More bad news on new drugs

The Infectious Diseases Society of America (IDSA) has published a new report that fills in the background on last week's news below, and confirms: The landscape for new drugs against MRSA and other multi-drug resistant organisms is bleak. (The organisms, summarized in the acronym ESKAPE, are: E. faecium, MRSA, Klebsiella, Acinetobacter, Pseudomonas aeruginosa and Enterobacter.)

The report, published in the journal Clinical Infectious Diseases, is both an update of surveys of the new-drug landscape done in 2004 and 2006, and also a call to action that asks for broad federal effort to encourage pharma companies to produce new drugs.

Here are the highlights:

• Since the last iteration of the survey in 2006, only one new antimicrobial, doripenem — a very broad-spectrum injectable that is most active against the Gram-negative bacterium P. aeruginosa — has been approved.
• Only three new compounds — ceftobiprole, dalbavancin and Paratek Pharmaceutical's PTK-0796 — are in their final rounds of trials. (The report was obviously written before the latest news about ceftobiprole and dalbavancin.)
• Four of seven efforts to achieve a staph vaccine have been terminated.
  
• Though the pharma industry, through its lobbying arm PhRMA, claims "388 infectious diseases medicines and vaccines and 83 antibacterial drugs in development", that number is misleading:

Careful review of these data reveals that most are preclinical and phase 1 compounds. Also included are topical and nonabsorbable antimicrobials, which we do not consider here, and several compounds for which development has been terminated. Finally, ... many of the listed drugs are previously approved agents that are being studied for new indications.

Just to make sure no one misses the big picture, the authors emphasize:

...The number of new antibacterials that make it through the complete development process and ultimately receive FDA approval has precipitously decreased over the past 25 years. Indeed, we found a 75% decrease in systemic antibacterials approved by the FDA from 1983 through 2007, with evidence of continued decrease in approvals, even during the most recent 5-year period.

What are the answers? IDSA is candid, as in its earlier reports, that it believes incentives for drug companies are the only way to improve the situation: financial boosts, patent extensions and changes in trial requirements. Two things are critical, the group says:

• Novel intravenous and oral drugs to treat both hospitalized and community-based patients are needed, as opposed to “me too” drugs that provide minimal improvement over existing therapies.
• Priority should be given to antimicrobials with the potential to treat serious infections that are resistant to current antibacterial agents.

Bad news on the new-drugs front

Via the very robust pharma blogosphere, reports that two much-anticipated new antibiotics will be remaining in the pipeline a while longer:

Fierce Biotech says that Pfizer has withdrawn its US and European applications for dalbavancin, a much-awaited new MRSA drug, and will conduct another Phase III trial.

Pharmalot reports (via Reuters) that the Food and Drug Administration has asked for additional trials for ceftobiprole, another much-anticipated new drug for MRSA, coming from Johnson & Johnson. Shearlings Got Plowed has more detail, speculates that a "new game face" is emerging at the FDA, and notes that J&J's partner in ceftobiprole, Basilea, acknowledged that the FDA raises "issues of data integrity" regarding the current application. J&J's press release is here.

So it's back to vancomycin, again, for now.

MRSA in newborns on Prince Edward Island: HA? CA? Matters?

There's been a running story for several weeks now about the Queen Elizabeth Hospital on Prince Edward Island (home to mussels and Anne of Green Gables). The hospital struggled earlier this year with an outbreak of MRSA and a second outbreak of VRE among adult patients. It got those under control, but since earlier this month has been dealing with a new outbreak of MRSA in its newborn nursery, according to the PEI Guardian:

Nine newborns and one mother have now tested positive for MRSA. Five of those nine cases can be connected to the same source. (Byline: Wayne Thibodeau)

The stories are detailed, for a small paper — they go into depth about the cleaning measures the hospital is taking — and yet they don't answer the questions that we here want to know. Does "tested positive" mean colonized or infected? Does "connected to the same source" mean they all have the same strain, or does it mean there is an epidemiologic link?

In the latest news (Tuesday's paper and online edition), the hospital reports that it is doing nasal swabs on more than 300 staff, with the intention to do a 7-day decolonization regimen on anyone who turns up positive. They won't however, disclose the source when they find it — though, again, it's not clear whether that means not identifying the staffer (appropriate) or not admitting that it is a nosocomial outbreak (inappropriate and at this stage lacking in credibility):

Rick Adams, CEO of the Queen Elizabeth Hospital, said about 290 staffers have already been screened.
“In terms of the test results, we’re not going to be making anything public,’’ Adams told The Guardian.
“We want to make sure the environment here is supportive of staff and create a climate where they can feel comfortable and open to come forward and be screened knowing that any results will be kept strictly confidential.’’
Adams said he realizes a solid argument can be made that the public should be informed if the source is found and that source is a staff member.
But he said the public should also realize the hospital is doing everything it can to prevent a further spread of the superbug.
“The staff are under enormous pressure. They feel like they are under a microscope.’’ (Byline: Wayne Thibodeau)

Some readers may know that it is outbreaks among newborns that have demonstrated that the designations "community-associated" and "hospital-acquired" are passing out of usefulness. There have been several MRSA outbreaks in newborns and their mothers in the US (in New York City, Houston, Chicago, Los Angeles and Houston again because Baylor College of Medicine has been particularly alert to this) that were clearly nosocomial, and yet when the microbiology was done, were found to be caused by community strains.

Why does this matter? Well, for the PEI hospital, it may not: They have an outbreak, it appears to be nosocomial in nature, and whether it is HA left over from their earlier outbreak, or CA that came in via a health care worker or a pregnant woman, mostly affects what drugs they give the children and mothers if those patients do in fact have infections. And for those of us who are primarily concerned with nosocomial infections, the distinction may also feel not-relevant: Failures of infection control are failures of infection control and should not happen period full stop.

But for those of us who are are also interested in the natural history of this perplexing bug, the answer to what is going on at the Queen Elizabeth will be an important piece of information, because it could underline that the distinction between HA and CA is becoming increasingly artificial. The epidemics are converging.

British infection control: Epic fail

Via the Guardian comes news that British hospitals are failing miserably at hygiene and infection-control targets set by the Healthcare Commission, a government-funded but independent watchdog agency somewhat analogous to the United States' Joint Commission (formerly called JCAHO).

While community-associated MRSA is still a somewhat new story in the the UK, hospital or nosocomial MRSA is a major epidemic, with resistant Clostridium difficile ("C.diff") coming close behind. So there has been significant attention paid in the UK to improving infection control programs in hospitals, through the vehicle of benchmarks set for the National Health Service trusts (essentially, regional organizational groupings of hospitals).

And the results, according to unannounced spot-checks made by the UK commission, are appalling. Only 5 of 51 trusts ( 51 = 30% of all acute-care hospitals in the UK) that were checked hit the mark. For those slow at math, that means 3% of UK hospitals are doing what they should to protect patients from infections they cause. (UPDATE: To be fair, if we assume the "5 out of 51" holds true across the NHS, then 10% are doing what they should. That's still appalling.)

"At nearly all trusts we have found gaps that need closing," said Anna Walker, the commission's chief executive. "It is important to be clear that at these trusts we are not talking about the most serious kind of breaches. But these are important warning signs to trust boards that there may be a weakness in their systems." (Byline: Sarah Boseley)

How weak? This weak, according to the commission's own report:

• 27 of the 51 trusts inspected were failing to keep all areas of their premises clean and well maintained. These lapses covered issues ranging from basic cleanliness, to clutter which makes cleaning difficult, to poorly maintained hospital interiors.
• One in five trusts in this sample did not comply with all requirements for the decontamination of instruments and other equipment used in the care of patients. Trusts that breached this duty tended to have no clear strategy for decontamination or to lack an effective process to assure compliance.
• In one in eight trusts, the provision of isolation facilities was not adequate. The containment of infections is extremely important to managing outbreaks. Hospitals without adequate facilities must ensure they have contingency plans so that the risk of infections spreading between patients is minimised.
• For over one in five trusts there were issues related to staff training, information and supervision. While training on preventing and controlling infection was often in place, boards could not always ensure that training days were well attended or that staff used their knowledge in practice.

UK hospitals have until next April to learn to hit these benchmarks or be held accountable under a new Care Quality Commission.

For infection-control geeks, the full text of the "hygiene code" which the hospitals must abide by is here. Details of inspections at individual trusts are here.

A moment of silence

Constant readers, I am very sad to tell you that Lori Hall Steele, the writer and single mother afflicted with amyotrophic lateral sclerosis, died Wednesday. As I told you back in September, she could no longer work, could not pay her mortgage or her medical bills, and was about to lose her house to foreclosure, leaving her 7-year-old son homeless at the same time that she was about to be hospitalized with what is inevitably a fatal disease. The news prompted a blogathon on her behalf by fellow freelancers around the country that raised almost $20,000 more than $30,000, enough to ensure that her house was safe for as long as necessary.

A heartbreaking essay that she wrote about her son, before she knew she was sick, is here.

Many of you told me privately how much this story touched you. (And readers outside the US expressed shock that the cost of healthcare could turf a dying young mother out of her home.)

I send sincere thanks to all of you who sent Lori (whom I never met) money, or prayers, or warm thoughts for her and for her son. I am confident that none of it was in vain.

UPDATE: Lori's obituary is here.

Contributing to resistance: fake drugs?

There's news this morning that Interpol has seized $6.65 million of counterfeit medicines in the culmination of a 5-month undercover investigation that stretched across Cambodia, China, Laos, Myanmar, Singapore, Thailand and Vietnam. The fakes included purported antiretrovirals for HIV, anti-TB drugs, antimalarials (especially artemisinin) — and, chillingly for our purposes here, fake antibiotics for pneumonia and other bacterial illnesses.

Bloomberg News says:

Under Operation Storm, which ran from April 15 to Sept. 15, police seized more than 16 million pills...
Asia is the world's biggest producer of all counterfeit products, the Organization for Economic Cooperation and Development said in a report last year. About 40 percent of 1,047 arrests related to fake drugs worldwide last year were made in Asia, according to the Washington-based Pharmaceutical Security Institute.
Counterfeits account for as much as 30 percent of all drugs in developing nations and less than 1 percent of all medicines in developed nations such as the U.S. (Byline Simeon Bennett.)

Counterfeiting medicines is both a huge business — the World Health Organization estimates that "counterfeit drug sales will reach US$ 75 billion globally in 2010, an increase of more than 90% from 2005" — and an appalling crime that attacks the most vulnerable people at their most vulnerable moments. In a recent issue brief, the WHO recounts a number of instances of counterfeiting that led to deaths in a number of countries.

Why should we care here? Because some counterfeits are not complete fakes; they contain a small amount of the active ingredient of the drug they purport to be. That means that, if someone takes a faked version of an antibiotic, they may not be going untreated. Instead, they may be undertreated, the exact situation that can lead to the emergence of resistance. Just last year, according to the Pharmaceutical Security Institute, known counterfeiting episodes involving anti-infective drugs rose 26%.

Now, NB: Activism against counterfeit drugs is politically complicated; it is supported by the pharma industry (PSI is a coalition of 26 manufacturers) and is tangled up with opposition to online pharmaceutical sales and to decisions by developing-world countries to abrogate Western drug patents. But that turf-defending by the pharma industry does not alter the reality that counterfeit drugs are an enormous international problem that imperil not only people unfortunate enough to take them, but anyone who contracts a resistant strain that those drugs helped foster.

And anyone concerned about MRSA will already know that resistant strains do not stay where they are generated. They have already demonstrated their ability to move rapidly around the world.

New newspaper series on HA-MRSA

The Seattle Times this morning launched an three-day investigative project on incidence of HA-MRSA in Washington State that is worth reading.

As readers here already know, MRSA is not a reportable disease, and there are no diagnosis codes that directly correspond to MSRA that make infection or death easily trackable through hospital records or death certificates. The Times' team came up with some innovative data-drilling techniques and apparently did a massive amount of number-crunching to come up with the incidence estimates that underpin their reporting. They use those to challenge hospitals' reluctance to undertake surveillance and treatment that would wipe out MRSA on colonized patients and thus reduce the likelihood of MRSA infecting those patients or spreading to others via healthcare workers who neglect infection control. (NB, Michael Berens, the series' co-author, did a huge project on nosocomial infections when he was at the Chicago Tribune a number of years ago.)

I am puzzled by one thing I am seeing on the story's web page — one of the items in the break-out box that sums the story up very quickly to attract eyeballs to it. It says: "About 85 percent of people infected with MRSA get the germ at a hospital or other health-care facility. " That figure doesn't make sense to me; it sounds as though it is a mis-translation of the CDC finding a year ago (in the Klevens JAMA paper) that approximately 85% of invasive cases of MRSA have hospital-associated risk factors. Constant readers will remember that estimate has been challenged by researchers on community MRSA, who believe that CA-MRSA accounts for a much larger proportion of the current epidemic than has been acknowledged, and think that the wide spread of the community strain is the actual driver of the overall epidemic. I can't see where in the text the Times team has done the math to support that assertion, so if anyone else spots it, or knows the reference it comes from, please let me know.