SCCM Resource Library-45-Pharmacokinetic Evaluation of Cefazolin in the Cerebral Spinal Fluid of Critically Ill Patients

Video Transcription

Hello, my name is Allison Novak, and I'm currently a critical care and emergency medicine pharmacist at the University of Colorado Hospital, also known as UCHealth.  Today I will be presenting on the pharmacokinetic evaluation of cefazolin in the cerebral spinal fluid of critically ill patients.  My project team and I took a very COVID-friendly picture this year, as you can see on the right-hand side of the slide.  Their names are listed below with special acknowledgments as well. None of us have any conflicts of interest to disclose.  To get into a little bit of background, cefazolin is a very commonly used first-generation cephalosporin. However, the distribution into the CSF is not well known.  Cefazolin and vancomycin are both used as first-line therapy for EVD prophylaxis in the clinical practice setting.  Due to the frequent monitoring of vancomycin in a more extensive side effect profile, cefazolin  is more commonly used in patients without a contraindication, as there is no difference in surgical site or intracranial infection rates between the two.  Beta-lactams are also preferred over vancomycin for MSSA infections. In addition, cefazolin has also been shown to be as effective as oxacillin or nafcillin  for the treatment of severe MSSA infections and may be better tolerated, including its lower risk of mortality and similar odds of recurrent infections.  Case reports have also demonstrated that cefazolin at both continuous and intermittent dosing has the potential to achieve adequate concentrations in the CSF.  However, we don't have extensive data at this time. This project was a single-center, prospective, observational pharmacokinetic analysis.  UCHealth is a level 1 trauma center, comprehensive stroke, and academic medical center. We have a neurosurgical intensive care unit that is a 24-bed dedicated independent ICU.  The inclusion criteria for my project included hospitalized patients 18 years or older located in the neuro-ICU with an active inpatient medication order for IV cefazolin.  They also had to have an EVD placed and open to drain and clinical lab tests ordered as a standard of care.  Exclusion criteria included any other beta-lactam antibiotics active on the inpatient medication list as these may interfere with our assay.  All patients included in the data analysis were evaluated manually by a single study investigator, myself.  Once we would identify the patients and the doses, we would collect the CSF samples from waste in the EVD and store them at negative 80 degrees Celsius.  The blood samples were then obtained from the institution's clinical lab on campus after the clinically indicated tests for the affirmative blood draws were completed.  The blood samples were then spun down and stored at negative 80 degrees Celsius as well. All samples were sent for analysis in April of 2020.  Our samples were then analyzed by a liquid chromatography mass spec machine at a lab called IC42 on campus, and then cefazolin concentrations were quantified in both the  plasma and CSF samples. These were then plotted relative to the patient-specific dose administered and the tentative pharmacokinetic  estimations were done by investigators in my study group using Excel. The table one results are displayed on this slide.  We had a total of 15 patients, mainly being white females around the age of 55. The cefazolin dose used was two grams, which was adjusted for renal insufficiency to approximate  exposure of two grams administered IV every eight hours. The majority of our patients had relatively good creatinine clearance and did not need any dose adjustments.  Most of our patients were admitted with a subarachnoid hemorrhage. However, some had intraparenchymal hemorrhages and intraventricular hemorrhages as well.  The EVD output in 24 hours was significant at around 110 milliliters. The data in this table is reported as number of percent or mean with a standard deviation.  This slide displays our provisional systemic pharmacokinetic analysis of cefazolin in the plasma for our patients.  We used a single compartment Excel best fit model, and we presented the data in the median with the interquartile range.  I'd like to draw your attention to the first column, which included all 15 patients. The subsequent columns were broken out for patients who were dosed at every eight hours,  every 12 hours, and every 24 hours based on their creatinine clearance. In that first column, the median dose was two grams.  The C max was noted at 78.73 micrograms per mil with a C min of 10.68 micrograms per mil. We had a calculated half-life of about three hours with a volume of distribution in liters  per kilogram of 0.33. The EUC for the dosing interval was around 300 milligram hours per liter.  Overall, we concluded that the volume of distribution was relatively high, which happens sometimes in critical illness, hence a lower extrapolated C max.  This table is set up very similarly to the previous. However, this is for CSF pharmacokinetic analysis of cefazolin.  We again used an Excel best fit analysis for the measured EVD concentrations relative to the cefazolin administration times.  Of note, this ignores the distribution lag into the CSF compartment and assumes instantaneous EVD runoff mixing.  We are also assuming that the EVD runoff from these patients was heterogeneous from these measurements.  Drawing your attention to the first column, which was all 15 patients, the C max that we found was 2.97 micrograms per mil with the C min of 1.59 micrograms per mil.  The CSF half-life we calculated to be about 6.4 hours with an AUC for the dosing interval of being around 18.19 milligram hours per liter.  The half-life appears to be much longer than anticipated, likely due to the EVD runoff being heterogeneous.  When collected, each blood and CSF sample was allocated into three separate vials, so I had duplicate samples of each.  We originally sent our samples to the core lab and sadly this lab went down during analysis and also had other delays from COVID.  So we sent another set of the samples to the second lab, IC42, also on campus. As these were more complete, those values were the ones displayed in our prior tables.  These labs both showed consistent results when considering distribution into the CSF. The CSF AUC to plasma AUC was similar between the labs, 8.3% versus 6.7%.  And a point-by-point, if allowing for zero to three-hour blood to CSF timing, was similar as well at 8% and 6.4% respectively.  Overall, these results truly give hope that cefazolin distribution into the CSF is high enough to achieve appropriate concentrations to potentially treat infections.  Our study did come with some limitations. We had 15 patients total, although that is not a lot, it is adequate for a pharmacokinetic study and especially for a CSF study.  We also calculated all of these values using a basic one compartment estimate. Thus, these are tentative results.  We are currently running a more sophisticated analysis with sparse sampling and compartment modeling that will provide more accurate results of our data.  In addition, we also have some blood tins samples in the CSF that we don't entirely know how to correlate yet.  We also don't know the degree of meningeal inflammation in the patients as this may affect our distribution of cefazolin into the CSF as well.  EVD indications varied between our patients also. Lastly, our samples were deemed as waste, so the blood samples were obtained after the  fact as leftovers, so to speak, and we cannot control the storage of these until after the indicated tests were complete.  Similarly, the CSF was drained from an open EVD at room temperature, not direct ventricle sampling, so there could potentially be delayed mixing there as well.  In conclusion, intermittent cefazolin doses at 2 grams every 8 hours or respectively adjusted  for renal function achieved appropriate concentrations in the CSF based off of our calculations.  Although our patients did not have active documented infections in the CNS at the time of measurement, our cefazolin CSF concentrations suggest that it may be a reasonable treatment  option at these commonly prescribed doses of about 6 grams per day for pathogens depending  on the organism MIC, as our lower interquartile range concentration remained above 0.5 micrograms per milliliter.  It is important to note that our study did not model probability of target attainment and we did not analyze a time above the MIC, as a larger prospective study would be needed  to analyze that. However, we think our data provides reasonable evidence that cefazolin can decently penetrate the CSF.  If cefazolin is chosen, and especially if continued, for the neurosurgery prophylaxis and treatment of CNS infections, it would be important to collect levels for therapeutic  drug monitoring directly in the CSF to check for patient-specific efficacy. Better yet, we would need a proper prospective evaluation and modeling, which would obviate  the need for such monitoring before changing the practice overall. The results in this presentation are also aligned with similar pharmacokinetic studies of cefazolin in the CNS.  Please direct any questions to the email below. Thank you so much for listening to my presentation. I will welcome any questions.

Video Summary

The speaker, Allison Novak, a critical care and emergency medicine pharmacist at UCHealth, presents her research on the pharmacokinetic evaluation of cefazolin in the cerebral spinal fluid (CSF) of critically ill patients. Cefazolin is commonly used but its distribution into the CSF is not well known. The study involved 15 patients in a single-center, prospective, observational analysis. The results showed that cefazolin achieved appropriate concentrations in the CSF, suggesting it may be a reasonable treatment option for CNS infections. However, further research is needed to analyze probability of target attainment and time above minimum inhibitory concentration.

Asset Subtitle

Pharmacology, Neuroscience, 2021

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2021 Critical Care Congress held virtually from January 31-February 12, 2021.

Alison R. Novak

Introduction/Hypothesis: Recent studies have shown that cefazolin is at least as effective as oxacillin or nafcillin for the treatment of severe methicillin-susceptible Staphylococcus aureus infections and may have a better safety profile. However, the ability of this agent to achieve appropriate therapeutic concentrations in the cerebrospinal fluid (CSF) remains unknown. This study evaluated cefazolin concentrations in the CSF using human waste of drained CSF and excess blood from clinical lab draws.

Methods: This was a prospective pharmacokinetic evaluation of cefazolin following an external ventricular drain (EVD) placement. Patients who received cefazolin with an EVD aged 18 years or older between September 1st, 2019 and March 1st, 2020 were evaluated. Serial plasma and CSF samples were obtained at up to three time points within a dosing interval for analysis. Cefazolin concentrations were determined utilizing LC-MS/MS. Pharmacokinetic parameters were compared over time.

Results: This study enrolled 15 patients with a median age of 56 [51,60], 80% of patients were female, 66.7% white, with a mean creatinine clearance of 126.4 Â± 69.7 mL/min and a mean EVD output in 24 hours of 109.4 Â± 50.0 mL. The dose of cefazolin was standard at two grams dosed every eight hours, adjusted in both dose and frequency for renal function in two of the fifteen patients. The peak analyzed concentration of cefazolin in the CSF was 5.72 mcg/mL and the trough CSF concentration measured was 0.78 mcg/mL.

Conclusions: Intermittent cefazolin doses achieved concentrations in the CSF for all of the patients treated with cefazolin as a prophylactic agent. Although these patients did not have active documented CNS infections at the time of measurement, cefazolin CSF penetration suggests it may be a reasonable treatment option for CNS infections at commonly prescribed doses depending on organism MIC.

Meta Tag

Content Type Presentation

Knowledge Area Pharmacology

Knowledge Area Neuroscience

Knowledge Level Advanced

Membership Level Select

Tag Cerebrospinal Fluid

Tag Antibiotics

Year 2021

Keywords

Allison Novak

pharmacokinetic evaluation

cefazolin

cerebral spinal fluid

critically ill patients

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