scholarly journals Pharmacokinetic-Pharmacodynamic Relationships Describing the Efficacy of Oritavancin in Patients with Staphylococcus aureus Bacteremia

2006 ◽  
Vol 50 (3) ◽  
pp. 994-1000 ◽  
Author(s):  
Sujata M. Bhavnani ◽  
Julie A. Passarell ◽  
Joel S. Owen ◽  
Jeffrey S. Loutit ◽  
Steven B. Porter ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Odds Ratio ◽  
Regression Tree ◽  
Bloodstream Infections ◽  
Free Drug ◽  
Classification And Regression Tree ◽  
Population Pharmacokinetic ◽  
Dose Selection ◽  
Staphylococcus Aureus Bacteremia ◽  
Drug Concentrations

ABSTRACT Bloodstream infections due to antimicrobial-resistant Staphylococcus aureus occur with increasing frequency and represent an important cause of morbidity and mortality. To date, the evaluation of pharmacokinetic-pharmacodynamic relationships for efficacy among patients with bacteremia has been limited. The objectives of these analyses were to evaluate relationships between microbiological and clinical responses for patients with S. aureus bacteremia and exposures for oritavancin, a novel bactericidal glycopeptide in development. Bayesian oritavancin exposure predictions, following treatment with 5, 6.5, 8, or 10 mg/kg of body weight/day, were derived using a validated population pharmacokinetic model for 55 patients with S. aureus bacteremia. Using classification and regression tree analysis, a breakpoint of the percentage of the dosing interval duration for which free-drug concentrations were above the MIC (free-drug % time > MIC) of 22% was identified for microbiological response; the probabilities of success greater than or equal to and less than this value were 93% and 76%, respectively. Using logistic regression, a relationship was found between microbiological response and free-drug % time > MIC (odds ratio = 4.42, P = 0.09, and odds ratio = 8.84, P = 0.05, when one patient, a medical outlier, was excluded). A similar relationship was found for clinical response. These results will be valuable in supporting dose selection of oritavancin for patients with S. aureus bacteremia.

scholarly journals Defining Clinical Exposures of Cefepime for Gram-Negative Bloodstream Infections That Are Associated with Improved Survival

2015 ◽  
Vol 60 (3) ◽  
pp. 1401-1410 ◽  
Author(s):  
Nathaniel J. Rhodes ◽  
Joseph L. Kuti ◽  
David P. Nicolau ◽  
Scott Van Wart ◽  
Anthony M. Nicasio ◽  
...  
Keyword(s):  
Regression Tree ◽  
Bloodstream Infections ◽  
Classification And Regression Tree ◽  
Apache Ii Score ◽  
Population Pharmacokinetic ◽  
Model Parameters ◽  
Gram Negative ◽  
Cart Analysis ◽  
Categorical Representation ◽  
Drug Concentrations

The percentage of time that free drug concentrations remain above the MIC (fT>MIC) that is necessary to prevent mortality among cefepime-treated patients with Gram-negative bloodstream infections (GNBSI) is poorly defined. We conducted a retrospective study of adult patients with GNBSI. Eligible cases were frequency matched to ensure categorical representation from all MICs. Organism, MIC, infection source, gender, age, serum creatinine, weight, antibiotic history, and modified APACHE II score were collected from hospital records. Two population pharmacokinetic models (models 1 and 2) were used to impute exposures over the first 24 h in each patient from mean model parameters, covariates, and dosing history. From the imputed exposures, survival thresholds forfT>MICwere identified using classification and regression tree (CART) analysis and analyzed as nominal variables for univariate and multivariate regressions. A total of 180 patients were included in the analysis, of whom 13.9% died and 86.1% survived. Many patients (46.7% [n= 84/180]) received combination therapy with cefepime. Survivors had higher mean (standard deviation [SD])fT>MICthan those who died (model 1, 74.2% [29.6%] versus 52.1% [33.8%],P< 0.001; model 2, 85.9% [24.0%] versus 64.4% [31.4%],P< 0.001). CART identifiedfT>MICthreshold values for greater survival according to models 1 and 2 at >68% and >74%, respectively. Survival was improved for those withfT>MICof >68% (model 1 adjusted odds ratio [aOR], 7.12; 95% confidence interval [CI], 1.90 to 26.7;P= 0.004) and >74% (model 2 aOR, 6.48; 95% CI, 1.90 to 22.1) after controlling for clinical covariates. Similarly, each 1% increase in cefepimefT>MICresulted in a 2% improvement in multivariate survival probability (P= 0.015). Achieving a cefepimefT>MICof 68 to 74% was associated with a higher odds of survival for patients with GNBSI. Regimens targeting this exposure should be aggressively pursued.

scholarly journals Pharmacodynamic Analysis of Daptomycin-treated Enterococcal Bacteremia: It Is Time to Change the Breakpoint

2018 ◽  
Vol 68 (10) ◽  
pp. 1650-1657 ◽  
Author(s):  
Lindsay M Avery ◽  
Joseph L Kuti ◽  
Maja Weisser ◽  
Adrian Egli ◽  
Michael J Rybak ◽  
...  
Keyword(s):  
Regression Tree ◽  
Classification And Regression Tree ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Regression Tree Analysis ◽  
Lactam Antibiotic ◽  
Infection Source ◽  
High Doses ◽  
Susceptibility Breakpoint ◽  
Enterococcal Bacteremia

Abstract Background Currently, there is debate over whether the daptomycin susceptibility breakpoint for enterococci (ie, minimum inhibitory concentration [MIC] ≤4 mg/L) is appropriate. In bacteremia, observational data support prescription of high doses (&gt;8 mg/kg). However, pharmacodynamic targets associated with positive patient outcomes are undefined. Methods Data were pooled from observational studies that assessed outcomes in daptomycin-treated enterococcal bacteremia. Patients who received an additional antienterococcal antibiotic and/or a β-lactam antibiotic at any time during treatment were excluded. Daptomycin exposures were calculated using a published population pharmacokinetic model. The free drug area under the concentration-time curve to MIC ratio (fAUC/MIC) threshold predictive of survival at 30 days was identified by classification and regression tree analysis and confirmed with multivariable logistic regression. Monte Carlo simulations determined the probability of target attainment (PTA) at clinically relevant MICs. Results Of 114 patients who received daptomycin monotherapy, 67 (58.8%) were alive at 30 days. A fAUC/MIC &gt;27.43 was associated with survival in low-acuity (n = 77) patients (68.9 vs 37.5%, P = .006), which remained significant after adjusting for infection source and immunosuppression (P = .026). The PTA for a 6-mg/kg/day (every 24 hours) dose was 1.5%–5.5% when the MIC was 4 mg/L (ie, daptomycin-susceptible) and 91.0%–97.9% when the MIC was 1 mg/L. Conclusions For enterococcal bacteremia, a daptomycin fAUC/MIC &gt;27.43 was associated with 30-day survival among low-acuity patients. As pharmacodynamics for the approved dose are optimized only when MIC ≤1 mg/L, these data continue to stress the importance of reevaluation of the susceptibility breakpoint.

scholarly journals 212. Outcomes of Adults with Uncomplicated Staphylococcus aureus Bacteremia Receiving Short-Course Vs. Prolonged-Course Antibiotic Therapy in a Multicenter, Propensity Score–Matched Cohort

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S125-S126
Author(s):  
Louise Thorlacius-Ussing ◽  
Jette Nissen ◽  
Jon J Rasmussen ◽  
Robert Skov ◽  
Magnus Arpi ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Propensity Score ◽  
Antibiotic Therapy ◽  
Antibiotic Treatment ◽  
Nearest Neighbor ◽  
Bloodstream Infections ◽  
Staphylococcus Aureus Bacteremia ◽  
Short Course ◽  
Short Courses

Abstract Background The recommended duration of antibiotic treatment for uncomplicated Staphylococcus aureus bloodstream infections is 14 days. We compared the outcomes of patients receiving short-course (6–10 days) vs. prolonged-course (11–16 days) antibiotic therapy for S. aureus bacteremia (SAB). Methods 30-day outcome of patients with penicillin (PSSAB, n = 202)) or methicillin-susceptible SAB (MSSAB, n = 203) treated with in vitro active therapy in the range of 6–16 days was analyzed using pooled data from two previously published, observational studies. Individuals were matched 1:1 by nearest neighbor propensity score matching without replacement. Regression analysis was performed to estimate the risk of all-cause mortality within 30 days after the end of antibiotic treatment. Eligible individuals had to have >1 day of follow-up after discontinuation of antimicrobials. Individuals with a diagnosis of endocarditis, bone infection, meningitis or pneumonia were excluded. Results There were 107 well-balanced matched pairs; 58 in the PSSAB and 39 in the MSSAB cohort. For PSSAB, the median duration of therapy was 8 (interquartile range [IQR], 7–10) in the short-course group and 12 days (IQR, 10–13) in the prolonged-course group. For the MSSAB cohort, these numbers were 9 days (IQR, 7–10) and 14 days (IQR, 13–16 days), respectively. No difference in mortality between short-course and prolonged-course treatment was observed (adjusted hazard ratio [aHR], 0.74; 95% confidence interval [CI], .23–2.41) and 1.14; 95% CI, 0.31–4.20), respectively for PSSAB and MSSAB. Conclusion Short courses of antibiotic therapy yielded similar clinical outcomes as prolonged courses of antibiotic therapy for S. aureus bacteremia. The findings warrant a randomized clinical trial to study the safety and efficacy of shortened antimicrobial therapy for the treatment of uncomplicated SAB. Disclosures All authors: No reported disclosures.

scholarly journals Effect of Ertapenem Protein Binding on Killing of Bacteria

2004 ◽  
Vol 48 (9) ◽  
pp. 3419-3424 ◽  
Author(s):  
David E. Nix ◽  
Kathryn R. Matthias ◽  
Emily C. Ferguson
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Activity ◽  
Protein Binding ◽  
Human Serum ◽  
High Performance ◽  
Enterobacter Cloacae ◽  
Free Drug ◽  
Drug Concentrations ◽  
Kill Rate ◽  
Total Concentrations

ABSTRACT The effect of protein binding on the antimicrobial activity of ertapenem was evaluated using the bacterial kill rate and concentration-response studies. Various proportions of human serum were utilized to determine the total and free-drug concentrations using a validated high-performance liquid chromatography assay. The MICs and kill curves were determined for test isolates of Enterobacter cloacae and Staphylococcus aureus at various percentages of human serum. The killing of bacteria was analyzed in relation to the free and total concentrations of ertapenem at various proportions of human serum. It was determined that unbound ertapenem was responsible for the antimicrobial activity against the test isolates.

scholarly journals Clinical Pharmacodynamics of Cefepime in Patients Infected with Pseudomonas aeruginosa

2009 ◽  
Vol 54 (3) ◽  
pp. 1111-1116 ◽  
Author(s):  
Jared L. Crandon ◽  
Catharine C. Bulik ◽  
Joseph L. Kuti ◽  
David P. Nicolau
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Urinary Tract ◽  
Confidence Interval ◽  
Free Drug ◽  
Classification And Regression Tree ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Minimum Concentration ◽  
Skin Structure ◽  
Tract Infections

ABSTRACT We evaluated cefepime exposures in patients infected with Pseudomonas aeruginosa to identify the pharmacodynamic relationship predictive of microbiological response. Patients with non-urinary tract P. aeruginosa infections and treated with cefepime were included. Free cefepime exposures were estimated by using a validated population pharmacokinetic model. P. aeruginosa MICs were determined by Etest and pharmacodynamic indices (the percentage of the dosing interval that the free drug concentration remains above the MIC of the infecting organism [f T > MIC], the ratio of the minimum concentration of free drug to the MIC [f C min/MIC], and the ratio of the area under the concentration-time curve for free drug to the MIC [fAUC/MIC]) were calculated for each patient. Classification and regression tree analysis was used to partition the pharmacodynamic parameters for prediction of the microbiological response. Monte Carlo simulation was utilized to determine the optimal dosing regimens needed to achieve the pharmacodynamic target. Fifty-six patients with pneumonia (66.1%), skin and skin structure infections (SSSIs) (25%), and bacteremia (8.9%) were included. Twenty-four (42.9%) patients failed cefepime therapy. The MICs ranged from 0.75 to 96 μg/ml, resulting in median f T > MIC, f C m in/MIC, and fAUC/MIC exposures of 100% (range, 0.8 to 100%), 4.3 (range, 0.1 to 27.3), and 206.2 (range, 4.2 to 1,028.7), respectively. Microbiological failure was associated with an f T > MIC of ≤60% (77.8% failed cefepime therapy when f T > MIC was ≤60%, whereas 36.2% failed cefepime therapy when f T > MIC was >60%; P = 0.013). A similar f T > MIC target of ≤63.9% (P = 0.009) was identified when skin and skin structure infections were excluded. While controlling for the SSSI source (odds ratio [OR], 0.18 [95% confidence interval, 0.03 to 1.19]; P = 0.07) and combination therapy (OR, 2.15 [95% confidence interval, 0.59 to 7.88]; P = 0.25), patients with f T > MIC values of ≤60% were 8.1 times (95% confidence interval, 1.2 to 55.6 times) more likely to experience a poor microbiological response. Cefepime doses of at least 2 g every 8 h are required to achieve this target against CLSI-defined susceptible P. aeruginosa organisms in patients with normal renal function. In patients with non-urinary tract infections caused by P. aeruginosa, achievement of cefepime exposures of >60% f T > MIC will minimize the possibility of a poor microbiological response.

scholarly journals Model Based Identification of Linezolid Exposure–toxicity Thresholds in Hospitalized Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Jie Fang ◽  
Xiao-Shan Zhang ◽  
Chun-Hong Zhang ◽  
Zi-Ye Zhou ◽  
Lu Han ◽  
...  
Keyword(s):  
Steady State ◽  
Serum Albumin ◽  
White Cell Count ◽  
Plasma Concentrations ◽  
Regression Tree ◽  
Predictive Performance ◽  
Volume Of Distribution ◽  
Classification And Regression Tree ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic

Evidence supports linezolid therapeutic drug monitoring as the exposure–response relationship has been identified for toxicity among patients receiving linezolid, but the data to establish the upper limit are limited and the published toxicity thresholds range widely. The purpose of this study was to determine the linezolid exposure–toxicity thresholds to improve the safety of linezolid. This is a multicenter retrospective study of adult patients treated with linezolid from 2018 to 2019. The population pharmacokinetic model of linezolid was established based on 270 plasma concentrations in 152 patients, which showed creatinine clearance and white cell count are covariates affecting the clearance of linezolid, and serum albumin is the covariate affecting the volume of distribution. Classification and regression tree analysis was used to determine the linezolid exposure thresholds associated with an increased probability of toxicity. Among 141 patients included for toxicity analysis, the rate of occurring toxicity was significantly higher among patients with an AUC0-24, d1 ≥163 mg h/L, AUC0-24, d2 ≥207 mg h/L, AUC0-24, ss ≥210 mg h/L, and Cmin,d2 ≥6.9 mg/L, Cmin,ss ≥6.9 mg/L, while no threshold was discovered for Cmin, d1. Those exposure thresholds and duration of linezolid treatment were independently associated with linezolid-related toxicity in the logistic regression analyses. In addition, the predictive performance of the AUC0-24 and Cmin thresholds at day 2 and steady state were close. Considering that the AUC estimation is cumbersome, Cmin threshold at 48 h and steady state with a value of ≥6.9 mg/L is recommended to improve safety, especially for patients with renal insufficiency and patients with low serum albumin.

scholarly journals Targeting leukocidin-mediated immune evasion protects mice from Staphylococcus aureus bacteremia

2020 ◽  
Vol 217 (9) ◽  
Author(s):  
Kayan Tam ◽  
Keenan A. Lacey ◽  
Joseph C. Devlin ◽  
Maryaline Coffre ◽  
Alexis Sommerfield ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Evasion ◽  
Murine Model ◽  
Neutralizing Antibodies ◽  
Bloodstream Infections ◽  
Recurrent Infections ◽  
Host Protection ◽  
Host Pathogen Interaction ◽  
Staphylococcus Aureus Bacteremia

Staphylococcus aureus is responsible for various diseases in humans, and recurrent infections are commonly observed. S. aureus produces an array of bicomponent pore-forming toxins that target and kill leukocytes, known collectively as the leukocidins. The contribution of these leukocidins to impair the development of anti–S. aureus adaptive immunity and facilitate reinfection is unclear. Using a murine model of recurrent bacteremia, we demonstrate that infection with a leukocidin mutant results in increased levels of anti–S. aureus antibodies compared with mice infected with the WT parental strain, indicating that leukocidins negatively impact the generation of anti–S. aureus antibodies in vivo. We hypothesized that neutralizing leukocidin-mediated immune subversion by vaccination may shift this host-pathogen interaction in favor of the host. Leukocidin-immunized mice produce potent leukocidin-neutralizing antibodies and robust Th1 and Th17 responses, which collectively protect against bloodstream infections. Altogether, these results demonstrate that blocking leukocidin-mediated immune evasion can promote host protection against S. aureus bloodstream infection.

scholarly journals Repurposed drugs block toxin-driven platelet clearance by the hepatic Ashwell-Morell receptor to clear Staphylococcus aureus bacteremia

2021 ◽  
Vol 13 (586) ◽  
pp. eabd6737
Author(s):  
Josh Sun ◽  
Satoshi Uchiyama ◽  
Joshua Olson ◽  
Yosuke Morodomi ◽  
Ingrid Cornax ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Critical Role ◽  
Bloodstream Infections ◽  
Therapeutic Benefit ◽  
High Morbidity ◽  
Staphylococcus Aureus Bacteremia ◽  
Sialidase Inhibitor ◽  
Repurposed Drugs ◽  
Genetic Deletion ◽  
Improve Patient

Staphylococcus aureus (SA) bloodstream infections cause high morbidity and mortality (20 to 30%) despite modern supportive care. In a human bacteremia cohort, we found that development of thrombocytopenia was correlated to increased mortality and increased α-toxin expression by the pathogen. Platelet-derived antibacterial peptides are important in bloodstream defense against SA, but α-toxin decreased platelet viability, induced platelet sialidase to cause desialylation of platelet glycoproteins, and accelerated platelet clearance by the hepatic Ashwell-Morell receptor (AMR). Ticagrelor (Brilinta), a commonly prescribed P2Y12 receptor inhibitor used after myocardial infarction, blocked α-toxin–mediated platelet injury and resulting thrombocytopenia, thereby providing protection from lethal SA infection in a murine intravenous challenge model. Genetic deletion or pharmacological inhibition of AMR stabilized platelet counts and enhanced resistance to SA infection, and the anti-influenza sialidase inhibitor oseltamivir (Tamiflu) provided similar therapeutic benefit. Thus, a “toxin-platelet-AMR” regulatory pathway plays a critical role in the pathogenesis of SA bloodstream infection, and its elucidation provides proof of concept for repurposing two commonly prescribed drugs as adjunctive therapies to improve patient outcomes.

scholarly journals Risk factors for methicillin-resistant Staphylococcus aureus bacteremia: A multicenter matched case-control study

Biomédica ◽  
2016 ◽  
Vol 36 (4) ◽  
pp. 612 ◽  
Author(s):  
Paola Mariana Arias-Ortiz ◽  
Libia Del Pilar Calderón ◽  
Juan Sebastián Castillo ◽  
José Moreno ◽  
Aura Lucía Leal ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Odds Ratio ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Case Control Study ◽  
Case Control ◽  
Staphylococcus Aureus Bacteremia ◽  
Factores De Riesgo ◽  
Matched Case ◽  
Matched Case Control Study ◽  
Control Study

Introducción. Staphylococcus aureus resistente a la meticilina es uno de los agentes patógenos más frecuentes en las unidades de cuidados intensivos. Su presencia prolonga las hospitalizaciones y aumenta el riesgo de mortalidad en los pacientes con bacteriemia. Sin embargo, la etiología de este marcador de resistencia no ha sido completamente estudiada.Objetivo. Determinar los factores asociados con la aparición de S. aureus resistente a la meticilina causante de bacteriemia en pacientes atendidos en unidades de cuidados intensivos en Bogotá.Materiales y métodos. Se hizo un estudio retrospectivo de casos y controles emparejados, anidado en una cohorte de pacientes con diagnóstico de bacteriemia por S. aureus atendidos en unidades de cuidados intensivos de Bogotá entre 2006 y 2008. Los casos fueron pacientes con hemocultivo positivo para resistencia a la meticilina, emparejados 1 a 1 con controles con hemocultivos sensibles a la meticilina de la misma institución y año de hospitalización. Se analizaron mediante regresión logística condicional los factores de riesgo asociados con la presencia de resistencia, con énfasis en el tratamiento previo con antibióticos.Resultados. Se incluyeron 372 pacientes con bacteriemia por S. aureus. Factores como el uso de dispositivos previos a la hospitalización: vasculares (Odds ratio, OR=1,986; IC95% 1,038-3,801) y urinarios (OR=2,559; IC95% 1,170-5,596), así como el número de antibióticos administrado previamente, se asociaron con la aparición de resistencia. Se registró un efecto de gradiente con el número de antibióticos usados previamente, especialmente carbapenémicos.Conclusiones. El uso racional de antibióticos y la vigilancia de la exposición a procedimientos quirúrgicos o al uso de dispositivos invasivos, son intervenciones que podrían disminuir la aparición de S. aureus resistente a meticilina causante de bacteriemia.

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