Fran Lowry

May 31, 2012

May 31, 2012 (Fort Lauderdale, Florida) — An outbreak of streptococcus endophthalmitis after injection with intravitreal bevacizumab that occurred recently in South Florida is a reminder to clinicians to make sure they know exactly what they are injecting and where it comes from.

In a study presented here at the Association for Research in Vision and Ophthalmology 2012 Annual Meeting, Roger A. Goldberg, MD, MBA, from the Bascom Palmer Eye Institute, Miami, Florida, reported 12 cases of streptococcus endophthalmitis that presented 1 to 6 days after bevacizumab injection.

The injections were done in the community offices of 4 practitioners in Miami-Dade and Broward counties. None of the cases originated at Bascom Palmer, but 9 of the 12 patients presented to the emergency department there for treatment when their symptoms developed, and 3 other patients were seen in consultation, Dr. Goldberg said.

Many of the patients had good visual acuity prior to their injection, but visual outcomes have been poor. Eleven of 12 patients have lost all functional vision, and 7 lost an eye, he reported.

All patients received bevacizumab prepared by the same compounding pharmacy. Microbiology cultures for 10 patients were found to be positive for Streptococcus mitis or Streptococcus oralis.

Seven unused syringes of bevacizumab prepared at the same time as those related to the outbreak were also positive for S mitis or S oralis, he said.

Dr. Goldberg and his team reported some of the findings from a site visit by investigators from the US Food and Drug Administration (FDA) to the compounding pharmacy to try to understand how the contamination occurred.

Bevacizumab's Journey to the Clinic Is Complex

Unlike ranibizumab, which is sent from the manufacturer to a distributor to the clinician, who draws up 1 syringe from 1 vial to treat 1 patient, bevacizumab is sent from the manufacturer to the distributor and then to a compounding pharmacy, which divides the drug into multiple syringes and sends the syringes to one or more physicians, who then treat multiple patients.

"The supply chain for [bevacizumab] in this outbreak was even more complicated. It went from the manufacturer to a distributor to a pharmacy, which then sent the [it] to a secondary compounding pharmacy that was responsible for the syringe preparation, and then back to the first compounding pharmacy, which sent the syringes on to the 4 physicians who injected the 12 patients," Dr. Goldberg explained.

During their site visit, the FDA investigators found poor sterile technique, inadequate documentation, and insufficient testing and monitoring of the equipment.

Among the more egregious examples of poor sterile technique, the investigators documented the use of nonsterile gloves while handling supplies, the use of a water-based instead of alcohol-based hand sanitizer, a pharmacist leaning his body under a laminar flow hood, a hairnet that covered the head but not a 15-inch ponytail, and a pharmacist who wiped vials with nonsterile pads immediately prior to puncture.

In addition, written documentation of procedures to ensure that the compounded products had the right identity, strength, quality, and purity was lacking, as were procedures to ensure that equipment was properly cleaned and calibrated.

Clinicians, Take Heed

There are several lessons for clinicians from this outbreak, Dr. Goldberg said.

"Up to this point, so much of the clinician's attention has been on preventing endophthalmitis at the patient's bedside at the time of injection; of course , this is still critically important. But this outbreak raises the issue of what has happened to the medication prior to its arrival at the patient's clinic chair," he told Medscape Medical News in an interview after his talk.

"This outbreak reminds us as physicians to think about all of the steps in the drug-preparation process and to do our part as clinicians to both minimize the risk of a contamination and to minimize or mitigate an outbreak, should one occur," he said.

As a precaution, lot numbers of agents injected into each patient should be carefully documented and contact information for each patient should be accurate.

"Having contact information ended up being important in this outbreak. We were able to contact the patients who had been seen in those community clinics and quickly get a handle on what was happening," Dr. Goldberg said.

Physicians also need to be aware of the pharmacy or pharmacies that supply the drugs they use.

"I don't think many clinicians thought that much about the pharmacy selection process before this outbreak was publicized, but now we know that we need to make sure that our pharmacies are in compliance with US Pharmacopeia (USP) Chapter 797," which regulates the use and preparation of medications for intravitreal use, he said.

Physicians can consider doing a site visit to their compounding pharmacy, or hire a consulting pharmacist to do either a 1-time inspection or periodic monitoring of the compounding pharmacy.

They can also choose to use a compounding pharmacy that is certified by the Pharmacy Compounding Accreditation Board (PCAB), he said.

Dr. Goldberg added that he still regularly uses bevacizumab and that, when properly prepared in accordance with USP 797 guidelines, the risk for endophthalmitis after intravitreal injection is very low (and no greater with bevacizumab than with ranibizumab).

Medscape Medical News invited American Academy of Ophthalmology (AAO) clinical correspondent George A. Williams, MD, from Oakland University William Beaumont School of Medicine, Rochester, Minnesota, to comment on this report.

"The AAO recognizes the value and efficacy of off-label use of FDA-approved drugs, such as [bevacizumab] for the treatment of blinding eye diseases," Dr. Williams said.

"The recent episodes of contaminated [bevacizumab] in Florida and elsewhere emphasize the need for optimal compounding practice. The AAO recommends that ophthalmologists obtain any compounded drug for ocular use from a PCAB-accredited pharmacy," he said.

Dr. Goldberg and Dr. Williams have disclosed no relevant financial relationships.

Association for Research in Vision and Ophthalmology (ARVO) 2012 Annual Meeting: Abstract 2252. Presented May 7, 2012.

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