Protein binding of cefazolin is saturable <i>in vivo</i> both between and within patients

Vella-Brincat, Jane; Begg, Evan J.; Kirkpatrick, Carl M.; Zhang, Mei; Chambers, Stephen T.; Gallagher, Kate

doi:10.1111/j.1365-2125.2006.02827.x

Cited by 62 publications

(35 citation statements)

References 18 publications

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“…A study by Hutschala et al, administering 4 g of cefazolin 60 min prior to skin incision and an additional 2 g during closure of the incision to cardiac surgical patients, used microdialysis to determine muscle and subcutaneous tissue concentrations (14). Those authors concluded that muscle and subcutaneous tissue concentrations remained well above the MIC 90 of 1 g/ml for S. aureus, a potential wound pathogen, for at least 10 h. While free plasma concentrations were not reported, it is likely, based on total plasma concentrations and approximate cefazolin protein binding of 80 to 85%, that free-drug concentrations in plasma were similar to the tissue concentrations observed (16,17). Although the prophylaxis dosing scheme differs substantially from the standard dosing scheme for treatment administered to the patients in the current study, the overall findings of free-drug concentrations in plasma paralleling those in tissue are similar.…”

Section: Discussionmentioning

confidence: 99%

Tissue Pharmacokinetics of Cefazolin in Patients with Lower Limb Infections

Bhalodi

Housman

Shepard

et al. 2013

Antimicrob Agents Chemother

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c Cefazolin, a first-generation cephalosporin with activity against methicillin-susceptible Staphylococcus aureus and streptococci, is often used to treat lower limb infections caused by these pathogens. Antimicrobial penetration is often limited in these patients due to compromised vasculature. Therefore, we sought to evaluate the exposure profile of cefazolin in serum and tissue in patients with lower limb infections. An in vivo microdialysis catheter was inserted into the tissue near the margin of the wound and constantly perfused with lactated Ringer's solution. Steady-state serum and tissue samples were simultaneously collected over a dosing interval. Serum protein binding was also assessed. Serum concentrations were analyzed by noncompartmental analysis. Tissue concentrations were corrected for percent in vivo recovery by using the retrodialysis technique. Seven patients with a mean weight of 95.45 ؎ 18.51 kg and a mean age of 54 ؎ 19 years were enrolled. Six patients received 1 g every 8 h, and one patient received 2 g every 24 h due to acute kidney injury. The free area under the curve from 0 to 8 h (fAUC 0 -8 ) values for serum and wound were 48.0 ؎ 18.66 and 56.35 ؎ 41.17 g · h/ml, respectively, for the patients receiving 1 g every 8 h. The fAUC 0 -24 values for serum and wound were 1,326.1 and 253.9 g · h/ml, respectively, for the single patient receiving 2 g every 24 h. The mean tissue penetration ratio (tissue/serum fAUC ratio) was 1.06. These data suggest that the amount of time that free-drug concentrations remain above the MIC (fT>MIC) for cefazolin in wound tissue is adequate to treat patients with lower limb infections.

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Section: Discussionmentioning

confidence: 99%

Tissue Pharmacokinetics of Cefazolin in Patients with Lower Limb Infections

Bhalodi

Housman

Shepard

et al. 2013

Antimicrob Agents Chemother

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“…Ceftriaxone, cefazolin, cefonicid, and ertapenem are examples of antimicrobials for which nonlinear protein binding has been reported in the literature (4)(5)(6)(7). Binding to protein can occur in both intra-and extravascular spaces and is an important determinant of a drug's pharmacokinetics (PK), as it will impact distribution and elimination processes.…”

Section: Introductionmentioning

confidence: 99%

Importance of Relating Efficacy Measures to Unbound Drug Concentrations for Anti-Infective Agents

2013

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SUMMARY For the optimization of dosing regimens of anti-infective agents, it is imperative to have a good understanding of pharmacokinetics (PK) and pharmacodynamics (PD). Whenever possible, drug efficacy needs to be related to unbound concentrations at the site of action. For anti-infective drugs, the infection site is typically located outside plasma, and a drug must diffuse through capillary membranes to reach its target. Disease- and drug-related factors can contribute to differential tissue distribution. As a result, the assumption that the plasma concentration of drugs represents a suitable surrogate of tissue concentrations may lead to erroneous conclusions. Quantifying drug exposure in tissues represents an opportunity to relate the pharmacologically active concentrations to an observed pharmacodynamic parameter, such as the MIC. Selection of an appropriate specimen to sample and the advantages and limitations of the available sampling techniques require careful consideration. Ultimately, the goal will be to assess the appropriateness of a drug and dosing regimen for a specific pathogen and infection.

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“…After removal of one outlier, cefazolin only achieved a C exudate :C plasma ratio of 0.51, which is at least 40% lower than the ratios achieved by all the other antibiotics tested in this study. Cefazolin as well as other antibiotics may not penetrate wounds in patients undergoing NPWT because of the high protein binding of cefazolin 21 relative to the other antibiotics observed in this study. [22][23][24][25][26] Notably, other pharmacokinetic and pharmacodynamic variables, such as elimination half-life, were in agreement with previously established values (Supplementary Table S1).…”

Section: Discussionmentioning

confidence: 99%

Wound Penetration of Cefazolin, Ciprofloxacin, Piperacillin, Tazobactam, and Vancomycin During Negative Pressure Wound Therapy

Rowan

Niece

Rizzo

et al. 2017

Advances in Wound Care

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Objective: Negative pressure wound therapy (NPWT) uses subatmospheric pressure as a noninvasive adjunct to treat wounds and has demonstrated clinical efficacy by accelerating healing of a variety of acute and chronic wounds. NPWT may also play a role in preventing or treating wound infections, possibly by increasing wound penetration of antibiotics. However, clinical data in patients undergoing antibiotic and NPWT treatment are limited. Approach: To evaluate the wound penetration of antibiotics in NPWT patients, we conducted a prospective, observational study of burn and trauma patients treated with NPWT and systemic antibiotics. We evaluated the plasma pharmacokinetic profile of systemic vancomycin, ciprofloxacin, cefazolin, and piperacillin/tazobactam, as well as total and unbound antibiotic concentrations in wound exudate from the same patients. Results: Data from 32 patients with 37 wounds undergoing NPWT demonstrated that vancomycin, ciprofloxacin, and piperacillin/tazobactam all penetrated wounds with exudate to plasma concentration ratios more than 0.8. Cefazolin did not penetrate wounds in patients undergoing NPWT as effectively, with an average exudate to plasma concentration ratio of 0.51. Innovation: Clinical data on the wound penetration of antibiotics in patients undergoing NPWT are limited, but these data suggest that antibiotics have different capacities for wound penetration during NPWT that should be considered when making clinical decisions. Conclusion: This initial report suggests that (1) vancomycin, ciprofloxacin, and piperacillin/tazobactam effectively penetrate wounds during NPWT and (2) cefazolin as well as other antibiotics may not penetrate wounds during NPWT.Keywords: antibiotic, burn, exudate, pharmacokinetics, trauma, WoundVac INTRODUCTIONVacuum-assisted closure, or negative pressure wound therapy (NPWT), uses subatmospheric pressure as a noninvasive adjuvant therapy to treat wounds. NPWT has shown clinical benefit for a variety of acute and chronic wounds, 1-3 especially complex wounds. 4 In addition to isolating the wound environment and stabilizing osmotic gradients through the evacuation of fluid with accompanying electrolytes and proteins, An additional benefit of NPWT may be an overall decrease in the bacterial burden in the wound bed, but the effect of NPWT on bioburden remains controversial.7 Furthermore, the hypothesized mechanisms responsible for any potential reduction remain unclear. Evidence has shown a reduction in counts of Gram-negative bacilli with NPWT compared with conventional wet-to-dry dressings, 8 but reductions in Gram-positive bacilli, such as Staphylococcus aureus, are not consistently observed 8,9 and highlight the need for studies on the relationship between NPWT and wound infections. NPWT produces changes in localized blood flow, tissue oxygenation and inflammation, and directly removes pathogens through vacuum pressure, 10-12 all of which have been suggested to play a role in the overall reduction in bacterial load during NPWT 4 but may also impact the p...

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Protein binding of cefazolin is saturable in vivo both between and within patients

Cited by 62 publications

References 18 publications

Tissue Pharmacokinetics of Cefazolin in Patients with Lower Limb Infections

Tissue Pharmacokinetics of Cefazolin in Patients with Lower Limb Infections

Importance of Relating Efficacy Measures to Unbound Drug Concentrations for Anti-Infective Agents

Wound Penetration of Cefazolin, Ciprofloxacin, Piperacillin, Tazobactam, and Vancomycin During Negative Pressure Wound Therapy

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