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1.
Artigo em Inglês | MEDLINE | ID: mdl-33974185

RESUMO

Carbapenemase-producing organisms (CPOs) pose a serious clinical threat and rapid detection tools are essential to aid in patient management. We developed rapid and simple molecular tests to detect blaNDM-type and blaVIM-type carbapenemase genes using recombinase polymerase amplification (RPA) combined with a lateral flow detection. The tests could provide results in approximately 15 min when using DNA extracts, with limits of detection of 9.2 copies/µl for the blaNDM-type assay and 7.5 copies/µl for blaVIM-type assay, and successfully detected all isolates harbouring the carbapenemase encoding genes in a panel of 57 isolates. These RPA tests may be suitable for use in low-resource settings to tailor rapid implementation of infection control precautions and antibiotic stewardship.

2.
Trials ; 22(1): 301, 2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888139

RESUMO

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.

3.
ACS Infect Dis ; 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33834753

RESUMO

Carbapenem-resistant Klebsiella pneumoniae 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-ß-lactamase (NDM)-producing K. pneumoniae. However, the mechanism(s) underpinning their synergistic killing are not well studied. We employed an in vitro pharmacokinetic/pharmacodynamic model to mimic the pharmacokinetics of the antibiotics in patients and examined bacterial killing against NDM-producing K. pneumoniae 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 K. pneumoniae 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.

4.
BMJ Open ; 11(2): e041968, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33526501

RESUMO

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 (Staphylococcus aureus, Escherichia coli, Enterococcus faecium, Klebsiella pneumoniae, Enterobacter sp and Acinetobacter baumannii) 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.

5.
Clin Pharmacol Ther ; 109(4): 1104-1115, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33550617

RESUMO

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.

6.
J Antimicrob Chemother ; 76(3): 550-560, 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33332545

RESUMO

Cefepime, a wide-spectrum ß-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 ß-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.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33373684

RESUMO

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.

9.
Clin Infect Dis ; 2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33354717

RESUMO

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.

10.
Artigo em Inglês | MEDLINE | ID: mdl-33168603

RESUMO

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 in vitro activity against many Gram-negative bacilli than currently used carbapenems, ß-lactam/ß-lactamase inhibitor combinations, and cephalosporins. Thus, we investigated the in vitro activity of cefiderocol against a total of 246 clinical isolates of Burkholderia pseudomallei from Queensland, Australia. The collection was comprised primarily of bloodstream (56.1%), skin and soft tissue (16.3%) and respiratory isolates (15.9%). Minimum inhibitory concentrations (MIC) of cefiderocol ranged from ≤0.03 to 16 mg/L, where the MIC90 was 0.125 mg/L. Based upon CLSI clinical breakpoints for cefiderocol against Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia, three isolates (1.2%) would be classified as non-susceptible (MIC >4 mg/L). Using EUCAST non-species specific (PK/PD) clinical breakpoints, or those set for Pseudomonas aeruginosa, four isolates (1.6%) would be resistant (MIC >2 mg/L). Further testing for co-resistance to meropenem, ceftazidime, trimethoprim-sulfamethoxazole, amoxicillin-clavulanate and doxycycline was performed on the four isolates with elevated cefiderocol MICs (>2 mg/L), 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 in vitro against B. pseudomallei primary clinical isolates. This compound shows great potential for the treatment of melioidosis in endemic countries and should be explored further.

11.
Sci Transl Med ; 12(570)2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33208501

RESUMO

The emergence of polymyxin resistance in carbapenem-resistant and extended-spectrum ß-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 Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa 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 E. coli containing a plasmid-borne mcr-1 gene or K. pneumoniae carrying a chromosomal mgrB mutation. Using a highly invasive K. pneumoniae strain engineered for polymyxin resistance through mgrB 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.

12.
Infect Dis Clin North Am ; 34(4): 709-722, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33011046

RESUMO

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.

13.
Artigo em Inglês | MEDLINE | ID: mdl-33046493

RESUMO

Carbapenem sparing regimens are needed for the treatment of ESBL/AmpC producing Enterobacterales infections. We sought to compare the clinical efficacy of ceftazidime/avibactam and carbapenems against ESBL/AmpC producing Enterobacterales spp. A systematic review and meta-analysis of randomized controlled trials comparing ceftazidime/avibactam with carbapenems for the treatment of ESBL/AmpC producing Enterobacterales was conducted. Five RCTs with ESBLs/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 TOC versus 240 of 271 (89%) patients in the carbapenem arm (RR 1.02, 95% CI 0.97-1.08, P=0.45, I 2=0%). Clinical response for AmpC producers in the ceftazidime/avibactam and carbapenem arms were 32/40 (80%) and 37/42 (88%), respectively (RR 0.91, 95% CI 0.76-1.10, 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 intraabdominal infections caused by ESBL producing Enterobacterales spp. and the data are 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 these.

14.
Lancet Infect Dis ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33058795

RESUMO

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.

15.
Clin Infect Dis ; 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33104186

RESUMO

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.

17.
Clin Infect Dis ; 2020 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-32772111

RESUMO

BACKGROUND: Diphtheria is a potentially fatal respiratory disease caused by toxigenic Corynebacterium diphtheriae. Although resistance to erythromycin has been recognised, ß-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 ß-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 ß-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), ß-lactam/ß-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.

18.
Antimicrob Agents Chemother ; 64(11)2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-32816734

RESUMO

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-ß-lactamases, which are not expected to be overcome by new ß-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.

19.
Nat Microbiol ; 5(11): 1340-1348, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32807890

RESUMO

The IncC family of broad-host-range plasmids enables the spread of antibiotic resistance genes among human enteric pathogens1-3. Although aspects of IncC plasmid conjugation have been well studied4-9, 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.

20.
Clin Infect Dis ; 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32797225

RESUMO

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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