In the April issue of JAMA Internal Medicine published last year¹, an outbreak of bacteremia due to Burholderia contaminans (BCC) was linked to intravenous fentanyl produced by the compounding pharmacy at Duke University Hospital. The blood cultures of 7 patients during a 7 day period were positive for this pan-susceptible organism. Two of 7 patients died before discharge, although their deaths were due to underlying conditions and not due to BCC bacteremias.
The risk factor common to all these patients was receipt of continuous fentanyl infusion prepared by their institutional compounding pharmacy (odds ratio, 11.22; 95% CI 2.09 - ∞, p =0.01). The outbreak was terminated after all compounded fentanyl was sequestered. Molecular analyses using repetitive element polymerase chain reaction and pulsed field gel electrophoresis confirmed a clonal B. contaminans strain from the patients’ blood cultures, fentanyl preparation, and two environmental samples.
The inherent risk involved in compounding sterile pharmaceuticals is well established and has resulted in multiple previously reported outbreaks in the literature, including the largest outbreak in the history of this country attributed to the New England Compounding Center in Massachusetts.² The USP and FDA have standards/guidance documents that address the practice of sterile compounding of preparations, and adherence to these standards is paramount to patient safety. Yet even under the best of circumstances, contamination of sterile compounded preparations continues to happen on a sporadic basis.
What has intrigued me as a member of the USP Expert Compounding Committee is the human factors that come into play with the complex task of sterile compounding. This outbreak reported by the Hospital Epidemiology team at Duke University Hospital is no exception. Two environmental cultures were positive for the outbreak organism, which included the clean room pH 7 probe calibration fluid and the anteroom sink drain.
A mock demonstration of the entire compounding procedure was completed after resolution of the outbreak to gain “lessons learned.” Two observations during the mock demonstration were of particular note:
Gloves were not changed between compounding steps (gloves were disinfected using sterile alcohol according to current USP 797 standards) that involved manipulation of sterile items.
The pH probe was submerged into the entire volume of the preparation instead of testing small aliquots at a time.
Needless to say, human error or equipment malfunction during the filtration procedure may have gone undetected for the particular lot that caused this outbreak, but the real truth surrounding the cause of this outbreak will remain unknown. A commonly accepted opinion among compounders is that the final filtration step is adequate to resolve possible contamination events that may occur prior to the delivery of the final “sterile” preparation.
“It must be remembered that there is nothing more difficult to plan, more doubtful of success, not more dangerous to manage, than the creation of a new system; for the initiator has the enmity of all who would profit by the preservation of the old institution, and merely lukewarm defenders in those who would gain by the new one.” – Machiavelli - The Prince, 1513.‖
Sterile compounding of preparations, like infection prevention, is a complex adaptive system that is also a social-technical system. We continue to focus on the tasks involved with sterile compounding when adverse events occur, and a simple change in one task will reverberate through the system in planned and unplanned ways.
Which essential tasks need to be incorporated into these standards, one may ask? The goal is to promote joint optimization so all system components that involve sterile compounding processes and associated human factors fit together with utmost clarity (no ambiguity), so human and technology errors are kept to a minimum. This is the charge of the USP Expert Compounding Committee as they start a new five year cycle this coming July. We look forward to the publication of the new Chapter 800 Hazardous Drugs and the revised USP 797 Pharmaceutical Compounding – Sterile Preparations in USP National Formulary.
It is high time we establish a new paradigm for medication safety in this country, and this “medication safety blueprint” endorsed by the FDA, CDC, and the State Board of Pharmacies will require accountability at the pharmacist, pharmacy technician, and practitioner level, with ongoing close monitoring for compliance and timely feedback with all required elements of performance.
¹Outbreak of Bacteremia Due to Burkholderia contaminans Linked to Intravenous Fentanyl From an Institutional Compounding Pharmacy; Rebekah W. Moehring, Sarah S. Lewis, et.al; JAMA Intern Med, 2014, 174(4): 606-612.
²Fungal Infections Associated with Methylpredisolone Injections; Rachael M. Smith, Melissa K. Schaefer, et.al, NEJM, 2013, 369, pp. 1598-1609.