The stream of news from the E. coli O104:H4 outbreak in Germany has been so steady that it’s been hard to catch my breath long enough to post on it. The Robert Koch Institute in Germany said today that they think the epidemic curve is cresting, which makes me unusually late to the party. Nevertheless, since there are likely to be more cases and more deaths — and a long struggle still to understand what happened — I thought it would be useful to count up the things that we can say for sure, and those that remain puzzlingly open questions.
First: Is this the largest E. coli outbreak ever? According to food-safety uber-attorney Bill Marler, this outbreak — more than 2,600 victims, 13 countries, 26 deaths (Nature News has a great graphic of cases by country) — is dwarfed only by a 1996 epidemic in Japan. (Here’s Marler’s list). If it’s not the largest, it is likely to have produced the largest percentage of serious illness: As of today, there are 725 cases of hemolytic uremic syndrome (689 in Germany, 33 in the rest of Europe, three in the United States), according to WHO-Europe.
Those case counts pose a second question: Is there something different about the strain in this outbreak? As Richard Knox of NPR points out, the outbreak has put about one out of every three victims in the hospital, compared to one in 10 for previously known toxin-producing strains. That raises two possibilities: Either the strain is different — more on that in a moment — or the case-finding has not turned up the mild cases that would change the denominator and therefore dilute the percentage back to something more normative.
So, then, third: Is this strain different? In certain key ways, yes — and we know that thanks to a global, largely volunteer, crowdsourced genetic analysis, which by itself is something new. And which is spread across many blogs and sites, but the best round-ups are probably at Mike the Mad Biologist, who has added some crucial analysis of his own, and The Alignment Gap. (Also look at GitHub. And, important, much of this analysis was facilitated by the Beijing Genomics Institute making their data open-access.) Among the differences noted between this strain and its apparent recent ancestor, isolated in Germany in 2001, is a change in the gene for the adhesion protein that makes the bacterium “sticky” in the gut, prolonging the course of illness.
From my point of view, the most important difference between this strain, its 2001 ancestor, and just about any previously known outbreak strain of Shiga toxin-producing E. coli or STEC — including any of the O157 outbreaks dating back to the 1992-3 Jack-in-the-Box one that made O157 an household name — is that this one is massively drug resistant. The Guardian was kind enough to ask me to write a piece about this on Sunday (which on Monday was named one of The Atlantic’s “Five Best Monday Columns“; thanks, Atlantic!).
It’s not fair use or good blogging to quote myself lavishly, so here’s the key point. According to the Koch Institute, the German O104 strain is resistant to at least a dozen antibiotics in eight different drug classes: penicillins; streptomycin; tetracycline; the quinolone nalidixic acid; the sulfa drug combination trimethoprim-sulfamethoxazol; three generations of cephalosporins; and the combination drugs amoxicillin/clavulanic acid, piperacillin-sulbactam, and piperacillin-tazobactam. Put all those together, and what they signal is that O104 possesses what is called ESBL resistance (for “extended spectrum beta-lactamase”). According to the Koch Institute’s analysis, the strain has acquired two genes that confer that resistance, TEM-1 and CTX-M-15. if this were a strain that needed to be treated with antibiotics, there are only a few antibiotics that would work, notably the carbapenems, the drugs of last resort for Gram-negative bacteria.
If there is any good luck in this outbreak story, it is that STECs are not usually treated with antibiotics, because killing the organisms causes them to release their toxins, which then starts a cascade that brings on HUS. So the finding that this strain is resistant is not clinically relevant. (I’ve taken a beating at the Guardian and on Twitter from clinicians who think I don’t understand this point, even though my piece said just that.) But it’s of huge microbiological significance, because it underlines yet again how resistance DNA is moving between bacteria in a largely untracked fashion. ESBL resistance has been spreading through Europe for a decade in hospital organisms such as Klebsiella, but a community outbreak of this size is surely unprecedented.
Some questions that still need answers:
What’s the source? The suspect food has been cucumbers, then sprouts, then not sprouts, then cucumbers again just today, and also today, maybe sprouts again. Related question: With so many cases, and therefore presumably so many interviews of victims going back several weeks, why hasn’t the source been narrowed down?
Where is Europe’s traceability system? In the wake of the 2006 US outbreak of O157 in fresh spinach, a lot of attention was paid to creating more complete records of chains of custody of produce, so that a harvest batch could be tracked through the entire distribution system instead of just from its last stop to its next one. Wasn’t Europe supposed to do this better?
How many steps away from agriculture is this outbreak? As Mark Bittman emphasized today, sooner or later it all comes back to manure, because E. coli is a gut bug. Is the source wildlife, as it may have been in 2006? Sick farm workers, as the German government has asserted? Can the newly acquired resistance genes throw any light on its source? CTX-M-15 has been found in E. coli in chickens.
Finally, will this outbreak cause the U.S. to at last take seriously the STEC strains that are not O157? The CDC on Tuesday released data from its FoodNet surveillance system (more on that in a future post, I hope), which showed that for the first time, the non-O157 STECs, including O104, are more commonly detected in the US than O157 is. That’s in part because, post-Jack-in-the-Box, O157 was declared an official adulterant of meat and came under increased scrutiny and concerted control efforts — so as O157 has been beaten back, the threat of O104 and the other five or six STECs of concern have emerged from its shadow.
But, the CDC’s Dr. Chris Braden said Tuesday, there has probably always been more non-O157 STEC foodborne illness than was suspected — possibly more than was ever caused by O157. “We think that that’s probably been the case all along,” he said, “that these other organisms are likely to be more common.”