A highly drug-resistant bacteria that was linked to eyedrops imported from India and that spread from person to person in a Connecticut long-term care center has prompted concerns that the strain could gain a foothold in U.S. health care settings, according to the Centers for Disease Control and Prevention.
Infectious disease specialists said the strain had not been previously detected in the United States, and that it was particularly difficult to treat with existing antibiotics.
In recent months, three deaths, eight cases of blindness and dozens of infections have been traced to EzriCare artificial tears, according to the C.D.C., leading to a widespread recall this year.
The Food and Drug Administration, which regulates over-the-counter medicine, has stopped imports of the product. But these outbreaks highlight regulatory gaps in controlling imports of overseas medications.
The F.D.A. confirmed that it had not inspected the factory where the eyedrops were made in India before the infections were reported, but that the agency had since visited the plant, which is operated by Global Pharma Healthcare.
The agency has long been criticized for lapses in inspections of overseas manufacturing in China and India, which are the two major producers of drugs and raw ingredients for medicines. Other instances of contaminated products from overseas included blood pressure medications suspected of containing a possible carcinogen and deadly batches of heparin, both of which prompted mass recalls.
The F.D.A. said it was continuing to work with the C.D.C. and had urged retailers to make sure the products were removed from shelves.
In the latest instance, the eyedrops are linked to bacteria that is even more drug-resistant than a similar bacteria that the C.D.C. tends to see in about 150 cases per year, mostly in intensive-care settings, according to Maroya Walters, lead investigator for the C.D.C.’s antimicrobial resistance team.
Dr. Walters said the spread of the newest strain “really could change the outlook for that.”
The bacteria showed signs of spreading within the Connecticut center among asymptomatic patients who had the bacteria colonized in their bodies. Such spread tends to occur when patients touch common items or when health care workers transmit the germs.
The bacterium linked to the eyedrops, drug-resistant Pseudomonas aeruginosa, is already a top concern for health care providers, especially among those with compromised immune systems, nursing home residents and patients with invasive medical devices like catheters and breathing tubes.
Dr. David van Duin, an infectious disease specialist at the University of North Carolina School of Medicine, said resistant pseudomonas was especially difficult to eradicate, both from health care facilities, where it clings tenaciously to sink drains, water faucets and other moist environments, and from patients who develop bloodstream infections.
“It’s very hard to get rid of,” he said.
By now, cases associated with the eyedrops have largely been contained, thanks to a product recall and widespread attention from the news media, Dr. Walters said. The F.D.A. had also announced the recall of Delsam Pharma’s Artificial Eye ointment, which was made in the same factory as the eyedrops, because of possible contamination.
The C.D.C. is asking doctors to work with public health labs to determine the genetic fingerprint of hard-to-treat Pseudomonas infections in the eye and throughout the body.
“I think we are going to see the impact of this play out over the course of months to years,” Dr. Walters said.
In late December, the C.D.C. linked the EzriCare drops to an outbreak that has affected 68 patients in 16 states, including eight patients who lost their vision and four who had an eyeball removed.
The F.D.A. has not said how much of the product made by Global Pharma Healthcare in Chennai, India, was imported.
However, records provided to The New York Times by Panjiva, the supply chain research unit of S&P Global Market Intelligence, show that Global Pharma sent U.S. distributors four shipments in 2021 and 2022 amounting to tens of thousands of half-ounce bottles of EzriCare artificial tears.
While the F.D.A. requires a pre-approval inspection of plants that manufacture prescription drugs, there is no such mandate for those that make over-the-counter medicines like artificial tears. Compounding the problem, the number of inspections the agency conducts has plummeted since the pandemic began.
Representative Rosa DeLauro, Democrat of Connecticut, expressed concern about the F.D.A.’s ability to oversee what she described as “substandard safety practices” at U.S. and foreign plants, and called for providing the agency with more funding and greater authority to recall products. “Lives are at stake,” she said in a statement.
On Jan. 3, the F.D.A. blocked Global Pharma’s imports, saying the company had provided “an inadequate response to a records request” and violated manufacturing rules. Shannon P. Hatch, a spokeswoman for the agency, said that the import alert was unrelated to the outbreak.
The F.D.A. also said it recommended a voluntary recall on Feb. 2 over a “lack of appropriate microbial testing,” formulation issues and the absence of proper controls around tamper-evident packaging. The agency conducted an unannounced inspection at the India plant from Feb. 20 through March 2 and found a litany of problems with the plant’s sterility practices, according to an inspection report that was first reported by STAT news.
Clean-room operators were not qualified for the job, and they wore discolored and worn-out foot covers, the report said. An inspector noted “a black, brown colored greasy deposit” on machinery in a room where bottles were filled with the eye drops. One worker acknowledged to an inspector that there was no procedure for cleaning one of the filling machines, according to the report.
Global Pharma did not respond to questions in March. But on Feb. 1, the company said it had “not determined whether our manufacturing facility is the source of the contamination.” EzriCare said on its website that it marketed the drops, but that it had no role in the “actual manufacturing of this product.” Wal-Mart and Amazon, among the larger retailers that sold the drops, did not respond to requests for comment.
Clara Elvira Oliva, 68, a contact lens wearer from Florida, began using EzriCare Artificial Tears to moisturize her eyes at the recommendation of the ophthalmologist at her health clinic.
One morning in August, she woke up to find her right eye red and itchy and oozing liquid. Alarmed, she returned that day to the ophthalmologist, who prescribed antibiotic drops. But in the weeks that followed, she said, the irritation persisted and her eyesight began to deteriorate, stumping eye care providers who prescribed an ever-changing variety of antibiotic and antifungal drops.
All the while, she kept using the EzriCare drops in both eyes. “No one told me to stop using them,” Ms. Oliva said in an interview.
By the end of August, the infection in her right eye had become so dire that specialists told her she would need a cornea transplant. After the operation, she was told the eye was so ravaged by infection that doctors had no choice but to remove it.
“Since that day, my life has never been the same,” said Ms. Oliva, a retired cosmetologist who lives with her son in Miramar.
Dr. Walters collected mounting reports of antibiotic-resistant infections in several states that had a strikingly similar genetic fingerprint.
C.D.C. investigators examined an outbreak of about two dozen cases at the long-term care center in Connecticut, where they saw evidence of bacterial spread among residents. That investigation pointed to eyedrops, but the center’s records made it difficult to tell what type had been used.
By late December, the C.D.C. had tested 23 open bottles of eyedrops. Eleven of the EzriCare artificial tear bottles harbored bacteria, and seven of those matched the outbreak strain, Dr. Walters said.
While the finding is not definitive proof that the bacteria came from the bottle and not from touching an infected eye, the evidence was compelling, Dr. Walters said.
For Ms. Oliva, the vision in her left eye, already compromised by scarring, continues to deteriorate, making it difficult to drive, cook and read. Unsteady on her feet, she avoids going out. “Sometimes I bump into people because I don’t see them, but they think I’m just not paying attention,” she said.
Ms. Oliva’s lawyer, Natasha Cortes, said she was investigating two cases of patients who went to the same clinic and developed vision problems, as well as five others.
The outbreak has renewed longstanding concerns about the quality and frequency of the F.D.A.’s overseas inspections.
In June 2020, Senator Chuck Grassley, Republican of Iowa, held an oversight hearing on the F.D.A.’s foreign inspection process, noting that the plants were given 12 weeks’ advance notice, “plenty of time to doctor up a facility to make sure that it passes inspection.” The agency has since received budget authority to conduct unannounced overseas inspections.
The F.D.A. paused overseas inspections during the height of the coronavirus pandemic, and the number of foreign inspections remained low last year, at 684 compared with 3,272 in 2019, according to agency data.
The F.D.A. has 4,000 overseas facilities to inspect, with about 20 percent in India; one of its six inspector positions in that country was vacant in late 2021, according to a report issued last year by the Government Accountability Office.
For over-the-counter drugs, the F.D.A. uses a system that essentially lists a medication recipe. Companies can make the products without express agency approval but are expected to follow agency rules for manufacturing quality products, said John Serio, a lawyer with Withers who has pharmaceutical clients.
“If you’re not out there inspecting facilities,” Mr. Serio said, “these sorts of problems will crop up because there’s no threat that if you’re out of compliance that the inspector will come knocking at your door.”
Dr. Vicente Diaz, the chief of ophthalmology at Yale Health Plan in Connecticut who specializes in infectious diseases, said the infections evading the “big gun” antibiotics had alarmed experts. He worries that if doctors use ineffective antibiotics for too long or wait to culture a bug, “that gives the bacteria more time to multiply and get more aggressive,” he said.
EzriCare drops do not contain preservatives, a fact that Dr. Diaz found troubling. He said he had never seen another reusable eye product without preservatives or other safety features to limit bacterial growth. Preservative-free drops usually come in single-use bottles, given the risk, he said.
“I’m surprised that formulation was allowed to go on the market without more scrutiny,” he said. “It’s kind of like the perfect storm.”