Maryn McKenna

Journalist and Author

Once again, flu and bacterial co-infection

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With the H1N1 pandemic trending down, it may seem that the question of how much bacterial co-infection affects the outcome of flu is less important than it was. But though the pandemic is subsiding — for ever, for this season, or just until a third wave, who can say — researchers are just now getting enough good data to be able to make solid observations about what happened during the past 10 months.

Case in point: Writing in the journal Public Library of Science (PLoS) ONE, a team of researchers from Australia has pinpointed the incidence of MRSA co-infection during flu in two hospitals in Perth last summer, which was the Australian winter and the height of their flu season. Of 252 patients admitted for H1N1 infection, 3 were identified during treatment as having MRSA pneumonia. They survived, but two other patients who died were found to have MRSA pneumonia during post-mortem exams.

There were 3 female and 2 males, aged between 34 and 79 years… Two patients lived at the same long-term care facility, whilst the other patients lived independently in the community. Four of the 5 patients had conditions that may have increased their risk of pneumonia, including quadriplegia (two patients) asthma (one patient), cirrhosis (one patient) and diabetes mellitus (one patient). Two of the 5 cases (patients 3 and 4) had known MRSA infection/colonization prior to the onset of their illness (with the same cMRSA clone that subsequently caused their co-infection).

 There are some interesting points embedded here. First, incidence: In the Australian patients, MRSA pneumonia was much more common. The Perth researchers found 5 MRSA cases out of 252 flu patients. When the CDC analyzed the occurrence of MRSA pneumonia in flu last summer, it found only 1 case out of 272. Second, treatment: None of the 5 patients got antibiotics that would have affected MRSA — even though two of them were already known to be MRSA carriers. The possibility of MRSA pneumonia subsequent to flu seems not to have occurred to the health professionals taking care of them.

And third, the pathogen: The 5 Australian cases were caused by 3 community MRSA strains that are common in Australia — but only one of the 3 made PVL, the toxin that has so frequently been associated with MRSA pneumonia. That is interesting, and troubling at the same time. At this point, the association of PVL and necrotizing pneumonia has become practically taken for granted; and yet here are two strains that did not make PVL and yet caused severe and fatal pneumonia. It may be an indication that the inflammation that flu causes in the lung can open the door to more severe damage even when PVL is not present; it’s certainly an indication that the absence of PVL does not signal a mild or not-dangerous strain.

The cite is: Murray RJ, Robinson JO, White JN, et al. 2010 Community-Acquired Pneumonia Due to Pandemic A(H1N1)2009 Influenzavirus and Methicillin Resistant Staphylococcus aureus Co-Infection. PLoS ONE 5(1): e8705. doi:10.1371/journal.pone.0008705.
Simultaneously, a new paper in the American Journal of Pathology seeks to clarify how often and in what circumstances bacterial superinfection becomes a risk during flu. Using a range of mice — both healthy ones, and “knockout” mice bred to be without particular immune-system components — researchers from San Diego confirmed that infections with flu and with Haemophilus influenzae can be lethal when the flu infection precedes the bacterial one. That was true even for infections that, if experienced separately, would not have been lethal; it was the synergy of the two infections, flu first followed by the bacterial infection, that caused the high mortality rate. The results may not be directly applicable to human medicine (Do you all know the old flu-research saying, “Mice lie and ferrets mislead?”), but they are an important indicator both of the seriousness of bacterial infection after flu, and also of the potential vulnerability of even healthy beings to that one-two punch.
The cite is: Lee LN, Dias P, Han D, et al.: A mouse model of lethal synergism between influenza virus and Haemophilus influenzae. Am J Pathol 176: 800-811.

News round-up!

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As promised, lots to catch up on — so here’s a quick round-up of some great reading that I have been stashing and that you may have missed in the past few weeks.

BBC News: Disinfectants may train bacteria to resist antibiotics
The BBC Health page (bookmark it!) translates a paper from the journal Microbiology on Pseudomonas aeruginosa’s newly recognized ability to pump the active ingredient in disinfectants out of its cells — and then to apply that same ability to the antibiotic Ciprofloxacin, even when it has never been exposed to Cipro before. Money quote: “... Residue from incorrectly diluted disinfectants left on hospital surfaces could promote the growth of antibiotic-resistant bacteria.”

Associated Press:  Solution to killer superbug found in Norway
In the latest installment in a 6-month series, AP writers Martha Mendoza and Margie Mason examine Norway’s success in forcing down rates of hospital MRSA. chiefly by extremely strict control of antibiotics dispensed in hospitals. I have some disagreements with this story; I don’t think they account for how much easier it is to do antibiotic stewardship, as it’s called, in a single-payer health system such as Norway or their second example, England, compared to the extremely complex US system. But I’m very glad to see the AP (and the Nieman Foundation at Harvard, where Mason was a fellow) support public exploration of antibiotic resistance, which I obviously feel gets insufficient attention. (Stay tuned for SUPERBUG’s discussion of one US stewardship program that has worked and may be replicable.)

Time: Should weight factor into antibiotic dosage?
Time.com looks at a provocative new paper in the Lancet that questions whether standard prescribed dosing of antibiotics isn’t really a form of inappropriate use. Money quote: “Dosage according to body mass is standard in anesthetics, pediatrics, oncology and other fields, [but] when it comes to antibiotics and antimicrobials the dosing guidelines are too broad… and may undermine a medications efficacy. …In the face of both widespread obesity and the increasing prevalence of antibiotic-resistance, tailoring dosage for optimal results is increasingly important.“

And finally, new today:
Science Daily: Bacteria Are More Capable of Complex Decision-Making Than Thought
University of Tennessee researchers explore the ability of a bacterium (the soil bacterium Azospirillum brasilense) to sense changes in its environment, process that information and make surprisingly complex decisions in response.

Warning on ST398: Monitor this now

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Drawing your attention: I have a story up tonight at CIDRAP on a new paper by Dr. Jan Kluytmans, a Dutch physician and microbiologist and one of the lead researchers tracking “pig MRSA,” ST398. (All past stories on ST398 here.) It’s a review paper, which is to say that it summarizes key existing findings rather than presenting original research.

Still, it’s important reading because Kluytmans is one of the few scientists who have some history with this bug and understand how quickly and unpredictably it has spread across borders and oceans, from pigs to other livestock, to pig farmers and veterinarians, into health care workers and hospital patients who have no known livestock contact, and now into retail meat in Europe, Canada and the United States.

Take-away: A plea and warning for better surveillance, so that we can track not only the bug’s vast range, but also its evolution as it moves into new ecological niches — including humans who are buying that retail meat and possibly becoming colonized with it as they prep it for cooking in their home kitchens.

To honor fair use (and in hopes you’ll kindly click over to CIDRAP), I won’t quote much, but here’s the walk-off:

Because the novel strain has spread so widely and has already been identified as a cause of hospital outbreaks, it should not be allowed to spread further without surveillance, Kluytmans argues.”It is unlikely that this reservoir will be eradicated easily,” he writes. “Considering the potential implications of the reservoir in food production animals and the widespread presence in meat, the epidemiology of [MRSA] ST398 in humans needs to be monitored carefully.”

The cite is: Kluytmans JAJW. Methicillin-resistant Staphylococcus aureus in food products: cause for concern or case for complacency? Clin Microbiol Infect 2010 Jan;16(1):11-5. The abstract is here.

MRSA in pets – a closer look

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From the research team at the University of Guelph Ontario Veterinary College — who have probably done more than any other group to elucidate MRSA in companion animals — comes a look at MRSA infections in dogs.

In order to get better data, the team used a study model that is much-employed in human epidemiology — and has often been used for MRSA — but under-employed in veterinary medicine: a case-control study matching MRSA infections against MSSA, or drug-sensitive staph. Studies matching MRSA against MSSA have been able, for instance, to show that certain (human) MRSA infections have higher death rates, keep patients in the hospital longer, and cause more healthcare expense.

The Guelph team used the same method to compare the presentation and outcome for 40 MRSA-infected dogs and 80 dogs with MSSA who were seen between 2001 and 2007 in three veterinary hospitals, in Guelph, Philadelphia and Boston. Their verdict:
MRSA is an emerging problem in dogs, and the risk factors for MRSA infections are similar to those in humans, particularly the use of IV catheters and both beta-lactam and fluoroquinolone antibiotics.

The researchers were not able to say whether MRSA in dogs causes more deaths than MSSA, because the infections that were recorded by the hospitals were mostly superficial ones in skin and ears:

Infection types for which death would be a more realistic possible outcome were limited… Comparison of mortality rates between patients with MRSA or MSSA infections would be best performed among on ly those with invasive infections and should be considered for future studies. Here, mortality rate information was obtained retrospectively and only recorded up to the time of discharge. Therefore, whether dogs died from their infections after discharge from the referral hospital, causing an underestimate of deaths, is unknown.

Dr. Scott Weese, senior author of this paper and chief of the Guelph group, has an excellent blog on infections in companion animals, called Worms and Germs. (It’s in the blogroll.) And if you are looking for further information on MRSA in pets, the best resource I know of is the UK-based, but international, Bella Moss Foundation, named for a dog that died of a MRSA infection.

One surgical infection with MRSA: $61,000

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From a multi-state, public-private research team — Duke University, Wayne State University, and the Durham, NC VA — comes a precise and alarming calculation of MRSA’s costs in hospitals: For one post-surgery infection, $61,681.

The group compared the course, costs and final outcome of three matched groups of patients from one tertiary-care center and six community hospitals in one infection-control network run by Duke. The three groups were: patients with a MRSA surgical-site infection; patients with a surgical-site infection (SSI) due to MSSA, drug-sensitive staph; and surgery patients who did not experience infections, matched to the other two groups by hospital, type of procedure, and year when the procedure took place. (This same cohort has been described in an earlier prospective study that looked at risks for MRSA SSIs.) Altogether, there were 150 patients with MRSA SSIs, 128 with MSSA SSIs, and 231 uninfected surgery patients to serve as controls.

Here’s what they found. Patients with post-surgical MRSA infections:

  • stayed in the hospital 23 days longer
  • incurred an average extra cost of $61,681
  • were more likely to be readmitted to the hospital within 90 days
  • were more likely to die before 90 days had passed.

The authors write:

Our study represents the largest study to date of outcomes due to SSI due to MRSA. Our findings confirm that SSIs due to MRSA lead to significant patient suffering and provide quantitative estimates of the staggering costs of these infections. SSI due to MRSA led to a 7-fold increased risk of death, a 35-fold increased risk of hospital readmission, more than 3 weeks of additional hospitalization, and more than $60,000 of additional charges compared to uninfected controls.

For just the patients in this study, the excess costs (across 7 hospitals) totalled $19 million.

This is a highly useful study on several axes. First, remarkably, there has not been agreement over whether and how much of a problem MRSA poses in post-surgical settings, particularly when compared to drug-sensitive staph. This study provides careful, thoughtful, well-documented proof that combating MRSA infection is worthwhile. (NB, MRSA infections did not increase the risk of death relative to MSSA infections, which should remind us both of the often-forgotten virulence of MSSA, and also that MRSA’s perils can lie in extended illness and disability as much or more as in early death.) Second, by putting a very specific number on the cost of a post-surgical MRSA infection, it gives healthcare administrators a benchmark against which they can judge the cost of a prevention program. We’ve all heard complaints that prevention programs can be costly and their benefit is hard to measure in a bottom-line way. With this very specific number, that complaint should no longer be valid.

There’s a final point that is implied in the paper but not called out, so let me call it out on the authors’ behalf. These results are very likely an under-estimate of MRSA’s costs. That’s because, first, the specific procedures the patients underwent were cardiothoracic and orthopedic; those are not the surgical procedures most likely to be followed by a MRSA infection. And second, data collection for this study ceased in 2003, about a year after the first emergence of USA300 and several years before that very successful community strain began its current move into hospitals. However much MRSA was extant in 2003, there is more now.

The cite is: Anderson DJ, Kaye KS, Chen LF, Schmader KE, Choi Y, et al. 2009 Clinical and Financial Outcomes Due to Methicillin Resistant Staphylococcus aureus Surgical Site Infection: A Multi-Center Matched Outcomes Study. PLoS ONE 4(12): e8305. doi:10.1371/journal.pone.0008305

Antibiotics in animals – a warning from the poultry world

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Constant reader Pat Gardiner guided me to an enlightening post at the website of the agricultural magazine World Poultry that questions the routine use of antibiotics in food animals. It’s written by Wiebe van der Sluis, a Netherlands journalist from a farming background, founder of World Poultry and also the magazines Pig Progress and Poultry Processing.

The Netherlands, let’s recall, is the place where MRSA ST398 first emerged, and also the place where that livestock-MRSA strain has caused the most serious human cases and triggered the largest changes in hospital infection-control practices. In the Netherlands, swine farmers and veterinarians are considered serious infection risks because of their exposure to animals, and are pre-emptively isolated when they check into hospitals until they can be checked for MRSA colonization.

Van der Sluis takes seriously the tie between the use of antibiotics in animals and the emergence of MRSA:

Although most of the time MRSA is linked to pig production, it is also related to the veal and poultry industry. The industry, therefore, cannot shrug its shoulders and move on if nothing was wrong. In this case it would be wise to redefine the term prudent use of antibiotics. Time is up for those who use antibiotics to cover up bad management, poor housing conditions or insufficient health care. The standard rule should be: Do not use antibiotics unless there is a serious health issue and no other remedy applies. Veterinary practitioners, who usually authorise producers to use antibiotics, should also take responsibility and prevent unnecessary antibiotic use and the development of antibiotic resistance in animals and humans.

It’s unusual in the US context so hear someone so immersed in agriculture speak so candidly about antibiotic use. It’s refreshing.

Bad news from California: MRSA quadrupled

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Via the Fresno Business Journal and the Torrance Daily Breeze come reports of a new study by California’s Office of Statewide Health Planning and Development: Known MRSA cases in the state’s hospitals increased four-fold between 1999 and 2007, from 13,000 to 52,000 cases per year.

From the Torrance paper:

The good news is that the percentage of people who die of MRSA has decreased, from about 35 percent in 1999 to 24 percent in 2007. The raw number of deaths, however, more than doubled to about 12,500. (Byline: Melissa Evans)

From the Fresno paper (no byline):

Fresno, Kings, Madera and Tulare counties were among 38 counties in California that had 61 to 80% of patients with staph infections.
Only one county, Sierra, fared worse. Eight-one to 100% of patients ended up with staph infections in that county’s hospitals.
In 1999, Kings and Madera counties were in the 0 to 20% range and Fresno and Tulare counties were in the 21 to 40% range.

100%??



NEJM: Antibiotics for pneumonia in H1N1

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The New England Journal of Medicine has been running an open-access blog on H1N1 flu, and they’ve put up a post on when to give antibiotics to prevent secondary bacterial pneumonia, including MRSA pneumonia, in flu patients.

There’s a table of key clinical points to consider, and these important points are made:

For the child or adult admitted to a hospital intensive care unit in respiratory distress, we believe that empirical initial therapy with broad-spectrum antibiotics to include coverage for MRSA, as well as Streptococcus pneumoniae and other common respiratory pathogens, is appropriate.
For the previously healthy child or adult with influenza who requires admission to a community hospital and has features that suggest a secondary pneumonia (Table 1), we would recommend empirical treatment with a drug such as intravenous second- or third-generation cephalosporin, after an effort has been made to prove the association with influenza and to get adequate lower respiratory tract specimens for Gram’s stain and bacterial culture.
If the Gram’s stain suggests the presence of staphylococci or if there is a rapidly progressive or necrotizing pneumonia, an additional antimicrobial agent to cover MRSA is appropriate. …
We do not believe that initial coverage for MRSA is indicated in all patients who are thought to have secondary bacterial pneumonia.

So, to recap:

  • Development of apparent pneumonia in the presence of flu should be met with antibiotics that will treat drug-sensitive bacteria, along with a test to show which bacteria are causing the illness.
  • If staph is present (or the pneumonia appears very serious), then the antibiotics should be upped to one that can control MRSA.
  • But if the pneumonia is serious enough to send a patient straight to the ICU, then drugs that can quell MRSA should be started right away.

For anyone concerned about pneumonia in the aftermath of H1N1, this is worth bookmarking.

Antibiotics – the EU pipeline is empty too

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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

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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