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Efficacious Cefazolin Prophylactic Dose for Morbidly Obese Women Undergoing Bariatric Surgery Based on Evidence from Subcutaneous Microdialysis and Populational Pharmacokinetic Modeling

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Abstract

Purpose

To determine the efficacious cefazolin prophylactic dose for bariatric surgery using free subcutaneous concentrations accessed by microdialysis after 2 g or 3 g i.v. bolus dosing to morbidly obese women and POPPK modeling.

Methods

A POPPK model with variable plasma and subcutaneous tissue protein binding was developed to simultaneously describe plasma and tissue data sets. The outcomes was predicted for common surgical site infection (SSI) bacteria over 3, 4, 5 and 6 h periods postdose, as probability of target attainment (PTA) using Monte Carlo simulation.

Results

CFZ 2 g warrant up to 5 h SSI prophylaxis for bacteria with MICs ≤1 mg/L such as Escherichia coli and Staphylococcus aureus. For species such as Klebsiella pneumoniae, which present MIC distribution frequency of 2 mg/L, the maintenance of PTA ≥ 90% occurs with a 3 g dose for surgeries lasting up to 5 h, and 2 g dose provide an adequate response up to 4 h (PTA of 89%).

Conclusions

Effectiveness of CFZ 2 g is similar to 3 g against bacteria with a MIC up to 2 mg/L, especially if the surgery does not last for more than 4 h.

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Abbreviations

ASHP:

American society of health-system pharmacists

AUCplasma,free :

Area under curve of unbound plasma concentration

AUCplasma,total :

Area under curve of total plasma concentration

AUCsubcutaneous,free :

Area under curve of unbound subcutaneous tissue concentration

AUCsubcutaneous,total :

Area under curve of total subcutaneous tissue concentration

Bmax(p) :

Maximal binding capacity of CFZ to plasma albumin

Bmax(t) :

Maximal binding capacity of CFZ to tissue albumin

BMI:

Body mass index

CFZ:

Cefazolin

CL:

Total body clearance

Cplasma,total :

Total plasma cefazolin concentration

DFtissue :

Tissue distribution factor

dp:

Dilution factor of albumin concentration in interstitial space fluid

fT > MIC:

Unbound tissue CFZ concentration above the minimum inhibitory concentration

FuP:

Unbound plasma fraction

FuT:

Unbound subcutaneous tissue fraction

HNSC:

Nossa Senhora da Conceição Hospital

HPLC:

High-performance liquid chromatography

Kdp :

Dissociation constant for CFZ binding to plasma albumin

Kdt :

Dissociation constant for CFZ binding to tissue albumin

MIC:

Minimum inhibitory concentration

NCA:

Non-compartmental pharmacokinetic analysis

POPPK:

Populational pharmacokinetics

PTA:

Probability of target attainment

Q:

Inter-compartmental clearance

SSI:

Surgical site infection

V1:

Volume of distribution of the central compartment

V2:

Volume of distribution of the subcutaneous tissue compartment

VPC:

Visual predictive check

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Funding

This work was supported by the PPSUS/FAPERGS, Rio Grande do Sul, Brazil [#1298–255/13–8].

Author information

Authors and Affiliations

  1. Pharmacokinetics and PK/PD Modeling Laboratory, Pharmaceutical Sciences Graduate Program, Faculty of Pharmacy, Federal University of Rio Grande do Sul, Av. Ipiranga, 2752, Porto Alegre, RS, 90.610-000, Brazil

    Eduardo Celia Palma, BibianaVerlindo de Araújo & Teresa Dalla Costa

  2. Center for Obese Class III Care, Nossa Senhora Conceição Hospital (HNSC), Porto Alegre, RS, Brazil

    Nelson Guardiola Meinhardt & Airton Tetelbom Stein

  3. Pharmaceutical Sciences Graduate Program, Faculty of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil

    Isabela Heineck & Maria Isabel Fischer

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  1. Eduardo Celia Palma
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  7. Teresa Dalla Costa
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Correspondence to Teresa Dalla Costa.

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Electronic Supplementary Material

Supplementary Figure S1

Individual and population fitted total (upper panel), free plasma (middle panel) and free subcutaneous tissue (lower panel) profiles using nonlinear mixed-effect modeling approach. Patients received a single 2 g (1–4) or 3 g (5–6) intravenous bolus dose of CFZ. Black dots: observations; solid line: individual model predictions; dashed line: population model. (GIF 54 kb)

High Resolution Image (TIFF 253 kb)

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Palma, E.C., Meinhardt, N.G., Stein, A.T. et al. Efficacious Cefazolin Prophylactic Dose for Morbidly Obese Women Undergoing Bariatric Surgery Based on Evidence from Subcutaneous Microdialysis and Populational Pharmacokinetic Modeling. Pharm Res 35, 116 (2018). https://doi.org/10.1007/s11095-018-2394-5

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