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Fierce Biotech says that Pfizer has withdrawn its US and European applications for dalbavancin, a much-awaited new MRSA drug, and will conduct another Phase III trial.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

Despite stewardship efforts, antibiotic use increasing

Well, this is bad news.

I hope we can all agree that antibiotic use creates antibiotic resistance. (Proof, if any were needed, that the universe has a captious sense of humor; but then it has had millennia to practice. OK, sorry for the anthropomorphizing.) The more pressure bacteria are placed under, the more resistant mutants emerge and survive. So the challenge in using antibiotics is to use them sufficiently and not too much: enough to quell infection and save lives, but not so much that the benefit of successful treatment is outweighed by the cost of increased resistance.

That's the theory, anyway. In practice, according to a paper published today in the Archives of Internal Medicine, we're not living up to the plan.

Amy L. Pakyz, Pharm.D. and colleagues at Virginia Commonwealth University surveyed antibiotic use at 22 academic medical centers — tertiary care teaching hospitals, ones that would be most likely to have high awareness of the dangers of resistance and good antibiotic stewardship programs — between 2002 and 2006. And found: Despite all that awareness, antibiotic use is going up, and the use of broad-spectrum agents and vancomycin, MRSA's drug of last resort, is going up most of all.

The third significant observation is the marked increase in vancomycin use during the 5-year period such that it became the single most commonly used antibacterial in this sample of hospitals from 2004 to 2006. ...
The reasons for the continued increase in vancomycin use are likely multifactorial, including the increasing numbers of hospital-acquired infections caused by MRSA and the emergence of community-associated MRSA, all of which encourage greater empirical use of vancomycin.

With only a few new drugs of comparative effectiveness on the market, and none that are significantly better, this is bad news, the authors underline:

Vancomycin use is a risk factor for emergence of vancomycin-intermediate S aureus and vancomycin-resistant S aureus, although these strains are rare in the United States. Of greater concern may be the emergence of low-level resistance in MRSA to vancomycin, referred to as minimum inhibitory concentration (MIC) “creep,” and this is far more common. Strains of MRSA having vancomycin MICs of 2.0 μg/mL are associated with longer median times to clearance of bacteremia compared with strains having MICs of 1.0 μg/mL or less, as well as frank treatment failures.

The cite is: Pakyz, AL et al. Trends in Antibacterial Use in US Academic Health Centers 2002 to 2006. Arch Intern Med. 2008;168(20):2254-2260.

MRSA in meat in Louisiana: pig meat, human strain

On Nov. 3, I posted on an enterprising group of TV stations in the Pacific Northwest who had retail meat in four states tested for MRSA. I said at the time that it was the first finding of MRSA in meat in the US that I knew of.

Turns out that I was wrong by three days. On Oct. 31, the journal Applied and Environmental Microbiology published an electronic version of a study that they will be printing in the paper journal on some future date. Journals do this when a finding is so important or timely that it should see the light immediately, rather than wait through the additional weeks or months of print production.

And this finding is certainly timely. Shuaihua Pu, Feifei Han, and Beilei Ge of the Louisiana State University Agricultural Center have made what appears to be the first scientifically valid identification of MRSA in retail meat in the United States. But — and this is an important point — it is not the swine strain, ST 398, that has been found in meat in Canada and Europe, and in hospital patients in Scotland and the Netherlands, and in pigs in Iowa; and in humans in New York, though that strain was drug-sensitive.

Instead, what the researchers found (in 5 pork and 1 beef samples, out of 120 bought in 30 grocery stores in Baton Rouge, La. over 6 weeks in February-March 2008) was USA300, the dominant community MRSA strain, and USA100, the main hospital-infection strain. In other words, they found meat that had been contaminated during production by an infected or colonized human, not by a pig. As they say:

...the presence of MRSA in meats may pose a potential threat of infection to individuals who handle the food. ... (G)reat attention needs to be taken to prevent the introduction of MRSA from human carriers onto the meats they handle and thereby spreading the pathogen.

As we've discussed before, the primary danger from MRSA in meat is not that people will take the bug in by mouth (though that is a danger, since S. aureus because of its toxin production can cause severe foodborne illness — and these researchers found, overall, an S. aureus contamination rate of 46% of their pork samples and 20% of their beef samples). Rather, the danger is that people handling the raw meat will be careless in preparing it, and will colonize themselves by touching the meat and then touching their own noses or mucous membranes, leading to a possible future infection. As reader Rhoda pointed out in a comment last week, people could also infect themselves directly, by getting MRSA-laden juice or blood into an abrasion or cut.

So: Be careful in the kitchen, keep meat separate from other foods, wash cutting boards and knives, and (say it with me, now) wash your hands, wash your hands, wash your hands.

The cite for the new paper: Pu, S. et al. Isolation and Characterization of Methicillin-Resistant Staphylococcus aureus from Louisiana Retail Meats. Appl. Environ. Microbiol. doi:10.1128/AEM.01110-08. Epub ahead of print 31 Oct 08.

Housekeeping note: This is the 16th post I've written on MRSA in food animals and/or meat. Providing all the links to the previous posts is starting to obstruct the new news. So if you are looking for all those past posts, go to the labels at the end of this post, below the time-stamp, and click on "food." You should get something that looks like this.

New report and recommendations, "Why Infectious Diseases Are a Threat to America"

I'm still catching up post-ICAAC - and in addition am on the road reporting, again. But I'm trying to keep all y'all informed. (That's a clue to my destination. Where in the US is "y'all" a single noun and "all y'all" the plural? Hint: It's the same place where "barbecue" is only made of beef... Oh, OK, I'm in Texas, enough with the quiz already.)

While the ICAAC-IDSA meeting was happening, the very good nonprofit organization Trust for America's Health released a report that, just in time for the election, proposed a policy framework for emerging infections and infectious diseases generally. "Germs Go Global: Why Emerging Infectious Diseases Are a Threat to America" lists five major, ongoing, under-appreciated threats:

• Emerging infectious diseases that appear without warning (SARS, H5N1)
• Re-emerging infectious diseases (measles, pertussis/whooping cough)
• "Neglected” infectious diseases (dengue)
• Diseases used as agents of bioterrorism (smallpox, anthrax)
• Rising/spreading antibiotic resistance.

The report makes a number of important, well-argued recommendations for the next administration to consider. Several concern us particularly:

The U.S. government, professional health organizations, academia, health care delivery systems, and industry should expand efforts to decrease the inappropriate use of antimicrobials in human medicine, agriculture and aquaculture.
The U.S. Congress should amend the Orphan Drug Act to explicitly address infectious diseases like MRSA, or create a parallel incentive system to address the unique concerns in this area.

The entire report is worth reading. (If you're short on time, there is an executive summary that covers the main points.) I recommend it.

Final report from ICAAC-IDSA 08 (news from ICAAC, 3)

The ICAAC-IDSA (48th Interscience Conference on Antimicrobial Agents and Chemotherapy and 46th annual meeting of the Infectious Diseases Society of America) meeting ended a week ago, and I'm still thrashing my way through the thousands of abstracts.

Here's my final, highly unscientific selection of papers that caught my eye:

* Evidence that the community-strain clone USA300 is a formidable pathogen: It first appeared in the San Francisco jail in 2001. By last year, it had become the sole MRSA strain found in the jail — it crowded out all others. (P. Tattevin, abstract C2-225)
* Another paper from the same UCSF research group finds that the emergence of USA300 has caused a dramatic increase in bloodstream infections, most of which are diagnosed in the ER, not after patients are admitted to the hospital. (B. Diep, abstract C2-226)
* And the CDC finds that USA300 is picking up additional resistance factors, to clindamycin, tetracycline and mupirocin, the active ingredient in the decolonization ointment Bactroban. (L. McDougal, abstract C1-166)
* An example of the complexity of "search and destroy," the active surveillance and testing program that seeks to identify colonized patients before they transmit the bug to others in a health care institution: Patients spread the bug within hours, often before test results judging them positive have been returned from the lab. (S. Chang, abstract K-3379b)
* In addition to the report from Spain I posted on during the meeting, there is a report of emerging linezolid resistance in France. (F. Doucet-Populaire, abstract C1-188)
* And in addition to the abundant new news about MRSA in pork, and "pork-MRSA" or ST 398, in humans, over the past few days, there were reports of MRSA in milk in Brazil (W. Gebreyes, abstract C2-1829) and Turkey (S. Turkyilmaz, abstract C2-1832), and beef and chicken in Korea (YJ Kim, abstract C2-1831), as well as ST 398 itself acquiring resistance to additional drugs. (Kehrenberg, abstract C1-171)
* Echoing many earlier findings that MRSA seems most common among the poor, the poorly housed and the incarcerated, BR Makos of the University of Texas found that children are more likely to be diagnosed with the bug if they are indigent, or from the South (which I imagine is a proxy for lower socio-economic status, since the South is a more rural, more poor region). (abstract G2-1314)
* And finally, to the long list of objects (ER curtains, stethoscopes) that harbor MRSA, here are more: The ultrasound probes in emergency rooms (B. Wessman, abstract K-3377). Also: Dentures. (Ick.) (D. Ready, abstract K-3354)

Everyone, everyone, everyone: Vote.

I hope my constant readers outside the US will forgive me for a moment if I speak just to my countrymen.

Folks: This is the most extraordinary election of my lifetime, and I suspect of yours too.
Please vote.
The strength of our democracy depends on the participation of all of us.

And non-US readers, hold a thought in your hearts for us today.
The past eight years have displayed so much that is not good about America.
We profoundly hope for change — and we hope equally to be brave, and civil to each other, in creating it.

Thank you all.

TV stations find MRSA in retail pork in Pacific Northwest

In the comments, Coilin Nunan of the UK's Soil Association (which published the wonderful 2007 report MRSA in Farm Animals and Meat report) calls attention to a report that I also spotted over the weekend.

A network of TV stations in Washington, Idaho, Oregon and California did a joint report in which they bought 97 packages of ground pork or pork cutlets and sent them to a laboratory for testing. The lab found that three of the packages, all ground pork, contained MRSA.

I believe this is the first time anyone has found (or, perhaps, looked for) MRSA in retail pork in the US. You'll remember that MRSA ST 398 has been found in meat in Canada and Europe, and in hospital patients in Scotland and the Netherlands, and in pigs in Iowa; and MSSA ST 398 in humans in New York City.

There are some important unanswered questions about this report:

• We aren't told the strain. If it's ST 398, that would be information on the spread of ST 398 in the US. If it's USA300, on the other hand, it could be contamination from an infected or colonized human, perhaps someone in the preparation chain.
• We aren't told the provenance of the pork. Was it bought from a variety of markets, or one chain of supermarkets that might have one regional supplier? Was it organic v. conventional? Small-farm versus feedlot?
• We can't draw any broad conclusions from this. I am a poor biostatistician, but to me, this is purely a convenience sample. (If anyone disagrees with me, please weigh in.) In other words, it's one data point. It says: There is MRSA in these packages of pork — which is an important piece of information — but it doesn't say: 3% of all US pork contains MRSA.

Also, while the written version of the report that I linked above isn't bad, overall, it contains one significant error. It says:

This drug-resistant bacteria is already responsible for more deaths in the US than AIDS. What makes MRSA so potentially dangerous is the bacteria can cause sickness just by touching it.

Well, not exactly. The concern with MRSA in meat is that, if you handle it without strict cleanliness, you might become colonized with the bacteria. That is not at all the same as developing a MRSA infection, much less the invasive MRSA the first sentence of that quote refers to. And yes, colonization can lead to infection. But to say that touching MRSA-contaminated meat will inevitably cause an invasive MRSA infection is alarmist.

I'm assuming the stations undertook this because it is sweeps month. (For those who have so far been spared the internals of TV news, "sweeps" are months — usually February, May, July and November — when stations' audiences are measured to determine market rank and advertising rates. Because it is in the stations' interest to attract as much audience as possible during those months, sweeps is usually when news stations run big investigative projects.) Interesting that they chose this topic. I think we can take this as an indicator — again, just one data point, but an interesting one — of emerging US concern over MRSA in meat.

New drugs for MRSA, at various experimental stages

As you might guess by the name, ICAAC (the Interscience Conference on Antimicrobial Agents and Chemotherapy) features much research on the pharma side of things. There were many research reports this past week on drugs at various stages that I was intending to write up for you, but I just noticed that Reuters got there first and did quite a good job. So consider checking this story, which discusses PTK 0796, iclaprim, ceftobiprole, dalbavancin and televancin:

Two experimental antibiotics appear to work safely against an increasingly common and dangerous form of infection called methicillin-resistant Staphylococcus aureus or MRSA, researchers said on Sunday.
Doctors are clamoring for drugs that can fight the so-called superbug infection, which kills an estimated 19,000 people a year in the United States alone. (Reuters)

An important consideration that is not much discussed: It is not enough just to have new drugs; what we need are new classes of drugs. That's because, when staph acquires protection against one drug, it is likely to be acquiring protecting against all chemically similar drugs — thus, not just methicillin but all the synthetic penicillins; not just Keflex but all the first-generation (and second- and third-generation) cephalosporins.