Optimising antibiotic dosing regimens based on pharmacodynamic target attainment against Pseudomonas aeruginosa collected in Hungarian hospitals

2006 ◽  
Vol 28 (5) ◽  
pp. 433-438 ◽  
Author(s):  
Endre Ludwig ◽  
Marianne Konkoly-Thege ◽  
Joseph L. Kuti ◽  
David P. Nicolau
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Target Attainment ◽  
Dosing Regimens ◽  
Antibiotic Dosing

scholarly journals Evaluating Ciprofloxacin Dosing for Pseudomonas aeruginosa Infection by Using Clinical Outcome-Based Monte Carlo Simulations

2005 ◽  
Vol 49 (10) ◽  
pp. 4009-4014 ◽  
Author(s):  
Sheryl Zelenitsky ◽  
Robert Ariano ◽  
Godfrey Harding ◽  
Alan Forrest
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Monte Carlo ◽  
Clinical Outcome ◽  
Monte Carlo Simulations ◽  
Standard Dose ◽  
High Dose ◽  
Target Attainment ◽  
Real Patient ◽  
Dosing Regimens ◽  
Cure Rates

ABSTRACT Pseudomonas aeruginosa causes serious infections whose outcome is highly dependent on antimicrobial therapy. The goal of this study was to predict the relative efficacies of three ciprofloxacin dosing regimens for P. aeruginosa infection using clinical outcome-based Monte Carlo simulations (MCS) with “real patient” demographics, pharmacokinetics, MICs, and pharmacodynamics (PDs). Each cohort consisted of 1,000 simulated study subjects. Three ciprofloxacin dosing regimens were studied, including (i) the recommended standard dose of 400 mg given intravenously (i.v.) every 12 h (q12h), (ii) the recommended high dose of 400 mg i.v. q8h, and (iii) a novel, PD-targeted regimen to attain a ƒAUC/MIC value of >86. Probability of target attainment (PTA) and probability of cure (POC) were determined for each regimen. POC with the standard dose was at least 0.90 if pathogen MICs were ≤0.25 μg/ml but only 0.59 or 0.27 if MICs were 0.5 or 1 μg/ml, respectively. Predicted cure rates in these MIC categories were significantly higher at 0.72 and 0.40 with the high dose and 0.91 and 0.72 with the PD-targeted regimen(P < 0.0001). Analyses based on the local susceptibility profile produced PTA and POC estimates of 0.44 and 0.74 with the standard ciprofloxacin dose, 0.58 and 0.81 with the high dose, and 0.84 and 0.93 with the PD-targeted regimen, respectively. In conclusion, as demonstrated by clinical outcome-based MCSs, the highest recommended ciprofloxacin dose of 400 mg i.v. q8h should be used in the treatment of P. aeruginosa infection to improve PD target attainment and clinical cure. However, even this appears ineffective if pathogen MICs are 1 μg/ml, warranting the consideration of a lower MIC breakpoint, ≤0.5 μg/ml.

scholarly journals Population Pharmacokinetics of Piperacillin in Sepsis Patients: Should Alternative Dosing Strategies Be Considered?

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Maria Goul Andersen ◽  
Anders Thorsted ◽  
Merete Storgaard ◽  
Anders N. Kristoffersson ◽  
Lena E. Friberg ◽  
...  
Keyword(s):  
Free Drug ◽  
Free Drug Concentration ◽  
Total Clearance ◽  
Prolonged Infusion ◽  
Target Attainment ◽  
Content Type ◽  
Optimal Dosing ◽  
Dosing Regimens ◽  
Dosing Strategies ◽  
Antibiotic Dosing

ABSTRACTSufficient antibiotic dosing in septic patients is essential for reducing mortality. Piperacillin-tazobactam is often used for empirical treatment, but due to the pharmacokinetic (PK) variability seen in septic patients, optimal dosing may be a challenge. We determined the PK profile for piperacillin given at 4 g every 8 h in 22 septic patients admitted to a medical ward. Piperacillin concentrations were compared to the clinical breakpoint MIC forPseudomonas aeruginosa(16 mg/liter), and the following PK/pharmacodynamic (PD) targets were evaluated: the percentage of the dosing interval that the free drug concentration is maintained above the MIC (fTMIC) of 50% and 100%. A two-compartment population PK model described the data well, with clearance being divided into renal and nonrenal components. The renal component was proportional to the estimated creatinine clearance (eCLCR) and constituted 74% of the total clearance in a typical individual (eCLCR, 83.9 ml/min). Patients with a high eCLCR(>130 ml/min) were at risk of subtherapeutic concentrations for the current regimen, with a 90% probability of target attainment being reached at MICs of 2.0 (50%fTMIC) and 0.125 mg/liter (100%fTMIC). Simulations of alternative dosing regimens and modes of administration showed that dose increment and prolonged infusion increased the chance of achieving predefined PK/PD targets. Alternative dosing strategies may therefore be needed to optimize piperacillin exposure in septic patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02569086.)

scholarly journals Pharmacodynamic Profiling of Antimicrobials against Gram-negative Respiratory Isolates from Canadian Hospitals

2011 ◽  
Vol 22 (4) ◽  
pp. 132-136 ◽  
Author(s):  
Rebecca A. Keel ◽  
George G. Zhanel ◽  
Sheryl Zelenitsky ◽  
David P. Nicolau
Keyword(s):  
Escherichia Coli ◽  
Pseudomonas Aeruginosa ◽  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Enterobacter Cloacae ◽  
The Other ◽  
Prolonged Infusion ◽  
Target Attainment ◽  
Dosing Regimens ◽  
Dose Dependent

The objective of this study was to assess the profile of a variety of dosing regimens for common intravenous antibiotics against contemporaryEnterobacter cloacae,Escherichia coli,Klebsiella pneumoniaeandPseudomonas aeruginosaisolates collected in Canada during 2009, using pharmacodynamic modelling techniques. Monte Carlo simulation was conducted for standard and/or prolonged infusion regimens of cefepime, ceftazidime, ceftriaxone, ciprofloxacin, doripenem, ertapenem, meropenem and piperacillin/tazobactam. The cumulative fraction of response (CFR) was calculated using bactericidal targets for each regimen against each species. All cefepime, doripenem, ertapenem and meropenem regimens achieved optimal exposures against Enterobacteriaceae, whereas target attainment was organism and dose dependent for the other agents. These results support that the currently recommended antimicrobial dosing regimens generally attain acceptable exposures to achieve the requisite pharmacodynamic targets against the Enterobacteriaceae species; however, they fall short of obtaining optimal bactericidal exposures againstP aeruginosa.BACKGROUND: With diminishing antimicrobial potency, the choice of effective empirical therapy has become more challenging. Thus, the pharmacodynamic evaluation of potential therapies is essential to identify optimal agents, doses and administration strategies.METHODS: Monte Carlo simulation was conducted for standard and/or prolonged infusion regimens of cefepime, ceftazidime, ceftriaxone, ciprofloxacin, doripenem, ertapenem, meropenem and piperacillin/tazobactam. Minimum inhibitory concentrations were obtained forEscherichia coli(n=64 respiratory isolates),Enterobacter cloacae(n=53),Klebsiella pneumoniae(n=75) andPseudomonas aeruginosa(n=273) throughout Canada. The cumulative fraction of response (CFR) was calculated using bactericidal targets for each regimen against each species. A CFR ≥90% was defined as optimal.RESULTS: All cefepime, doripenem, ertapenem and meropenem regimens achieved optimal exposures against Enterobacteriaceae, whereas target attainment was organism and dose dependent for the other agents. Prolonged infusion doripenem and meropenem 1 g and 2 g every 8 h, along with standard infusion doripenem and meropenem 2 g every 8 h, were the only regimens to attain optimal exposures againstP aeruginosa. Ciprofloxacin had the lowest CFR againstP aeruginosa,followed by cefepime. Among theP aeruginosaisolates collected in the intensive care unit (ICU) compared with the wards, differences of 0.5% to 10% were noted in favour of non-ICU isolates for all agents; however, marked differences (10% to 15%) in CFR were observed for ciprofloxacin in favour of ICU isolates.CONCLUSION: Standard dosing of cefepime, doripenem, ertapenem and meropenem has a high likelihood of obtaining optimal pharmacodynamic indexes against these Enterobacteriaceae. ForP aeruginosa, aggressive treatment with high-dose and/or prolonged infusion regimens are likely required to address the elevated resistance rates of respiratory isolates from Canada.

scholarly journals Variation in target attainment of β‐lactam antibiotic dosing between international pediatric formularies

2021 ◽  
Author(s):  
Silke Gastine ◽  
Yingfen Hsia ◽  
Michelle Clements ◽  
Charlotte IS Barker ◽  
Julia Bielicki ◽  
...  
Keyword(s):  
Target Attainment ◽  
International Pediatric ◽  
Lactam Antibiotic ◽  
Antibiotic Dosing

scholarly journals Population Pharmacokinetics and Probability of Target Attainment of Different Dosing Regimens of Ceftazidime in Critically Ill Patients with a Proven or Suspected Pseudomonas aeruginosa Infection

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 612
Author(s):  
Annabel Werumeus Buning ◽  
Caspar J. Hodiamont ◽  
Natalia M. Lechner ◽  
Margriet Schokkin ◽  
Paul W. G. Elbers ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Hematologic Malignancy ◽  
Compartment Model ◽  
Target Attainment ◽  
Worst Case ◽  
Optimal Dosing ◽  
Population Pk ◽  
Pseudomonas Aeruginosa Infection

Altered pharmacokinetics (PK) of hydrophilic antibiotics in critically ill patients is common, with possible consequences for efficacy and resistance. We aimed to describe ceftazidime population PK in critically ill patients with a proven or suspected Pseudomonas aeruginosa infection and to establish optimal dosing. Blood samples were collected for ceftazidime concentration measurement. A population PK model was constructed, and probability of target attainment (PTA) was assessed for targets 100% T > MIC and 100% T > 4 × MIC in the first 24 h. Ninety-six patients yielded 368 ceftazidime concentrations. In a one-compartment model, variability in ceftazidime clearance (CL) showed association with CVVH. For patients not receiving CVVH, variability in ceftazidime CL was 103.4% and showed positive associations with creatinine clearance and with the comorbidities hematologic malignancy, trauma or head injury, explaining 65.2% of variability. For patients treated for at least 24 h and assuming a worst-case MIC of 8 mg/L, PTA was 77% for 100% T > MIC and 14% for 100% T > 4 × MIC. Patients receiving loading doses before continuous infusion demonstrated higher PTA than patients who did not (100% T > MIC: 95% (n = 65) vs. 13% (n = 15); p < 0.001 and 100% T > 4 × MIC: 20% vs. 0%; p = 0.058). The considerable IIV in ceftazidime PK in ICU patients could largely be explained by renal function, CVVH use and several comorbidities. Critically ill patients are at risk for underexposure to ceftazidime when empirically aiming for the breakpoint MIC for P. aeruginosa. A loading dose is recommended.

scholarly journals 2562. Re-Appraisal of Aminoglycoside (AG) Susceptibility Testing Breakpoints Based on the Application of Pharmacokinetics–Pharmacodynamics (PK-PD) and Contemporary Microbiology Surveillance Data

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S71-S71 ◽  
Author(s):  
Sujata M Bhavnani ◽  
Nikolas J Onufrak ◽  
Jeffrey P Hammel ◽  
David R Andes ◽  
John S Bradley ◽  
...  
Keyword(s):  
Susceptibility Testing ◽  
Surveillance Data ◽  
Simulated Patients ◽  
High Dose ◽  
Target Attainment ◽  
In Vitro Susceptibility ◽  
Population Pk ◽  
Dosing Regimens

Abstract Background Resistance to AGs and numerous other classes continues to emerge. To ensure that susceptibility is accurately characterized and that clinicians have reliable data to select effective agents, appropriate in vitro susceptibility testing interpretive criteria (susceptible breakpoints [BKPTs]) are crucial to ensure optimal patient care. Recently, USCAST, the USA voice to EUCAST/EMA, evaluated the BKPTs for the 3 most commonly used AGs, gentamicin, tobramycin, and amikacin [Bhavnani et al., IDWeek 2016; P-1977]. As a result of consultation from interested parties, which included evaluating AG dosing regimens provided in the US-FDA product package inserts and simulated patients with varying creatinine clearance, these BKPTS were reassessed. Methods Data sources considered included longitudinal US reference MIC distributions using in vitro surveillance data collected over 18 years, QC performance (MIC, disk diffusion), population pharmacokinetics (PK), and in vivo PK-PD models. Using population PK models, PK-PD targets for efficacy and Monte Carlo simulation, percent probabilities of PK-PD target attainment by MIC after administration of traditional and extended interval AG dosing regimens were evaluated among simulated patients. Epidemiological cut-off and PK-PD BKPTs were considered when recommending BKPTs for AG–pathogen pairs. Results An example of PK-PD target attainment analysis output is provided in Figure 1 and a subset of recommended AG BKPTs for 3 pathogens is shown in Table 1. Updated USCAST BKPTs, which were based on the application of population PK and PK-PD models, simulation techniques, and contemporary MIC distribution statistics, are generally lower than those of EUCAST/EMA, USA-FDA, and CLSI. Adequate PK-PD target attainment was not achieved for some AG-pathogen pairs, even when high-dose AG dosing regimens and PK-PD targets for stasis were evaluated (e.g., gentamicin vs. P. aeruginosa; amikacin vs. S. aureus). Conclusion These revised AG BKPT recommendations, which will be made freely available to EUCAST, USA-FDA, and CLSI, will be finalized after considering comments from additional interested stakeholders. This process will be followed in an effort to bring harmonization to global BKPTs for AGs. Disclosures All authors: No reported disclosures.

scholarly journals Adaptive resistance of Pseudomonas aeruginosa induced by aminoglycosides and killing kinetics in a rabbit endocarditis model.

1997 ◽  
Vol 41 (4) ◽  
pp. 823-826 ◽  
Author(s):  
Y Q Xiong ◽  
J Caillon ◽  
M F Kergueris ◽  
H Drugeon ◽  
D Baron ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Single Dose ◽  
Ex Vivo ◽  
Day Treatment ◽  
Total Daily Dose ◽  
Once Daily ◽  
Adaptive Resistance ◽  
Dosing Regimens

Adaptive resistance following the first exposure to aminoglycosides is a recently described in vitro phenomenon in Pseudomonas aeruginosa and other aerobic gram-negative bacilli. We investigated the in vivo relevance of adaptive resistance in P. aeruginosa following a single dose of amikacin in the experimental rabbit endocarditis model. Rabbits with P. aeruginosa endocarditis received either no therapy (control) or a single intravenous (i.v.) dose of amikacin (80 mg/kg of body weight) at 24 h postinfection, after which they were sacrificed at 5, 8, 12, 16, or 24 h postdose. Excised aortic vegetations were subsequently exposed ex vivo to amikacin at 2.5, 5, 10 or 20 times the MIC for 90 min. In vivo adaptive resistance was identified when amikacin-induced pseudomonal killing within excised aortic vegetations was less in animals receiving single-dose amikacin in vivo than in vegetations from control animals not receiving amikacin in vivo. Maximal adaptive resistance occurred between 8 and 16 h after the in vivo amikacin dose, with complete refractoriness to ex vivo killing by amikacin seen at 12 h postdose. By 24 h postdose, bacteria within excised vegetations had partially recovered their initial amikacin susceptibility. In a parallel treatment study, we demonstrated that amikacin given once daily (but not twice daily) at a total dose of 80 mg/kg i.v. for 1-day treatment significantly reduced pseudomonal densities within aortic vegetations versus those in untreated controls. When therapy was continued for 3 days with the same total daily dose (80 mg/kg/day), amikacin given once or twice daily significantly reduced intravegetation pseudomonal densities versus those in controls. However, amikacin given once daily was still more effective than the twice-daily regimen. These data confirm the induction of aminoglycoside adaptive resistance in vivo and further support the advantages of once-daily aminoglycoside dosing regimens in the treatment of serious pseudomonal infections.

scholarly journals Optimizing Pharmacodynamic Target Attainment Using the MYSTIC Antibiogram: Data Collected in North America in 2002

2004 ◽  
Vol 48 (7) ◽  
pp. 2464-2470 ◽  
Author(s):  
Joseph L. Kuti ◽  
Charles H. Nightingale ◽  
David P. Nicolau
Keyword(s):  
Escherichia Coli ◽  
North America ◽  
Bacterial Species ◽  
Empirical Therapy ◽  
Target Attainment ◽  
The World ◽  
Dosing Regimens ◽  
Higher Doses ◽  
Initial Empirical Therapy ◽  
Different Parts

ABSTRACT The OPTAMA Program is intended to examine typical antimicrobial regimens used in the treatment of common nosocomial pathogens and the likelihood of these regimens attaining appropriate pharmacodynamic exposure in different parts of the world. A 5,000-subject Monte Carlo simulation was used to estimate pharmacodynamic target attainment for meropenem, imipenem, ceftazidime, cefepime, piperacillin-tazobactam, and ciprofloxacin against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Standard dosing regimens from North America were used. Pharmacokinetic parameter variability was derived from existing healthy volunteer data, and MIC data came from the 2002 MYSTIC Program. Ciprofloxacin displayed the lowest target attainment against all bacterial species (41 to 46% for A. baumannii, 53 to 59% for P. aeruginosa, and 80 to 85% for the Enterobacteriaceae). Increasing the dose to 400 mg every 8 h did not significantly increase target attainment against nonfermenters. Piperacillin-tazobactam target attainments were similar to that of ceftazidime against all pathogens. Higher doses of both compounds were needed to achieve better target attainments against P. aeruginosa. Overall, meropenem, imipenem, and cefepime attained the highest probabilities of attainment against the Enterobacteriaceae (99 to 100%). The carbapenems appear to be the most useful agents against A. baumannii (88 to 92%), and these agents, along with higher doses of any of the β-lactams, would be the most appropriate choices for empirical therapy for P. aeruginosa infection. Given the lack of agreement between percent susceptibility and probability of target attainment for certain antimicrobial regimens, a methodology employing stochastic pharmacodynamic analyses may be a more useful tool for differentiating the most-optimal compounds and dosing regimens in the clinical setting of initial empirical therapy.

Limited Postpartum Versus 24-Hour Antibiotic Dosing Regimens Following Intrapartum Chorioamnionitis [11A]

2020 ◽  
Vol 135 ◽  
pp. 11S
Author(s):  
Keren Hood ◽  
Alexander Ulfers ◽  
Michelle Mersch ◽  
German Cuadra ◽  
Robert Stevenson ◽  
...  
Keyword(s):  
Dosing Regimens ◽  
Antibiotic Dosing
Sign in / Sign up

Export Citation Format

Share Document