5' to pre-miR-608, which elevated mature miR-608 levels by 100-fold in transfected mouse- and human-originated cells. This highlighted a regulatory role of the 5' flank as enabling miR-608 expression. Moreover, pull-down of the 150-base 5' sequence revealed its interaction with ribosomal protein L24 (RPL24), implicating an additional mechanism controlling miR-608 levels. Furthermore, RPL24 knockdown altered the expression of multiple miRs, and RPL24 immunoprecipitation indicated that up- or down-regulation of the mature miRs depended on whether their precursors bind RPL24 directly. Finally, further tests showed that RPL24 interacts directly with DDX5, a component of the large microprocessor complex, to inhibit miR processing. Our findings reveal that RPL24, which has previously been shown to play a role in miR processing in Arabidopsis thaliana, has a similar evolutionarily conserved function in miR biogenesis in mammals. We thus characterize a novel extra-ribosomal role of RPL24 in primate miR regulation.

Comparing single versus multiple virus detection in pediatric acute gastroenteritis postimplementation of routine multiplex RT-PCR diagnostic testing.

Utilizing multiplex real time polymerase chain reaction (RT-PCR) for rapid diagnosis of gastroenteritis, enables simultaneous detection of multiple pathogens. A comparative analysis of disease characteristics was conducted between cases with single and multiple viruses. Rotavirus vaccine was introduced in 2010, reaching a 70% coverage in 2 years. All rectal swabs collected from diarrheic children (<5 years) between December 2017 and March 2022 were included. Detection of the same viruses within 2 months was considered a single episode. Episodes with positive stool bacterial PCR were excluded. A total of 5879 samples were collected, revealing 86.9% (1509) with single virus detection and 13.1% (227) with multiple viruses. The most frequent combination was rotavirus and norovirus (27.8%), these infections followed a winter-spring seasonality akin to rotavirus. Children with multivirus infections exhibited higher immunodeficiency (OR 2.06) rates, but lower food allergy (OR 0.45) and prematurity rates (OR 0.55) compared to single infections. Greater disease severity, evaluated by the Vesikari score, was observed in multivirus episodes (p < 0.001, OR 1.12). Multivirus infections accounted for 13.1% of symptomatic cases in hospitalized young children. Despite vaccination efforts, rotavirus remained prominent, frequently in co-infections with norovirus. Overall, multivirus infections were linked to more severe diseases than single virus cases.

Lysine tRNA fragments and miR-194-5p co-regulate hepatic steatosis via ß-Klotho and perilipin 2.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) involves hepatic accumulation of intracellular lipid droplets via incompletely understood processes. Here, we report distinct and cooperative NAFLD roles of LysTTT-5'tRF transfer RNA fragments and microRNA miR-194-5p. METHODS: Combined use of diet induced obese mice with human-derived oleic acid-exposed Hep G2 cells revealed new NAFLD roles of LysTTT-5'tRF and miR-194-5p. RESULTS: Unlike lean animals, dietary-induced NAFLD mice showed concurrent hepatic decrease of both LysTTT-5'tRF and miR-194-5p levels, which were restored following miR-132 antisense oligonucleotide treatment which suppresses hepatic steatosis. Moreover, exposing human-derived Hep G2 cells to oleic acid for 7 days co-suppressed miR-194-5p and LysTTT-5'tRF levels while increasing lipid accumulation. Inversely, transfecting fattened cells with a synthetic LysTTT-5'tRF mimic elevated mRNA levels of the metabolic regulator ß-Klotho while decreasing triglyceride amounts by 30% within 24 h. In contradistinction, antisense suppression of miR-194-5p induced accumulation of its novel target, the NAFLD-implicated lipid droplet-coating PLIN2 protein. Further, two out of 15 steatosis-alleviating screened drug-repurposing compounds, Danazol and Latanoprost, elevated miR-194-5p or LysTTT-5'tRF levels. CONCLUSION: Our findings highlight the different yet complementary roles of miR-194-5p and LysTTT-5'tRF and offer new insights into the complex roles of small non-coding RNAs and the multiple pathways involved in NAFLD pathogenesis.

Intermittent alternating magnetic fields diminish metal-associated biofilm in vivo.

Prosthetic joint infection (PJI) is a complication of arthroplasty that results in significant morbidity. The presence of biofilm makes treatment difficult, and removal of the prosthesis is frequently required. We have developed a non-invasive approach for biofilm eradication from metal implants using intermittent alternating magnetic fields (iAMF) to generate targeted heating at the implant surface. The goal of this study was to determine whether iAMF demonstrated efficacy in an in vivo implant biofilm infection model. iAMF combined with antibiotics led to enhanced reduction of biofilm on metallic implants in vivo compared to antibiotics or untreated control. iAMF-antibiotic combinations resulted in a > 1 - log further reduction in biofilm burden compared to antibiotics or iAMF alone. This combination effect was seen in both S. aureus and P. aeruginosa and seen with multiple antibiotics used to treat infections with these pathogens. In addition, efficacy was temperature dependent with increasing temperatures resulting in a greater reduction of biofilm. Tissue damage was limited (< 1 mm from implant-tissue interface). This non-invasive approach to eradicating biofilm could serve as a new paradigm in treating PJI.

Physical health status of individuals convicted of sexual offences: Results from an Australian prisoner cohort.

Although the poor health of prisoners poses a serious public health problem, very little is known about the health of specific offender groups. Three waves of an Australian Inmate Health Survey were used to describe the self-reported and objectively tested health of men incarcerated for sexual offences against children only (ISOC), adults only (ISOA), and against both (age-polymorphous; ISOP) compared to men incarcerated without sexual offences. ISOC and ISOP were found to have the poorest self-reported health of all groups, with higher rates of eyesight and cardiovascular problems; however, lower rates of Hepatitis B and Hepatitis C as objectively measured. There are important implications for the correctional and public health systems for addressing the health needs of specific offenders.

Self-reported traumatic brain injury in a sample of impulsive violent offenders: neuropsychiatric correlates and possible "dose effects".

Background: Traumatic brain injury (TBI) is a major public health problem that may be associated with numerous behavioral problems, including impulsivity, aggression and violence. Rates of self-reported TBI are high within offender populations, but the extent to which TBI is causally implicated in causing illegal behavior is unclear. This study examined the psychological and functional correlates of histories of traumatic brain injury in a sample of impulsive violent offenders. Methods: Study participants, all men, had been recruited to participate in a randomized controlled trial of sertraline to reduce recidivism. Study entry criteria were an age of at least 18 years, a documented history of two or more violent offenses and a score of 70 or above on the Barratt Impulsiveness Scale. An extensive list of standardized questionnaires was administered to obtain information on previous TBI and other neuropsychiatric conditions or symptoms. Results: In the sample of 693 men, 66% were aged between 18 and 35 years old, and 55% gave a history of TBI ("TBI+"). Overall, 55% of study participants reported at least one TBI. High levels of neuropsychiatric symptomatology were reported. In 75% of TBI+ individuals, their most severe TBI (by self-report) was associated with loss of consciousness (LOC) < 30 min. Compared to TBI- (those without history of TBI) participants, TBI+ individuals were more impulsive (Eysenck Impulsivity), irritable, angry, and reported higher levels of assaultive behavior, depressive symptomology, alcohol use disorder, suicidal ideation, suicide attempts, and lower quality of life. Potential "dose effects" of TBI severity and frequency in terms of neuropsychiatric symptomatology were identified. Conclusion: Like other studies of offender populations, single and multiple TBIs were very common. The associations of TBI, TBI severity, and TBI frequency (i.e., TBI "burden") with adverse neuropsychiatric phenomena suggest TBI contributes importantly to offender morbidity but the select nature of the sample and cross-sectional study design constrain the interpretation of these findings.

Neuropsychiatric correlates of olfactory identification and traumatic brain injury in a sample of impulsive violent offenders.

Background: Olfactory deficits have a diverse etiology and can be detected with simple olfactory tests. Key olfactory pathways are located within the frontal and temporal lobes where they are vulnerable to damage due to head trauma. Orbitofrontal cortex (OFC) integrity is important for olfaction and aspects of behavioral regulation. We measured olfactory identification ability in a sample of impulsive violent offenders to determine its associations with history of traumatic brain injury (TBI) and a range of neuropsychiatric indices, including proxies for cognitive ability, impulsivity and social connectedness. Methods: Male participants were drawn from the ReINVEST study, a randomized controlled trial of sertraline to reduce recidivism in violent impulsive offenders. Criteria for participation in the study included a minimum age of 18 years, a documented history of two or more violent offenses, and a score of 70 or above on the Barratt Impulsiveness Scale (BIS-11). The 16-item "Sniffin sticks" (SS) odor identification test (OI) was administered as were standardized questionnaires regarding previous TBI, additional measures to screen cognition [word reading test of the Wechsler Individuals Achievement Test (WIAT), social connectedness (the Duke Social Support Scale), and a range of other neuropsychiatric conditions or symptoms]. The sample SS scores were compared against published age-specific norms. Univariate and multivariate analyses were performed with SS score (linear regression, within those without hyposmia) or hyposmia (logistic regression) as the outcome. Results: The mean OI scores were lower than population norms and 16% of participants were classified as hyposmic. Univariate analyses showed associations of SS score with age, WIAT score, impulsivity, TBI and TBI severity, social connectedness, childhood sexual abuse, suicidality and current use of heroin. In multivariate analyses, age, TBI severity and WIAT remained as significant independent predictors of SS score (within the normosmic range) or hyposmia (logistic regression). Conclusion: Olfactory performance was associated with multiple behavioral phenomena in a pattern that would be consistent with this serving as a proxy for orbitofrontal functioning. As such, OI testing may have utility in further studies of offenders. In future, we will examine whether olfactory score predicts recidivism or response to the administration of sertraline, in terms of reducing recidivism.

Genetic determinants underlying the progressive phenotype of ß-lactam/ß-lactamase inhibitor resistance in Escherichia coli.

IMPORTANCE: The increased feasibility of whole-genome sequencing has generated significant interest in using such molecular diagnostic approaches to characterize difficult-to-treat, antimicrobial-resistant (AMR) infections. Nevertheless, there are current limitations in the accurate prediction of AMR phenotypes based on existing AMR gene database approaches, which primarily correlate a phenotype with the presence/absence of a single AMR gene. Our study utilized a large cohort of cephalosporin-susceptible Escherichia coli bacteremia samples to determine how increasing the dosage of narrow-spectrum ß-lactamase-encoding genes in conjunction with other diverse ß-lactam/ß-lactamase inhibitor (BL/BLI) genetic determinants contributes to progressively more severe BL/BLI phenotypes. We were able to characterize the complexity of the genetic mechanisms underlying progressive BL/BLI resistance including the critical role of ß-lactamase encoding gene amplification. For the diverse array of AMR phenotypes with complex mechanisms involving multiple genomic factors, our study provides an example of how composite risk scores may improve understanding of AMR genotype/phenotype correlations.

Knockout of the longevity gene Klotho perturbs aging- and Alzheimer's disease-linked brain microRNAs and tRNA fragments.

Overexpression of the longevity gene Klotho prolongs, while its knockout shortens lifespan and impairs cognition via altered fibroblast growth factor signaling that perturbs myelination and synapse formation; however, comprehensive analysis of Klotho's knockout consequences on mammalian brain transcriptomics is lacking. Here, we report the altered levels under Klotho knockout of 1059 long RNAs, 27 microRNAs (miRs) and 6 tRNA fragments (tRFs), reflecting effects upon aging and cognition. Perturbed transcripts included key neuronal and glial pathway regulators that are notably changed in murine models of aging and Alzheimer's Disease (AD) and in corresponding human post-mortem brain tissue. To seek cell type distributions of the affected short RNAs, we isolated and FACS-sorted neurons and microglia from live human brain tissue, yielding detailed cell type-specific short RNA-seq datasets. Together, our findings revealed multiple Klotho deficiency-perturbed aging- and neurodegeneration-related long and short RNA transcripts in both neurons and glia from murine and human brain.

SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy.

Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (P = 7.5 × 10-9) and 10p11.21 (P = 3.6 × 10-8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10-3). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (P = 0.0005) including NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila polypeptide with the highest homology to SLCO5A1, causes over-reactive startling behaviour (P = 8.7 × 10-3) and increased seizure-like events (P = 6.8 × 10-7). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10-3). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.

Testing the performance, adequacy, and applicability of an artificial intelligence model for pediatric pneumonia diagnosis.

BACKGROUND: Community-acquired Pneumonia (CAP) is a common childhood infectious disease. Deep learning models show promise in X-ray interpretation and diagnosis, but their validation should be extended due to limitations in the current validation workflow. To extend the standard validation workflow we propose doing a pilot test with the next characteristics. First, the assumption of perfect ground truth (100% sensitive and specific) is unrealistic, as high intra and inter-observer variability have been reported. To address this, we propose using Bayesian latent class models (BLCA) to estimate accuracy during the pilot. Additionally, assessing only the performance of a model without considering its applicability and acceptance by physicians is insufficient if we hope to integrate AI systems into day-to-day clinical practice. Therefore, we propose employing explainable artificial intelligence (XAI) methods during the pilot test to involve physicians and evaluate how well a Deep Learning model is accepted and how helpful it is for routine decisions as well as analyze its limitations by assessing the etiology. This study aims to apply the proposed pilot to test a deep Convolutional Neural Network (CNN)-based model for identifying consolidation in pediatric chest-X-ray (CXR) images already validated using the standard workflow. METHODS: For the standard validation workflow, a total of 5856 public CXRs and 950 private CXRs were used to train and validate the performance of the CNN model. The performance of the model was estimated assuming a perfect ground truth. For the pilot test proposed in this article, a total of 190 pediatric chest-X-ray (CXRs) images were used to test the CNN model support decision tool (SDT). The performance of the model on the pilot test was estimated using extensions of the two-test Bayesian Latent-Class model (BLCA). The sensitivity, specificity, and accuracy of the model were also assessed. The clinical characteristics of the patients were compared according to the model performance. The adequacy and applicability of the SDT was tested using XAI techniques. The adequacy of the SDT was assessed by asking two senior physicians the agreement rate with the SDT. The applicability was tested by asking three medical residents before and after using the SDT and the agreement between experts was calculated using the kappa index. RESULTS: The CRXs of the pilot test were labeled by the panel of experts into consolidation (124/176, 70.4%) and no-consolidation/other infiltrates (52/176, 29.5%). A total of 31/176 (17.6%) discrepancies were found between the model and the panel of experts with a kappa index of 0.6. The sensitivity and specificity reached a median of 90.9 (95% Credible Interval (CrI), 81.2-99.9) and 77.7 (95% CrI, 63.3-98.1), respectively. The senior physicians reported a high agreement rate (70%) with the system in identifying logical consolidation patterns. The three medical residents reached a higher agreement using SDT than alone with experts (0.66±0.1 vs. 0.75±0.2). CONCLUSIONS: Through the pilot test, we have successfully verified that the deep learning model was underestimated when a perfect ground truth was considered. Furthermore, by conducting adequacy and applicability tests, we can ensure that the model is able to identify logical patterns within the CXRs and that augmenting clinicians with automated preliminary read assistants could accelerate their workflows and enhance accuracy in identifying consolidation in pediatric CXR images.

The impact of pneumococcal conjugate vaccine on ceftriaxone consumption in the community among young children.

OBJECTIVES: Following pneumococcal conjugate vaccine (PCV) introduction, community pediatric dispensed prescription rates (DPR) of oral antibiotics declined, in parallel to respiratory tract infection (RTI). We assessed the dynamics of outpatient parenteral ceftriaxone DPR. METHODS: Computerized data for children <5 years were examined during 13 years (including 4 pre-PCV years). DPR from clinics with ≥50 insured children, active both before and after PCV implementation were included. Interrupted time series with segmented regression stratified by age and ethnicity, and adjusted for seasonality was applied to show monthly DPR trends. RESULTS: A total of 29,226 prescriptions were dispensed. No significant trends in ceftriaxone DPR were seen pre-PCV. Shortly after PCV implementation, DPR abruptly and significantly declined, stabilizing in late-PCV period (5 years postimplementation). The dynamics were compared between the two ethnic groups in the region, Jewish and Bedouin children (the latter with higher crowding and respiratory disease rates). Among Jewish children, ceftriaxone was mainly dispensed during winter vs no seasonality among Bedouin children. CONCLUSIONS: In southern Israel, outpatient ceftriaxone DPR declined post-PCV in young children, similar to the trends of RTIs and oral antibiotic prescriptions, suggesting a causative role of PCVs. The differences between the two ethnic groups suggest possible involvement of additional factors.

Dynamics of Pediatric Antibiotic Use Differ between High- and Low-Prescribing Clinics after Pneumococcal Conjugate Vaccines.

OBJECTIVE: To compare dispensed oral antibiotic prescription rates (DAPRs) after implementation of pneumococcal conjugate vaccine (PCV) in high antibiotic-prescribing clinics (HPC) with low antibiotic-prescribing clinics (LPC) in 2 distinct ethnic groups of children (Jewish and Bedouin children) <5 years of age. METHODS: Clinics with ≥50 insured children, active both pre-PCV (2005-2009) and post-PCV (2010-2018) implementation, were included. HPC and LPC were defined by DAPRs above or below the median in each age and ethnic group. Monthly dispensed antibiotic prescription rate (DAPR) trends (adjusted for age and ethnicity) were calculated using interrupted time series. Mean yearly incidence rate-ratios (late PCV13 vs pre-PCV) were calculated. RESULTS: Bedouin HPC had the highest pre-PCV overall-DAPR per 1000 child-years ± SD (2520.4 ± 121.2), followed by Jewish HPC (1885.5 ± 47.6), Bedouin LPC (1314.8 ± 81.6), and Jewish LPC (996.0 ± 19.6). Shortly after PCV implementation, all DAPRs and amoxicillin/amoxicillin-clavulanate DAPRs declined in all groups except Jewish LPC, stabilizing within 4-5 years post-PCV. The rates and magnitudes of declines were directly proportional to the pre-PCV DAPR magnitudes, achieving near-complete closure of the pre-PCV DAPR gaps between the 4 groups (rates during late-PCV13 ranging from 1649.4 ± 23.5 [Bedouin HPC] to 1200.3 ± 72.4 [Jewish LPC]). CONCLUSIONS: PCVs are a powerful tool in reducing outpatient antibiotic consumption among young children, especially in HPC, resulting in partial closure of DAPR gap between HPC and LPC. The higher impact on HPC suggests that PCV-associated declines of respiratory disease may strongly contribute to a judicious antibiotic approach in clinics with high antibiotic consumption.

Implementing a multiplex-PCR test for the diagnosis of acute gastroenteritis in hospitalized children: Are all enteric viruses the same?

BACKGROUND: Multiplex-PCR is a valuable tool for diagnosing viral acute gastroenteritis (AGE), enabling the detection of multiple pathogens. However, distinguishing between active disease and shedding poses challenges. This study aimed to evaluate viral AGE epidemiology and compare clinical characteristics among the five most common viruses. METHODS: Rotavirus vaccine was introduced in 2010, with 70% coverage achieved in southern Israel in two years. All rectal swabs for multiplex-PCR targeting rotavirus, norovirus, adenovirus, astrovirus and sapovirus from hospitalized diarrheic children <5 years were included, from December 2017 through March 2022. Detection of the same virus within two months was considered a single episode. Clinical analysis included episodes with single-virus detection and negative bacterial PCR. RESULTS: Among 5,879 rectal swabs, 2,662 (45.3%) tested positive for at least one virus, with 245 (9.2%) showing multiple virus detection. Rotavirus was the most prevalent. While rotavirus exhibited typical winter-spring seasonality in 2018-19, an unusual off-season surge was observed during the second year of the COVID-19 pandemic. Among negative bacterial PCR episodes, 34.6% had mucus stool, 5.9% had bloody stool, and 29.3% received antibiotics. Astrovirus or sapovirus infections were associated with higher rates of hospital-acquired AGE and immunodeficiency (P<0.05), whereas rotavirus infections had higher rates of dehydration severity and acute kidney injury (P<0.05). DISCUSSION: Enteric viruses were detected in 45.3% of rectal swabs from hospitalized children with diarrhea. Despite vaccination efforts, rotavirus remained prevalent and caused more severe disease. Continuous surveillance using multiplex-PCR is crucial for accurate management and future prevention strategies for viral AGE.

Ceftolozane/tazobactam heteroresistance in cystic fibrosis-related Pseudomonas aeruginosa infections.

Objectives: Cystic fibrosis (CF) patients are often colonized with Pseudomonas aeruginosa. During treatment, P. aeruginosa can develop subpopulations exhibiting variable in vitro antimicrobial (ABX) susceptibility patterns. Heteroresistance (HR) may underlie reported discrepancies between in vitro susceptibility results and clinical responses to various ABXs. Here, we sought to examine the presence and nature of P. aeruginosa polyclonal HR (PHR) and monoclonal HR (MHR) to ceftolozane/tazobactam in isolates originating from CF pulmonary exacerbations. Methods: This was a single-centre, non-controlled study. Two hundred and forty-six P. aeruginosa isolates from 26 adult CF patients were included. PHR was defined as the presence of different ceftolozane/tazobactam minimum inhibitory concentration (MIC) values among P. aeruginosa isolates originating from a single patient specimen. Population analysis profiles (PAPs) were performed to assess the presence of MHR, defined as ≥4-fold change in the ceftolozane/tazobactam MIC from a single P. aeruginosa colony. Results: Sixteen of 26 patient specimens (62%) contained PHR P. aeruginosa populations. Of these 16 patients, 6 (23%) had specimens in which PHR P. aeruginosa isolates exhibited ceftolozane/tazobactam MICs with categorical differences (i.e. susceptible versus resistant) compared to results reported as part of routine care. One isolate, PSA 1311, demonstrated MHR. Canonical ceftolozane/tazobactam resistance genes were not found in the MHR isolates (MHR PSA 1311 or PHR PSA 6130). Conclusions: Ceftolozane/tazobactam PHR exists among P. aeruginosa isolates in this work, and approximately a quarter of these populations contained isolates with ceftolozane/tazobactam susceptibiilty interpretations different from what was reported clinically, supporting concerns surrounding the utility of traditional susceptibility testing methodology in the setting of CF specimens. Genome sequencing of isolates with acquired MHR to ceftolozane/tazobactam revealed variants of unknown significance. Future work will be centred on determining the significance of these mutations to better understand these data in clinical context.

Prospective role of cefiderocol in the management of carbapenem-resistant Acinetobacter baumannii infections: Review of the evidence.

Carbapenem-resistant Acinetobacter baumannii (CRAB) has been classified by the World Health Organization as being in the critical category of pathogens requiring urgent new antibiotic treatment options. Cefiderocol, the first approved siderophore cephalosporin, was designed for the treatment of carbapenem-resistant Gram-negative pathogens, particularly the non-fermenting species A. baumannii and Pseudomonas aeruginosa. Cefiderocol is mostly stable against hydrolysis by serine ß-lactamases and metallo-ß-lactamases, which are leading causes of carbapenem resistance. This review collates the available evidence on the in vitro activity, pharmacokinetics/pharmacodynamics, and efficacy and safety of cefiderocol, and outlines its current role in the management of CRAB infections. In vitro surveillance data show susceptibility rates of >90% for cefiderocol against CRAB isolates as well as in vitro synergism with a variety of antibiotics recommended in guidelines. Clinical efficacy of cefiderocol monotherapy against CRAB infections has been demonstrated in the descriptive, open-label CREDIBLE-CR and the non-inferiority, double-blind APEKS-NP randomised clinical trials as well as in real-world cases in patients with underlying health problems. To date, the frequency of on-therapy development of cefiderocol resistance in A. baumannii appears to be low, but monitoring is highly recommended. Within current treatment guidelines for moderate-to-severe CRAB infections, cefiderocol is recommended for infections in which other antibiotics failed and in combination with other active antibiotics. In vivo pre-clinical data support the combination of sulbactam or avibactam with cefiderocol to enhance efficacy and to suppress the emergence of cefiderocol resistance. The benefit of combination therapy in the clinical setting is yet to be determined in prospective studies.