Therapeutic Drug Monitoring of Beta-Lactam Antibiotics in Burns Patients—A One-Year Prospective Study

Patel, Bhavik; Paratz, Jennifer; See, Natalie C.; Müller, Michael; Rudd, Michael; Paterson, David L.; Briscoe, Scott; Ungerer, Jacobus P.J.; McWhinney, Brett; Lipman, Jeffrey; Roberts, Jason A.

doi:10.1097/ftd.0b013e31824981a6

Cited by 68 publications

(71 citation statements)

References 13 publications

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“…Although this was a point-prevalence study without interventional optimal beta-lactam dosing, its conclusions can undoubtedly be extended to support the need for monitoring antibiotic levels even when individual PK/PD considerations are employed. Patel and colleagues found in a prospective study including 50 burn patients that the trough concentrations of beta-lactams were less than the target MIC in 60% of the patients, thus suggesting the need for dose adjustment (135). Another prospective study by Aubert and colleagues reported that serum ceftazidime concentrations among 92 ICU patients were lower than target MICs in 37% of patients and excessive in 27% of them (136).…”

Section: Therapeutic Drug Monitoringmentioning

confidence: 99%

Continuous and Prolonged Intravenous β-Lactam Dosing: Implications for the Clinical Laboratory

2016

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SUMMARYBeta-lactam antibiotics serve as a cornerstone in the management of bacterial infections because of their wide spectrum of activity and low toxicity. Since resistance rates among bacteria are continuously on the rise and the pipeline for new antibiotics does not meet this trend, an optimization of current beta-lactam treatment is needed. This review provides an overview of optimization through use of prolonged- and continuous-infusion dosing strategies compared with more traditional intermittent infusions. Included is an overview of the scientific basis for using these nontraditional prolonged- and continuous-infusion-based regimens, with a focus on major areas in which the clinical laboratory can support the clinical use of these regimens.

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Section: Therapeutic Drug Monitoringmentioning

confidence: 99%

Continuous and Prolonged Intravenous β-Lactam Dosing: Implications for the Clinical Laboratory

2016

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“…Following imipenem treatment, nausea and vomiting were observed in one patient (out of 45 patients in the study); these symptoms were considered to be probably due to rapid infusion, as they disappeared after the duration of infusion was increased (46). Several studies demonstrated that therapeutic drug monitoring (TDM) may be a valuable strategy to optimize antibiotic exposure and minimize toxicity in critically ill patients (42,47,48). This approach may help to attain effective imipenem concentrations using 2 or 4 g imipenem per day.…”

Section: Yadav Et Al Antimicrobial Agents and Chemotherapymentioning

confidence: 99%

Optimization of Synergistic Combination Regimens against Carbapenem- and Aminoglycoside-Resistant Clinical Pseudomonas aeruginosa Isolates via Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling

Yadav

Bulitta

Nation

et al. 2017

Antimicrob Agents Chemother

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Optimizing antibiotic combinations is promising to combat multidrugresistant Pseudomonas aeruginosa. This study aimed to systematically evaluate synergistic bacterial killing and prevention of resistance by carbapenem and aminoglycoside combinations and to rationally optimize combination dosage regimens via a mechanism-based mathematical model (MBM). We studied monotherapies and combinations of imipenem with tobramycin or amikacin against three difficult-to-treat double-resistant clinical P. aeruginosa isolates. Viable-count profiles of total and resistant populations were quantified in 48-h static-concentration time-kill studies (inoculum, 10 7.5 CFU/ml). We rationally optimized combination dosage regimens via MBM and Monte Carlo simulations against isolate FADDI-PA088 (MIC of imipenem [MIC imipenem ] of 16 mg/liter and MIC tobramycin of 32 mg/liter, i.e., both 98th percentiles according to the EUCAST database). Against this isolate, imipenem (1.5ϫ MIC) combined with 1 to 2 mg/liter tobramycin (MIC, 32 mg/liter) or amikacin (MIC, 4 mg/liter) yielded Ն2-log 10 more killing than the most active monotherapy at 48 h and prevented resistance. For all three strains, synergistic killing without resistance was achieved by Ն0.88ϫ MIC imipenem in combination with a median of 0.75ϫ MIC tobramycin (range, 0.032ϫ to 2.0ϫ MIC tobramycin ) or 0.50ϫ MIC amikacin (range, 0.25ϫ to 0.50ϫ MIC amikacin ). The MBM indicated that aminoglycosides significantly enhanced the imipenem target site concentration up to 3-fold; achieving 50% of this synergistic effect required aminoglycoside concentrations of 1.34 mg/liter (if the aminoglycoside MIC was 4 mg/liter) and 4.88 mg/liter (for MICs of 8 to 32 mg/liter). An optimized combination regimen (continuous infusion of imipenem at 5 g/day plus a 0.5-h infusion with 7 mg/kg of body weight tobramycin) was predicted to achieve Ͼ2.0-log 10 killing and prevent regrowth at 48 h in 90.3% of patients (median bacterial killing, Ͼ4.0 log 10 CFU/ml) against double-resistant isolate FADDI-PA088 and therefore was highly promising.

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“…For the commonly used family of antibiotics, the betalactams, these PK changes, including those relating to altered protein binding, have been shown in numerous studies to result in high proportions of critically ill patients manifesting subtherapeutic or toxic concentrations when standard dosing approaches are used (7)(8)(9)(10)(11)(12). Given the association between therapeutic antibiotic exposure and improved patient outcomes (13,14), the use of therapeutic drug monitoring (TDM) to optimize beta-lactam exposures has been proposed as potentially useful for dose optimization in critically ill patients (8,(15)(16)(17)(18).…”

mentioning

confidence: 99%

Protein Binding of β-Lactam Antibiotics in Critically Ill Patients: Can We Successfully Predict Unbound Concentrations?

Wong

Briscoe

Adnan

et al. 2013

Antimicrob Agents Chemother

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199

144

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cThe use of therapeutic drug monitoring (TDM) to optimize beta-lactam dosing in critically ill patients is growing in popularity, although there are limited data describing the potential impact of altered protein binding on achievement of target concentrations. The aim of this study was to compare the measured unbound concentration to the unbound concentration predicted from published protein binding values for seven beta-lactams using data from blood samples obtained from critically ill patients. From 161 eligible patients, we obtained 228 and 220 plasma samples at the midpoint of the dosing interval and trough, respectively, for ceftriaxone, cefazolin, meropenem, piperacillin, ampicillin, benzylpenicillin, and flucloxacillin. The total and unbound beta-lactam concentrations were measured using validated methods. Variabilities in both unbound and total concentrations were marked for all antibiotics, with significant differences being present between measured and predicted unbound concentrations for ceftriaxone and for flucloxacillin at the mid-dosing interval (P < 0.05). The predictive performance for calculating unbound concentrations using published protein binding values was poor, with bias for overprediction of unbound concentrations for ceftriaxone (83.3%), flucloxacillin (56.8%), and benzylpenicillin (25%) and underprediction for meropenem (12.1%). Linear correlations between the measured total and unbound concentrations were observed for all beta-lactams (R 2 ‫؍‬ 0.81 to 1.00; P < 0.05) except ceftriaxone and flucloxacillin. The percent protein binding of flucloxacillin and the plasma albumin concentration were also found to be linearly correlated (R 2 ‫؍‬ 0.776; P < 0.01). In conclusion, significant differences between measured and predicted unbound drug concentrations were found only for the highly protein-bound beta-lactams ceftriaxone and flucloxacillin. However, direct measurement of unbound drug in research and clinical practice is suggested for selected beta-lactams.

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Therapeutic Drug Monitoring of Beta-Lactam Antibiotics in Burns Patients—A One-Year Prospective Study

Abstract: We found TDM to be a reliable intervention for burn injury patients in a ward environment. This study supports pharmacokinetic data that burns patients may be at risk of subtherapeutic dosing, which may prolong the duration of antibiotic therapy.

Cited by 68 publications

References 13 publications

Continuous and Prolonged Intravenous β-Lactam Dosing: Implications for the Clinical Laboratory

Continuous and Prolonged Intravenous β-Lactam Dosing: Implications for the Clinical Laboratory

Optimization of Synergistic Combination Regimens against Carbapenem- and Aminoglycoside-Resistant Clinical Pseudomonas aeruginosa Isolates via Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling

Protein Binding of β-Lactam Antibiotics in Critically Ill Patients: Can We Successfully Predict Unbound Concentrations?

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