This photo provided by the Minnesota Department of Health shows shows vials of the injectable steroid product made by New England Compounding Center implicated in a fungal meningitis outbreak. (Minnesota Department of Health/AP)

Pharmacy compounding, the mixing of drugs for individual patients, was once a quaint activity depicted on drug-store calendars from the 1950s. It has roared back in the 21st century, driven by the rise of out-of-hospital surgical care, the high prices and shortages of drugs, and the real or imagined benefit of “personalized medicine.”

Today, nearly every place medical care occurs — hospitals, doctor’s offices, home-health companies — now gets at least some of its drugs in forms that aren’t available off the shelf from pharmaceutical houses.

The practice burst into the national spotlight this month when cases of a rare brain infection, widely scattered across the country, were linked to a drug mixed by a compounding pharmacy in Massachusetts. As of Saturday, 198 illnesses and 15 deaths had been reported from 13 states.

Hospital pharmacists no longer compound drugs just for premature infants or patients with unusual conditions. Corner druggists see compounding as a more lucrative and interesting job than bagging blister-pack prescriptions. Chain drug stores are getting into the business. And entrepreneurs are taking up mortar and pestle to meet the demand, one of them being the New England Compounding Center, which is at the middle of the current outbreak.

That company in Framingham, Mass., shipped nearly 18,000 vials of methylprednisolone acetate, a steroid injected around the spinal cord to relieve pain, to buyers in 23 states. How many of the vials were contaminated is unknown. About 14,000 people have been injected with material from the three tainted lots. Health officials expect more cases of fungal meningitis to appear.

Whether that volume of sales tipped the company out of the category of “compounding pharmacy” and into that of “drug manufacturer” is a matter of dispute. So is the issue of who has principal responsibility — Massachusetts’s pharmacy board or the federal government’s Food and Drug Administration — to oversee such operations and prevent disasters like the one that’s happening.

What’s not in dispute is how much U.S. medicine has come to rely on this little-known and little-regulated part of the economy.

Compounded drug benefits

“It’s like buying your electricity from a different supplier. It looks like you’re getting the same stuff, but evidently you’re not,” says a physician at one of the seven outpatient treatment centers in Maryland that received methylprednisolone from a contaminated lot from the New England Compounding Center. A pain specialist, he’s been using compounding pharmacies “for at least five years, closer to 10.” He spoke on the condition of anonymity on the advice of his lawyer.

Compounders are especially important for patients with multiple sclerosis who get a mixture of drugs that are not commercially available and are continuously infused into the spinal canal. The clinic also turns to compounders for preservative-free injectable steroids because some of the doctors there think that alcohol preservatives in conventional preparations can be irritating.

Compounded drugs are also sometimes cheaper; the steroid the clinic bought from the Massachusetts company was about $2 less per vial. Compounding pharmacies often have supplies of such workhorse pain medicines as fentanyl, midazolam and propofol when the usual suppliers have run out.

According to a guidance document issued in 2002, the FDA says the distinguishing feature of compounding pharmacies is that they make “drug products . . . on a customized basis for an individual patient.” A similar assertion appears in the warning letter the agency sent to the New England Compounding Center in 2006.

Reuters news service reported on Saturday that a dozen e-mail messages it obtained show that the Massachusetts company regularly filled orders without having individual patient prescriptions in hand, as is required by state law. The requirement to have patient-specific prescriptions appears to have been violated by other companies as well.

For example, the Maryland physician said that when he orders drugs for his few multiple sclerosis patients, he sends prescriptions with their names on them. But “for everything else,” he said, “we just send [compounders] a script for a case of 50 or whatever we’re buying, and they send us the drug.”

He’s never really thought of compounding pharmacies as different, less regulated, under-the-radar enterprises.

“From our perspective, they look like any of our other vendors,” he said. “They’re licensed and inspected; they have nice, pretty Web sites and sales teams and inspections. They look no different from Upjohn.”

Uses at Johns Hopkins

Johns Hopkins Hospital stocks 3,000 different drugs or dosage forms in its pharmacy. Twenty-six come from three compounding pharmacies, although Daniel Ashby, director of the hospital pharmacy, thinks of those suppliers more as “repackagers.”

There are several reasons an institution as august as Johns Hopkins Hospital uses compounders. Sometimes they are the only source of a drug in short supply. Sometimes they can provide a safer formulation of a medicine. Compounders reformulate some drugs into pediatric doses and label them in a way that clearly distinguishes them from adult doses. A third reason involves the concept of “beyond use dating.”

Ashby explained that some drugs have to be on hand for immediate use by patients. However, if a dose is drawn into a syringe from a large vial and not used within a specified period of time — usually 24 hours — it has to be thrown away.

Compounders prepare such doses (usually in small bags of IV fluid) and then test them for sterility and potency after a specified period, usually a month or longer. If the drugs pass the tests, the compounders are allowed to sell such repackaged drugs with a labeled shelf-life of weeks or months (although never as long as the shelf-life of the vial they came from). This allows the hospital to create a small stockpile of the drugs with the confidence that most of it won’t have to be thrown away.

“We would buy quantities from them that could be dispensed to multiple patients,” Ashby said.

One of the compounders Johns Hopkins Hospital uses is Ameridose, a company that has common ownership with the New England Compounding Center and that has temporarily ceased operation as state and federal officials review its safety and sterility procedures.

Another is AnazaoHealth in Tampa. It supplies certain specialty pain medications but only in response to patient-specific prescriptions for them, both Ashby and the company said.

The third is PharMEDium of Lake Forest, Ill. One of the drugs Hopkins gets from them is calcium gluconate, sometimes used in severe heart-rhythm disorders; another is magnesium sulfate, used to treat a life-threatening condition of pregnancy called pre-eclampsia. Ashby said the hospital does not send patient-specific prescriptions with orders for those drugs.

The company wouldn’t make anyone available to answer the question of whether PharMEDium ships drugs only in response to orders naming individual patients.

A Chicago public relations firm provided a statement saying that PharMEDium follows FDA guidelines and that the agency “has inspected our compounding pharmacies regularly over the years.” But it didn’t answer the question.

‘A really unfortunate event’

A year ago in July, an elderly woman came to the Bascom Palmer Eye Institute at the University of Miami, groaning in pain and with a cloudy eye whose vision was disappearing.

Roger A. Goldberg, an ophthalmology resident, quickly determined the interior of the woman’s eye was infected. She told him that one day earlier it had been injected with Avastin, a drug for people with macular degeneration.

Goldberg thought the complication, which occurs in 1 in 2,000 injections, was supremely bad luck. But when the next patient he saw was another woman with nauseating pain and an infected eye who had been injected with Avastin by the same doctor, he knew something was up.

Both women had gotten Avastin in prefilled syringes made by a compounding pharmacy. It was contaminated with a virulent strain of Streptococcus bacteria.

In all, seven women and five men treated at four South Florida clinics got the infection. Only one has recovered full sight. Seven lost complete vision in the injected eye, and in five the eye was removed. One person, injected in the only useful eye, is blind.

“It’s been a really unfortunate event,” said Goldberg, who published an account of the outbreak in the American Journal of Ophthalmology this year.

But he doesn’t think the way to prevent tragedies is to ban compounding pharmacies from providing Avastin to eye doctors — it’s just too good a deal for patients.

Avastin is a cancer drug sold by its manufacturer, Genentech, in 4- and 16-milliliter vials. Eye doctors need only 0.1 of a milliliter to treat macular degeneration. Compounding pharmacies repackage the drug into the tiny amounts required by ophthalmologists and sell them for $50 a dose. This is officially an “off-label use” of Avastin because the FDA hasn’t approved it for eye disease.

The alternative is a slightly different medicine called Lucentis. It has gone through all the testing required to get FDA approval for use in the eye. It sells for $2,000 a dose and is also made by Genentech.

Most patients with macular degeneration need to be treated every month. Many must pay 20 percent of the cost of the drug, which is delivered in an outpatient procedure. So the co-pays are $10 for Avastin or $400 for Lucentis.

Goldberg, who is 34 and now in fellowship training in Boston, said he would hate to see compounded Avastin become a casualty of the tainted steroid scandal.

“I truly believe that Avastin can be prepared safely,” he said. He cites the Miami hospital where he trained; it prepared 60,000 syringes without a single contaminated one. But, he added, “there may need to be some more regulation of compounding pharmacies.”

Working on a smaller scale

Johnson Compounding & Wellness Center is a drug store in Waltham, Mass., that opened in 1852. Stephen Bernardi and his wife are only the third family to own it. Four years ago, they sold the regular retail business to a supermarket and went into compounding — a throwback to the store’s 19th-century origins.

“I liked compounding much more than the other stuff,” he said.

The pharmacy fills 75 to 100 prescriptions a day and “every single order is an individual order.” He makes up estrogen and testosterone creams from a dozen slightly different recipes. He custom-mixes drugs for dogs, cats, ferrets and parrots. He makes eye drops in which the liquid is serum from the patient’s own blood — virtually ensured not to irritate.

In the past two years, he has added two work rooms, one sterile and one non-sterile, to his business. They were built to FDA specifications. But the FDA didn’t inspect them; the state pharmacy board did.

He’s a little mystified by the goings-on down the road in Framingham. Tens of thousands of identical doses of a drug shipped around the country — it’s not his idea of a compounding pharmacy. He’s similarly mystified when he goes to conventions and sees compounding pharmacies promoting those services.

“I just figured they had a different kind of license,” he said last week. “I don’t think they’d be at a big trade show in front of thousands of attendees advertising something that was illegal.”

All he knows is that his license won’t allow it, and he won’t do it.