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1.
Clin Infect Dis ; 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38321565

RESUMO

A 32-year-old female with advanced HIV infection presented to an Australian hospital with subacute but worsening symptoms of encephalitis. Metagenomic sequencing and Dengue NS3 antigen staining of brain tissue confirmed active Dengue virus (DENV) encephalitis. The most recent possible DENV exposure was months prior in West Africa, indicating chronicity.

2.
Emerg Infect Dis ; 30(7): 1493-1495, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38916864

RESUMO

To determine antimicrobial susceptibility of Neisseria gonorrhoeae, we analyzed phenotypes and genomes of 72 isolates collected in Cambodia in 2023. Of those, 9/72 (12.5%) were extensively drug resistant, a 3-fold increase from 2022. Genomic analysis confirmed expansion of newly emerging resistant clones and ongoing resistance emergence across new phylogenetic backbones.


Assuntos
Antibacterianos , Gonorreia , Testes de Sensibilidade Microbiana , Neisseria gonorrhoeae , Organização Mundial da Saúde , Neisseria gonorrhoeae/efeitos dos fármacos , Neisseria gonorrhoeae/genética , Camboja/epidemiologia , Humanos , Gonorreia/microbiologia , Gonorreia/epidemiologia , Gonorreia/tratamento farmacológico , Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Filogenia , Masculino , Feminino , Adulto
3.
J Antimicrob Chemother ; 79(4): 891-896, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38412336

RESUMO

OBJECTIVES: This study aims to elucidate the genomic dynamics driving the emergence of antimicrobial resistance (AMR), with a specific focus on the interplay between AMR and antimicrobial usage. METHODS: We conducted a comprehensive analysis using a ST239 methicillin-resistant Staphylococcus aureus (MRSA) dataset over a continuous 12-year period from a single hospital. Genomic analyses were performed tracking the changes in MRSA populations, particularly the emergence of reduced vancomycin susceptibility, and assessing the impact of glycopeptide use on these emergence events. RESULTS: Our findings reveal a significant correlation between hospital glycopeptide usage and the selection of MRSA strains with reduced vancomycin susceptibility. Genomic analyses provided insights into the molecular mechanisms driving resistance emergence, including the slowing of the molecular clock rate in response to heightened antimicrobial consumption. CONCLUSIONS: In conclusion, this study the highlights the complex dynamics between AMR and antimicrobial use at the hospital level. The observed correlation between antimicrobial consumption and the development of less susceptible MRSA strains underscores the importance of antimicrobial stewardship programmes and the establishment of optimal consumption thresholds for mitigating AMR effectively.


Assuntos
Anti-Infecciosos , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Staphylococcus aureus Resistente à Meticilina/genética , Vancomicina/farmacologia , Vancomicina/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Glicopeptídeos , Testes de Sensibilidade Microbiana
4.
J Antimicrob Chemother ; 78(6): 1499-1504, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37071589

RESUMO

OBJECTIVES: There is clinical uncertainty over the optimal treatment for penicillin-susceptible Staphylococcus aureus (PSSA) infections. Furthermore, there is concern that phenotypic penicillin susceptibility testing methods are not reliably able to detect some blaZ-positive S. aureus. METHODS: Nine S. aureus isolates, including six genetically diverse strains harbouring blaZ, were sent in triplicate to 34 participating laboratories from Australia (n = 14), New Zealand (n = 6), Canada (n = 12), Singapore (n = 1) and Israel (n = 1). We used blaZ PCR as the gold standard to assess susceptibility testing performance of CLSI (P10 disc) and EUCAST (P1 disc) methods. Very major errors (VMEs), major error (MEs) and categorical agreement were calculated. RESULTS: Twenty-two laboratories reported 593 results according to CLSI methodology (P10 disc). Nineteen laboratories reported 513 results according to the EUCAST (P1 disc) method. For CLSI laboratories, the categorical agreement and calculated VME and ME rates were 85% (508/593), 21% (84/396) and 1.5% (3/198), respectively. For EUCAST laboratories, the categorical agreement and calculated VME and ME rates were 93% (475/513), 11% (84/396) and 1% (3/198), respectively. Seven laboratories reported results for both methods, with VME rates of 24% for CLSI and 12% for EUCAST. CONCLUSIONS: The EUCAST method with a P1 disc resulted in a lower VME rate compared with the CLSI methods with a P10 disc. These results should be considered in the context that among collections of PSSA isolates, as determined by automated MIC testing, less than 10% harbour blaZ. Furthermore, the clinical relevance of phenotypically susceptible, but blaZ-positive S. aureus, remains unclear.


Assuntos
Antibacterianos , Infecções Estafilocócicas , Humanos , Antibacterianos/farmacologia , Staphylococcus aureus/genética , Penicilinas/farmacologia , Testes de Sensibilidade Microbiana , Tomada de Decisão Clínica , Incerteza
5.
J Med Virol ; 95(12): e29273, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-38050831

RESUMO

Detection of HIV drug resistance (HIVDR) is vital to successful anti-retroviral therapy (ART). HIVDR testing to determine drug-resistance mutations is routinely performed in Australia to guide ART choice in newly diagnosed people living with HIV or in cases of treatment failure. In 2022, our clinical microbiology laboratory sought to validate a next-generation sequencing (NGS)-based HIVDR assay to replace the previous Sanger-sequencing (SS)-based ViroSeq. NGS solutions for HIVDR offer higher throughput, lower costs and higher sensitivity for variant detection. We sought to validate the previously described low-cost probe-based NGS method (veSEQ-HIV) for whole-genome recovery and HIVDR-testing in a diagnostic setting. veSEQ-HIV displayed 100% and 98% accuracy in major and minor mutation detection, respectively, and 100% accuracy of subtyping (provided > 1000 mapped reads were obtained). Pairwise comparison exhibited low inter-and intrarun variability across the whole-genome (Jaccard index [J] = 0.993; J = 0.972) and the Pol gene (J = 0.999; J = 0.999), respectively. veSEQ-HIV met all our pre-set criteria based on WHO recommendations and successfully replaced ViroSeq in our laboratory. Scaling-down veSEQ-HIV to a limited batch size and sequencing on Illumina iSeq. 100, allowed easy implementation of the assay into the workflow of a small sequencing laboratory with minimal staff and equipment and the ability to meet clinically relevant test turn-around times. As HIVDR-testing moves from SS- to NGS-based methods and new ART drugs come to market (particularly those with targets outside the Pol region), whole-genome recovery using veSEQ-HIV provides a robust, cost-effective and "future-proof" NGS method for HIVDR-testing.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Humanos , HIV-1/genética , Austrália , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Mutação , Sequenciamento Completo do Genoma , Farmacorresistência Viral/genética , Genótipo
6.
Nephrology (Carlton) ; 28(11): 639-643, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37635271

RESUMO

We present the case of a recent ABO incompatible kidney transplant recipient with persistent SARS-CoV-2 infection and pneumonitis. Serial whole genome sequencing confirmed intra-host viral evolution, which was used as a surrogate to confirm active viral replication and support re-treatment with antivirals, late in the course of infection. A prolonged course of remdesivir combined with immunosuppression modulation resulted in successful clearance of virus and clinical improvement. The diagnostic process undertaken in this case provides a useful guide for other clinicians when approaching similar patients.


Assuntos
COVID-19 , Transplante de Rim , Pneumonia , Humanos , Sistema ABO de Grupos Sanguíneos , Incompatibilidade de Grupos Sanguíneos , COVID-19/diagnóstico , Rejeição de Enxerto , Terapia de Imunossupressão , Transplante de Rim/efeitos adversos , Transplante de Rim/métodos , SARS-CoV-2/genética , Masculino , Pessoa de Meia-Idade , Antivirais/uso terapêutico , Pneumonia/tratamento farmacológico
7.
Clin Infect Dis ; 75(11): 2027-2034, 2022 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-35717634

RESUMO

Staphylococcus aureus bloodstream (SAB) infection is a common and severe infectious disease, with a 90-day mortality of 15%-30%. Despite this, <3000 people have been randomized into clinical trials of treatments for SAB infection. The limited evidence base partly results from clinical trials for SAB infections being difficult to complete at scale using traditional clinical trial methods. Here we provide the rationale and framework for an adaptive platform trial applied to SAB infections. We detail the design features of the Staphylococcus aureus Network Adaptive Platform (SNAP) trial that will enable multiple questions to be answered as efficiently as possible. The SNAP trial commenced enrolling patients across multiple countries in 2022 with an estimated target sample size of 7000 participants. This approach may serve as an exemplar to increase efficiency of clinical trials for other infectious disease syndromes.


Assuntos
Bacteriemia , Infecções Estafilocócicas , Humanos , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus
8.
Br J Clin Pharmacol ; 88(2): 669-679, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34289135

RESUMO

AIMS: The purpose of the study was to assess the status of emerging therapeutic drug monitoring (TDM) of anti-infective agents in Australian hospitals. METHODS: A nationwide cross-sectional survey of all Australian hospitals operating in the public and private health sector was conducted between August and September 2019. The survey consisted of questions regarding institutional TDM practice for anti-infective agents and clinical vignettes specific to ß-lactam antibiotics. RESULTS: Responses were received from 82 unique institutions, representing all Australian states and territories. All 29 (100%) of principal referral (major) hospitals in Australia participated. Five surveys were partially complete. Only 25% (20/80) of hospitals had TDM testing available on-site for any of the eight emerging TDM candidates considered: ß-lactam antibiotics, anti-tuberculous agents, flucytosine, fluoroquinolones, ganciclovir, human immunodeficiency virus (HIV) drugs, linezolid and teicoplanin. A considerable time lag was noted between TDM sampling and reporting of results. With respect to ß-lactam antibiotic TDM, variable indications, pharmacodynamic targets and sampling times were identified. The three greatest barriers to local TDM performance were found to be (1) lack of timely assays/results, (2) lack of institutional-wide expertise and/or training and (3) lack of guidelines to inform ordering of TDM and interpretation of results. The majority of respondents favoured establishing national TDM guidelines and increasing access to dose prediction software, at rates of 89% and 96%, respectively. CONCLUSION: Translating emerging TDM evidence into daily clinical practice is slow. Concerted efforts are required to address the barriers identified and facilitate the implementation of standardised practice.


Assuntos
Anti-Infecciosos , Monitoramento de Medicamentos , Antibacterianos/uso terapêutico , Anti-Infecciosos/uso terapêutico , Austrália , Estudos Transversais , Monitoramento de Medicamentos/métodos , Hospitais , Humanos , beta-Lactamas/uso terapêutico
9.
Crit Care Med ; 49(10): e952-e960, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33938713

RESUMO

OBJECTIVES: It is recommended that therapeutic monitoring of vancomycin should be guided by 24-hour area under the curve concentration. This can be done via Bayesian models in dose-optimization software. However, before these models can be incorporated into clinical practice in the critically ill, their predictive performance needs to be evaluated. This study assesses the predictive performance of Bayesian models for vancomycin in the critically ill. DESIGN: Retrospective cohort study. SETTING: Single-center ICU. PATIENTS: Data were obtained for all patients in the ICU between 1 January, and 31 May 2020, who received IV vancomycin. The predictive performance of three Bayesian models were evaluated based on their availability in commercially available software. Predictive performance was assessed via bias and precision. Bias was measured as the mean difference between observed and predicted vancomycin concentrations. Precision was measured as the sd of bias, root mean square error, and 95% limits of agreement based on Bland-Altman plots. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 466 concentrations from 188 patients were used to evaluate the three models. All models showed low bias (-1.7 to 1.8 mg/L), which was lower with a posteriori estimate (-0.7 to 1.8 mg/L). However, all three models showed low precision in terms of sd (4.7-8.8 mg/L) and root mean square error (4.8-8.9 mg/L). The models underpredicted at higher observed vancomycin concentrations (bias 0.7-3.2 mg/L for < 20 mg/L; -5.1 to -2.3 for ≥ 20 mg/L) and the Bland-Altman plots showed a great deviation between observed and predicted concentrations. CONCLUSIONS: Bayesian models of vancomycin show not only low bias, but also low precision in the critically ill. Thus, Bayesian-guided dosing of vancomycin in this population should be used cautiously.


Assuntos
Monitoramento de Medicamentos/normas , Vancomicina/análise , Adulto , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/análise , Área Sob a Curva , Teorema de Bayes , Estudos de Coortes , Estado Terminal/terapia , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Estudos Retrospectivos , Vancomicina/administração & dosagem
10.
J Antimicrob Chemother ; 77(1): 31-37, 2021 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-34718605

RESUMO

BACKGROUND: A marked genotype shift among vancomycin-resistant Enterococcus faecium (VREfm) from vanB to vanA in Australia between 2011 and 2015 is a well-known phenomenon. It is hypothesized that this was caused by multiple independent clones emerging simultaneously in different settings and/or regions. OBJECTIVES: To gain insights into the circumstances surrounding the shift from vanB to vanA VREfm in one Australian hospital. METHODS: The genomes of 69 vanA VREfm isolates from St George Hospital collected between 2009 and 2018 were studied. An expansion of ST80 vanA VREfm was noted following a single introduction. ST80 isolates were thus further characterized using hybrid sequencing and contextualized through comparisons with other published Australian ST80 isolates. Phylogenies were constructed with plasmid sequences compared with the index isolate. RESULTS: The 2011 expansion of ST80 vanA VREfm isolates in our institution originated from the 2009 index isolate, from a patient transferred from overseas. Phylogenetic analysis with other Australian ST80 vanA VREfm isolates showed that the 2011 expansion event was unique, with limited spread to adjacent local health districts. Plasmid analysis showed multiple variants, which can also be traced back to the 2009 isolate, consistent with ongoing plasmid adaptation over time. CONCLUSIONS: These findings confirm an expansion event following a VREfm introduction event leading to a sustained clonal and plasmid outbreak over several years. Moreover, it demonstrates the complexity of countrywide replacement events. This study also highlights the use of hybrid sequencing in establishing an epidemiological relationship to the index isolate that was initially inapparent.


Assuntos
Infecção Hospitalar , Enterococcus faecium , Infecções por Bactérias Gram-Positivas , Enterococos Resistentes à Vancomicina , Austrália/epidemiologia , Proteínas de Bactérias/genética , Infecção Hospitalar/epidemiologia , Surtos de Doenças , Enterococcus faecium/genética , Infecções por Bactérias Gram-Positivas/epidemiologia , Humanos , Filogenia , Vancomicina/farmacologia , Enterococos Resistentes à Vancomicina/genética
11.
Ther Drug Monit ; 43(4): 505-511, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33941739

RESUMO

BACKGROUND: Intravenous tobramycin treatment requires therapeutic drug monitoring (TDM) to ensure safety and efficacy when used for prolonged treatment, as in infective exacerbations of cystic fibrosis. The 24-hour area under the concentration-time curve (AUC24) is widely used to guide dosing; however, there remains variability in practice around methods for its estimation. The objective of this study was to determine the potential for a sparse-sampling strategy using a single postinfusion tobramycin concentration and Bayesian forecasting to assess the AUC24 in routine practice. METHODS: Adults with cystic fibrosis receiving once-daily tobramycin had paired concentrations measured 2 hours (c1) and 6 hours (c2) after the end of infusion as routine monitoring. AUC24 exposures were estimated using Tucuxi, a Bayesian forecasting application that incorporates a validated population pharmacokinetic model. Simulations were performed to estimate AUC24 using the full data set using c1 and c2, compared with estimates using depleted data sets (c1 or c2 only), with and without concentration data from earlier in the course. The agreement between each simulation condition and the reference was assessed graphically and numerically using the median difference (∆) AUC24 and (relative) root mean square error (rRMSE) as measures of bias and accuracy, respectively. RESULTS: A total of 55 patients contributed 512 concentrations from 95 tobramycin courses and 256 TDM episodes. Single concentration methods performed well, with median ∆AUC24 <2 mg·h·L-1 and rRMSE of <15% for sequential c1 and c2 conditions. CONCLUSIONS: Bayesian forecasting implemented in Tucuxi, using single postinfusion concentrations taken 2-6 hours after tobramycin administration, yield similar exposure estimates to more intensive (two-sample) methods and are suitable for routine TDM practice.


Assuntos
Antibacterianos , Fibrose Cística , Tobramicina , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Teorema de Bayes , Fibrose Cística/tratamento farmacológico , Esquema de Medicação , Humanos , Tobramicina/administração & dosagem , Tobramicina/farmacocinética
12.
Intern Med J ; 51 Suppl 7: 143-176, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34937136

RESUMO

Invasive aspergillosis (IA) in haematology/oncology patients presents as primary infection or breakthrough infection, which can become refractory to antifungal treatment and has a high associated mortality. Other emerging patient risk groups include patients in the intensive care setting with severe respiratory viral infections, including COVID-19. These guidelines present key diagnostic and treatment recommendations in light of advances in knowledge since the previous guidelines in 2014. Culture and histological-based methods remain central to the diagnosis of IA. There is increasing evidence for the utility of non-culture methods employing fungal biomarkers in pre-emptive screening for infection, as well as for IA diagnosis when used in combination. Although azole resistance appears to be uncommon in Australia, susceptibility testing of clinical Aspergillus fumigatus complex isolates is recommended. Voriconazole remains the preferred first-line antifungal agent for treating primary IA, including for extrapulmonary disease. Recommendations for paediatric treatment broadly follow those for adults. For breakthrough and refractory IA, a change in class of antifungal agent is strongly recommended, and agents under clinical trial may need to be considered. Newer immunological-based imaging modalities warrant further study, while surveillance for IA and antifungal resistance remain essential to informing the relevance of current treatment recommendations.


Assuntos
Aspergilose , COVID-19 , Adulto , Antifúngicos/uso terapêutico , Aspergilose/diagnóstico , Aspergilose/tratamento farmacológico , Aspergillus fumigatus , Criança , Farmacorresistência Fúngica , Humanos , SARS-CoV-2 , Voriconazol/uso terapêutico
13.
Mycoses ; 64(3): 257-263, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33185290

RESUMO

OBJECTIVES: Candidaemia carries a mortality of up to 40% and may be related to increasing complexity of medical care. Here, we determined risk factors for the development of candidaemia. METHODS: We conducted a prospective, multi-centre, case-control study over 12 months. Cases were aged ≥18 years with at least one blood culture positive for Candida spp. Each case was matched with two controls, by age within 10 years, admission within 6 months, admitting unit, and admission duration at least as long as the time between admission and onset of candidaemia. RESULTS: A total of 118 incident cases and 236 matched controls were compared. By multivariate analysis, risk factors for candidaemia included neutropenia, solid organ transplant, significant liver, respiratory or cardiovascular disease, recent gastrointestinal, biliary or urological surgery, central venous access device, intravenous drug use, urinary catheter and carbapenem receipt. CONCLUSIONS: Risk factors for candidaemia derive from the infection source, carbapenem use, host immune function and organ-based co-morbidities. Preventive strategies should target iatrogenic disruption of mucocutaneous barriers and intravenous drug use.


Assuntos
Candida/patogenicidade , Candidemia/etiologia , Idoso , Antifúngicos/uso terapêutico , Candidemia/tratamento farmacológico , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/complicações , Transplante de Órgãos/efeitos adversos , Estudos Prospectivos , Fatores de Risco , Centros de Atenção Terciária/estatística & dados numéricos
14.
J Antimicrob Chemother ; 75(5): 1112-1116, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32016400

RESUMO

BACKGROUND: Early identification of MRSA by diagnostic medical microbiology laboratories enables improved antimicrobial choice and outcomes. The Cepheid Xpert® MRSA/SA BC test rapidly identifies Staphylococcus aureus bloodstream infections through spa gene detection and methicillin resistance via mecA gene detection. Recent emergence of S. aureus with deletions in the spa gene has resulted in false-negative results for this test, leading to misidentification of infections with this organism, particularly MRSA ST45. OBJECTIVES: To investigate the emergence and prevalence of ST45 MRSA in New South Wales (NSW), Australia. METHODS: WGS read data from six NSW hospitals were collected for 131 ST45 MRSA isolates and analysed. RESULTS: Of the 131 ST45 MRSA investigated, 88.5% (116/131) contained a deletion in the spa gene that appeared to have arisen once in approximately 2010 followed by clonal expansion. Given the successful establishment of this 'spa-deletion' MRSA clone, the Cepheid Xpert® MRSA/SA BC test became unreliable for confirming S. aureus bacteraemia in NSW. Subsequently, the algorithm used by this test has been updated and evaluated to take into account the presence of S. aureus with either a spa deletion or SCCmec target variations. CONCLUSIONS: This study highlighted the applied use of WGS for assessing diagnostic assays and informing necessary changes to ensure the viability of the Cepheid Xpert® MRSA/SA BC test in the context of the new 'spa-deletion' MRSA clone. It demonstrated how continued surveillance through WGS can reveal evolutionary events that may impact diagnostic assays, allowing corrective modifications to be made in real time.


Assuntos
Bacteriemia , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Austrália/epidemiologia , Surtos de Doenças , Humanos , Staphylococcus aureus Resistente à Meticilina/genética , Testes de Sensibilidade Microbiana , New South Wales/epidemiologia , Infecções Estafilocócicas/epidemiologia , Staphylococcus aureus
15.
Mycoses ; 63(5): 437-442, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32080902

RESUMO

OBJECTIVES: Invasive fungal infections caused by Lomentospora prolificans are associated with very high mortality rates and can be challenging to treat given pan-drug resistance to available antifungal agents. The objective of this study was to describe the clinical presentation and outcomes in a cohort of patients with invasive L prolificans infections. METHODS: We performed a retrospective review of medical records of patients with invasive L prolificans infection in the FungiScope® registry of rare invasive fungal infections. Patients diagnosed between 01 January 2008 and 09 September 2019 were included in for analysis. RESULTS: The analysis included 41 patients with invasive L prolificans infection from eight different countries. Haematological/oncological malignancies were the most frequent underlying disease (66%), disseminated infection was frequent (61%), and the lung was the most commonly involved organ (44%). Most infections (59%) were breakthrough infections. Progression/deterioration/treatment failure was observed in 23/40 (58%) of patients receiving antifungal therapy. In total, 21/41 (51%) patients, and 77% of patients with underlying haematological/oncological malignancy, had a fatal outcome attributed to invasive fungal infection. Combination antifungal therapy was frequent (24/40) and associated with improved survival. In particular, treatment regimens including terbinafine were significantly associated with higher treatment success at final assessment (P = .012), with a positive trend observed for treatment regimens that included voriconazole (P = .054). CONCLUSIONS: Lomentospora prolificans infections were associated with mortality rates of 77% and above in patients with underlying haematological/oncological malignancies and those with disseminated infections. While combination therapy is the preferred option for now, the hope lies with novel antifungals currently under development.


Assuntos
Antifúngicos/uso terapêutico , Infecções Fúngicas Invasivas/tratamento farmacológico , Scedosporium/patogenicidade , Idoso , Feminino , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/microbiologia , Humanos , Internacionalidade , Infecções Fúngicas Invasivas/mortalidade , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Resultado do Tratamento
16.
JAMA ; 323(6): 527-537, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32044943

RESUMO

Importance: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a ß-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted. Objective: To determine whether combining an antistaphylococcal ß-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia. Design, Setting, and Participants: Open-label, randomized clinical trial conducted at 27 hospital sites in 4 countries from August 2015 to July 2018 among 352 hospitalized adults with MRSA bacteremia. Follow-up was complete on October 23, 2018. Interventions: Participants were randomized to standard therapy (intravenous vancomycin or daptomycin) plus an antistaphylococcal ß-lactam (intravenous flucloxacillin, cloxacillin, or cefazolin) (n = 174) or standard therapy alone (n = 178). Total duration of therapy was determined by treating clinicians and the ß-lactam was administered for 7 days. Main Outcomes and Measures: The primary end point was a 90-day composite of mortality, persistent bacteremia at day 5, microbiological relapse, and microbiological treatment failure. Secondary outcomes included mortality at days 14, 42, and 90; persistent bacteremia at days 2 and 5; acute kidney injury (AKI); microbiological relapse; microbiological treatment failure; and duration of intravenous antibiotics. Results: The data and safety monitoring board recommended early termination of the study prior to enrollment of 440 patients because of safety. Among 352 patients randomized (mean age, 62.2 [SD, 17.7] years; 121 women [34.4%]), 345 (98%) completed the trial. The primary end point was met by 59 (35%) with combination therapy and 68 (39%) with standard therapy (absolute difference, -4.2%; 95% CI, -14.3% to 6.0%). Seven of 9 prespecified secondary end points showed no significant difference. For the combination therapy vs standard therapy groups, all-cause 90-day mortality occurred in 35 (21%) vs 28 (16%) (difference, 4.5%; 95% CI, -3.7% to 12.7%); persistent bacteremia at day 5 was observed in 19 of 166 (11%) vs 35 of 172 (20%) (difference, -8.9%; 95% CI, -16.6% to -1.2%); and, excluding patients receiving dialysis at baseline, AKI occurred in 34 of 145 (23%) vs 9 of 145 (6%) (difference, 17.2%; 95% CI, 9.3%-25.2%). Conclusions and Relevance: Among patients with MRSA bacteremia, addition of an antistaphylococcal ß-lactam to standard antibiotic therapy with vancomycin or daptomycin did not result in significant improvement in the primary composite end point of mortality, persistent bacteremia, relapse, or treatment failure. Early trial termination for safety concerns and the possibility that the study was underpowered to detect clinically important differences in favor of the intervention should be considered when interpreting the findings. Trial Registration: ClinicalTrials.gov Identifier: NCT02365493.


Assuntos
Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Daptomicina/uso terapêutico , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas/tratamento farmacológico , Vancomicina/uso terapêutico , beta-Lactamas/uso terapêutico , Adulto , Idoso , Antibacterianos/efeitos adversos , Bacteriemia/microbiologia , Bacteriemia/mortalidade , Cefazolina/uso terapêutico , Cloxacilina/uso terapêutico , Quimioterapia Combinada , Endocardite Bacteriana/tratamento farmacológico , Feminino , Floxacilina/uso terapêutico , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/mortalidade , Falha de Tratamento , beta-Lactamas/efeitos adversos
17.
J Antimicrob Chemother ; 74(10): 3049-3055, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31360992

RESUMO

BACKGROUND: SUper BioAvailability-itraconazole (SUBA®-itraconazole) was introduced into Australia in April 2014 as a substitute for standard itraconazole on the basis of improved bioavailability, tolerance and interpatient variability. Shortly after its introduction, our centre converted to the novel formulation for mould prophylaxis in patients undergoing allogeneic HSCT, autologous HSCT or treatment for haematological malignancies with an intermediate/high risk of invasive fungal infection (IFI). METHODS: A single-institution, investigator-initiated retrospective cohort study was conducted between June 2016 and April 2018 to assess therapeutic drug concentrations, safety and tolerability of a standard prophylactic dose of SUBA®-itraconazole. RESULTS: A total of 74 patients were assessed across 98 admissions with 178 measured itraconazole trough concentrations. The median duration of prophylaxis was 15.5 (1-59) days. No significant correlation was identified between trough concentrations and patient demographics including gender and weight. Drug concentrations were reduced by gastric acid suppression and diarrhoea. Therapeutic itraconazole trough concentrations (≥0.5 mg/L) were achieved at a median of 7 (95% CI = 6-8) days, with 87% of patients achieving therapeutic concentrations at day 14 (expected steady-state). One (1%) proven/probable IFI and 5 (5%) possible breakthrough IFIs were identified. Although adverse events were experienced by 42% of the cohort, only a single event was directly attributable to SUBA®-itraconazole, resulting in change of prophylactic agent. CONCLUSIONS: SUBA®-itraconazole achieved rapid therapeutic trough concentrations, was associated with low rates of IFI and was well tolerated in the study population. This formulation should be considered a realistic and safe first-line agent for the prevention of IFIs in those undergoing HSCT and intermediate/high-risk therapy for haematological malignancies.


Assuntos
Antifúngicos/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Infecções Fúngicas Invasivas/tratamento farmacológico , Itraconazol/uso terapêutico , Adulto , Idoso , Antibioticoprofilaxia/métodos , Austrália , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante de Células-Tronco/métodos , Adulto Jovem
18.
Med Mycol ; 57(7): 905-908, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30500920

RESUMO

Whole genome sequencing (WGS) was used to demonstrate the wide genetic variability within Sporothrix schenckii sensu lato and establish that there are two main species of Sporothrix within Australian clinical isolates-S. schenckii sensu stricto and Sporothrix globosa. We also demonstrated southwest Western Australia contained genetically similar S. schenckii ss strains that are distinct from strains isolated in the eastern and northern states of Australia. Some genetic clustering by region was also noted for northern NSW, Queensland, and Northern Territory. Phylogenetic analysis of WGS data provided greater phylogenetic resolution compared to analysis of the calmodulin gene alone.


Assuntos
Variação Genética , Filogenia , Sporothrix/classificação , Sporothrix/genética , Sequenciamento Completo do Genoma , Adulto , Idoso , Austrália , Calmodulina/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA , Esporotricose/microbiologia
19.
Emerg Infect Dis ; 24(2): 393-394, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29350166

RESUMO

Cronobacter sakazakii neonatal infections are often epidemiologically linked to the consumption of contaminated powdered infant formula. We describe a case resulting from consumption of contaminated expressed breast milk, as confirmed by whole-genome sequencing. This case highlights potential risks associated with storage and acquisition of expressed breast milk.


Assuntos
Cronobacter sakazakii/isolamento & purificação , Infecções por Enterobacteriaceae/microbiologia , Leite Humano/microbiologia , Austrália/epidemiologia , Extração de Leite/instrumentação , Extração de Leite/métodos , Infecções por Enterobacteriaceae/epidemiologia , Contaminação de Equipamentos , Evolução Fatal , Feminino , Microbiologia de Alimentos , Humanos , Recém-Nascido , Masculino
20.
Artigo em Inglês | MEDLINE | ID: mdl-29844046

RESUMO

Mutations associated with linezolid resistance within the V domain of 23S rRNA are annotated using an Escherichia coli numbering system. The 23S rRNA gene varies in length, nucleotide sequence, and copy number among bacterial species. Consequently, this numbering system is not intuitive and can lead to confusion when mutation sites are being located using whole-genome sequencing data. Using the mutation G2576T as an example, we demonstrate the difficulties associated with using the E. coli numbering system.


Assuntos
Linezolida/farmacologia , Antibacterianos/farmacologia , Farmacorresistência Bacteriana/genética , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Testes de Sensibilidade Microbiana , Mutação , RNA Ribossômico 23S/genética , Sequenciamento Completo do Genoma
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