Antibiotics - the EU pipeline is empty too

We've talked before about the shrinking number of drugs available to treat MRSA and about the challenges of getting new drugs to market. Well, it's not just a problem in the United States.

A new report from the European Centre for Disease Prevention and Control (ECDC) and the European Medicines Agency (EMEA) — that's the CDC and the FDA of the European Union — analyzes the bench-to-market "pipeline" of new drug development in the EU and finds... not good news. Out of 167 antibacterial agents that are somewhere in the pipeline of development, only 15 look likely to improve treatment of resistant organisms over drugs that already exist — and 10 of those 15 are in early-stage trials and will not come to market anytime soon.

That leaves 5 potential new drugs, for an epidemic of antibiotic resistance that, just in the EU, causes 25,000 deaths and $1.5 billion Euros ($2.27 billion) in extra healthcare spending each year.

(Within that epidemic of resistance, by the way, the single most common organism is MRSA.)

It's worth understanding how the agencies conducted their analysis. When we look for new drugs to treat resistant organisms, we ideally need several things:

• a formula or molecule that is new (and not just an improved version of an existing one, because if bacteria have developed resistance against the existing one, they have a head start in developing resistance against the new one)
• a new mechanism or target on the bacterial cell, and not an improved version of an existing one (ditto)
• evidence that it works in living organisms, and not just in lab dishes (in vivo, not just in vitro)
• evidence that it can be given internally, not just topically (necessary for addressing the most serious infections)
• and some indication that it is making its way through the regulatory approval process in time to achieve some practical good.

Here's what the EU pipeline looks like:

• 167 agents in process
• 90 that have shown effectiveness in vivo
• 66 that are new substances
• 27 that have a new target or mechanism
• 15 that can be administered systemically

If you're wondering whether you should be depressed, the answer is Yes.

... it is unclear if any of these identified agents will ever reach the market, and if they do, they may be indicated for use in a very limited range of infections.

The agencies call for a concerted government effort to turn this around, and ask for quick action because it takes years to get drugs through the pipeline:

...a European and global strategy to address this serious problem is urgently needed, and measures that spur new antibacterial drug development need to be put in place.

This echoes a call that has already been made in this country by the Infectious Diseases Society of America, which has asked for changes in incentives to drug-makers, and has backed what's known as the STAAR Act (STrategies to Address Antimicrobial Resistance). With this latest EU report — which comes on the heels of a US-ER agreement to work cooperatively on resistance — the IDSA is asking for an international commitment to bringing forth 10 new drugs in 10 years, what they are calling 10 x '20.

New pig strain in China

Via Emerging Infectious Diseases comes the full version of a piece of research I posted on in September that was presented at the London conference Methicillin-resistant Staphylococci in Animals: Veterinary and Public Health Implications. A new MRSA variant — not ST398 — has been spotted in pigs in China.

Luca Guardabassi and Arshnee Moodley of the University of Copenhagen and Margie O'Donoghue, Jeff Ho, and Maureen Boost of the Hong Kong Polytechnic University report that they found a pig-adapted MRSA strain in 16 of 100 pig carcasses collected at 2 wet markets in Hong Kong. By multi-locus sequence typing, the strain is ST9, previously found in pigs in France; by PFGE, they fall into categories that tend to carry the community-strain cassettes SCCmec IV and V.

Here's the bad news: This strain possesses resistance factors that resemble human hospital-associated MRSA more than they do ST398.

Twelve isolates displayed a typical multiple resistance pattern, including resistance to chloramphenicol, ciprofloxacin, clindamycin, cotrimoxazole, erythromycin, gentamicin, and tetracyline. The remaining 4 isolates were additionally resistant to fusidic acid. ... All isolates were negative for Panton-Valentine leukocidin and susceptible to vancomycin and linezolid.

The further bad news, of course, is that this is being found in Hong Kong, adjacent to China, which is the world's single largest producer of pork, raising tens of millions of tons of pig meat per year. Most of the pigs sold in Hong Kong come from the Chinese mainland, not from the SAR. Pig surveillance for MRSA in China is practically non-existent (which is not much of a criticism since it does not exist in the United States, either). A human infection with ST9 has already been recorded in Guangzhou, the province adjacent to Hong Kong.

The question, for this strain as for all MRSA strains in pigs, is what is its zoonotic potential? Here again, the news is not good. According to Maureen Boost, who presented this research at the London conference, the isolates were obtained by the researchers from intact heads from butchered pigs; the researchers took the snouts to the lab and and swabbed them there. Pig snout happens to be a desirable meat in China; it is bought in markets, taken home and made into soup. Boiling in broth would probably kill MRSA bacteria — but home butchering of a pig snout could pass the bug on to the human cutting it up, or to that human's kitchen environment, long before the snout ever got into the pot.

The cite is: Guardabassi L, O'Donoghue M, Moodley A, Ho J, Boost M. Novel lineage methicillin-resistant Staphylococcus aureus, Hong Kong. Emerg Infect Dis. 2009 Dec. DOI: 10.3201/eid1512.090378

"Pig MRSA" in the EU - long-awaited survey

It's not very likely that people will be eating much pork today — OK, maybe some pancetta in the Brussels sprouts — and that's good, because there's lots of news today about MRSA in pigs.

(In fact, there's a ton of news just this week. Make it stop.)

The European Food Safety Authority has published a long-awaited, European Union-wide survey looking for the presence of MRSA in pigs. Here's the key points: Investigators found MRSA on 1 out of 4 farms where pigs were being raised and in 17 of the 24 EU states. (Two non-member states were included in the analysis.)

Strictly speaking, this is not a survey of MRSA in pigs; the study samples not the pigs themselves, but the dust in pig-raising sheds. The sites were 1,421 breeding farms and 3,176 farms where pig are raised to slaughter age. By far the most common strain was MRSA ST398, though other strains were detected, including some known human strains. The prevalence in various countries went from a low of 0 to as high as 46% of farms. (Highest, in descending order: Spain, Germany, Belgium, Italy, Portugal. The Netherlands, where St398 was first identified, had a prevalence of 12.8%. Countries reporting no MRSA: Bulgaria, Cyprus, Denmark, Estonia, Finland, Hungary, Ireland, Latvia. Lithuania, Luxembourg, Sweden, the United Kingdom, Norway and Switzerland.)

The report closes by recommending comprehensive monitoring of pigs for MRSA, as well as monitoring of poultry and cattle.

About the potential of ST398 crossing to humans, it has this to say:

In humans, colonisation with MRSA ST398 originating from pigs has been identified as an occupational health risk for farmers and veterinarians and their families. Although MRSA ST398 represents only a small proportion of the total number of reports of human MRSA infections in the EU... in some countries with a low prevalence of human MRSA infection, CC398 is a major contributor to the overall MRSA burden.
In most cases, colonisation with MRSA ST398 in humans is not associated with disease, although clinical cases associated with MRSA ST398 have been reported. MRSA ST398 can be introduced into hospitals via colonised farmers and other persons in a region with intensive pig farming. Therefore, MRSA ST398 may add substantially to the MRSA introduced in health care settings. However, it seems that the capacity for dissemination in humans (patient-to-patient transmission) of livestock-origin MRSA, in particular ST398, is lower as compared to hospital-associated MRSA).
... Food may be contaminated by MRSA (including ST398), however there is currently no evidence for increased risk of human colonisation or infection following contact or consumption of food contaminated by ST398 both in the community and in hospital.

Britain's Soil Association, which pressed for the study to be done, has released a statement quoting the food safety agency warning that the testing method may have underestimated MRSA's presence on farms, and warning that if ST398 is not yet in England, it is certainly soon to arrive. Germany's Federal Institute for Risk Assessment also released a statement, admitting that ST398 in German pig stocks is "widespread."

The report is here, executive summary here, and press release here. All well worth reading.

CDC warns of deaths from H1N1 flu + bacterial infections

Over at CIDRAP, my colleague Lisa Schnirring writes tonight about the CDC's concern over increasing numbers of deaths from bacterial pneumonia in people who have come down with H1N1 flu.

We've talked about this before here. Our concern of course has been MRSA, and there is good evidence that there have been fatal MRSA infections in flu victims. But the primary culprit now is not MRSA but pneumococcus (S. pneumoniae):

Anne Schuchat, MD, director of the CDC's National Center for Immunization and Respiratory Diseases, told reporters at a press briefing that the CDC is seeing an increasing number of invasive pneumococcal disease cases around the country, but the numbers were particularly high in Denver at a time when pandemic H1N1 activity was peaking in the area.
Over the past 5 years the Denver area averaged 20 pneumococcal disease cases in October, but this year the area recorded 58, and most were in adults between the ages of 20 and 59, many of whom had underlying medical conditions.
Health officials expect to see more pneumococcal disease when seasonal flu circulates, but the infections typically strike people who are older than 65. In past pandemics secondary bacterial pneumonia infections, particularly those involving Streptococcus pneumoniae, frequently contributed to illnesses and deaths.

This is particularly troubling and sad because we have good vaccines for pneumococcus, one for adults and a different one for children. Only, people are not taking them: Uptake is only about 25% in high-risk groups and much lower in the general population, despite urgings from CDC and other health advisory boards.

Perhaps it's not surprising that people have not heeded advice to get the pneumococcus vaccine as a protection against flu's worst effects, given that uptake of the flu vaccine itself has been so low. But if you or someone you love is in a high-risk group, it would be a really good idea to rethink that.

Two good reports published elsewhere

Some holiday reading:

• Mike the Mad Biologist, who often blogs about MRSA, has an analysis up about the varying degrees of attention that the Senate and House healthcare reform bills give antibiotic resistance and healthcare infections
• And Jacob Goldstein at the Wall Street Journal's WSJHealth blog describes and links to a program at UCLA Medical Center that uses volunteer undergraduate observers to make sure healthcare staff wash their hands. (h/t @ePatientDave)
  

Community MRSA rates rising, and epidemics converging

A study published Tuesday in Emerging Infectious Diseases makes me happy, despite its grim import, because it confirms something that I will say in SUPERBUG: Community MRSA strains are moving into hospitals, blurring the lines between the two epidemics.

The study is by researchers at the excellent Extending the Cure project of Resources for the Future, a group that focuses on applying rational economic analysis (think Freakonomics) to the problem of reducing inappropriate antibiotic use. (Here's a post from last year about their work.)

Briefly, the researchers used a nationally representative, commercial (that is, not federal) database of isolates submitted to clinical microbiology labs, separated out MRSA isolates, divided them into whether they originated from hospitals or outpatient settings (doctors' offices, ambulatory surgery centers, ERs), and analysed them by resistance profile, which has been a good (thogh not perfect) indicator of whether strains are hospital or community types (HA-MRSA or CA-MRSA). They cut the data several different ways and found:

• Between 1999 and 2006, the percentage of staph isolates from outpatient settings that were MRSA almost doubled, increasing 10% every year and ending up at 52.9%. Among inpatients, the increase was 25%, from 46.7% to 58.5%.
• Among outpatients, the proportion of MRSA isolates that were CA-MRSA increased 7-fold, going from 3.6% of all MRSA to 28.2%. Among inpatients, CA-MRSA also increased 7-fold, going from 3.3% of MRSA isolates to 19.8%.
• Over those 7 years, HA-MRSA did not significantly decrease, indicating that CA-MRSA infections are not replacing HA-MRSA, but adding to the overall epidemic.

So what does this mean? There are a number of significant aspects — let's say, bad news, good news, bad news.

Bad: CA-MRSA strains are entering hospitals in an undetected manner. That could simply be because patients entering the hospital are colonized by the bug and carry it with them. But it could also be because healthcare staff who move back and forth between outpatient and in-patient settings — say, an ambulatory surgical center and a med-surg ward — could be carrying the bug with them as well.

Good: If they are detected (analyzed genotypically or for drug sensitivity), CA-MRSA strains are less expensive to treat because they are resistant to fewer drugs, and some of the drugs to which they are susceptible are older generics, meaning that they are cheaper.

Very Bad: The entrance of CA-MRSA strains into hospitals risks the trading of resistance factors and genetic determinants of transmissibility and colonization aptitude in a setting where bacteria are under great selective pressure. Several research teams have already seen this: In several parts of the country, CA-MRSA strains have become resistant to multiple drug families.

Is there a response? The work of Extending the Cure focuses on developing incentives that will drive changes in behavior around antibiotic use. These results, lead author Eili Klein told me, call for developing incentives for creating rapid diagnostic tests that will identify not just that a bug is MRSA, but what strain it is, so that it can be treated appropriately and not overtreated.

The results also underline the need for something that is particularly important to me: enhanced, appropriately funded surveillance that will define the true size of the MRSA epidemic and delineate the behavior of the various strains within it. Right now, surveillance is patchy and incomplete, done partially by various CDC initiatives and partially by the major MRSA research teams at academic medical centers. As we've discussed, there is no national requirement for surveillance of patients, and very few state requirements; there is no incentive for insurance companies to pay for surveillance, since it benefits public health, not the patient whose treatment the insurance is paying for; and there is a strong disincentive for hospitals to disclose surveillance results, because they will be tarred as dirty or problematic. Yet to know what to do about the MRSA epidemic, we first have to know the size and character of what we are dealing with, and we do not now.

The cite is: Klein E, Smith DL, Laxminarayan R. Community-associated methicillin-resistant Staphylococcus aureus in outpatients, United States, 1999–2006. Emerg Infect Dis. DOI: 10.3201/eid1512.081341

Antibiotic misuse in animals - one example

Via the Minneapolis Star Tribune and the excellent blog Fair Food Fight comes the story of two cows, from two Minnesota farms, that have been reprimanded by the US Food and Drug Administration for bringing cows to slaughter that turned out to have been massively overdosed with antibiotics.

From the Strib:

In a rare move, federal officials sent stern warning letters to two central Minnesota dairy farms, which were among only 30 farms nationwide reprimanded so far this year for violating the rules governing how animal drugs can be used.
J&L Dairy, in Clarissa, Minn., sent a dairy cow to slaughter in March, even though it was drugged with 129 times the amount of penicillin allowed under federal regulations.
Another farm, Evergreen Acres Dairy, LLC, in Paynesville, Minn., was warned by the FDA last month, after one of its cows was found to have more than four times the allowed amount for a certain type of antibiotic. Further inspection found that the farm had misused 10 other drugs. (Byline Lora Pabst)

From one of the FDA's reprimand letters, to J&L Dairy of Clarissa, Minn.:

Our investigation ... found that you hold animals under conditions that are so inadequate that medicated animals bearing potentially harmful drug residues are likely to enter the food supply. ... Our investigation found that you routinely administered penicillin G procaine to dairy cows without following the daily dosage amount or dosage amount per injection site as stated in the approved labeling. Your extralabel use of penicillin G procaine was not under the supervision of a licensed veterinarian, in violation of 21 CFR 530.11 (a), and your extralabel use of penicillin G procaine resulted in illegal drug residue, in violation of 21 CFR 530.11(d).

From the other reprimand letter, to Evergreen Acres Dairy of Paynesville, Minn.:

Our investigation ... found that you hold animals under conditions that are so inadequate that medicated animals bearing potentially harmful drug residues are likely to enter the food supply.
...The investigation ... found that you adulterated the new animal drugs neomycin sulfate, sulfadimethoxine oral solution, oxytetracycline injection, oxytetracycline hydrochloride injection, ceftiofur hydrochloride, ceftiofur crystalline free acid, ceftiofur sodium, penicillin G procaine aqueous suspension, florfenicol, tetracycline hydrochloride soluble powder, and tylosin. Specifically, the investigation revealed that you did not use these drugs as directed by their approved labeling. Use of these drugs contrary to their approved labeling is an extralabel use.

There are some important points to make here.

As we've talked about before, many of the antibiotics used in food animals are effectively over-the-counter drugs; farmers can buy them in feed stores and administer them without a veterinarian's supervision. (Putting an end to OTC animal antibiotics is the goal of Rep. Louise Slaughter's legislation, the Preservation of Antibiotics for Medical Treatment Act (PAMTA), supported by the Obama Administration supports; post here.) Without such supervision, it is easier for a farmer to make a mistake in dosing, or to give the drugs too close to animal's slaughter time, so that the drug's don't wash out of the animal's system but remain in its meat after death.

A second important point is that we talk a lot here about the dangers of industrial-scale farming, in which antibiotics are given to animals that are not sick, either in small doses as growth promoters or in treatment-size doses to prevent illness spreading through a flock or herd. Antibiotic misuse has become linked in the public mind with the enormous animal-raising operations known as CAFOs. But both these reprimanded farms were family farms, not CAFOs. These reprimands underline that inappropriate antibiotic use is not a function of farm size — it's a by-product of market pressure.

It's (European) Antibiotic Awareness Day

UK and EU readers can hug themselves with self-congratulation this morning (OK, admittedly, for you it's afternoon already): It's Antibiotic Awareness Day across the European Union, featuring a slate of public-awareness activities, public-service announcements, educational efforts, and random appearances by the charming little hedgehog above (kicking antibiotics, don't you see). It's all meant to convince people that antibiotics are a precious resource and that misusing them encourages antibiotic resistance.

The campaign is organized by the European Centre for Disease Prevention and Control (the EU equivalent of the US CDC) and is being carried out by an enviably long list of national agencies within the EU. It's accompanied by the publication in the journal Eurosurveillance of an article setting out the challenges of controlling antibiotic resistance across such diverse nationalities and geographies.

There are materials on the site that would be useful for anyone attempting to get the message of antibiotic stewardship across to physicians, family members or friends: There's a fact sheet for the general public, one for physicians and other experts, and one that specifically addresses the temptation to take antibiotics in cases of H1N1 flu.

There's also a short film explaining the genesis of Antibiotic Awareness Day and the basics of antibiotic resistance, and a marvelous set of pull-no-punches short video spots. This one — comparing antibiotics to a lightbulb slowly burning out — is my favorite.

Antibiotic resistance: international news

Constant readers, we've often talked about MRSA and other resistant pathogens as a global problem (cf. these posts for resistance issues in Europe and these for resistance around the world).

But now there has been formal recognition that resistant bacteria respect no borders. On Nov. 3, the US government and the European Union signed an agreement to form a joint task force to investigate and combat antibiotic resistance. From the Joint Declaration, posted on WhiteHouse.gov:

[We therefore agree}... To establish a transatlantic task force on urgent antimicrobial resistance issues focused on appropriate therapeutic use of antimicrobial drugs in the medical and veterinary communities, prevention of both healthcare- and community-associated drug-resistant infections, and strategies for improving the pipeline of new antimicrobial drugs, which could be better addressed by intensified cooperation between us.

You may not have heard much about it here, but in Europe, this declaration was big news. Here's a story from the Swedish newspaper Arbetarbladet (Sweden currently holds the EU Presidency) and another from the Irish Times. But while it merited barely a blink in the US mainstream media, US nonprofits were deeply involved in the declaration, notably the Infectious Diseases Society of America and the Pew Charitable Trusts:

"Antimicrobial resistance and the lack of new antimicrobial agents to effectively treat resistant infections are problems that no country can deal with alone -- they threaten the very foundation of medical care," said Richard Whitley, MD, FIDSA, president of the Infectious Diseases Society of America (IDSA). "Without effective antimicrobial drugs, modern medical treatments such as operations, transplants, intensive care, cancer treatment and care of premature babies will become very risky if not impossible." Dr. Whitley joined with Javier Garau, MD, president of European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Shelley A. Hearne, managing director of the Pew Health Group in welcoming the multi-country initiative.
..."Antibiotic resistant bacteria respect no political borders, so we must work together to combat them," Dr. Hearne said. "Resistance takes a terrible toll on health worldwide and is measured in lives lost, greater suffering and higher health care costs. One way that U.S. leaders can demonstrate their commitment to solving this issue is by immediately joining the EU in banning non-judicious antibiotic uses in food animal production." (Pew press release)

This fresh focus on the problem of resistance will be sharpened in Europe this week with the celebration of European Antibiotic Awareness Day. (We should be so lucky.) More on that on Wednesday.

Antibiotic-resistant infections: millions in cost to hospitals, families, all of us

Folks, I mentioned that I'm way behind in working down a stack of great articles. Here's a very good one that I missed when it came out two weeks ago and is well worth your time.

A team from John H. Stroger Hospital (the new location of the iconic Cook County Hospital, public hospital for downtown Chicago) and from the Alliance for the Prudent Use of Antibiotics at Tufts University (headed by Dr. Stuart Levy, dean of antibiotic resistance scholarship in the US) has analyzed the direct and distributed costs of resistant infections, and their results are stunning. They took a random sample of patients seen at the hospital, sorted out a subgroup that suffered from resistant infections, and computed the costs that those infections imposed: in medical costs, increased length of stay, and excess deaths. Those sort of calculations have been done before at other institutions (cf. for instance the excellent work of Susan Cosgrove of Johns Hopkins), but what makes this Chicago study striking is an additional layer of analysis that computes the "social cost" to the families of those infected.

In the study's words:

In a sample of 1391 patients, 188 (13.5%) had [antibiotic-resistant infections]. The medical costs attributable to ARI ranged from $18,588 to $29,069 per patient in the sensitivity analysis. Excess duration of hospital stay was 6.4–12.7 days, and attributable mortality was 6.5%. The societal costs were $10.7–$15.0 million.

(Just to underline: These are almost certainly underestimates of the current problem and its current costs — because to get very solid data, the Stroger team went back in their database to patients who were treated in 2000. That's before the emergence and dominance of CA-MRSA USA300 nationwide, and its subsequent movement into hospitals. Since 2000, the MRSA epidemic has gotten worse.)

An accompanying editorial takes the next step in logic, stressing that if we're not going to work to reduce ARIs because it is good medicine to do so, we should do it because it is critically cost-saving:

...[T]he findings of Roberts et al [11] are significant, making a strong case for both the medical and financial benefits of reducing antimicrobial resistance. This is an important and timely question, considering the national focus on the prevention of health care–acquired infections, a significant proportion of which are caused by antimicrobial-resistant organisms, and the call for institutions to develop antimicrobial stewardship programs. These data should help inform decisions regarding the structure and implementation of health care initiatives designed to improve patient care while controlling unnecessary costs.

The cite for the study is: Rebecca R. Roberts, Bala Hota, Ibrar Ahmad et al. Hospital and Societal Costs of Antimicrobial‐Resistant Infections in a Chicago Teaching Hospital: Implications for Antibiotic Stewardship. Clinical Infectious Diseases 2009 49:8, 1175-1184.

It's World Pneumonia Day

Readers, we talk all the time here about the unexpected and deadly attack of MRSA pneumonia, both on its own and as a sequela of influenza infection. But we should acknowledge that MRSA pneumonia is part of an epidemic of pneumonia, an under-appreciated disease of severe lung inflammation that takes the lives of 2 million children each year around the world.

Today, Nov. 2, has been declared World Pneumonia Day by an enormous coalition of global health organizations that includes UNICEF and Save the Children. (Mis amigos Latinos sabrán que está hoy también Dia de los Muertos. Fitting, no?) From their press release: "Pneumonia takes the lives of more children under 5 than measles, malaria and AIDS combined. The disease takes the life of one child every 15 seconds, and accounts for 20% of all deaths of children under 5 worldwide."

World Pneumonia Day is being marked by events around the globe (here's a clickable map) and by the release of a World Health Organization report, the Global Action Plan for Prevention and Control of Pneumonia. The plan has three main goals, aimed at the recourse-poor countries where most pneumonia deaths occur:

• promote breastfeeding to ensure children's nutrition and good immune status
• protect immunity by guaranteeing the distribution in the developing world of the pneumonia vaccines we take for granted in the industrialized world, against Haemophilus influenzae and Strep pneumoniae (pneumococcus)
• treat children when they need it by making sure that there is adequate, local primary care and — important for our purposes especially — also making sure that antibiotics are used appropriately, but not overused.

The international organization GAVI (formerly known as the Global Alliance for Vaccines and Immunization, now going just by its acronym) has announced plans to immunize 130 million children worldwide against pneumonia and other diseases by 2015.

I want to underline that pneumonia is of interest to us for several reasons: not just because we are concerned for MRSA pneumonia, but also because we are in the midst of the H1N1 pandemic, and as we have talked about before, bacterial infections appear to be playing a role in a significant percentage of the deaths. There is no MRSA vaccine, but there are Hib and pneumo vaccines, which might have prevented some of those deaths. So increasing the administration of pneumonia vaccines could affect the course of this pandemic right now, as well as the fates of children all over the world who have not contracted this flu but will be in danger of bacterial pneumonia in the future.