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Background. Antimicrobial 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 . Objectives. We 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 in P. aeruginosa . Methods. Following assay validation, the gyrA248 and gyrA259 SYBR-MAMAs were tested on 84 Australian clinical P. aeruginosa isolates, 46 of which demonstrated intermediate/full ciprofloxacin resistance according to antimicrobial susceptibility testing. Results. Our two SYBR-MAMAs correctly predicted an AMR phenotype in the majority (83%) of isolates with intermediate/full FQ resistance. All FQ-sensitive strains were predicted to have a sensitive phenotype. Whole-genome sequencing confirmed 100 % concordance with SYBR-MAMA genotypes. Conclusions. Our GyrA SYBR-MAMAs provide a rapid and cost-effective method for same-day identification of FQ AMR in P. 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.

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.

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.

Although recent reports of extensively antibiotic-resistant strains have highlighted the importance of Morganella morganii as an emerging pathogen, the epidemiology of serious infections due to this organism is not well defined. The objective of this study was to determine the incidence, determinants, and outcomes of Morganella morganii bloodstream infections (BSIs). Retrospective, population-based surveillance for Morganella morganii BSIs was conducted in Queensland, Australia, in 2000 to 2019; 709 cases were identified, for an annual incidence of 9.2 cases per million population. Most cases were of community onset, with 280 (39.5%) community-associated cases and 226 (31.9%) health care-associated cases. Morganella morganii BSIs were rare in children and young adults, and the incidence increased markedly with advancing age. The most common foci of infection were skin and soft tissue (131 cases [18.5%]), genitourinary (97 cases [13.7%]), and intraabdominal (90 cases [12.7%]). Most patients (580 cases [81.8%]) had at least one comorbid medical illness, with diabetes mellitus (250 cases [35.3%]), renal disease (208 cases [29.3%]), and congestive heart failure (167 cases [23.6%]) being most prevalent. Resistance to one or more of quinolones, co-trimoxazole, aminoglycosides, or carbapenems was observed in 67 cases (9.5%), and this did not change significantly over the study. The 30-day all-cause case fatality rate was 21.2%, and increasing age, nonfocal infection, heart failure, dementia, and cancer were independently associated with increased risk of death. Morganella morganii BSIs are increasing in our population, and elderly male subjects and individuals with comorbidities are at highest risk. Although antibiotic resistance is not a major contributor to the current burden in Queensland, ongoing surveillance is warranted.

The epidemiology of bloodstream infections caused by Shewanella spp. is not well defined. Our objective was to define the incidence and determinants of Shewanella spp. bloodstream infections by using population-based surveillance in Queensland, Australia during 2000‒2019. The incidence was 1.0 cases/1 million persons annually and was highest during summer and in the tropical Torres and Cape region. Older persons and male patients were at highest risk. At least 1 concurrent condition was documented in 75% of case-patients, and 30-day all cause case-fatality rate was 15%. Aging populations in warm climates might expect an increasing burden of these infections.

Small case series and reports suggest that Sphingomonas paucimobilis is predominantly a cause of nosocomial bloodstream infections (BSI) with very low associated mortality. Our objective was to describe the epidemiology and outcome of Sphingomonas species BSI in a large Australian population.We included all residents of Queensland, Australia, with BSI because of Sphingomonas species identified within the publicly funded system from 2000 to 2019.A total of 282 incident episodes of Sphingomonas species BSI were identified for an age- and sex-adjusted incidence of 3.2 per million population annually. Incidence rates were highest in the tropical regions of the state. Most (94%) of the isolates were confirmed as Sphingomonas paucimobilis. In addition, 77% of the infections were community-onset, of which 48% were community-associated, and 30% were healthcare-associated. The very young, the old, and male patients were at the highest risk. Patients with community-associated disease were, on average, younger, had fewer co-morbidities, and were less likely to have polymicrobial infections. At least 1 co-morbidity was identified in 62% of patients, with malignancy, diabetes, and lung disease most prevalent. The overall all-cause 30-day case-fatality rate was 6%.Sphingomonas paucimobilis BSI is a predominantly community-onset disease associated with a significant risk of death.

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.

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.

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.

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.

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.

Primary cutaneous Mycobacterium avium complex (MAC) infection is a rare diagnosis in both immunocompetent and immunocompromised hosts. Disseminated MAC almost always occurs in the setting of advanced HIV infection and typically results from initial pulmonary or gastrointestinal disease. We describe a case of a 70-year-old female with systemic sclerosis and severe tumoral calcinosis that developed disseminated MAC infection secondary to deep cutaneous disease. Treatment was complicated by multiple significant drug interactions, patient comorbidities, as well as an inability to safely and completely surgically resect her infected soft tissue for source control.

Antimicrobial resistance is a major threat to the delivery of effective care and already causes 700000 excess deaths per year worldwide. International consensus on action to combat antimicrobial resistance was reached in 2015. Australia is implementing a national strategy. The clinical consequences of antimicrobial resistance are seen most acutely in multi-drug resistant Gram-negative bacterial infections, where they cause increased mortality and morbidity and threaten the delivery of once routine medical care. The solution to antimicrobial resistance is complex and multifaceted. Antimicrobial stewardship, that is optimising the use of the antibiotics we currently have, is the most rapidly deployable mitigation. Several novel antibiotics with activity against a range of drug-resistant bacteria are now available clinically, leading to hope that innovative solutions will reduce the impact of resistance. It is critical that these new drugs are protected from inappropriate use.

Invasive infections due to carbapenem-resistant Enterobacteriaceae (CRE) are becoming increasingly more prevalent and provide significant morbidity and mortality. Providing curative therapy and overcoming bacterial resistance are difficult tasks with limited antibiotic options. Alternative antibiotics and approaches to therapy are required, with often a compromise in patient outcome.To demonstrate the effective use of therapeutic drug monitoring (TDM) in difficult-to-treat infections due to multiresistant gram-negative bacteria.A case of an elderly woman with an invasive cervical spine infection due to CRE is presented. Her protracted therapeutic course was complicated by multiple treatment failures and severe cervical spine instability. Therapeutic success, as determined by wound healing, cervical spine stability, and continued suppression of inflammatory markers, was obtained by continuous daily ertapenem infusions with TDM guiding the optimal drug dosing.In this unusual setting, TDM was utilized successfully to achieve favorable serum antibiotic concentrations and lead to control of the infection. TDM may be a useful tool in difficult-to-treat infections caused by multiresistant bacteria.