Pharmacokinetics of Cefazolin in Patients With Obesity Undergoing Surgery Requiring Cardiopulmonary Bypass

Poltak, Justin M.; Connors, Christopher W.; Nicolau, David P.; Liu, Jiajun; Mercuro, Nicholas J; Wungwattana, Minkey

doi:10.1053/j.jvca.2022.01.029

Cited by 3 publications

(7 citation statements)

References 15 publications

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“…This is consistent with prior evidence that reported suboptimal ertapenem PTA at MICs ≥0.5 mcg/mL in obese patients 55,56 . Moreover, Chambers, et al found that one dose of ertapenem 1 g achieved PTA in bone of ≤45% when the MIC was ≥0.25 mg/L, suggesting obese patients with bone and joint infections are at greatest risk of suboptimal ertapenem dosing (median BMI 37.8 kg/m 2 ) 32–44,57 . This problem may be more pronounced in gram‐positive or mixed infections given differences in MIC breakpoints (CLSI breakpoint for Enterobacterales ≤0.5 mg/L, Streptococci ≤1 mg/L) 28…”

Section: Review Of Specific Antimicrobial Agentssupporting

confidence: 88%

“…Additionally, the use of a simple weight cutoff for dose increase may be flawed as it does not account for differences in body size and composition 2 . Small, retrospective, and/or single‐center studies of a variety of surgical procedures continue to emerge and demonstrate conflicting results on adequacy of cefazolin adipose tissue or interstitial fluid concentrations in obesity, despite adequate plasma concentrations 1,14,40–44 …”

Section: Review Of Specific Antimicrobial Agentsmentioning

confidence: 99%

“…2 Small, retrospective, and/ or single-center studies of a variety of surgical procedures continue to emerge and demonstrate conflicting results on adequacy of cefazolin adipose tissue or interstitial fluid concentrations in obesity, despite adequate plasma concentrations. 1,14,[40][41][42][43][44] A recent systematic review of cefazolin dosing in obesity (15 pharmacokinetic studies and three clinical studies of caesarian section and elective surgeries) described conflicting results but ultimately concluded that increased preoperative cefazolin doses (3-4 g) are not needed in obese patients (BMI > 30 kg/m 2 ) undergoing surgeries lasting up to 4 h. 45 This conclusion was driven by three case-control studies and PK data derived from three randomized controlled trials (RCTs); eight cohort studies and four case series were evenly split in results. Authors caution readers that their conclusions draw upon PK studies in which there was large heterogeneity in study variables (e.g., MIC targets used, sample size, sampling, and simulation methodology).…”

Section: More Intensive Cefazolin Dosing Regimens Have Been Suggestedmentioning

confidence: 99%

“…55,56 Moreover, Chambers, et al found that one dose of ertapenem 1 g achieved PTA in bone of ≤45% when the MIC was ≥0.25 mg/L, suggesting obese patients with bone and joint infections are at greatest risk of suboptimal ertapenem dosing (median BMI 37.8 kg/m 2 ). [32][33][34][35][36][37][38][39][40][41][42][43][44]57 This problem may be more pronounced in gram-positive or mixed infections given differences in MIC breakpoints (CLSI breakpoint for Enterobacterales ≤0.5 mg/L, Streptococci ≤1 mg/L). 28 Despite these PK findings, retrospective and post hoc studies have demonstrated that ertapenem 1 g every 24 h yields similar clinical outcomes in obese and non-obese patients with moderate to severe diabetic foot infections, cIAI and pneumonia or when used for surgical prophylaxis.…”

Section: Summary Of Previous Recommendationsmentioning

confidence: 99%

See 3 more Smart Citations

Comprehensive guidance for antibiotic dosing in obese adults: 2022 update

Meng

Mui

et al. 2023

Pharmacotherapy

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Drug dosing in obese patients continues to be challenging due to a lack of high-quality evidence to guide dosing recommendations. We first published guidance for antibiotic dosing in obese adults in 2017, in which we critically reviewed articles identified from a broad search strategy to develop dosing recommendations for 35 antimicrobials. In this updated narrative review, we searched Pubmed, Web of Science, and the Cochrane Library using Medical Subject Headings including anti-infectives, specific generic antimicrobial names, obese, pharmacokinetics, and others. We reviewed 393 articles, cross-referenced select cited references, and when applicable, referenced drug databases, package inserts, and clinical trial data to update dosing recommendations for 41 antimicrobials. Most included articles were pharmacokinetic studies, other less frequently included articles were clinical studies (mostly small, retrospective), case reports, and very rarely, guidelines. Pharmacokinetic changes are frequently reported, can be variable, and sometimes conflicting in this population, and do not always translate to a documented difference in clinical outcomes, yet are used to inform dosing strategies. Extended infusions, high doses, and therapeutic drug monitoring remain important strategies to optimize dosing in this population. Additional studies are needed to clinically validate proposed dosing strategies, clarify optimal body size descriptors, dosing weight scalars, and estimation method of renal function in obese patients.

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Section: Review Of Specific Antimicrobial Agentssupporting

confidence: 88%

Section: Review Of Specific Antimicrobial Agentsmentioning

confidence: 99%

Section: More Intensive Cefazolin Dosing Regimens Have Been Suggestedmentioning

confidence: 99%

Section: Summary Of Previous Recommendationsmentioning

confidence: 99%

See 2 more Smart Citations

Comprehensive guidance for antibiotic dosing in obese adults: 2022 update

Meng

Mui

et al. 2023

Pharmacotherapy

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show abstract

“…37 Additionally, several drugs commonly administered in the ECMO population have been studied in cardiopulmonary bypass. [38][39][40][41][42][43][44][45][46][47] However, several key differences between the two modalities exist including patient population, duration of support provided, anticoagulation strategy, and circuit mechanics (open vs. closed system). 48,49 Because of these differences, it is not known whether the findings from PK studies in cardiopulmonary bypass can be extrapolated to ECMO.…”

Section: Discussionmentioning

confidence: 99%

Drug Administration Patterns in Patients on Extracorporeal Membrane Oxygenation

Green,

Norris,

McKnite

et al. 2024

J Pediatr Intensive Care

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This study aimed to identify drug administration patterns in patients of all ages supported with extracorporeal membrane oxygenation (ECMO) across multiple institutions and determine which of the most commonly administered drugs lack published dosing guidance.We conducted a retrospective, multicenter database study using the TriNetX data network and the Pediatric Health Information Systems database. All adults and children supported with ECMO were included for analysis. Drug exposure and days of use were described according to age category (Infants [<2 years], Children [≥2 and <18 years], and Adults [≥18 years]). The literature was reviewed for the top 50 most commonly administered drugs in all ages; all pharmacokinetic and ex vivo studies were included.A total of 17,909 patients were analyzed. The patient population comprised 24% adults (n = 4,253), 18% children (n = 3266), and 58% infants (n = 10,390). The 10 most commonly administered drugs, by days of use, were heparin, furosemide, midazolam, morphine, fentanyl, vancomycin, milrinone, hydrocortisone, epinephrine, and lorazepam. Published literature comprised 86 studies, including 66 pharmacokinetic studies (77%) and 20 ex vivo studies (23%). Of these, 29% (n = 19) were conducted in adults, 14% (n = 9) were conducted in children, and 60% (n = 39) were performed in infants. ECMO-specific dosing guidance for any age was available for only 28% (n = 14) of the top 50 most commonly administered drugs.Sedatives, antimicrobials, and cardiovascular agents are among the most commonly administered drugs in patients supported with ECMO. This study highlights an urgent need for evidence-based dosing guidance in this patient population.

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Morphomics‐informed population pharmacokinetic and physiologically‐based pharmacokinetic modeling to optimize cefazolin surgical prophylaxis

Liu,

Matvekas,

Naimi

et al. 2023

Pharmacotherapy

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IntroductionCefazolin is the leading antibiotic used to prevent surgical site infections worldwide. Consensus guidelines recommend adjustment of the cefazolin dose above and below 120 kg without regard to body composition. Algorithms exist to repurpose radiologic data into body composition (morphomics) and inform dosing decisions in obesity.ObjectivesTo compare the current standard of body weight to morphomic measurements as covariates of cefazolin pharmacokinetics and aid dose stratification of cefazolin in patients with obesity undergoing colorectal surgery.MethodsThis prospective study measured cefazolin plasma, fat, and colon tissue concentrations in colorectal surgery patients in order to develop a morphomics‐informed population pharmacokinetic (PopPK) model to guide dose adjustments. A physiologically‐based pharmacokinetic (PBPK) model was also constructed to inform tissue partitioning in morbidly obese patients (n=21, body mass index ≥ 35 kg/m2 with one or more co‐morbid conditions).ResultsMorphomics and pharmacokinetic data were available in 58 patients with a median [min, max] weight and age of 95.9 [68.5, 148.8] kg and 55 [25, 79] years, respectively. The plasma‐to‐subcutaneous fat partition coefficient was predicted to be 0.072 and 0.060 by the PopPK and PBPK models, respectively. The estimated creatinine clearance (eCLcr) and body depth at the third lumbar vertebra (body depth_L3) were identified as covariates of cefazolin exposure. The probability of maintaining subcutaneous fat concentrations above 2 μg/mL for 100% of a 4‐hour surgical period was below 90% when eCLcr ≥ 105 mL/min and body depth_L3 ≥ 300 mm and less sensitive to the rate of infusion between 5 and 60 minutes.ConclusionsKidney function and morphomics were more informative than body weight as covariates of cefazolin target site exposure. Data from more diverse populations, consensus on target cefazolin exposure, and comparative studies are needed before a change in practice can be implemented.

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Pharmacokinetics of Cefazolin in Patients With Obesity Undergoing Surgery Requiring Cardiopulmonary Bypass

Cited by 3 publications

References 15 publications

Comprehensive guidance for antibiotic dosing in obese adults: 2022 update

Comprehensive guidance for antibiotic dosing in obese adults: 2022 update

Drug Administration Patterns in Patients on Extracorporeal Membrane Oxygenation

Morphomics‐informed population pharmacokinetic and physiologically‐based pharmacokinetic modeling to optimize cefazolin surgical prophylaxis

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