Intravenous Cefazolin Achieves Sustained High Interstitial Concentrations in Open Lower Extremity Fractures

Abstract

Background: Infection remains a serious clinical concern in patients with open fractures, despite timely antibiotic administration and surgical debridement. Soft tissue and periosteal stripping may alter local tissue homeostasis and antibiotic pharmacokinetics in the injured limb. The tissue (interstitial) concentration of intravenously administered antibiotics at an open fracture site has not been characterized using direct sampling techniques.

Question/purpose: We performed this study to evaluate the concentration and pharmacokinetics of intravenously delivered cefazolin at an open fracture site after surgical debridement.

Methods: Twelve patients with an open fracture distal to the knee who presented at a regional Level I trauma center were approached for enrollment in this nonrandomized, observational study. Of the 12 patients, eight adults (one female, seven male) with a median age of 32 years (range 23 to 51 years) were enrolled and underwent successful sample collection for analysis. Three patients had incomplete datasets because of equipment malfunction and one elected not to participate. Seven patients had open tibia fractures, and one patient had an open fibula fracture associated with a closed tibia fracture. There were six Gustilo-Anderson Type II injuries and two Type IIIA injuries. Empiric antibiotics were administered in the prehospital setting or in the emergency department according to institutional protocol. When patients were taken to the operating room, a 2-g intravenous dose of cefazolin was administered. After surgical debridement, fracture stabilization, and wound closure, a microdialysis catheter was placed transdermally into the injury zone (within 5 cm of the fracture site) and a second catheter was placed in the contralateral uninjured (control) limb. Additional doses of cefazolin were administered every 8 hours postoperatively. Baseline and periodic interstitial fluid and whole blood (plasma) samples were collected in the operating room and at prespecified times for 24 hours postoperatively. Free cefazolin in the interstitial fluid and plasma samples were analyzed by ultra-high-performance liquid chromatography using C 18 column separation with quadrupole time-of-flight mass spectrometry detection. Data from the second postoperative dose of cefazolin were used to characterize pharmacokinetic parameters through a noncompartmental analysis using time-concentration curves of free cefazolin and assuming first-order elimination. For pharmacodynamic analyses, the modal cefazolin minimum inhibitory concentration (MIC) of Staphylococcus aureus (1 µg/mL) was used.

Results: With the samples available, no difference was observed in the median free cefazolin exposure over 24 hours ( f area under the curve [AUC] 0→24hrs ) between injured limbs (352 μg∙hr/mL [IQR 284 to 594 μg∙hr/mL]) and uninjured limbs (341 μg∙hr/mL [IQR 263 to 438 μg∙hr/mL]; p = 0.64). The median time to achieve the maximum concentration of free cefazolin ( f T max ) for injured limbs was delayed (2.7 hours [IQR 2.2 to 3.1 hours]) compared with control limbs (1.7 hours [IQR 1.2 to 2.0 hours]; p = 0.046). The time to the maximum concentration for plasma was not different from that of control limbs (p = 0.08). The time the cefazolin concentration was above the modal S. aureus MIC (T > MIC) in the injured and control limbs over 24 hours was 100% (IQR 100% to 100%) and 100% (IQR 97% to 100%), respectively.

Conclusion: These preliminary findings suggest that current prophylactic cefazolin dosing regimens result in successful antibiotic delivery to the traumatized limb in moderately severe open fractures. Although cefazolin delivery to open-fracture wound beds was delayed compared with healthy tissues, the cefazolin concentration was sustained above the European Union Committee Antimicrobial Susceptibility Testing modal MIC for S. aureus , demonstrating a high likelihood of a prophylactic antimicrobial environment at an open fracture site with this empiric antimicrobial regimen. Importantly, patients in this analysis had Gustilo-Anderson Types II and IIIA injuries. Further research with a larger patient cohort is needed to determine whether antibiotic delivery to traumatized soft tissues in patients with higher-grade open fractures (Gustilo-Anderson Types IIIB and IIIC) demonstrates similar pharmacokinetic characteristics.

Level of evidence: Level II, therapeutic study.

Fig. 1

These clinical photographs demonstrate (A) a traumatic wound associated with an acute tibia fracture after surgical debridement and (B) insertion of a microdialysis catheter using an angiocatheter.

Fig. 2

This graph represents the median total cefazolin exposure (AUC) over 24 hours for the injured limbs, control limbs, and plasma.

Fig. 3

This graph represents the median cefazolin concentrations immediately before and after the second postoperative dose of cefazolin for the injury site, control site, and plasma.