Publications by authors named "David L Paterson"

387 Publications

Synergy of the Polymyxin-Chloramphenicol Combination against New Delhi Metallo-β-Lactamase-Producing Is Predominately Driven by Chloramphenicol.

ACS Infect Dis 2021 Apr 9. Epub 2021 Apr 9.

Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.

Carbapenem-resistant has been classified as an Urgent Threat by the Centers for Disease Control and Prevention (CDC). The combination of two "old" antibiotics, polymyxin and chloramphenicol, displays synergistic killing against New Delhi metallo-β-lactamase (NDM)-producing . However, the mechanism(s) underpinning their synergistic killing are not well studied. We employed an pharmacokinetic/pharmacodynamic model to mimic the pharmacokinetics of the antibiotics in patients and examined bacterial killing against NDM-producing using a metabolomic approach. Metabolomic analysis was integrated with an isolate-specific genome-scale metabolic network (GSMN). Our results show that metabolic responses to polymyxin B and/or chloramphenicol against NDM-producing involved the inhibition of cell envelope biogenesis, metabolism of arginine and nucleotides, glycolysis, and pentose phosphate pathways. Our metabolomic and GSMN modeling results highlight the novel mechanisms of a synergistic antibiotic combination at the network level and may have a significant potential in developing precision antimicrobial chemotherapy in patients.
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http://dx.doi.org/10.1021/acsinfecdis.0c00661DOI Listing
April 2021

Evaluation of Meropenem-Ciprofloxacin Combination Dosage Regimens for the Pharmacokinetics of Critically Ill Patients With Augmented Renal Clearance.

Clin Pharmacol Ther 2021 Apr 12;109(4):1104-1115. Epub 2021 Mar 12.

Centre for Medicine Use and Safety, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.

Augmented renal clearance (ARC, creatinine clearance > 130 mL/minute) makes difficult achievement of effective concentrations of renally cleared antibiotics in critically ill patients. This study examined the synergistic killing and resistance suppression for meropenem-ciprofloxacin combination dosage regimens against Pseudomonas aeruginosa isolates within the context of ARC. Clinically relevant meropenem and ciprofloxacin concentrations, alone and in combinations, were studied against three clinical isolates with a range of susceptibilities to each of the antibiotics. Isolate Pa1280 was susceptible to both meropenem and ciprofloxacin, Pa1284 had intermediate susceptibility to meropenem and was susceptible to ciprofloxacin, and CR380 was resistant to meropenem and had intermediate susceptibility to ciprofloxacin. Initially, isolates were studied in 72-hour static-concentration time-kill (SCTK) studies. Subsequently, the pharmacokinetic profiles expected in patients with ARC receiving dosage regimens, including at the highest approved daily doses (meropenem 6 g daily divided and administered as 0.5-hour infusions every 8 hours, or as a continuous infusion; ciprofloxacin 0.4 g as 1-hour infusions every 8 hours), were examined in a dynamic hollow-fiber infection model (HFIM) over 7-10 days. In both SCTK and HFIM, combination regimens were generally synergistic and suppressed growth of less-susceptible subpopulations, these effects being smaller for isolate CR380. The time-courses of total and less-susceptible bacterial populations in the HFIM were well-described by mechanism-based models, which enabled conduct of Monte Carlo simulations to predict likely effectiveness of approved dosage regimens at different creatinine clearances. Optimized meropenem-ciprofloxacin combination dosage regimens may be a viable consideration for P. aeruginosa infections in critically ill patients with ARC.
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http://dx.doi.org/10.1002/cpt.2191DOI Listing
April 2021

Budget impact analysis of routinely using whole-genomic sequencing of six multidrug-resistant bacterial pathogens in Queensland, Australia.

BMJ Open 2021 Feb 1;11(2):e041968. Epub 2021 Feb 1.

The University of Queensland, Centre for Clinical Research, Brisbane, Queensland, Australia.

Objective: To predict the cost and health effects of routine use of whole-genome sequencing (WGS) of bacterial pathogens compared with those of standard of care.

Design: Budget impact analysis was performed over the following 5 years. Data were primarily from sequencing results on clusters of multidrug-resistant organisms across 27 hospitals. Model inputs were derived from hospitalisation and sequencing data, and epidemiological and costing reports, and included multidrug resistance rates and their trends.

Setting: Queensland, Australia.

Participants: Hospitalised patients.

Interventions: WGS surveillance of six common multidrug-resistant organisms (, , , , sp and ) compared with standard of care or routine microbiology testing.

Primary And Secondary Outcomes: Expected hospital costs, counts of patient infections and colonisations, and deaths from bloodstream infections.

Results: In 2021, 97 539 patients in Queensland are expected to be infected or colonised with one of six multidrug-resistant organisms with standard of care testing. WGS surveillance strategy and earlier infection control measures could avoid 36 726 infected or colonised patients and avoid 650 deaths. The total cost under standard of care was $A170.8 million in 2021. WGS surveillance costs an additional $A26.8 million but was offset by fewer costs for cleaning, nursing, personal protective equipment, shorter hospital stays and antimicrobials to produce an overall cost savings of $30.9 million in 2021. Sensitivity analyses showed cost savings remained when input values were varied at 95% confidence limits.

Conclusions: Compared with standard of care, WGS surveillance at a state-wide level could prevent a substantial number of hospital patients infected with multidrug-resistant organisms and related deaths and save healthcare costs. Primary prevention through routine use of WGS is an investment priority for the control of serious hospital-associated infections.
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http://dx.doi.org/10.1136/bmjopen-2020-041968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852923PMC
February 2021

Population Pharmacokinetics Analysis of Amikacin Initial Dosing Regimen in Elderly Patients.

Antibiotics (Basel) 2021 Jan 20;10(2). Epub 2021 Jan 20.

Department of Clinical Infectious Diseases, Aichi Medical University, Aichi 480-1195, Japan.

There are limited data of amikacin pharmacokinetics (PK) in the elderly population. Hence, we aimed to describe the population PK of amikacin in elderly patients (>70 years old) and to establish optimized initial dosing regimens. We simulated individual maximum concentrations in plasma (Cmax) and minimal concentrations (Cmin) for several dosing regimens (200-2000 mg every 24, 48, and 72 h) for patients with creatinine clearance (CCr) of 10-90 mL/min and analyzed efficacy (Cmax/minimal inhibitory concentration (MIC) ≥ 8) for MICs of 4, 8, and 16 mg/L and safety (Cmin < 4 mg/L). A one-compartment model best described the data. CCr was the only covariate associated with amikacin clearance. The population PK parameter estimates were 2.25 L/h for clearance and 18.0 L for volume of distribution. Dosing simulations recommended the dosing regimens (1800 mg) with dosing intervals ranging 48-72 h for patients with CCr of 40-90 mL/min based on achievement of both efficacy for the MIC of 8 mg/L and safety. None of the dosing regimens achieved the targets for an MIC of 16 mg/L. We recommend the initial dosing regimen using a nomogram based on CCr for an MIC of ≤8 mg/L in elderly patients with CCr of 40-90 mL/min.
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http://dx.doi.org/10.3390/antibiotics10020100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909551PMC
January 2021

Cutibacterium (Proprionibacterium) acnes in Shoulder Surgery: a Scoping Review of Strategies for Prevention, Diagnosis and Treatment.

J Shoulder Elbow Surg 2020 Dec 26. Epub 2020 Dec 26.

University of Queensland Centre for Clinical Research, RBWH Campus, Brisbane QLD, Australia. Electronic address:

Background: Cutibacterium (formerly Proprionibacterium) acnes is a commensal, gram-positive, facultatively anaerobic bacillus that resides in the dermis. Historically thought to be a contaminant when identified on cultured specimens, recent advances in diagnostic technology have now implicated it as the most common organism responsible for postoperative shoulder infections. Despite a recognition of the role of this organism and a significant research interest in recent years, there is clear lack of consensus guideline on strategies to prevent, diagnose and treat postoperative shoulder infection.

Method: The electronic databases Pubmed, MEDLINE, CINAHL, Scopus, and Web of Science were searched in March 2020. All experimental and nonexperimental studies that investigate C. acnes in shoulder surgery were included. Inclusion was limited to articles published after 2000 and written in English; reviews, grey literatures or abstracts were excluded. A total of 70 studies were included in this review. This scoping review was performed in accordance with the Extended Preferred Reporting Items of Systematic Reviews and Meta-Analyses Statement for Scoping Reviews (PRISMA-ScR).

Results: Standard surgical prophylactic regimens such as intravenous antibiotics and topical chlorhexidine are ineffective at removing C. acnes from the deep layer of the dermis, and there is a shift towards using topical benzoyl peroxide with significantly improved efficacy. An improved understanding of the bacteria has demonstrated that a prolonged culture time of up to 14 days is needed, especially in cases of established infection. Advances in diagnostics such as sonication and molecular-based testing are promising. Although usually thought to be susceptible to a broad range of antibiotics, resistance is emerging to clindamycin. An improved understanding of its ability to form a biofilm highlights the difficulty in treating an established infection.

Conclusion: The role of C. acnes causing postoperative infection following shoulder surgery is being increasingly recognized. Strategies for prevention, diagnosis and treatment have been outlined from both an antimicrobial and surgical perspective. A number of these strategies are emerging and require further research to demonstrate efficacy before implementation into clinical guidelines.

Level Of Evidence: Level IV; Scoping Review.
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http://dx.doi.org/10.1016/j.jse.2020.11.011DOI Listing
December 2020

Completing the Picture - Capturing the Resistome in Antibiotic Clinical Trials.

Clin Infect Dis 2020 Dec 23. Epub 2020 Dec 23.

Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Royal Brisbane and Women's Hospital Campus, Brisbane, Australia.

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 have become available that enable accurate descriptions of antibiotic effects on microbial communities in vivo over a period of time. 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.
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http://dx.doi.org/10.1093/cid/ciaa1877DOI Listing
December 2020

An update on cefepime and its future role in combination with novel β-lactamase inhibitors for MDR Enterobacterales and Pseudomonas aeruginosa.

J Antimicrob Chemother 2021 Feb;76(3):550-560

University of Queensland, Faculty of Medicine, UQ Centre for Clinical Research, Brisbane, Australia.

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.
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http://dx.doi.org/10.1093/jac/dkaa511DOI Listing
February 2021

Repurposing a neurodegenerative disease drug to treat Gram-negative antibiotic-resistant bacterial sepsis.

Sci Transl Med 2020 11;12(570)

School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Queensland 4072, Australia.

The emergence of polymyxin resistance in carbapenem-resistant and extended-spectrum β-lactamase (ESBL)-producing bacteria is a critical threat to human health, and alternative treatment strategies are urgently required. We investigated the ability of the hydroxyquinoline analog ionophore PBT2 to restore antibiotic sensitivity in polymyxin-resistant, ESBL-producing, carbapenem-resistant Gram-negative human pathogens. PBT2 resensitized , , , and to last-resort polymyxin class antibiotics, including the less toxic next-generation polymyxin derivative FADDI-287, in vitro. We were unable to select for mutants resistant to PBT2 + FADDI-287 in polymyxin-resistant containing a plasmid-borne gene or carrying a chromosomal mutation. Using a highly invasive strain engineered for polymyxin resistance through mutation, we successfully demonstrated the efficacy of PBT2 + polymyxin (colistin or FADDI-287) for the treatment of Gram-negative sepsis in immunocompetent mice. In comparison to polymyxin alone, the combination of PBT2 + polymyxin improved survival and reduced bacterial dissemination to the lungs and spleen of infected mice. These data present a treatment modality to break antibiotic resistance in high-priority polymyxin-resistant Gram-negative pathogens.
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http://dx.doi.org/10.1126/scitranslmed.abb3791DOI Listing
November 2020

Burkholderia pseudomallei Clinical Isolates Are Highly Susceptible to Cefiderocol, a Siderophore Cephalosporin.

Antimicrob Agents Chemother 2021 01 20;65(2). Epub 2021 Jan 20.

University of Queensland Centre for Clinical Research, Herston, Queensland, Australia

Cefiderocol is a cephalosporin designed to treat multidrug-resistant Gram-negative infections. By forming a chelated complex with ferric iron, cefiderocol is transported into the periplasmic space via bacterial iron transport systems and primarily binds to penicillin-binding protein 3 (PBP3) to inhibit peptidoglycan synthesis. This mode of action results in cefiderocol having greater activity against many Gram-negative bacilli than currently used carbapenems, β-lactam/β-lactamase inhibitor combinations, and cephalosporins. Thus, we investigated the activity of cefiderocol against a total of 246 clinical isolates of from Queensland, Australia. The collection was composed primarily of bloodstream (56.1%), skin and soft tissue (16.3%), and respiratory (15.9%) isolates. MICs of cefiderocol ranged from ≤0.03 to 16 mg/liter, whereas the MIC was 0.125 mg/liter. Based upon CLSI clinical breakpoints for cefiderocol against , , and , three isolates (1.2%) would be classified as nonsusceptible (MIC > 4 mg/liter). Using EUCAST non-species-specific (pharmacokinetic/pharmacodynamic [PK/PD]) clinical breakpoints or those set for , four isolates (1.6%) would be resistant (MIC > 2 mg/liter). Further testing for coresistance to meropenem, ceftazidime, trimethoprim-sulfamethoxazole, amoxicillin-clavulanate, and doxycycline was performed on the four isolates with elevated cefiderocol MICs (>2 mg/liter); all isolates exhibited resistance to amoxicillin-clavulanic acid, while three isolates also displayed resistance to at least one other antimicrobial. Cefiderocol was found to be highly active against primary clinical isolates. This compound shows great potential for the treatment of melioidosis in countries of endemicity and should be explored further.
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http://dx.doi.org/10.1128/AAC.00685-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848980PMC
January 2021

COVID-19 - Lessons Learned and Questions Remaining.

Clin Infect Dis 2020 Oct 26. Epub 2020 Oct 26.

University of California, San Diego School of Medicine, San Diego, CA, USA.

In this article, the editors of Clinical Infectious Diseases review some of the most important lessons they have learned about the epidemiology, clinical features, diagnosis, treatment and prevention of SARS-CoV-2 infection and identify essential questions about COVID-19 that remain to be answered.
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http://dx.doi.org/10.1093/cid/ciaa1654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797746PMC
October 2020

Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial.

Lancet Infect Dis 2021 02 12;21(2):226-240. Epub 2020 Oct 12.

Shionogi, Osaka, Japan. Electronic address:

Background: New antibiotics are needed for the treatment of patients with life-threatening carbapenem-resistant Gram-negative infections. We assessed the efficacy and safety of cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections.

Methods: We did a randomised, open-label, multicentre, parallel-group, pathogen-focused, descriptive, phase 3 study in 95 hospitals in 16 countries in North America, South America, Europe, and Asia. We enrolled patients aged 18 years or older admitted to hospital with nosocomial pneumonia, bloodstream infections or sepsis, or complicated urinary tract infections (UTI), and evidence of a carbapenem-resistant Gram-negative pathogen. Participants were randomly assigned (2:1 by interactive web or voice response system) to receive either a 3-h intravenous infusion of cefiderocol 2 g every 8 h or best available therapy (pre-specified by the investigator before randomisation and comprised of a maximum of three drugs) for 7-14 days. For patients with pneumonia or bloodstream infection or sepsis, cefiderocol treatment could be combined with one adjunctive antibiotic (excluding polymyxins, cephalosporins, and carbapenems). The primary endpoint for patients with nosocomial pneumonia or bloodstream infection or sepsis was clinical cure at test of cure (7 days [plus or minus 2] after the end of treatment) in the carbapenem-resistant microbiological intention-to-treat population (ITT; ie, patients with a confirmed carbapenem-resistant Gram-negative pathogen receiving at least one dose of study drug). For patients with complicated UTI, the primary endpoint was microbiological eradication at test of cure in the carbapenem-resistant microbiological ITT population. Safety was evaluated in the safety population, consisting of all patients who received at least one dose of study drug. Mortality was reported through to the end of study visit (28 days [plus or minus 3] after the end of treatment). Summary statistics, including within-arm 95% CIs calculated using the Clopper-Pearson method, were collected for the primary and safety endpoints. This trial is registered with ClinicalTrials.gov (NCT02714595) and EudraCT (2015-004703-23).

Findings: Between Sept 7, 2016, and April 22, 2019, we randomly assigned 152 patients to treatment, 101 to cefiderocol, 51 to best available therapy. 150 patients received treatment: 101 cefiderocol (85 [85%] received monotherapy) and 49 best available therapy (30 [61%] received combination therapy). In 118 patients in the carbapenem-resistant microbiological ITT population, the most frequent carbapenem-resistant pathogens were Acinetobacter baumannii (in 54 patients [46%]), Klebsiella pneumoniae (in 39 patients [33%]), and Pseudomonas aeruginosa (in 22 patients [19%]). In the same population, for patients with nosocomial pneumonia, clinical cure was achieved by 20 (50%, 95% CI 33·8-66·2) of 40 patients in the cefiderocol group and ten (53%, 28·9-75·6) of 19 patients in the best available therapy group; for patients with bloodstream infection or sepsis, clinical cure was achieved by ten (43%, 23·2-65·5) of 23 patients in the cefiderocol group and six (43%, 17·7-71·1) of 14 patients in the best available therapy group. For patients with complicated UTIs, microbiological eradication was achieved by nine (53%, 27·8-77·0) of 17 patients in the cefiderocol group and one (20%, 0·5-71·6) of five patients in the best available therapy group. In the safety population, treatment-emergent adverse events were noted for 91% (92 patients of 101) of the cefiderocol group and 96% (47 patients of 49) of the best available therapy group. 34 (34%) of 101 patients receiving cefiderocol and nine (18%) of 49 patients receiving best available therapy died by the end of the study; one of these deaths (in the best available therapy group) was considered to be related to the study drug.

Interpretation: Cefiderocol had similar clinical and microbiological efficacy to best available therapy in this heterogeneous patient population with infections caused by carbapenem-resistant Gram-negative bacteria. Numerically more deaths occurred in the cefiderocol group, primarily in the patient subset with Acinetobacter spp infections. Collectively, the findings from this study support cefiderocol as an option for the treatment of carbapenem-resistant infections in patients with limited treatment options.

Funding: Shionogi.
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http://dx.doi.org/10.1016/S1473-3099(20)30796-9DOI Listing
February 2021

Is Ceftazidime/Avibactam an Option for Serious Infections Due to Extended-Spectrum-β-Lactamase- and AmpC-Producing ?: a Systematic Review and Meta-analysis.

Antimicrob Agents Chemother 2020 12 16;65(1). Epub 2020 Dec 16.

University of Queensland, Faculty of Medicine, UQ Center for Clinical Research, Brisbane, Australia

Carbapenem-sparing regimens are needed for the treatment of infections caused by extended-spectrum-β-lactamase (ESBL)- and AmpC-producing members of the We sought to compare the clinical efficacy of ceftazidime/avibactam and carbapenems against ESBL- and AmpC-producing species. A systematic review and meta-analysis of randomized controlled trials comparing ceftazidime/avibactam with carbapenems for the treatment of ESBL- and AmpC-producing 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;  = 0.45;  = 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;  = 0.35;  = 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 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.
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http://dx.doi.org/10.1128/AAC.01052-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927835PMC
December 2020

Multidrug-Resistant Bacteria in the Community: An Update.

Infect Dis Clin North Am 2020 12 30;34(4):709-722. Epub 2020 Sep 30.

University of Queensland Centre for Clinical Research, Royal Brisbane & Women's Hospital Campus, Building 71/918, Herston, Queensland 4029, Australia.

Multidrug-resistant bacteria are among the most important current threats to public health. Typically, they are associated with nosocomial infections. However, some have become prevalent causes of community-acquired infections, such as Neisseria gonorrhoeae, Shigella, Salmonella, and Streptococcus pneumoniae. The community spread of multidrug-resistant bacteria is also a crucial development. An important global threat on the horizon is represented by production of carbapenemases by community-acquired hypervirulent Klebsiella pneumoniae. Such strains have already been found in Asia, Europe, and North America. Prevention of further community spread of multidrug-resistant bacteria is of the utmost importance, and will require a multidisciplinary approach involving all stakeholders.
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http://dx.doi.org/10.1016/j.idc.2020.08.002DOI Listing
December 2020

Reply to Rezahosseini and Nielsen.

Clin Infect Dis 2020 Sep 24. Epub 2020 Sep 24.

University of Queensland Centre for Clinical Research, Building 71/918 Royal Brisbane & Women's Hospital Campus, Herston, Brisbane, QLD, Australia.

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http://dx.doi.org/10.1093/cid/ciaa1449DOI Listing
September 2020

Clinical and Economic Outcomes of Genome Sequencing Availability on Containing a Hospital Outbreak of Resistant Escherichia coli in Australia.

Value Health 2020 08 13;23(8):994-1002. Epub 2020 Jul 13.

QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; Queensland Health, Pathology Queensland, Herston, Queensland, Australia; Queensland University of Technology (QUT), School of Nursing, Kelvin Grove, Queensland, Australia; School of Public Health, The University of Queensland, Herston, Queensland, Australia. Electronic address:

Objectives: To evaluate the outbreak size and hospital cost effects of bacterial whole-genome sequencing availability in managing a large-scale hospital outbreak.

Methods: We built a hybrid discrete event/agent-based simulation model to replicate a serious bacterial outbreak of resistant Escherichia coli in a large metropolitan public hospital during 2017. We tested the 3 strategies of using whole-genome sequencing early, late (actual outbreak), or not using it and assessed their associated outbreak size and hospital cost. The model included ward dynamics, pathogen transmission, and associated hospital costs during a 5-month outbreak. Model parameters were determined using data from the Queensland Hospital Admitted Patient Data Collection (N = 4809 patient admissions) and local clinical knowledge. Sensitivity analyses were performed to address model and parameter uncertainty.

Results: An estimated 197 patients were colonized during the outbreak, with 75 patients detected. The total outbreak cost was A$460 137 (US$317 117), with 6.1% spent on sequencing. Without sequencing, the outbreak was estimated to result in 352 colonized patients, costing A$766 921 (US$528 547). With earlier detection from use of routine sequencing, the estimated outbreak size was 3 patients and cost A$65 374 (US$45 054).

Conclusions: Using whole-genome sequencing in hospital outbreak management was associated with smaller outbreaks and cost savings, with sequencing costs as a small fraction of total hospital costs, supporting the further investigation of the use of routine whole-genome sequencing in hospitals.
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http://dx.doi.org/10.1016/j.jval.2020.03.006DOI Listing
August 2020

Infections and Treatment Options.

Antimicrob Agents Chemother 2020 10 20;64(11). Epub 2020 Oct 20.

University of Queensland, Faculty of Medicine, UQ Center for Clinical Research, Brisbane, Australia

is a genus of nonfermenting Gram-negative bacteria under order Although primarily isolated from respiratory tract of people with cystic fibrosis, 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. 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 infections. In this article, we aim to give an overview of the antimicrobial resistance in species, highlighting the possible place of new antibiotics in their treatment.
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http://dx.doi.org/10.1128/AAC.01025-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577122PMC
October 2020

Comprehensive analysis of IncC plasmid conjugation identifies a crucial role for the transcriptional regulator AcaB.

Nat Microbiol 2020 11 17;5(11):1340-1348. Epub 2020 Aug 17.

School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia.

The IncC family of broad-host-range plasmids enables the spread of antibiotic resistance genes among human enteric pathogens. Although aspects of IncC plasmid conjugation have been well studied, many roles of conjugation genes have been assigned based solely on sequence similarity. We applied hypersaturated transposon mutagenesis and transposon-directed insertion-site sequencing to determine the set of genes required for IncC conjugation. We identified 27 conjugation genes, comprising 19 that were previously identified (including two regulatory genes, acaDC) and eight not previously associated with conjugation. We show that one previously unknown gene, acaB, encodes a transcriptional regulator that has a crucial role in the regulation of IncC conjugation. AcaB binds upstream of the acaDC promoter to increase acaDC transcription; in turn, AcaDC activates the transcription of IncC conjugation genes. We solved the crystal structure of AcaB at 2.9-Å resolution and used this to guide functional analyses that reveal how AcaB binds to DNA. This improved understanding of IncC conjugation provides a basis for the development of new approaches to reduce the spread of these multi-drug-resistance plasmids.
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http://dx.doi.org/10.1038/s41564-020-0775-0DOI Listing
November 2020

Acute Myocardial Infarction and Community-Acquired Staphylococcus aureus Bloodstream Infection: an observational cohort study.

Clin Infect Dis 2020 Aug 14. Epub 2020 Aug 14.

University of Queensland Centre for Clinical Research, Building 71/918 Royal Brisbane & Women's Hospital Campus, Herston, Brisbane, QLD, Australia.

Background: The relationship between acute myocardial infarction and infection was recognised in the early 20th century during influenza epidemics. Most recently, a case control and self-control design study have identified an association between Staphylococcus aureus infection and acute myocardial infarction. We assessed the association of Community acquired Staphylococcus aureus bloodstream infection (CA-SABSI) with myocardial infarction in the 365 days following blood culture.

Methods: This was a cohort study design assessing incidence of myocardial infarction 365 days after blood culture for Staphylococcus aureus. Culture negative patients had blood cultures collected at hospital attendance and were matched to the CA-SABSI by sex, 5 year age strata and year of culture collection. Pathology information was linked to hospital administrative data and index of relative socio-economic advantage and disadvantage (ISRAD).

Results: The study included 5157 CA-SABSI cases matched to 10146 blood culture negative cases. Mortality was significantly higher in the CA-SABSI group at 10.9% (562/5157) compared to culture negative cases, 5·1% (521/10146) at 365 days (p &0·0001). In the seven days following index blood culture, excluding recurrent events, there were 89 (1·7%) and 37 (0·4%) myocardial infarction diagnoses in the CA-SABSI and culture negative cases respectively.Multivariable logistic regression for myocardial infarction demonstrated CA-SABSI remained significantly associated after adjusting for known risk factors (OR 5, 3·3 to 7·5, p &0·0001). Myocardial infarctions occurring in this short term risk period were associated with all-cause mortality in Cox proportional hazard model (OR 1·7, 95% CI 1·2-2·4, p&0<005).

Conclusions: CA-SABSI is associated with an increased short term risk of myocardial infarction which is associated with subsequent mortality.
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http://dx.doi.org/10.1093/cid/ciaa1197DOI Listing
August 2020

Fatal respiratory diphtheria caused by β-lactam-resistant Corynebacterium diphtheriae.

Clin Infect Dis 2020 Aug 9. Epub 2020 Aug 9.

School of Chemistry and Molecular Biosciences, University of Queensland, QLD, Australia.

Background: Diphtheria is a potentially fatal respiratory disease caused by toxigenic Corynebacterium diphtheriae. Although resistance to erythromycin has been recognised, β-lactam resistance in toxigenic diphtheria has not been described. Here, we report a case of fatal respiratory diphtheria caused by toxigenic C. diphtheriae resistant to penicillin and all other β-lactam antibiotics and describe a novel mechanism of inducible carbapenem resistance associated with the acquisition of a mobile resistance element.

Methods: Long-read whole genome sequencing was performed using Pacific Biosciences SMRT sequencing to determine the genome sequence of C. diphtheriae BQ11 and mechanism of β-lactam resistance. To investigate phenotypic inducibility of meropenem resistance, short read sequencing was performed using an Illumina NextSeq500 sequencer on the strain with and without exposure to meropenem.

Results: BQ11 demonstrated high-level resistance to penicillin (benzylpenicillin MIC ≥ 256 μg/ml), β-lactam/β-lactamase inhibitors and cephalosporins (amoxicillin/clavulanic acid MIC ≥ 256 μg/mL; ceftriaxone MIC ≥ 8 μg/L). Genomic analysis of BQ11 identified acquisition of a novel transposon carrying the penicillin binding protein Pbp2c, responsible for resistance to penicillin and cephalosporins. When strain BQ11 was exposed to meropenem, selective pressure drove amplification of the transposon in a tandem array and led to a corresponding change from a low level to high level meropenem resistant phenotype.

Conclusions: We have identified a novel mechanism of inducible antibiotic resistance whereby isolates that appear to be carbapenem susceptible on initial testing can develop in vivo resistance to carbapenems with repeated exposure. This phenomenon could have significant implications for treatment of C. diphtheriae infection and may lead to clinical failure.
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http://dx.doi.org/10.1093/cid/ciaa1147DOI Listing
August 2020

Pharmacokinetics/Pharmacodynamics of Antiviral Agents Used to Treat SARS-CoV-2 and Their Potential Interaction with Drugs and Other Supportive Measures: A Comprehensive Review by the PK/PD of Anti-Infectives Study Group of the European Society of Antimicrobial Agents.

Clin Pharmacokinet 2020 10;59(10):1195-1216

University of Queensland Centre for Clinical Research, Faculty of Medicine and Centre for Translational Anti-Infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia.

There is an urgent need to identify optimal antiviral therapies for COVID-19 caused by SARS-CoV-2. We have conducted a rapid and comprehensive review of relevant pharmacological evidence, focusing on (1) the pharmacokinetics (PK) of potential antiviral therapies; (2) coronavirus-specific pharmacodynamics (PD); (3) PK and PD interactions between proposed combination therapies; (4) pharmacology of major supportive therapies; and (5) anticipated drug-drug interactions (DDIs). We found promising in vitro evidence for remdesivir, (hydroxy)chloroquine and favipiravir against SARS-CoV-2; potential clinical benefit in SARS-CoV-2 with remdesivir, the combination of lopinavir/ritonavir (LPV/r) plus ribavirin; and strong evidence for LPV/r plus ribavirin against Middle East Respiratory Syndrome (MERS) for post-exposure prophylaxis in healthcare workers. Despite these emerging data, robust controlled clinical trials assessing patient-centred outcomes remain imperative and clinical data have already reduced expectations with regard to some drugs. Any therapy should be used with caution in the light of potential drug interactions and the uncertainty of optimal doses for treating mild versus serious infections.
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http://dx.doi.org/10.1007/s40262-020-00924-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385074PMC
October 2020

Comparative Genomics and Antimicrobial Resistance Profiling of Isolates Reveal Nosocomial Transmission and Susceptibility to Fluoroquinolones, Tetracyclines, and Trimethoprim-Sulfamethoxazole.

J Clin Microbiol 2020 08 24;58(9). Epub 2020 Aug 24.

University of Queensland Centre for Clinical Research, Royal Brisbane and Woman's Hospital, Herston, Queensland, Australia

The genus has gained global attention in recent years as containing sporadic, worldwide, nosocomial pathogens. spp. are intrinsically multidrug resistant, primarily infect immunocompromised individuals, and are associated with high mortality (∼20 to 40%). As yet, gaps remain in our understanding of transmission, global strain relatedness, antimicrobial resistance, and effective therapy. Over a 16-year period, 22 clinical and 6 hospital environmental isolates were collected from Queensland, Australia. Identification using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) (Vitek MS) and whole-genome sequencing was compared with a global strain data set. Phylogenomic reconstruction robustly identified 22 , 3 , 2 , and 1 isolates, most of which branched as unique lineages. Global analysis revealed that some Australian isolates are genetically closely related to strains from the United States, England, and Asia. Comparative genomics of clinical and environmental strains identified evidence of nosocomial transmission in patients, indicating probable infection from a hospital reservoir. Furthermore, broth microdilution against 39 antimicrobials revealed almost ubiquitous resistance to aminoglycosides, carbapenems, cephalosporins, and penicillins. Like other international strains, our isolates expressed susceptibility to minocycline and levofloxacin and the less common trimethoprim-sulfamethoxazole. Our study demonstrates important new insights into the genetic diversity, environmental persistence, and transmission of and potential effective therapy for Australian species.
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http://dx.doi.org/10.1128/JCM.00730-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448627PMC
August 2020

Transcriptomic responses of a New Delhi metallo-β-lactamase-producing Klebsiella pneumoniae isolate to the combination of polymyxin B and chloramphenicol.

Int J Antimicrob Agents 2020 Aug 20;56(2):106061. Epub 2020 Jun 20.

Biomedicine Discovery Institute, Infection and Immunity Program and Department of Microbiology, Monash University, Melbourne, Victoria, Australia. Electronic address:

The combination of polymyxins and chloramphenicol possesses synergistic killing activity against New Delhi metallo-β-lactamase (NDM)-producing Klebsiella pneumoniae. This systems study examined the transcriptomic responses to the polymyxin/chloramphenicol combination in clinical NDM-producing K. pneumoniae isolate S01. Klebsiella pneumoniae S01 (initial inoculum ~10 CFU/mL) was treated with polymyxin B (1 mg/L, continuous infusion) or chloramphenicol [maximum concentration (C) = 8 mg/L, half-life (t) = 4 h], alone or in combination, using an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model to mimic their pharmacokinetics in patients. Transcriptomic profiles of bacterial samples collected at 0, 0.25, 1, 4 and 24 h were examined using RNA sequencing (RNA-Seq). Chloramphenicol monotherapy significantly increased the expression of genes involved in ribosomal synthesis across the entire 24-h treatment, reflective of chloramphenicol-mediated inhibition of protein synthesis. The effect of polymyxin B was rapid and no major pathways were perturbed at later time points (4 h and 24 h). Combination treatment yielded the highest number of differentially expressed genes, including a large number observed following chloramphenicol monotherapy, in particular carbohydrate, nucleotide, amino acid and cell wall metabolism. Notably, chloramphenicol alone and in combination with polymyxin B significantly inhibited the expression of the arn operon that is responsible for lipid A modification and polymyxin resistance. These results indicate that the polymyxin/chloramphenicol combination displayed persistent transcriptomic responses over 24 h mainly on cell envelope synthesis and metabolism of carbohydrates, nucleotides and amino acids.
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http://dx.doi.org/10.1016/j.ijantimicag.2020.106061DOI Listing
August 2020

Oral cephalosporin and β-lactamase inhibitor combinations for ESBL-producing Enterobacteriaceae urinary tract infections.

J Antimicrob Chemother 2020 09;75(9):2384-2393

Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Royal Brisbane and Women's Hospital Campus, Brisbane, Australia.

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.
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http://dx.doi.org/10.1093/jac/dkaa183DOI Listing
September 2020

Antimicrobial Resistance in ESKAPE Pathogens.

Clin Microbiol Rev 2020 06 13;33(3). Epub 2020 May 13.

School of Chemistry and Molecular Biosciences, The University of Queensland, QLD, Australia

Antimicrobial-resistant ESKAPE ( , , , , , and species) pathogens represent a global threat to human health. The acquisition of antimicrobial resistance genes by ESKAPE pathogens has reduced the treatment options for serious infections, increased the burden of disease, and increased death rates due to treatment failure and requires a coordinated global response for antimicrobial resistance surveillance. This looming health threat has restimulated interest in the development of new antimicrobial therapies, has demanded the need for better patient care, and has facilitated heightened governance over stewardship practices.
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http://dx.doi.org/10.1128/CMR.00181-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227449PMC
June 2020

Antibiotics in the clinical pipeline in October 2019.

J Antibiot (Tokyo) 2020 06 10;73(6):329-364. Epub 2020 Mar 10.

Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Royal Brisbane and Women's Hospital Complex, Herston, Brisbane, QLD, 4072, Australia.

The development of new and effective antibacterial drugs to treat multi-drug resistant (MDR) bacteria, especially Gram-negative (G-ve) pathogens, is acknowledged as one of the world's most pressing health issues; however, the discovery and development of new, nontoxic antibacterials is not a straightforward scientific task, which is compounded by a challenging economic model. This review lists the antibacterials, β-lactamase/β-lactam inhibitor (BLI) combinations, and monoclonal antibodies (mAbs) first launched around the world since 2009 and details the seven new antibiotics and two new β-lactam/BLI combinations launched since 2016. The development status, mode of action, spectra of activity, lead source, and administration route for the 44 small molecule antibacterials, eight β-lactamase/BLI combinations, and one antibody drug conjugate (ADC) being evaluated in worldwide clinical trials at the end of October 2019 are described. Compounds discontinued from clinical development since 2016 and new antibacterial pharmacophores are also reviewed. There has been an increase in the number of early stage clinical candidates, which has been fueled by antibiotic-focused funding agencies; however, there is still a significant gap in the pipeline for the development of new antibacterials with activity against β-metallolactamases, orally administered with broad spectrum G-ve activity, and new treatments for MDR Acinetobacter and gonorrhea.
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http://dx.doi.org/10.1038/s41429-020-0291-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223789PMC
June 2020

Molecular and clinical epidemiology of carbapenem-resistant Enterobacterales in the USA (CRACKLE-2): a prospective cohort study.

Lancet Infect Dis 2020 06 6;20(6):731-741. Epub 2020 Mar 6.

Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, USA; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Departments of Pharmacology, Molecular Biology and Microbiology, Biochemistry, and Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, OH, USA; CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology, Cleveland, OH, USA.

Background: Carbapenem-resistant Enterobacterales (CRE) are a global threat. We aimed to describe the clinical and molecular characteristics of Centers for Disease Control and Prevention (CDC)-defined CRE in the USA.

Methods: CRACKLE-2 is a prospective, multicentre, cohort study. Patients hospitalised in 49 US hospitals, with clinical cultures positive for CDC-defined CRE between April 30, 2016, and Aug 31, 2017, were included. There was no age exclusion. The primary outcome was desirability of outcome ranking (DOOR) at 30 days after index culture. Clinical data and bacteria were collected, and whole genome sequencing was done. This trial is registered with ClinicalTrials.gov, number NCT03646227.

Findings: 1040 patients with unique isolates were included, 449 (43%) with infection and 591 (57%) with colonisation. The CDC-defined CRE admission rate was 57 per 100 000 admissions (95% CI 45-71). Three subsets of CDC-defined CRE were identified: carbapenemase-producing Enterobacterales (618 [59%] of 1040), non-carbapenemase-producing Enterobacterales (194 [19%]), and unconfirmed CRE (228 [22%]; initially reported as CRE, but susceptible to carbapenems in two central laboratories). Klebsiella pneumoniae carbapenemase-producing clonal group 258 K pneumoniae was the most common carbapenemase-producing Enterobacterales. In 449 patients with CDC-defined CRE infections, DOOR outcomes were not significantly different in patients with carbapenemase-producing Enterobacterales, non-carbapenemase-producing Enterobacterales, and unconfirmed CRE. At 30 days 107 (24%, 95% CI 20-28) of these patients had died.

Interpretation: Among patients with CDC-defined CRE, similar outcomes were observed among three subgroups, including the novel unconfirmed CRE group. CDC-defined CRE represent diverse bacteria, whose spread might not respond to interventions directed to carbapenemase-producing Enterobacterales.

Funding: National Institutes of Health.
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http://dx.doi.org/10.1016/S1473-3099(19)30755-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473597PMC
June 2020

Genomic Investigation Reveals Contaminated Detergent as the Source of an Extended-Spectrum-β-Lactamase-Producing Klebsiella michiganensis Outbreak in a Neonatal Unit.

J Clin Microbiol 2020 04 23;58(5). Epub 2020 Apr 23.

Microbiology Department, Central Laboratory, Pathology Queensland, Royal Brisbane and Women's Hospital, Herston, QLD, Australia

species are problematic pathogens in neonatal units and may cause outbreaks, for which the sources of transmission may be challenging to elucidate. We describe the use of whole-genome sequencing (WGS) to investigate environmental sources of transmission during an outbreak of extended-spectrum-β-lactamase (ESBL)-producing colonizing neonates. Ceftriaxone-resistant spp. isolated from neonates (or their mothers) and the hospital environment were included. Short-read sequencing (Illumina) and long-read sequencing (MinION; Oxford Nanopore Technologies) were used to confirm species taxonomy, to identify antimicrobial resistance genes, and to determine phylogenetic relationships using single-nucleotide polymorphism profiling. A total of 21 organisms (10 patient-derived isolates and 11 environmental isolates) were sequenced. Standard laboratory methods identified the outbreak strain as an ESBL-producing , but taxonomic assignment from WGS data suggested closer identity to Strains isolated from multiple detergent-dispensing bottles were either identical or closely related by single-nucleotide polymorphism comparison. Detergent bottles contaminated by had been used for washing milk expression equipment. No new cases were identified once the detergent bottles were removed. Environmental reservoirs may be an important source in outbreaks of multidrug-resistant organisms. WGS, in conjunction with traditional epidemiological investigation, can be instrumental in revealing routes of transmission and guiding infection control responses.
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http://dx.doi.org/10.1128/JCM.01980-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180233PMC
April 2020

New treatment options for multiresistant gram negatives.

Curr Opin Infect Dis 2020 04;33(2):214-223

University of Queensland Centre for Clinical Research.

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.
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http://dx.doi.org/10.1097/QCO.0000000000000627DOI Listing
April 2020

Fracture-related infection: current methods for prevention and treatment.

Expert Rev Anti Infect Ther 2020 04 19;18(4):307-321. Epub 2020 Feb 19.

AO Research Institute Davos, Davos, Switzerland.

: Fracture-related infection (FRI) is a serious complication related to orthopedic trauma, both from an infectious disease and a surgical point of view. The lack of scientific data with respect to diagnostic criteria and treatment principles of this entity has hampered efforts for an evidence-based approach and, as such, practices to prevent and treat FRI are often extrapolated from peri-prosthetic joint infection (PJI) literature. Recently, consensus guidelines were developed with respect to prevention, diagnosis and treatment of FRI.: This review will define FRI and approaches to prevent and treat this complication will be discussed, with an emphasis on antimicrobial and surgical considerations. Guidelines focusing on FRI will be highlighted and aspects of pre-clinical research with imminent translational potential described.: New strategies are currently under investigation to improve the outcome of this sometimes-devastating complication. Local delivery of antimicrobials seems to be a promising approach; however, further high-quality clinical research is necessary to demonstrate efficacy. Delivery mechanisms for local antimicrobials include polymethyl methacrylate, implant coatings, collagen fleece, hydrogels and ceramics. The reintroduction of antimicrobials such as bacteriophage therapy has demonstrated promise in the management of drug-resistant organisms.
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http://dx.doi.org/10.1080/14787210.2020.1729740DOI Listing
April 2020