Penetration of antibiotics into the surgical wound in a canine model

Abstract

The dose and timing of antimicrobial agents given for surgical wound prophylaxis should be based on the concentration-time profile of the drug in tissue at the site of contamination. However, concentrations of antimicrobial agents in surgical wounds are difficult to determine accurately. Since a surgical wound is a unique extravascular compartment with increased vascular permeability and a high surface area/volume ratio, antibiotic concentrations in sera and surgical wounds should be similar. To test this hypothesis, the pharmacokinetics of single intravenous doses of cefazolin (40 mg/kg) and gentamicin (4 mg/kg) in sera and surgical wounds in a clinically relevant surgical model using dogs were compared. Drug concentrations were determined in interstitial fluid in muscle biopsies taken randomly from wound surfaces and serial wound fluid samples collected after the incisions were closed. Protein binding of cefazolin and gentamicin in sera and wound fluids was low (c29 + 9%) in this canine model. Cefazolin and gentamicin equilibrated rapidly (s30 min) between serum and the surgical wound, and concentrations in the two sites declined in parallel. Values for the area under the concentration-time curve, mean residence time, and terminal half-life in serum and the surgical site for each drug were similar. Cefazolin concentrations in serum underestimated the time during which concentrations in surgical wounds exceeded the susceptibility breakpoint MIC for important pathogens by an average of 58 min (range, 26 to 109 min; P = 0.036); for gentamicin, the underestimation averaged 30 min (range, 10 to 60 min; P = 0.036). These data support the concept that the concentration-time profiles of antimicrobial agents in serum may prove valuable clinically as guides to determining the dose and timing of antibiotic administration necessary for effective antimicrobial prophylaxis in surgery. Further studies are needed to determine the surgical wound pharmacokinetics of highly protein-bound antibiotics.

Enhanced Absorption of Insulin Aspart as the Result of a Dispersed Injection Strategy Tested in a Randomized Trial in Type 1 Diabetic Patients

“…Liquid depots with a higher surface-to-volume ratio can be absorbed faster, because a larger depot surface involves more capillaries and enhances absorption into the vascular system. Enhanced drug absorption with increased surface-to-volume ratio has been demonstrated in a canine model (14), and in humans an increased volume slowed the speed of pharmacokinetics in large versus small skin blisters (15). By using micro-CT, a nondestructive 3D imaging technique, we were able to compare quantitatively the surface-to-volume ratio of subcutaneous insulin depots of a dispersed injection strategy (9 × 2 IU) with that of a single insulin injection (1 × 18 IU).…”

Cefazolin Concentration in Surgically Created Wounds Treated With Negative Pressure Wound Therapy Compared to Surgically Created Wounds Treated With Nonadherent Wound Dressings

“…Although presence of granulation tissue could have altered our findings, we used an acute wound model and biopsies were obtained before visual evidence of granulation tissue; and tissue samples were not submitted for histopathologic evaluation. Although cefazolin is reported to equilibrate well between canine plasma and the surgical wound, we believe this is the first study to investigate the effect of NPWT on tissue antibiotic concentrations when compared to those from conventionally bandaged wounds in dogs. NPWT did not hinder antibiotic concentration in tissue samples from wounds when compared with bandaged wounds, and both treatment groups had comparable cefazolin tissue concentrations at each biopsy time point.…”

“…By homogenizing tissue biopsies, the interstitial fluid, cells, and subcellular organelles were combined, which may have resulted in dilution and underestimation of cefazolin, a compound primarily distributed extracellularly . Although tissue is made of distinct compartments, surgical wounds create a unique extracellular environment in which systemic antibiotics equilibrate rapidly . The effect of NPWT or nonadherent dressings on local tissue cefazolin concentration was our primary objective, so our study does not provide information on cefazolin concentration in specific tissue compartments or local drug effect.…”

“…Systemic antibiotic administration is often used as an adjunctive therapy to local wound treatment and is ideally based on culture and susceptibility testing, local antimicrobial concentration and penetration, expected bacterial flora and bacterial resistance patterns . Cefazolin is a first generation cephalosporin commonly used in surgery because of its rapid distribution between soft tissues, bone, and surgical sites . Cefazolin is typically selected because of its spectrum of activity against a variety of bacterial pathogens commonly encountered .…”

Discovery and development of new antimicrobial agents

“…These tissue distribution studies define some potential advantages of azithromycin over the standard macrolide, erythromycin, and help with the design of clinical trials in humans (65). Among numerous other animal pharmacokinetic studies that have evaluated new antibiotics are studies to measure the penetration of azole antifungal compounds into the eyes of rabbits (139), models to study drug penetration into surgical wounds of dogs (133), and novel sampling methods to measure spinal fluid levels of antibiotics in rats (103).…”