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We report a fatal case of Aspergillus felis invasive rhinosinusitis with secondary cerebral abscesses in an immunocompetent host despite aggressive surgical debridement and combination antifungals. Whilst this organism is known to cause fatalities in cats, only a few cases in humans have been documented, all of which had significant immunosuppression. This is the first human death due to A. felis described in an immunocompetent host.

Over 1000 solid-organ and close to 2000 stem-cell transplants are performed annually in Australia.Antimicrobial stewardship activities in transplant units in Australia were reviewed.All health service organizations, and thus all transplant centers, in Australia are required to have an antimicrobial stewardship program. Despite this, in one recent survey, 23.5% of hospital antibiotic prescriptions were inappropriate. Vigorous efforts are being made to implement antifungal stewardship in Australian transplant programs, with guidelines for implementation published in December 2021. These guidelines include therapeutic antifungal drug monitoring and diagnostic stewardship as it pertains to the investigation of suspected invasive fungal infections.Infections with multidrug resistant pathogens and invasive fungi are sporadic issues in Australian transplant units, but stewardship efforts can optimize patient outcomes.

The objective of this study was to examine the occurrence, determinants, and outcome of S. aureus bloodstream infections (BSI) diagnosed based on single versus multiple positive initial cultures.All adults with first episodes of mono-microbial S. aureus BSI in Queensland during 2000-2019 were included.10,855 (67%) and 5,421 (33%) were diagnosed based on one and multiple positive initial cultures, respectively. Patients with multiple positive initial cultures were significantly younger, more likely to have community-associated disease, have a shorter time to culture positivity, less likely to have methicillin-resistant S. aureus BSI, and have a different distribution of comorbid medical illnesses and clinical foci. The 30-day all-cause case-fatality rate was 18% and single positive initial culture was an independent risk factor for death.Among patients with S. aureus BSI, those diagnosed by single positive initial blood cultures have different clinical features and a higher risk for death.

Invasive Streptococcus agalactiae (Group B streptococci, GBS) infections result in a large burden of disease globally. Changes in clinical and molecular epidemiology, as well as antibiotic resistance patterns, are being described globally amongst GBS isolates. Very little is known about the characteristics of invasive GBS disease in the Australian setting. Therefore, this study aimed to define the clinical and genomic characteristics of invasive GBS isolates from the Sunshine Coast region in Australia. Thirty-two isolates were identified over a 3-year period. Known risk factors for disease were present in 71.9% and the leading site of disease was the skin and soft tissue (40.6%). Sequence types (ST) 1, 17 and 23 made up 50% with ST17 making up 56.2% of the total. Serotype Ia was the most prevalent (9/32, 28.1%). Clindamycin and erythromycin resistance was seen in 12.5% and 25%, respectively. Active surveillance and local knowledge of GBS epidemiology and antibiotic resistance has both patient and public health importance. Vaccine candidates are currently in their clinical phase of development.

Background The quick sequential organ failure assessment (qSOFA) score predicts mortality in patients with suspected infection. We sought to understand how well qSOFA and the Systemic Inflammatory Response Syndrome (SIRS) criteria predict gram negative bacteraemia. Methods We prospectively evaluated 99 patients with gram negative bloodstream infection from a single tertiary centre. We assessed the utility of SIRS and qSOFA for their rate of positivity and association with early delivery of antibiotics ( Results The SIRS criteria had the highest positivity rate amongst patients with gram negative bacteraemia (85%) compared to the qSOFA criteria (25%) on the day of first positive culture. Positive SIRS criteria was the only score associated with delivery of antibiotics within 3 h (Relative risk 3.5, 95% Confidence interval 1.3 to 12.5, p= Conclusion In patients with gram negative bloodstream infection SIRS criteria was the most common positive risk score and had a higher association with early delivery of antibiotics when compared to qSOFA.

ESBL-producing Enterobacteriaceae as uropathogens have given rise to a sizeable amount of global morbidity. Community and hospital surveillance studies continue to report increasing proportions of these organisms as causes of urinary tract infection (UTI). Due to limited treatment options and the presence of cross-resistance amongst oral antibiotics of different classes, patients often require IV therapy, thereby increasing healthcare costs and reducing the effectiveness of delivering healthcare. Oral cephalosporin antibiotics are well known for their ability to achieve high urinary concentrations, in addition to achieving clinical success for treatment of uncomplicated UTI with a drug-susceptible pathogen. Novel cephalosporin/β-lactamase inhibitor combinations have been developed and demonstrate good in vitro activity against ESBL-producing isolates. A pooled analysis of in vitro activity of existing oral cephalosporin/clavulanate combinations in ESBL-producing Enterobacteriaceae has shown MIC50s of 0.5–1, 0.125–1 and 0.25 mg/L for cefpodoxime, ceftibuten and cefixime, respectively. A novel cyclic boronic acid β-lactamase inhibitor, QPX7728, was able to produce MIC50 values of 0.5 and ≤0.06 mg/L when paired with cefpodoxime and ceftibuten, respectively. Other novel combinations, cefpodoxime/ETX0282 and ceftibuten/VNRX7145, have also demonstrated excellent activity against ESBL producers. Clinical trials are now awaited.

Background Extended spectrum β-lactamase (ESBL) and AmpC-producing Gram-negative bacilli contribute significantly to the antimicrobial resistance (AMR) burden worldwide. Temocillin is an intravenous semisynthetic antibiotic that is stable to hydrolysis by ESBLs and AmpC. Temocillin may be a treatment option for serious infections due to these organisms. Methods Third-generation cephalosporin-resistant Escherichia coli and Klebsiella pneumoniae isolates from the MERINO trial were collected. The majority originated from the urinary tract. Isolates had previously undergone whole genome sequencing (WGS) to identify antimicrobial resistance genes. Temocillin minimum inhibitory concentration (MIC) values were determined by broth microdilution (BMD) with a concentration range of 2 to 128 mg/L. A recent EUCAST guideline has recommended clinical breakpoints for urinary E. coli, Klebsiella spp. (except K. aerogenes) and Proteus mirabilis (resistant >16 mg/L). Results 317 index bloodstream isolates (275 E. coli and 42 K. pneumoniae) were used. The frequency of β-lactamases among isolates was: CTX-M-15 (56%), OXA-1 (31%), CTX-M-27 (14%), CTX-M-14 (12%) and CMY-2 (8%). Overall, 95% of isolates were susceptible, increased exposure according to EUCAST clinical breakpoints v11.0. Summary MIC values were obtained: MIC50 was 8 mg/L and MIC90 was16 mg/L (range ≤2 to ≥128 mg/L) and did not differ markedly between species. Higher MIC values were seen among isolates that produced more than one β-lactamase but this did not appear to be specific to a single β-lactamase. Conclusions Temocillin demonstrated favourable in vitro activity against ceftriaxone-resistant Enterobacterales bloodstream isolates and may be a suitable agent to be trialled for treatment of serious infections due to these organisms.

BackgroundAntimicrobial resistance (AMR) is an ever-increasing global health concern. One crucial facet in tackling the AMR epidemic is earlier and more accurate AMR diagnosis, particularly in the dangerous and highly multi-drug resistant ESKAPE pathogen,Pseudomonas aeruginosa.ObjectivesWe aimed to develop two SYBR Green-based mismatch amplification mutation assays (SYBR-MAMAs) targeting GyrA T83I (gyrA248), and GyrA D87N, D87Y, and D87H (gyrA259). Together, these variants cause the majority of fluoroquinolone (FQ) AMR inP. aeruginosa.MethodsFollowing assay validation, thegyrA248 andgyrA259 SYBR-MAMAs were tested on 84 clinicalP. aeruginosaisolates from Queensland, Australia, 45 of which demonstrated intermediate/full ciprofloxacin resistance according to antimicrobial susceptibility testing.ResultsOur two SYBR-MAMAs correctly predicted an AMR phenotype in the majority (84%) of isolates with intermediate/full FQ resistance. Importantly, all FQ-sensitive strains were predicted to have a sensitive phenotype. Whole-genome sequencing confirmed 100% concordance with SYBR-MAMA genotypes.ConclusionsOur GyrA SYBR-MAMAs provide a rapid and cost-effective method for same-day identification of FQ AMR inP. aeruginosa. An additional SYBR-MAMA targeting the GyrB S466Y/S466F variants would increase FQ AMR prediction to 91%. Clinical implementation of our assays will permit more timely treatment alterations in cases where decreased FQ susceptibility is identified, leading to improved patient outcomes and antimicrobial stewardship.

Pasteurella species are infrequent but potentially severe causes of bloodstream infection (BSI). The objective of this study was to determine the incidence, risk factors, and outcomes of Pasteurella species BSI in a large Australian population. Retrospective, laboratory-based surveillance was conducted in Queensland, Australia (population ≈ 5 million) during 2000–2019, and clinical and outcome information was established by linkage to state hospital admissions and vital statistics databases. During more than 86 million person-years of surveillance, 272 incident Pasteurella species BSI occurred for an overall age- and sex-standardized annual incidence of 3.3 per million residents. The incidence of Pasteurella species BSI was highest in recent years and older individuals were at greatest risk. The median (interquartile range) Charlson Comorbidity Index was 2 (0–4) with scores of zero, 1, 2, and 3 + observed in 81 (30%), 37 (14%), 44 (16%), and 110 (40%) of cases. The 30-day all-cause case fatality was 9% (24/272) and patients who died had more comorbidities and were less likely to have community-associated disease. Although Pasteurella species are infrequent causes of BSI, older individuals and those with comorbidities are at highest risk. The burden of this disease may be expected to increase with an aging and more comorbid population.

Rickettsia species causing human illness are present globally and can cause significant disease. Diagnosis and identification of this intracellular bacteria are challenging with many available diagnostic modalities suffering from several shortcomings. Detection of antibodies directed against Rickettsia spp. via serological methods remains widely used with a broad range of sensitivity and specificity values reported depending on the assay. Molecular methods, including polymerase chain reaction (PCR) testing, enables species-specific identification with a fast turnaround time; however, due to resource requirements, use in some endemic settings is limited. Reports on the use of next-generation sequencing (NGS) and metagenomics to diagnose Rickettsia spp. infection have been increasing. Despite offering several potential advantages in the diagnosis and surveillance of disease, genomic approaches are currently only limited to reference and research laboratories. Continued development of Rickettsia spp. diagnostics is required to improve disease detection and epidemiological surveillance, and to better understand transmission dynamics.

Background Carbapenems are recommended treatment for serious infections caused by AmpC-producing gram-negative bacteria but can select for carbapenem resistance. Piperacillin-tazobactam may be a suitable alternative. Methods We enrolled adult patients with bloodstream infection due to chromosomal AmpC producers in a multicenter randomized controlled trial. Patients were assigned 1:1 to receive piperacillin-tazobactam 4.5 g every 6 hours or meropenem 1 g every 8 hours. The primary efficacy outcome was a composite of death, clinical failure, microbiological failure, and microbiological relapse at 30 days. Results Seventy-two patients underwent randomization and were included in the primary analysis population. Eleven of 38 patients (29%) randomized to piperacillin-tazobactam met the primary outcome compared with 7 of 34 patients (21%) in the meropenem group (risk difference, 8% [95% confidence interval {CI}, –12% to 28%]). Effects were consistent in an analysis of the per-protocol population. Within the subcomponents of the primary outcome, 5 of 38 (13%) experienced microbiological failure in the piperacillin-tazobactam group compared to 0 of 34 patients (0%) in the meropenem group (risk difference, 13% [95% CI, 2% to 24%]). In contrast, 0% vs 9% of microbiological relapses were seen in the piperacillin-tazobactam and meropenem arms, respectively. Susceptibility to piperacillin-tazobactam and meropenem using broth microdilution was found in 96.5% and 100% of isolates, respectively. The most common AmpC β-lactamase genes identified were blaCMY-2, blaDHA-17, blaCMH-3, and blaACT-17. No ESBL, OXA, or other carbapenemase genes were identified. Conclusions Among patients with bloodstream infection due to AmpC producers, piperacillin-tazobactam may lead to more microbiological failures, although fewer microbiological relapses were seen. Clinical Trials Registration NCT02437045.

Treatment options for multidrug-resistant (MDR) gram-negative infection are growing. However, postregistration, pragmatic, and clinician-led clinical trials in this field are few, recruit small sample sizes, and experience deficiencies in design and operations. MDR gram-negative therapeutic trials are often inefficient, only evaluating a single antibiotic or strategy at a time. Novel clinical trial designs offer potential solutions by attempting to obtain clinically meaningful conclusions at the end or during a trial, for many treatment strategies, simultaneously. An integrated, consensus approach to MDR gram-negative infection trial design is crucial.

Extended-spectrum-beta-lactamase (ESBL)-producing Enterobacterales continue to pose a major threat to human health worldwide. Given the limited therapeutic options available to treat infections caused by these pathogens, identifying additional effective antimicrobials or revisiting existing drugs is important. Ceftriaxone-resistant Escherichia coli and Klebsiella pneumoniae containing CTX-M-type ESBLs or AmpC, in addition to narrow-spectrum OXA and SHV enzymes, were selected from blood culture isolates obtained from the MERINO trial. Isolates had previously undergone whole-genome sequencing (WGS) to identify antimicrobial resistance genes. Cefotetan MICs were determined by broth microdilution (BMD) testing with a concentration range of 0.125 to 64 mg/liter; CLSI breakpoints were used for susceptibility interpretation. BMD was performed using an automated digital antibiotic dispensing platform (Tecan D300e). One hundred ten E. coli and 40 K. pneumoniae isolates were used. CTX-M-15 and CTX-M-27 were the most common beta-lactamases present; only 7 isolates had coexistent ampC genes. Overall, 98.7% of isolates were susceptible, with MIC50s and MIC90s of 0.25 mg/liter and 2 mg/liter (range, ≤0.125 to 64 mg/liter), respectively. MICs appeared higher among isolates with ampC genes present, with an MIC50 of 16 mg/liter, than among those containing CTX-M-15, which had an MIC50 of only 0.5 mg/liter. Isolates with an ampC gene exhibited an overall susceptibility of 85%. Presence of a narrow-spectrum OXA beta-lactamase did not appear to alter the cefotetan MIC distribution. Cefotetan demonstrated favorable in vitro efficacy against ESBL-producing E. coli and K. pneumoniae bloodstream isolates. IMPORTANCE Carbapenem antibiotics remain the treatment of choice for severe infection due to ESBL- and AmpC-producing Enterobacterales. The use of carbapenems is a major driver of the emergence of carbapenem-resistant Gram-negative bacilli, which are often resistant to most available antimicrobials. Cefotetan is a cephamycin antibiotic developed in the 1980s that demonstrates enhanced resistance to beta-lactamases and has a broad spectrum of activity against Gram-negative bacteria. Cefotetan holds potential to be a carbapenem-sparing treatment option. Data on the in vitro activity of cefotetan against ESBL-producing Enterobacterales remain scarce. Our study assessed the in vitro activity of cefotetan against ceftriaxone-nonsusceptible blood culture isolates obtained from patients enrolled in the MERINO trial.

Purpose of Review The aim of this article is to review current and emerging microbiological techniques that support the rapid diagnosis of bacterial infections in critically ill patients, including their performance, strengths and pitfalls, as well as available data evaluating their clinical impact. Recent Findings Bacterial infections and sepsis are responsible for significant morbidity and mortality in patients admitted to the intensive care unit and their management is further complicated by the increase in the global burden of antimicrobial resistance. In this setting, new diagnostic methods able to overcome the limits of traditional microbiology in terms of turn-around time and accuracy are highly warranted. We discuss the following broad themes: optimisation of existing culture-based methodologies, rapid antigen detection, nucleic acid detection (including multiplex PCR assays and microarrays), sepsis biomarkers, novel methods of pathogen detection (e.g. T2 magnetic resonance) and susceptibility testing (e.g. morphokinetic cellular analysis) and the application of direct metagenomics on clinical samples. The assessment of the host response through new “omics” technologies might also aid in early diagnosis of infections, as well as define non-infectious inflammatory states. Summary Despite being a promising field, there is still scarce evidence about the real-life impact of these assays on patient management. A common finding of available studies is that the performance of rapid diagnostic strategies highly depends on whether they are integrated within active antimicrobial stewardship programs. Assessing the impact of these emerging diagnostic methods through patient-centred clinical outcomes is a complex challenge for which large and well-designed studies are awaited.

Background COVID‐19 is known to cause an acute respiratory illness, although clinical manifestations outside of the respiratory tract may occur. Early reports have identified SARS‐CoV‐2 as a cause of subacute thyroiditis (SAT). Methods A systematic review was conducted in accordance with the PRISMA guidelines. MEDLINE, Web of Science and PubMed databases were queried in February 2021 for studies from December 2019 to February 2021. MeSH search terms “COVID‐19”, “SARS‐CoV‐2” and “coronavirus” along with search terms “thyroiditis”, “thyrotoxicosis”, “thyroid” were used. Descriptive statistics for continuous variables and proportions for categorical variables were calculated. Results 15 publications reporting on 17 individual cases of COVID‐19 induced SAT were identified. Age ranged from 18 to 69 years old. The majority of the cases were female (14 of 17, 82%). The delay between onset of respiratory symptoms and diagnosis of SAT ranged from 5 to 49 days (mean, 26.5). Systemic inflammatory response syndrome (SIRS) related to viral infection was uncommonly reported at the time of SAT diagnosis. Thyroid ultrasonography frequently reported an enlarged hypoechoic thyroid with decreased vascularity and heterogenous echotexture. Elevated CRP was common at the time of SAT diagnosis, with results ranging from 4.5 to 176 mg/L (mean, 41 mg/L). Anti‐thyroid antibodies were frequently negative. SAT specific treatment included corticosteroids for 12/17 (70.5%) patients. Most return to normal thyroid status. Conclusion COVID‐19 associated SAT may be difficult to identify in a timely manner due to potential absence of classic symptoms, as well as cross‐over of common clinical features between COVID‐19 and thyrotoxicosis. This article is protected by copyright. All rights reserved.

Third-generation cephalosporin-resistant (3GC-R) Enterobacteriaceae represent a major threat to human health. Here, we captured 288 3GC-R Enterobacteriaceae clinical isolates from 264 patients presenting at a regional Australian hospital over a 14-month period. In addition to routine mass spectrometry and antibiotic sensitivity testing, isolates were examined using rapid (∼40-min) real-time PCR assays targeting the most common extended-spectrum β-lactamases (ESBLs; bla(CTX-M-1) and bla(CTX-M-9) groups, plus bla(TEM), bla(SHV), and an internal 16S rRNA gene control). AmpC CMY β-lactamase (bla(CMY)) prevalence was also examined. Escherichia coli (80.2%) and Klebsiella pneumoniae (17.0%) were dominant, with Klebsiella oxytoca, Klebsiella aerogenes, and Enterobacter cloacae infrequently identified. Ceftriaxone and cefoxitin resistance were identified in 97.0% and 24.5% of E. coli and K. pneumoniae isolates, respectively. Consistent with global findings in Enterobacteriaceae, most (98.3%) isolates harbored at least one β-lactamase gene, with 144 (50%) harboring bla(CTX-M-1) group, 92 (31.9%) harboring bla(CTX-M-9) group, 48 (16.7%) harboring bla(SHV), 133 (46.2%) harboring bla(TEM), and 34 (11.8%) harboring bla(CMY) genes. A subset of isolates (n = 98) were subjected to whole-genome sequencing (WGS) to identify the presence of cryptic resistance determinants and to verify genotyping accuracy. WGS of β-lactamase-negative or carbapenem-resistant isolates identified uncommon ESBL and carbapenemase genes, including bla(NDM) and bla(IMP), and confirmed all PCR-positive genotypes. We demonstrate that our PCR assays enable the rapid and cost-effective identification of ESBLs in the hospital setting, which has important infection control and therapeutic implications.

Azoles are among the most effective and widely used class of antifungals for prophylaxis as well as empirical and directed therapy against yeast and mould infections. Their use appears to be increasing worldwide. All triazoles cause hepatotoxicity, drug-drug interactions, and QTc prolongation (except isavuconazole); however, there are growing concerns following increasing reports of off-target endocrinologic adverse events. Skeletal fluorosis, pseudohyperaldosteronism, adrenal insufficiency, hyponatraemia and hypogonadism have all been documented in relation to azole use, causing considerable morbidity. The following review provides new insights into the clinical incidence and underlying pathophysiology of azole-associated endocrinopathies. Routine clinical and biochemical monitoring (including therapeutic drug monitoring) of endocrinologic adverse events may play a role in their prevention and progression. Novel azoles in preclinical and clinical stages of development may offer therapeutic advantages due to their greater selectivity of binding to fungal CYP51. The integration of pharmacogenomics into routine clinical practice holds future promise in guiding antifungal drug and dose selection to reduce the risk of off-target phenomena, including endocrinologic adverse events.

Background Antimicrobial susceptibility testing (AST) is the standard of care for treating bacterial infections. In randomized clinical trials of new antimicrobials, AST might not be performed or reported in real time. Objectives To determine local, real-time laboratory AST performance, its usage in the trial flow, quality control (QC) of the local testing, central AST performance and the effect of using AST categorization on the trials' primary outcomes. Data sources We systematically searched PubMed, Embase, PsychINFO and Web of Science. Eligibility criteria We included registered randomized controlled trials published in journals between January 2015 and December 2019. Participants and interventions We included trials comparing different antibiotics for the treatment of infections caused predominantly by Gram-negative bacteria. Methods Primary outcomes for different trial populations were extracted and differences between trial arms were compared for patients with infections caused by susceptible versus non-susceptible bacteria. Results are described narratively. Results Of 32 randomized trials, 25 trials reported that local AST was performed, 1312 reported the local laboratory AST methods, no trial reported QC, but post-hoc referral for AST at a reference laboratory was common. Patients' outcomes were superior when patients with infections due to susceptible and non-susceptible pathogens were compared post hoc (median difference 14%, interquartile range 8%–24%) in trials allowing this comparison (seven antimicrobials), except for colistin, where 14-day mortality was 9% higher when patients were treated with colistin for colistin-susceptible versus colistin-resistant carbapenem-resistant Acinetobacter baumannii. When excluding patients with pathogens that were non-susceptible to either antimicrobial in the trials, the difference in the primary outcome between the trial arms was reduced in five out of six trials. Conclusions Trials should perform AST to guide patient inclusion or exclusion from the study and consider the impact of the central laboratory susceptibility results on the study outcomes when using post-hoc reference testing.

Cefepime, a wide-spectrum β-lactam antibiotic, has been in use for the treatment of serious bacterial infections for almost 25 years. Since its clinical development, there has been a dramatic shift in its dosing, with 2 g every 8 hours being preferred for serious infections to optimize pharmacokinetic/pharmacodynamic considerations. The advent of ESBLs has become a threat to its ongoing use, although future coadministration with β-lactamase inhibitors (BLIs) under development is an area of intense study. There are currently four new cefepime/BLI combinations in clinical development. Cefepime/zidebactam is generally active against MBL-producing Enterobacterales and Pseudomonas aeruginosa, in vitro and in animal studies, and cefepime/taniborbactam has activity against KPC and OXA-48 producers. Cefepime/enmetazobactam and cefepime/tazobactam are potential carbapenem-sparing agents with activity against ESBLs. Cefepime/enmetazobactam has completed Phase III and cefepime/taniborbactam is in Phase III clinical studies, where they are being tested against carbapenems or piperacillin/tazobactam for the treatment of complicated urinary tract infections. While these combinations are promising, their role in the treatment of MDR Gram-negative infections can only be determined with further clinical studies.

Carbapenem-sparing regimens are needed for the treatment of infections caused by extended-spectrum-β-lactamase (ESBL)- and AmpC-producing members of the Enterobacterales. We sought to compare the clinical efficacy of ceftazidime/avibactam and carbapenems against ESBL- and AmpC-producing Enterobacterales species. A systematic review and meta-analysis of randomized controlled trials comparing ceftazidime/avibactam with carbapenems for the treatment of ESBL- and AmpC-producing Enterobacterales was conducted. Five randomized controlled trials (RCTs) with ESBL- and AmpC-specific outcome data were compiled. Of the 246 patients infected with an ESBL-producing microorganism in the ceftazidime/avibactam arm, 224 (91%) had a clinical response at test of cure (TOC), versus 240 of 271 (89%) patients in the carbapenem arm (risk ratio [RR], 1.02; 95% confidence interval [CI], 0.97 to 1.08; P = 0.45; I(2) = 0%). Clinical response rates for AmpC producers in the ceftazidime/avibactam and carbapenem arms were 32/40 (80%) and 37/42 (88%), respectively (RR, 0.91; 95% CI, 0.76 to 1.10; P = 0.35; I(2) = 0%). Microbiological response and mortality rates were not reported specifically for ESBL/AmpC producers. Ceftazidime/avibactam may be a carbapenem-sparing option for the treatment of mild to moderate complicated urinary tract and intra-abdominal infections caused by ESBL-producing Enterobacterales species, and the data are too limited to provide any conclusive recommendations for the AmpC producers. Care should be taken before extrapolating this to severe infections, given that the representation of this population in the reviewed studies was negligible. Ceftazidime/avibactam is a costly drug active against carbapenem-resistant microorganisms and should be used judiciously to preserve its activity against them.

Background Extended-spectrum beta-lactamase (ESBL) and AmpC-producing Enterobacterales are common causes of bloodstream infection. ESBL-producing bacteria are typically resistant to third-generation cephalosporins and result in a sizeable economic and public health burden. AmpC-producing Enterobacterales may develop third-generation cephalosporin resistance through enzyme hyper-expression. In no observational study has the outcome of treatment of these infections been surpassed by carbapenems. Widespread use of carbapenems may drive the development of carbapenem-resistant Gram-negative bacilli. Methods This study will use a multicentre, parallel group open-label non-inferiority trial design comparing ceftolozane-tazobactam and meropenem in adult patients with bloodstream infection caused by ESBL or AmpC-producing Enterobacterales. Trial recruitment will occur in up to 40 sites in six countries (Australia, Singapore, Italy, Spain, Saudi Arabia and Lebanon). The sample size is determined by a predefined quantity of ceftolozane-tazobactam to be supplied by Merck, Sharpe and Dohme (MSD). We anticipate that a trial with 600 patients contributing to the primary outcome analysis would have 80% power to declare non-inferiority with a 5% non-inferiority margin, assuming a 30-day mortality of 5% in both randomised groups. Once randomised, definitive treatment will be for a minimum of 5 days and a maximum of 14 days with the total duration determined by treating clinicians. Data describing demographic information, risk factors, concomitant antibiotics, illness scores, microbiology, multidrug-resistant organism screening, discharge and mortality will be collected. Discussion Participants will have bloodstream infection due to third-generation cephalosporin non-susceptible E. coli and Klebsiella spp. or Enterobacter spp., Citrobacter freundii, Morganella morganii, Providencia spp. or Serratia marcescens. They will be randomised 1:1 to ceftolozane-tazobactam 3 g versus meropenem 1 g, both every 8 h. Secondary outcomes will be a comparison of 14-day all-cause mortality, clinical and microbiological success at day 5, functional bacteraemia score, microbiological relapse, new bloodstream infection, length of hospital stay, serious adverse events, C. difficile infection, multidrug-resistant organism colonisation. The estimated trial completion date is December 2024. Trial registration The MERINO-3 trial is registered under the US National Institute of Health ClinicalTrials.gov register, reference number: NCT04238390. Registered on 23 January 2020.

Achromobacter is a genus of nonfermenting Gram-negative bacteria under order Burkholderiales. Although primarily isolated from respiratory tract of people with cystic fibrosis, Achromobacter spp. can cause a broad range of infections in hosts with other underlying conditions. Their rare occurrence and ever-changing taxonomy hinder defining their clinical features, risk factors for acquisition and adverse outcomes, and optimal treatment. Achromobacter spp. are intrinsically resistant to several antibiotics (e.g., most cephalosporins, aztreonam, and aminoglycosides), and are increasingly acquiring resistance to carbapenems. Carbapenem resistance is mainly caused by multidrug efflux pumps and metallo-β-lactamases, which are not expected to be overcome by new β-lactamase inhibitors. Among the other new antibiotics, cefiderocol, and eravacycline were used as salvage therapy for a limited number of patients with Achromobacter infections. In this article, we aim to give an overview of the antimicrobial resistance in Achromobacter species, highlighting the possible place of new antibiotics in their treatment.

Despite the accepted dogma that antibiotic use is the largest contributor to antimicrobial resistance (AMR) and human microbiome disruption, our knowledge of specific antibiotic-microbiome effects remains basic. Detection of associations between new or old antimicrobials and specific AMR burden is patchy and heterogeneous. Various microbiome analysis tools are available to determine antibiotic effects on microbial communities in vivo. Microbiome analysis of treatment groups in antibiotic clinical trials, powered to measure clinically meaningful endpoints would greatly assist the antibiotic development pipeline and clinician antibiotic decision making.

SynopsisThird-generation cephalosporin-resistant (3GC-R) Enterobacteriaceae represent a major threat to human health. Here, we captured 288 3GC-R Enterobacteriaceae clinical isolates from 264 patients presenting at a regional Australian hospital over a 14-month period. Alongside routine mass spectrometry speciation and antibiotic sensitivity testing, isolates were examined using rapid (∼40 min) real-time PCR assays targeting the most common extended spectrum β-lactamases (ESBLs; CTX-M-1 and CTX-M-9 groups, plus TEM, SHV, and an internal 16S ribosomal DNA control). AmpC CMY β-lactamase prevalence was also examined. Escherichia coli (80.2%) and Klebsiella pneumoniae (17.0%) were dominant, with Klebsiella oxytoca, Klebsiella aerogenes and Enterobacter cloacae infrequently identified. Ceftriaxone and cefoxitin resistance were identified in 97.0% and 24.5% of E. coli and K. pneumoniae isolates, respectively. Consistent with global findings in Enterobacteriaceae, most (98.3%) isolates harbored at least one β-lactamase gene, with 144 (50%) encoding blaCTX-M-1 group, 92 (31.9%) blaCTX-M-9 group, 48 (16.7%) blaSHV, 133 (46.2%) blaTEM, and 34 (11.8%) blaCMY. A subset of isolates (n=98) were subjected to whole-genome sequencing (WGS) to identify the presence of cryptic resistance determinants, and to verify genotyping accuracy. WGS of β-lactamase negative or carbapenem-resistant isolates identified uncommon ESBLs and carbapenemases, including blaNDM and blaIMP, and confirmed all PCR-positive genotypes. We demonstrate that our PCR assays enable the rapid and cost-effective identification of ESBLs in the hospital setting, which has important infection control and therapeutic implications.

PURPOSE OF REVIEW: Multidrug-resistant (MDR) Gram-negative bacteria infections are listed among the top public health threats of the current era. As a result, there has been an increase in efforts to develop new therapeutic agents against MDR Gram-negatives. The purpose of this review is to summarize the clinical and preclinical findings associated with recently approved drugs and the drugs in clinical development against ESBL and carbapenemase-producing Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumannii infections. RECENT FINDINGS: There are a number of ESBL active agents in late stage clinical development that can help spare carbapenems. Likewise, recently approved β-lactam/β-lactamase inhibitor combinations allow a change in the treatment of KPC and OXA-48 producers and carbapenem-resistant P. aeruginosa from colistin to new, safer agents. Treatment of Meta-beta-lactamase (MBL) producers remains an unmet need - apart from cefiderocol, most agents with MBL activity are still in clinical development. Among the few agents with carbapenem-resistant A. baumannii activity, durlobactam/sulbactam in phase III clinical trials provides hope. SUMMARY: Armamentarium against MDR Gram-negatives has expanded with the dominance of agents active against ESBL and KPC producers. There is a need to prioritize MBL producers and carbapenem-resistant A. baumannii, as well as the need for clinical trials to test the new agents against serious infections.

Diarrhoea that occurs during or after recent travel is predominantly infectious in nature; however, in atypical or prolonged cases a broader range of aetiologies for diarrhoea must be considered, and a careful history and examination may reveal clues to more sinister causes of diarrhoea. We report two cases in which a recent travel history and a positive stool culture or polymerase chain reaction testing for bacterial pathogens delayed the diagnosis of ulcerative colitis. As a result of severe inflammatory bowel disease, colectomy was the final result in both cases. Early consideration of causes other than infection for traveller's diarrhoea may prevent unnecessary morbidity in young patients.