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1.
Clin Infect Dis ; 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38902929

RESUMO

The in vitro susceptibility testing interpretive criteria (STIC) for TZP against Enterobacterales were recently updated by the Food and Drug Administration (FDA), Clinical & Laboratory Standards Institute (CLSI), and European Committee on Antimicrobial Susceptibility Testing (EUCAST). The United States Committee on Antimicrobial Susceptibility Testing (USCAST) also recently reviewed TZP STIC for Enterobacterales and arrived at different STIC for Enterobacterales and herein we explain our recommendations and rationale behind them. Based on our review of the available data, USCAST does not recommend TZP STIC for certain Enterobacterales species that have a moderate to high likelihood of clinically significant AmpC production (E. cloacae, C. freundii, and K. aerogenes only) or for third-generation cephalosporin-non-susceptible (3GC-NS) Enterobacterales. USCAST recommends a TZP susceptibility breakpoint of ≤ 16/4 mg/L for third-generation cephalosporin-susceptible (3GC-S) Enterobacterales but only endorses the use of extended infusion TZP regimens for patients with infections due to these pathogens.

2.
Clin Infect Dis ; 78(4): 833-841, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-37823484

RESUMO

BACKGROUND: The gastrointestinal microbiota is an important line of defense against colonization with antimicrobial resistant (AR) bacteria. In this post hoc analysis of the phase 3 ECOSPOR III trial, we assessed impact of a microbiota-based oral therapeutic (fecal microbiota spores, live; VOWST Oral Spores [VOS], formerly SER-109]; Seres Therapeutics) compared with placebo, on AR gene (ARG) abundance in patients with recurrent Clostridioides difficile infection (rCDI). METHODS: Adults with rCDI were randomized to receive VOS or placebo orally for 3 days following standard-of-care antibiotics. ARG and taxonomic profiles were generated using whole metagenomic sequencing of stool at baseline and weeks 1, 2, 8, and 24 posttreatment. RESULTS: Baseline (n = 151) and serial posttreatment stool samples collected through 24 weeks (total N = 472) from 182 patients (59.9% female; mean age: 65.5 years) in ECOSPOR III as well as 68 stool samples obtained at a single time point from a healthy cohort were analyzed. Baseline ARG abundance was similar between arms and significantly elevated versus the healthy cohort. By week 1, there was a greater decline in ARG abundance in VOS versus placebo (P = .003) in association with marked decline of Proteobacteria and repletion of spore-forming Firmicutes, as compared with baseline. We observed abundance of Proteobacteria and non-spore-forming Firmicutes were associated with ARG abundance, while spore-forming Firmicutes abundance was negatively associated. CONCLUSIONS: This proof-of-concept analysis suggests that microbiome remodeling with Firmicutes spores may be a potential novel approach to reduce ARG colonization in the gastrointestinal tract.


Assuntos
Clostridioides difficile , Infecções por Clostridium , Microbiota , Adulto , Humanos , Feminino , Idoso , Masculino , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Transplante de Microbiota Fecal , Clostridioides difficile/genética , Farmacorresistência Bacteriana , Infecções por Clostridium/microbiologia , Bactérias , Firmicutes
3.
J Antimicrob Chemother ; 79(1): 82-95, 2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-37962080

RESUMO

BACKGROUND: Limited comparative data exist on acute kidney injury (AKI) risk and AKI-associated outcomes in hospitalized patients with carbapenem-resistant Gram-negative infections (CR-GNIs) treated with a newer ß-lactam/ß-lactam-ß-lactamase inhibitor (BL/BL-BLI)-, polymyxin (PB)- or aminoglycoside (AG)-containing regimen. This study quantified the risk of AKI and AKI-related outcomes among patients with CR-GNIs treated with a newer BL/BL-BLI-, PB- or AG-containing regimen. METHODS: A multicentre, retrospective, observational study was performed (2016-20). The study included adult hospitalized patients with (i) baseline estimated glomerular filtration rates ≥30 mL/min/1.73 m2; (ii) CR-GN pneumonia, complicated urinary tract infection or bloodstream infection; and (iii) receipt of newer BL/BL-BLI, PG or AG within 7 days of index CR-GN culture for ≥3 days. Outcomes included AKI, in-hospital mortality and hospital costs. RESULTS: The study included 750 patients and most (48%) received a newer BL/BL-BLI. The median (IQR) treatment duration was 8 (5-11), 5 (4-8) and 7 (4-8) days in the newer BL/BL-BLI group, AG group and PB group, respectively. The PB group had the highest adjusted AKI incidence (95% CI) (PB: 25.1% (15.6%-34.6%) versus AG: 8.9% (5.7%-12.2%) versus newer BL/BL-BLI: 11.9% (8.1%-15.7%); P = 0.001). Patients with AKI had significantly higher in-hospital mortality (AKI: 18.5% versus 'No AKI': 5.6%; P = 0.001) and mean hospital costs (AKI: $49 192 versus 'No AKI': $38,763; P = 0.043). CONCLUSIONS: The AKI incidence was highest among PB patients and patients with AKI had worse outcomes. Healthcare systems should consider minimizing the use of antibiotics that augment AKI risk as a measure to improve outcomes in patients with CR-GNIs.


Assuntos
Injúria Renal Aguda , Inibidores de beta-Lactamases , Adulto , Humanos , Inibidores de beta-Lactamases/efeitos adversos , beta-Lactamas , Carbapenêmicos/uso terapêutico , Polimixinas , Lactamas , Aminoglicosídeos/efeitos adversos , Estudos Retrospectivos , Incidência , Antibacterianos/farmacologia , Injúria Renal Aguda/induzido quimicamente
4.
J Antimicrob Chemother ; 79(10): 2421-2459, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39215642

RESUMO

Treatment of patients with serious infections due to resistant Gram-negative bacteria remains highly problematic and has prompted clinicians to use existing antimicrobial agents in innovative ways. One approach gaining increased therapeutic use is combination therapy with IV fosfomycin. This article reviews the preclinical pharmacokinetic/pharmacodynamic (PK/PD) infection model and clinical data surrounding the use of combination therapy with IV fosfomycin for the treatment of serious infections caused by resistant Gram-negative bacteria. Data from dynamic in vitro and animal infection model studies of highly resistant Enterobacterales and non-lactose fermenters are positive and suggest IV fosfomycin in combination with a ß-lactam, polymyxin or aminoglycoside produces a synergistic effect that rivals or surpasses that of other aminoglycoside- or polymyxin-containing regimens. Clinical studies performed to date primarily have involved patients with pneumonia and/or bacteraemia due to Klebsiella pneumoniae, Pseudomonas aeruginosa or Acinetobacter baumannii. Overall, the observed success rates with fosfomycin combination regimens were consistent with those reported for other combination regimens commonly used to treat these patients. In studies in which direct treatment comparisons can be derived, the results suggest that patients who received fosfomycin combination therapy had similar or improved outcomes compared with other therapies and combinations, especially when it was used in combination with a ß-lactam that (1) targets PBP-3 and (2) has exceptional stability in the presence of ß-lactamases. Collectively, the data indicate that combination therapy with IV fosfomycin should be considered as a potential alternative to aminoglycoside or polymyxin combinations for patients with antibiotic-resistant Gram-negative infections when benefits outweigh risks.


Assuntos
Antibacterianos , Quimioterapia Combinada , Fosfomicina , Infecções por Bactérias Gram-Negativas , Fosfomicina/farmacocinética , Fosfomicina/administração & dosagem , Fosfomicina/uso terapêutico , Humanos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Animais , Administração Intravenosa , Bactérias Gram-Negativas/efeitos dos fármacos , Adulto
5.
Artigo em Inglês | MEDLINE | ID: mdl-39258877

RESUMO

BACKGROUND: Ceftolozane/tazobactam and ceftazidime/avibactam are commonly used in patients with MDR-Pseudomonas aeruginosa (PSA) pneumonia (PNA). This study compared outcomes between non-COVID-19 hospitalized patients with MDR-PSA PNA who received ceftolozane/tazobactam or ceftazidime/avibactam. METHODS: The study included non-COVID-19 adult hospitalized patients with MDR-PSA PNA in the PINC AI Healthcare Database (2016-22) who received ceftolozane/tazobactam or ceftazidime/avibactam within 3 days of index culture for ≥2 days. Outcomes were mortality, recurrent MDR-PSA PNA, discharge destination, post-index culture day length of stay (LOS) and costs (in US dollars, USD), and hospital readmission. RESULTS: The final sample included 197 patients (117 ceftolozane/tazobactam, 80 ceftazidime/avibactam). No significant differences were observed in mortality and post-index culture LOS and costs between groups. In the multivariable analyses, patients who received ceftolozane/tazobactam versus ceftazidime/avibactam had lower recurrent MDR-PSA PNA (7.9% versus 18.0%, P = 0.03) and 60 day PNA-related readmissions (11.1% versus 28.5%, P = 0.03) and were more likely to be discharged home (25.8% versus 9.8%, P = 0.03). Compared with ceftazidime/avibactam patients, ceftolozane/tazobactam patients had lower adjusted median total antibiotic costs (5052 USD versus 8099 USD, P = 0.003) and lower adjusted median comparator (ceftolozane/tazobactam or ceftazidime/avibactam) antibiotic costs (3938 USD versus 6441 USD, P = 0.005). In the desirability of outcome ranking (DOOR) analysis, a ceftolozane/tazobactam-treated patient was more likely to have a more favourable outcome than a ceftazidime/avibactam-treated patient [DOOR probability: 59.6% (95% CI: 52.5%-66.8%)]. CONCLUSIONS: Early treatment with ceftolozane/tazobactam may offer some clinical and cost benefits over ceftazidime/avibactam in patients with MDR-PSA PNA. Further large-scale studies are necessary to comprehensively understand the outcomes associated with these treatments for MDR-PSA PNA.

6.
Clin Infect Dis ; 77(Suppl 4): S305-S313, 2023 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-37843118

RESUMO

Addressing the treatment and prevention of antibacterial-resistant gram-negative bacterial infections is a priority area of the Antibacterial Resistance Leadership Group (ARLG). The ARLG has conducted a series of observational studies to define the clinical and molecular global epidemiology of carbapenem-resistant and ceftriaxone-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii, with the goal of optimizing the design and execution of interventional studies. One ongoing ARLG study aims to better understand the impact of fluoroquinolone-resistant gram-negative gut bacteria in neutropenic patients, which threatens to undermine the effectiveness of fluoroquinolone prophylaxis in these vulnerable patients. The ARLG has conducted pharmacokinetic studies to inform the optimal dosing of antibiotics that are important in the treatment of drug-resistant gram-negative bacteria, including oral fosfomycin, intravenous minocycline, and a combination of intravenous ceftazidime-avibactam and aztreonam. In addition, randomized clinical trials have assessed the safety and efficacy of step-down oral fosfomycin for complicated urinary tract infections and single-dose intravenous phage therapy for adult patients with cystic fibrosis who are chronically colonized with P. aeruginosa in their respiratory tract. Thus, the focus of investigation in the ARLG has evolved from improving understanding of drug-resistant gram-negative bacterial infections to positively affecting clinical care for affected patients through a combination of interventional pharmacokinetic and clinical studies, a focus that will be maintained moving forward.


Assuntos
Fosfomicina , Infecções por Bactérias Gram-Negativas , Adulto , Humanos , Fosfomicina/uso terapêutico , Liderança , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Bactérias Gram-Negativas , Carbapenêmicos/uso terapêutico , Fluoroquinolonas/uso terapêutico , Pseudomonas aeruginosa , Farmacorresistência Bacteriana Múltipla , Testes de Sensibilidade Microbiana
7.
Clin Infect Dis ; 77(Suppl 4): S295-S304, 2023 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-37843115

RESUMO

The Antibacterial Resistance Leadership Group (ARLG) has prioritized infections caused by gram-positive bacteria as one of its core areas of emphasis. The ARLG Gram-positive Committee has focused on studies responding to 3 main identified research priorities: (1) investigation of strategies or therapies for infections predominantly caused by gram-positive bacteria, (2) evaluation of the efficacy of novel agents for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci, and (3) optimization of dosing and duration of antimicrobial agents for gram-positive infections. Herein, we summarize ARLG accomplishments in gram-positive bacterial infection research, including studies aiming to (1) inform optimal vancomycin dosing, (2) determine the role of dalbavancin in MRSA bloodstream infection, (3) characterize enterococcal bloodstream infections, (4) demonstrate the benefits of short-course therapy for pediatric community-acquired pneumonia, (5) develop quality of life measures for use in clinical trials, and (6) advance understanding of the microbiome. Future studies will incorporate innovative methodologies with a focus on interventional clinical trials that have the potential to change clinical practice for difficult-to-treat infections, such as MRSA bloodstream infections.


Assuntos
Infecções por Bactérias Gram-Positivas , Staphylococcus aureus Resistente à Meticilina , Sepse , Humanos , Criança , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Liderança , Qualidade de Vida , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/microbiologia , Bactérias Gram-Positivas , Sepse/tratamento farmacológico
8.
Antimicrob Agents Chemother ; 66(7): e0025622, 2022 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-35727059

RESUMO

Imipenem (IMI)/cilastatin/relebactam (REL) (I/R) is a novel ß-lactam/ß-lactamase inhibitor combination with expanded microbiologic activity against carbapenem-resistant non-Morganellaceae Enterobacterales (CR-NME) and difficult-to-treat (DTR) Pseudomonas aeruginosa. Relebactam, a bicyclic diazabicyclooctane, has no direct antimicrobial activity but provides reliable inhibition of many Ambler class A and class C enzymes. It is currently approved for the treatment of adult patients with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) and those with complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) when limited or no alternative treatments are available. Given the number of recently approved ß-lactams with expanded activity against highly resistant Gram-negative pathogens, this review summarizes the published literature on I/R, with a focus on its similar and distinguishing characteristics relative to those of other recently approved agents. Overall, available data support its use for the treatment of patients with HABP/VABP, cUTI, and cIAI due to CR-NME and DTR P. aeruginosa. Data indicate that I/R retains some activity against CR-NME and DTR P. aeruginosa isolates that are resistant to the newer ß-lactams and vice versa, suggesting that susceptibility testing be performed for all the newer agents to determine optimal treatment options for patients with CR-NME and DTR P. aeruginosa infections. Further comparative PK/PD and clinical studies are warranted to determine the optimal role of I/R, alone and in combination, for the treatment of patients with highly resistant Gram-negative infections. Until further data are available, I/R is a potential treatment for patients with CR-NME and DTR P. aeruginosa infections when the benefits outweigh the risks.


Assuntos
Compostos Azabicíclicos , Pneumonia Bacteriana , Adulto , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Compostos Azabicíclicos/farmacologia , Compostos Azabicíclicos/uso terapêutico , Carbapenêmicos , Humanos , Imipenem/farmacologia , Imipenem/uso terapêutico , Testes de Sensibilidade Microbiana , Pneumonia Bacteriana/tratamento farmacológico , Pseudomonas aeruginosa , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/uso terapêutico
9.
Antimicrob Agents Chemother ; 66(12): e0093522, 2022 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-36394316

RESUMO

This phase I study evaluated the safety of the optimal ceftazidime-avibactam (CZA) with aztreonam (ATM) regimens identified in hollow fiber infection models of MBL-producing Enterobacterales. Eligible healthy subjects aged 18 to 45 years were assigned to one of six cohorts: 2.5 g CZA over 2 h every 8 h (approved dose), CZA continuous infusion (CI) (7.5 g daily), 2 g ATM over 2 h every 6 h, ATM CI (8 g daily), CZA (approved dose) with 1.5 g ATM over 2 h every 6 h, and CZA (approved dose) with 2 g ATM over 2 h every 6 h. Study drug(s) were administered for 7 days. The most frequently observed adverse events (AEs) were hepatic aminotransferase (ALT/AST) elevations (n = 19 subjects). Seventeen of the 19 subjects with ALT/AST elevations received ATM alone or CZA-ATM. The incidence of ALT/AST elevations was comparable between the ATM-alone and CZA-ATM cohorts. Two subjects in the ATM CI cohort experienced severe ALT/AST elevation AEs. All subjects with ALT/AST elevations were asymptomatic with no other findings suggestive of liver injury. Most other AEs were of mild to moderate severity and were similar across cohorts, except for prolonged prothrombin time (more frequent in CZA-ATM cohorts). These results suggest that CZA-ATM administered as 2-h intermittent infusions is safe and that some caution should be exercised with the use of ATM CI at an ATM dose of 8 g daily. If CZA-ATM is prescribed, clinicians are advised to monitor liver function, hematologic, and coagulation parameters. Future controlled studies are required to better define the safety and efficacy of the CZA-ATM regimens evaluated in this phase I study.


Assuntos
Antibacterianos , Aztreonam , Humanos , Adulto , Aztreonam/efeitos adversos , Antibacterianos/efeitos adversos , Voluntários Saudáveis , Ceftazidima/efeitos adversos , Compostos Azabicíclicos/efeitos adversos , Combinação de Medicamentos , Voluntários , Testes de Sensibilidade Microbiana , beta-Lactamases
10.
Antimicrob Agents Chemother ; 66(12): e0093622, 2022 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-36394326

RESUMO

Scant pharmacokinetic (PK) data are available on ceftazidime-avibactam (CZA) and aztreonam (ATM) in combination, and it is unknown if CZA-ATM exacerbates alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevations relative to ATM alone. This phase 1 study sought to describe the PK of CZA-ATM and assess the associations between ATM exposures and ALT/AST elevations. Subjects (n = 48) were assigned to one of six cohorts (intermittent infusion [II] CZA, continuous infusion [CI] CZA, II ATM, CI ATM [8 g/daily], II CZA with II ATM [6 g/daily], and II CZA with II ATM [8 g/daily]), and study product(s) were administered for 7 days. A total of 19 subjects (40%) had ALT/AST elevations, and most (89%) occurred in the ATM/CZA-ATM cohorts. Two subjects in the CI ATM cohort experienced severe ALT/AST elevations, which halted the study. All subjects with ALT/AST elevations were asymptomatic with no other signs of liver injury, and all ALT/AST elevations resolved without sequalae after cessation of dosing. In the population PK (PopPK) analyses, CZA-ATM administration reduced total ATM clearance by 16%, had a negligible effect on total ceftazidime clearance, and was not a covariate in the avibactam PopPK model. In the exposure-response analyses, coadministration of CZA-ATM was not found to augment ALT/AST elevations. Modest associations were observed between ATM exposure (maximum concentration of drug in serum [Cmax] and area under the concentration-time curve [AUC]) and ALT/AST elevations in the analysis of subjects in the II ATM/CZA-ATM cohorts. The findings suggest that administration of CZA-ATM reduces ATM clearance but does not exacerbate AST/ALT elevations relative to ATM alone. The results also indicate that CI ATM should be used with caution.


Assuntos
Aztreonam , Ceftazidima , Humanos , Adulto , Ceftazidima/farmacocinética , Aztreonam/uso terapêutico , Inibidores de beta-Lactamases/farmacocinética , Testes de Sensibilidade Microbiana , Compostos Azabicíclicos/farmacocinética , Combinação de Medicamentos , Antibacterianos/uso terapêutico , Antibacterianos/farmacocinética
11.
Antimicrob Agents Chemother ; 66(3): e0207121, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35041506

RESUMO

Increasing antimicrobial resistance and medical device-related infections have led to a renewed interest in phage therapy as an alternative or adjunct to conventional antimicrobials. Expanded access and compassionate use cases have risen exponentially but have varied widely in approach, methodology, and clinical situations in which phage therapy might be considered. Large gaps in knowledge contribute to heterogeneity in approach and lack of consensus in many important clinical areas. The Antibacterial Resistance Leadership Group (ARLG) has convened a panel of experts in phage therapy, clinical microbiology, infectious diseases, and pharmacology, who worked with regulatory experts and a funding agency to identify questions based on a clinical framework and divided them into three themes: potential clinical situations in which phage therapy might be considered, laboratory testing, and pharmacokinetic considerations. Suggestions are provided as answers to a series of questions intended to inform clinicians considering experimental phage therapy for patients in their clinical practices.


Assuntos
Bacteriófagos , Terapia por Fagos , Ensaios de Uso Compassivo , Farmacorresistência Bacteriana , Humanos
12.
J Antimicrob Chemother ; 77(7): 1899-1902, 2022 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-35488862

RESUMO

OBJECTIVES: Dalbavancin is a lipoglycopeptide with a long half-life, making it a promising treatment for infections requiring prolonged therapy, such as complicated Staphylococcus aureus bacteraemia. Free drug concentration is a critical consideration with prolonged treatment, since free concentration-time profiles may best correlate with therapeutic effect. In support of future clinical trials, we aimed to develop a reliable and reproducible assay for measuring free dalbavancin concentrations. METHODS: The ultracentrifugation technique was used to determine free dalbavancin concentrations in plasma at two concentrations (50 and 200 mg/L) in duplicate. Centrifuge tubes and pipette tips were treated for 24 h before use with Tween 80 to assess adsorption. Dalbavancin concentrations were analysed from the plasma samples (total) and middle layer samples (free) by LC/MS/MS with isotopically labelled internal standard. Warfarin served as a positive control with known high protein binding. RESULTS: Measurement of free dalbavancin was sensitive to adsorption onto plastic. Treatment of tubes and pipette tips with ≥2% Tween 80 effectively prevented drug loss during protein binding experiments. By the ultracentrifugation method, dalbavancin's protein binding was estimated to be approximately 99%. CONCLUSIONS: Dalbavancin has very high protein binding. Given dalbavancin's high protein binding, accurate measurement of free dalbavancin concentrations should be a key consideration in future exposure-response studies, especially clinical trials. Future investigations should confirm if the active fraction is best predicted by the free or total fraction.


Assuntos
Bacteriemia , Infecções Estafilocócicas , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Humanos , Testes de Sensibilidade Microbiana , Polissorbatos/uso terapêutico , Ligação Proteica , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus , Espectrometria de Massas em Tandem , Teicoplanina/análogos & derivados , Teicoplanina/uso terapêutico
13.
Clin Infect Dis ; 72(9): 1497-1501, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33740042

RESUMO

The revised vancomycin consensus guidelines recommended area under the curve (AUC)-guided dosing/monitoring for patients with serious invasive methicillin-resistant Staphylococcus aureus (MRSA) infections as a measure to minimize vancomycin-associated acute kidney injury (VA-AKI) while maintaining similar effectiveness. Data indicate that the intensity of vancomycin exposure drives VA-AKI risk. Troughs of 15-20 mg/L will ensure an AUC ≥400 mg × hr/L but most patients will have daily AUCs >600. VA-AKI increases as a function of AUC, especially when >600. In addition to minimizing VA-AKI risk while maintaining similar efficacy, AUC-guided dosing/monitoring is a more precise way to conduct therapeutic drug monitoring for vancomycin relative to trough-only control.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Adulto , Antibacterianos/efeitos adversos , Área Sob a Curva , Criança , Humanos , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/tratamento farmacológico , Vancomicina/efeitos adversos
14.
Clin Infect Dis ; 73(11): e4560-e4567, 2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-32716506

RESUMO

INTRODUCTION: Although recent guidelines have recommended monitoring vancomycin (VAN) area under the curve (AUC)/minimum inhibitory concentration (MIC) to ensure clinical efficacy and minimize toxicity in methicillin-resistant Staphylococcus aureus (MRSA) for various infections, there are no recommendations regarding complicated skin and soft tissue infections (cSSTIs). We aimed to evaluate the association between VAN AUC and clinical outcomes in MRSA cSSTIs. METHODS: This was a retrospective cohort study of adult patients treated with ≥72 hours of VAN for MRSA cSSTI from 2008 to 2013 at Detroit Medical Center. The primary outcome was timely clinical success (TCS) defined as (1) resolution of signs and symptoms of infection within 72 hours, (2) stabilization and/or reduction in lesion size, (3) alternative agents not required due to VAN failure or toxicity as elected by the prescribing clinician. Classification and regression tree (CART) analysis was performed to determine the AUC associated with TCS in the cohort. Multivariable logistic regression was used to evaluate the association between VAN-AUC and the primary outcome. RESULTS: A total of 154 patients were included in this analysis. CART identifed an AUC ≥435 mg*hr/L for TCS. Overall, 60.9% of patients experienced TCS; 69.7% in the target-AUC group versus 52.5% in the below-target AUC group, (P = .013). Target-AUC attainment was independently associated with increased odds of TCS (adjusted odds ratio [aOR], 2.208; 95% confidence interval [CI], 1.047-4.659). CONCLUSIONS: In adults treated with VAN for MRSA cSSTI, target-AUC attainment was independently associated with improved clinical outcomes and maybe most warranted for patients at high risk of VAN failure or VAN-associated toxicity.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções dos Tecidos Moles , Infecções Estafilocócicas , Adulto , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Área Sob a Curva , Humanos , Testes de Sensibilidade Microbiana , Estudos Retrospectivos , Infecções dos Tecidos Moles/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Resultado do Tratamento , Vancomicina/farmacologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-33318004

RESUMO

Vancomycin induces exposure-related acute kidney injury. However, the pharmacokinetic-toxicodynamic (PK-TD) relationship remains unclear. Sprague-Dawley rats received intravenous (i.v.) vancomycin doses of 300 mg/kg/day and 400 mg/kg/day, divided into once-, twice-, three-times-, or four-times-daily doses (i.e., QD, BID, TID, or QID) over 24 h. Up to 8 samples plus a terminal sample were drawn during the 24-h dosing period. Twenty-four-hour urine was collected and assayed for kidney injury molecule-1 (KIM-1). Vancomycin was quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Following terminal sampling, nephrectomy and histopathologic analyses were conducted. PK analyses were conducted using Pmetrics. PK exposures (i.e., area under the concentration-time curve from 0 to 24 h [AUC0-24] and maximum concentration from 0 to 24 h [Cmax0-24]) were calculated for each rat, and PK-TD relationships were discerned. A total of 53-rats generated PK-TD data. A 2-compartment model fit the data well (Bayesian observed versus predicted concentrations; R2 = 0.96). KIM-1 values were greater in QD and BID groups (P for QD versus TID, <0.002; P for QD versus QID, <0.004; P for BID versus TID, <0.002; and P for BID versus QID, <0.004). Exposure-response relationships were observed between KIM-1 versus Cmax0-24 and AUC0-24 (R2 = 0.7 and 0.68). Corrected Akaike's information criterion showed Cmax0-24 as the most predictive PK-TD driver for vancomycin-induced kidney injury (VIKI) (-5.28 versus -1.95). While PK-TD indices are often intercorrelated, maximal concentrations and fewer doses (for the same total daily amount) resulted in increased VIKI in our rat model.


Assuntos
Espectrometria de Massas em Tandem , Vancomicina , Animais , Área Sob a Curva , Teorema de Bayes , Cromatografia Líquida , Rim , Ratos , Ratos Sprague-Dawley , Vancomicina/efeitos adversos
16.
Antimicrob Agents Chemother ; 65(10): e0106021, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34339278

RESUMO

Vancomycin area under the concentration curve (AUC) is known to predict vancomycin-induced acute kidney injury (AKI). Data were analyzed from a rat model (n = 48) and two prospective clinical studies (PROVIDE [n = 263] and CAMERA2 [n = 291]). A logit-link model was used to calculate the multiplicative factors between the probability of AKI from clinical studies and in the rat. The rat was 2.7 to 4.2 times more sensitive to AKI between AUCs of 199.5 and 794.3 mg·h/liter, respectively.


Assuntos
Injúria Renal Aguda , Vancomicina , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Animais , Antibacterianos/efeitos adversos , Área Sob a Curva , Estudos Prospectivos , Ratos , Vancomicina/efeitos adversos
17.
Artigo em Inglês | MEDLINE | ID: mdl-33168615

RESUMO

Intravenous (i.v.) minocycline is increasingly used to treat infections caused by multidrug-resistant (MDR) Acinetobacter baumannii Despite its being approved nearly 50 years ago, published information on its pharmacokinetic (PK) profile is limited. This multicenter study examined the PK and probability of pharmacokinetic-pharmacodynamic (PK-PD) target attainment profile of i.v. minocycline in critically ill patients, with suspected or documented infection with Gram-negative bacteria. The PK study population included 55 patients who received a single 200-mg i.v. dose of minocycline. Plasma PK samples were collected predose and 1, 4, 12, 24, 36, and 48 h after initiation of minocycline. Total and unbound minocycline concentrations were determined at each time point. Probabilities of achieving the PK-PD targets associated with stasis and 1-log killing (free area under the curve above the MIC [fAUC:MIC] of 12 and 18, respectively) in an immunocompetent animal pneumonia infection model of A. baumannii were evaluated. A two-compartment population PK model with zero-order i.v. input and first-order elimination, which estimated a constant fraction unbound (fub) for minocycline, best characterized the total and unbound plasma minocycline concentration-time data. The only two covariates retained in the final PK model were body surface area (associated with central volume of distribution) and albumin (associated with fub). In the PK-PD probability of target attainment analyses, minocycline 200 mg i.v. every 12 h (Q12H) was predicted to result in a suboptimal PK-PD profile for patients with A. baumannii infections with MIC values of >1 mg/liter. Like all PK-PD profiling studies of this nature, these findings need clinical confirmation.


Assuntos
Acinetobacter baumannii , Minociclina , Adulto , Animais , Antibacterianos/uso terapêutico , Estado Terminal , Humanos , Testes de Sensibilidade Microbiana
18.
J Antimicrob Chemother ; 76(7): 1661-1665, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-33843994

RESUMO

The need for precision dosing has been challenged on the basis of insufficient evidence. Herein, we argue that adequate evidence exists to conduct therapeutic drug monitoring (TDM) and precisely target antibiotic exposures. While achievement of any antibiotic concentration does not guarantee efficacy sans toxicity for any single patient, stochastic control optimizes the probability of achieving favourable responses across patients. We argue that variability in targets (such as the organism's MIC) can be considered with models. That is, complexity alone does not relegate the decision-making framework to 'clinician intuition'. We acknowledge the exposure-response relationships are modified by patient-specific factors (other drugs, baseline organ functional status etc.) and describe how precision dosing can inform clinical decision making rather than protocolize it. Finally, we call for randomized, controlled trials; however, we suggest that these trials are not necessary to make TDM standard of care for multiple classes of antibiotics.


Assuntos
Antibacterianos , Monitoramento de Medicamentos , Antibacterianos/uso terapêutico , Humanos
19.
Clin Infect Dis ; 71(4): 1095-1098, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31802119

RESUMO

In an infection with an Enterobacter sp. isolate producing Klebsiella pneumoniae Carbapenemase-4 and New Delhi Metallo-ß-Lactamase-1 in the United States, recognition of the molecular basis of carbapenem resistance allowed for successful treatment by combining ceftazidime-avibactam and aztreonam. Antimicrobial synergy testing and therapeutic drug monitoring assessed treatment adequacy.


Assuntos
Bacteriemia , Infecções por Klebsiella , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Compostos Azabicíclicos/uso terapêutico , Aztreonam/uso terapêutico , Bacteriemia/tratamento farmacológico , Proteínas de Bactérias , Ceftazidima/uso terapêutico , Combinação de Medicamentos , Enterobacter , Humanos , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/genética , Testes de Sensibilidade Microbiana , Estados Unidos , beta-Lactamases/genética
20.
Clin Infect Dis ; 71(6): 1361-1364, 2020 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-32658968

RESUMO

Recent clinical data on vancomycin pharmacokinetics and pharmacodynamics suggest a reevaluation of current dosing and monitoring recommendations. The previous 2009 vancomycin consensus guidelines recommend trough monitoring as a surrogate marker for the target area under the curve over 24 hours to minimum inhibitory concentration (AUC/MIC). However, recent data suggest that trough monitoring is associated with higher nephrotoxicity. This document is an executive summary of the new vancomycin consensus guidelines for vancomycin dosing and monitoring. It was developed by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists vancomycin consensus guidelines committee. These consensus guidelines recommend an AUC/MIC ratio of 400-600 mg*hour/L (assuming a broth microdilution MIC of 1 mg/L) to achieve clinical efficacy and ensure safety for patients being treated for serious methicillin-resistant Staphylococcus aureus infections.


Assuntos
Doenças Transmissíveis , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Área Sob a Curva , Criança , Doenças Transmissíveis/tratamento farmacológico , Humanos , Testes de Sensibilidade Microbiana , Farmacêuticos , Infecções Estafilocócicas/tratamento farmacológico , Estados Unidos , Vancomicina/farmacologia , Vancomicina/uso terapêutico
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