Introduction
Methicillin-susceptible
Staphylococcus aureus (MSSA) is one of the most common causes of complicated skin and soft tissue infection (cSSTI) [
1]. Among deeper cSSTI and those located in the lower limb of diabetic patients, Gram-negative bacilli,
Escherichia coli, Klebsiella pneumoniae, and
Proteus species, are also commonly isolated [
1,
2]. Based on this epidemiology, intravenous cefazolin has often been used to treat cSSTI for organisms proven susceptible in the hospital settings. However, dosing recommendations vary based on source and organism. Current US labeling for cefazolin includes a variety of dosing regimens as low as 250 mg every 8 h (q8h) up to 2 g q8h [
3].
Susceptibility breakpoints also vary for cefazolin; the U.S. Food and Drug Administration (FDA), the European Committee on Antimicrobial Susceptibility Testing (EUCAST), or the Clinical Laboratory Standards Institute (CLSI) breakpoints have not taken cefazolin tissue exposure into account when selecting susceptibility thresholds. The FDA susceptibility breakpoint for cefazolin against
S. aureus has remained ≤16 mg/L for decades [
3], while cefazolin minimum concentration at which 50% (MIC
50) and 90% (MIC
90) of the isolates were inhibited against MSSA was recently reported as 0.5 mg/L and 1 mg/L, respectively [
4]. EUCAST has not published a cefazolin susceptibility breakpoint for Enterobacteriaceae and relies on the cefoxitin disc test for determining universal susceptibility to first-generation cephalosporins. The CLSI uses a similar definition for
S. aureus, and more recently has modified its susceptibility breakpoint for Enterobacteriaceae twice since 2010. This was prompted by publications reporting treatment failures from cephalosporins in infections caused by Enterobacteriaceae that were previously categorized as susceptible [
5‐
7]. Initially, it was lowered from ≤8 mg/L to ≤1 mg/L in 2010 with the advent of in vitro susceptibility, pharmacodynamic, and clinical outcome data. It was then readjusted to ≤2 mg/L in 2011 with the recommendation of a 2 g q8h dosing regimen, so that it could still be a viable option for Enterobacteriaceae without intrinsic chromosomal cephalosporinases [
7].
In an effort to quantify drug concentrations in the interstitial fluid (ISF) of tissue to determine if appropriate pharmacodynamic targets are achieved at the site of infection, our group previously reported ISF exposure of cefazolin in seven chronic lower extremity wound infections utilizing in vivo microdialysis techniques [
8,
9]. The non-compartmental pharmacokinetic analysis from the study showed the mean and median tissue penetration ratios [ISF/serum free drug area under the curve (
fAUC)] of 1.06 and 0.88 with a wide range of 0.19–1.68. The percent of the dosing interval that free drug concentrations remained above the MIC (%
fT > MIC) in the sampled ISF was 100% at an MIC of 1 mg/L for five out of six patients who received 1 g q8h dose during the study.
In this study, we aimed to describe the population pharmacokinetics of cefazolin in both serum and ISF utilizing the data from the aforementioned study [
8]. We used this model to simulate the potential variability in penetration into ISF of tissue and to compare the likelihood of achieving targeted drug exposure (i.e.,
fT > MIC) in the ISF compartment between 1 g versus 2 g q8h regimens.
Discussion
The previously published cefazolin in vivo microdialysis study by our group evaluated ISF concentrations of intravenously administered cefazolin for the treatment of cSSTI [
8]. The primary goal of the current study was to describe the population pharmacokinetics using the same serum and ISF concentration data to assess variability in ISF penetration and the likelihood of achieving
fT > MIC in the ISF compartment between 1 g and 2 g q8h regimens.
A three-compartment model best described the pharmacokinetics of cefazolin in our population with normal renal function. The resultant CL of 3.78 ± 2.09 L/h from our population pharmacokinetic model was concordant with the values from the non-compartmental analysis, 3.72 ± 2.16 L/h [
8]. Cefazolin CL in this population was also similar to most other reported values. van Kralingen and colleagues [
17] have reported CL of 4.2 ± 0.1 L/h in patients with average ± SD age of 44 ± 11 years, TBW of 151 ± 35 kg, and BMI of 51 ± 10 kg/m
2 after a single prophylactic dose of 2 g prior to bariatric surgery. They also observed CL had a significant negative correlation with age, but not with body weight. Douglas and colleagues [
18] reported median CL of 3.01 L/h (interquartile range: 1.73–3.94 L/h) after a single 2 g cefazolin in patients undergoing abdominal aortic aneurysm open repair surgery. A tissue penetration study of cefazolin in morbidly obese versus non-obese patients reported a CL of approximately 23 L/h [
19]; however, this estimate was based on unbound cefazolin concentrations and is therefore not directly comparable. Nonetheless, this unbound CL estimate is feasible because cefazolin is highly protein bound; protein binding in our six patients was 85%.
The observed mean ± SD and median penetration ratios from our six patients using their individual Bayesian parameter estimates were 0.90 ± 0.48 and 0.72 (range 0.61–1.87), respectively; these values were similar to the original observed penetration ratios based on trapezoidal rule: 1.21 ± 0.67 and 0.90 (range 0.7–2.68), respectively [
8]. The Monte Carlo simulation incorporates variability between patients in the pharmacokinetic estimates, and as a result, the mean ± SD and median simulated penetration ratios were 1.36 ± 4.57 and 0.80, respectively. These penetration ratio are comparable with the values observed by Brill and colleagues [
19] who compared population pharmacokinetics of surgical prophylactic dose of cefazolin 2 g in both morbidly obese (BMI 47 ± 6 kg/m
2) and non-obese (BMI 28 ± 3 kg/m
2) patients using in vivo microdialysis. Their observed
fAUC
ISF/AUC
serum was 0.70 (range 0.68–0.83) in morbidly obese and 1.02 (range 0.85–1.41) in non-obese patients. The aforementioned study by Douglas and colleagues [
18] reported 85% penetration (range 78–106%). Taken collectively, these data consistently suggest that there is the potential for a wide range in the estimate for cefazolin penetration into ISF, which may unpredictably be greater than or less than exposures in serum.
While penetration ratio was calculated to display the relative exposure of cefazolin in ISF of tissue versus in serum, the pharmacodynamic target of interest for the efficacy of cefazolin in ISF remains
fT > MIC [
20‐
22]. Although the cefazolin target
fT > MIC in ISF needed for efficacy against MSSA and Enterobacteriaceae are unknown, 30% for MSSA [
22‐
24] and 50% for Enterobacteriaceae [
22,
25,
26] were employed as these are targets required in blood. A target of 100%
fT > MIC was also included for comparison. Consistent with current breakpoints, where applicable, PTAs for cefazolin 1 g q8h in serum were high at MICs of 1 mg/L and 2 mg/L (Table
3a). However, analysis of exposure probabilities in tissue revealed much lower PTA results. At the MIC
90 for MSSA of 1 mg/L, the PTA for a 1 g q8h dose in ISF was 96% using the 30%
fT > MIC target (Table
3b). At an MIC of 2 mg/L, the current-susceptible breakpoint for Enterobacteriaceae, a 1 g q8h regimen obtained a PTA of 71% for 50%
fT > MIC (Table
3b), but a 2 g q8h dosing regimen increased the PTA to 91% for the same target (Table
3b). PTAs for 50%
fT > MIC in tissue from our study for the 2 g dose are comparable with PTAs reported by Brill and colleagues [
19]: 96% and 91% (Table
3b) versus 100% and 96% at MIC of 1 mg/L and 2 mg/L, respectively.
The primary limitation of our study is its small sample size. Only six patients, all with normal renal function, were included in the final model. Despite the knowledge of correlation between cefazolin CL and renal dysfunction, the small number of patients with normal renal function in our study made it challenging to improve the model by adding this covariate. Additionally, while morbid obesity can be an important factor in determining cefazolin pharmacokinetics [
19], our small sample size did not allow us to use weight as a covariate and future studies are needed to further define optimal cefazolin dosing in this population. Nonetheless, this is the first study to address variability in cefazolin penetration among patients with chronic wound infections. Our results are also consistent with the current recommended dosing regimen for treatment of Enterobacteriaceae based on the CLSI breakpoint (i.e., 2 g q8h), as well as the dosage typically utilized for
S. aureus skin and soft tissue infections (i.e., 1 g q8h).
Acknowledgments
This work was supported internally by the Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA. We acknowledge Amira Bhalodi, PharmD and Seth Housman, PharmD for collection of the original cefazolin serum and tissue concentration data, and Michael Neely, MD for his guidance during the population pharmacokinetic analysis and Monte Carlo simulation. The contents of this article were presented as a poster at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy in Washington, DC, USA. All named authors meet the ICMJE criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.