In this episode I’ll:

1. Discuss an article about piperacillin-tazobactam pharmacokinetics in critically ill patients.

2. Answer the drug information question “How quickly must dantrolene be accessible to treat a case of malignant hyperthermia (MH)?”

3. Share a resource about false positive urine drug screens.

The article for this episode recently appeared in a weekly literature digest for members of my Critical Care Pharmacy Academy. Every week I send Academy members a summary of the most important critical care pharmacy articles, including my analysis of where the article fits in practice. You can find out more at pharmacyjoe.com/academy.

Article

Repeated Piperacillin-Tazobactam Plasma Concentration Measurements in Severely Obese Versus Nonobese Critically Ill Septic Patients and the Risk of Under– and Overdosing

Lead author: Boris Jung

Published in Critical Care Medicine May 2017

Background

There is a dearth of evidence regarding the use of piperacillin-tazobactam continuous IV infusion in critically ill obese patients. The authors of this study sought to compare the pharmacokinetics of piperacillin in severely obese and nonobese patients with severe sepsis or septic shock. Their hypothesis was that patients would experience both under and overdosing.

Methods

The study was a prospective comparative study performed in a single, 16 bed mixed medical/surgical ICU. Patients with a BMI >35 were counted as obese and those with a BMI < 30 were considered nonobese. A consecutive cohort of patients treated with 16 g/2 g/24 hr continuous piperacillin-tazobactam infusion was evaluated. Piperacillin plasma concentration was measured every 12 hours over a 7-day period.

Free piperacillin plasma concentration and the fraction of time above 64 mg/L (4 times the upper end of sensitive MIC for Pseudomonas) were compared between the two groups. The authors then performed 5000 Monte Carlo simulations for various dosing regimens and MICs and calculated the probability to spend 100% of the time over 64 mg/L.

Results

11 obese and 12 nonobese patients were studied with a total of 294 blood samples obtained. There was no difference in piperacillin plasma concentrations over time between groups. The fractional time over 64 mg/L was 64% and 93% in obese and nonobese patients, respectively. Five nonobese and two obese patients experienced potentially toxic piperacillin plasma concentrations. When a concentration of 64 mg/L was targeted, Monte Carlo simulations showed that 12 g/1.5 g/24 hr was inadequate in both groups and 16 g/2 g/24 hr was adequate only in nonobese patients.

Conclusion

The authors concluded:

Using a conventional dosing of 16 g/2 g/24 hr continuous infusion, obese patients were more likely than nonobese patients to experience piperacillin underdosing when facing high minimal inhibitory concentration pathogens. The present study suggests that piperacillin drug monitoring might be necessary for the sickest patients who are at the highest risk of unpredictable plasma concentration exposing them to overdose, toxicity, underdosing, and treatment failure.

Discussion

In the pharmacokinetic analysis, the clearance of piperacillin nearly doubled in obese patients. Plasma levels were extremely variable despite the use of a continuous infusion. Most patients achieved at least 50% of the time above the MIC of 16 mg/L for Pseudomonas. Five non-obese and two obese patients experienced very high piperacillin levels that have been associated with toxicity.

This study makes a good case for the use of therapeutic drug monitoring for piperacillin in critically ill patients. Unfortunately, the ability to check piperacillin levels for therapeutic drug monitoring is not commonplace.

Does your hospital lab have the ability to get piperacillin plasma levels for use in therapeutic drug monitoring? — Pharmacy Joe ?? (@PharmacyJoe) April 19, 2017

Drug information question

Q: How quickly must dantrolene be accessible to treat a case of malignant hyperthermia (MH)?

A: The entire dose of dantrolene should be able to be administered within 10 minutes of the decision to treat.

The Malignant Hyperthermia Association of the United States (MHAUS) now recommends that:

Dantrolene must be available for all anesthetizing locations within 10 minutes of the decision to treat for MH. Dantrolene must be available for all anesthetizing locations where MH trigger agents are used.

This timeframe is a slight change from the previous recommendation of 5 minutes. This change was based on a consensus discussion taking into account that triggering agents for MH may be administered far away from the operating room where dantrolene is typically stored. I discussed the diagnosis and treatment of MH back in episode 40.

Resource

An article hosted on uspharmacist.com provides a listing of medications that can cause a false positive urine drug screen. Some common examples are sertraline causing a false positive for benzodiazepines, and ibuprofen or naproxen causing a false positive for barbiturates and THC.

If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.

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