15 June 2010

Bad news: From MRSA to LRSA

This is an addition for archival purposes of a post that originally appeared at Scienceblogs

Via the Journal of the American Medical Association, a report from Spain: the first recorded outbreak, in a Madrid hospital, of Staphylococcus aureus resistant to linezolid (Zyvox), one of only a few drugs still available to treat very serious infections of drug-resistant staph, MRSA. This is bad news.

Background: The M in MRSA stands for methicillin, the first of the semi-synthetic penicillins, created by Beecham Laboratories in 1960 in response to a worldwide 1950s outbreak of penicillin-resistant staph. The central feature of the chemical structure of both penicillin and methicillin is an arrangement of four atoms, known as the beta-lactam ring, that governs both drugs' ability to interfere with bacterial cell-wall synthesis. That structure was copied into the formulas of a number of other drug families -- the cephalosporins, carbapenems and monobactams -- and so MRSA is resistant to them as well. And in addition, the bug has picked up resistance to yet other drug families through horizontal transfer; so increasing the census of new drugs that can treat resistant staph infections is a high priority for drug development. It's especially critical for severe infections such as ventilator-associated pneumonia, osteomyelitis, endocarditis and bacteremia, since all the remaining last-resort drugs have challenges from toxicities to ineffectiveness in certain organs.

Linezolid is a relatively new drug, out since 2000 (and, as a downside, still under patent and, according to patients who have been prescribed it, very expensive). It was the first of a new drug class, the oxazolidinones; since there were no "me too" similarities to older drugs, clinicians hoped that resistance to linezolid would be slow in coming.

No such luck.

The first recognized case of linezolid resistance in staph was recorded in 2001. Still, there have been relatively few cases of LRSA, or staph that possesses both linezolid and beta-lactam resistance: 8 cases in the US to date, 2 in Germany and 1 each in Brazil, Colombia and the UK.They have all been caused by a particular point mutation, G2576T.

This Spanish outbreak, though, had a different cause, the importation of the cfr gene, which also mediates resistance to the older drugs clindamycin and chloramphenicol, apparently on a plasmid, possibly from a staph strain common in cows. The outbreak caused by this new mechanism was as large as the entire known burden of LRSA to date: 12 patients, over 10 weeks in 2008, in 3 linked ICUs, pls 3 patients who were not in intensive care, but had had previous ICU stays. Six of the patients had ventilator-associated pneumonia and 3 were bacteremic. Six died -- though the authors are careful to say that all of these patients were critically ill, with brain tumor and esophageal cancer among other problems, and that LRSA was not directly responsible for all of the deaths.

More bad news: There were actually 4 clones of LRSA within this outbreak, with slightly different resistance patterns. Troublingly, one of the 4 had reduced sensitivity to glycopeptides; the chief glycopeptide is vancomycin, which has been the go-to drug for MRSA for 50 years.

The hospital checked its staff and the ICU environments, and found nothing of significance; there was no reservoir in the hospital that was passing this newly resistant strain to patients. With no obvious solution there, they dialed back sharply on their linezolid use, going from more than 200 doses per day in April 2008 to 25 doses per day in June. That aggressive antibiotic stewardship appears to have put the brakes on the outbreak, and after June, no additional cases were recorded.

An accompanying editorial underlines how critical antibiotic stewardship was in controlling this outbreak, while also pointing out how very liberal the hospital was in prescribing linezolid before the outbreak began -- suggesting that if the institution had used its antibiotics more conservatively from the start, this outbreak might not have arisen, or at least not have been as large.
No one doubts the importance of infection-control practices in limiting outbreaks with antibiotic-resistant organisms, but optimizing antibiotic use remains essential for successful control of such outbreaks...No longer can clinicians' unrestricted use of antibiotics and ignoring suggestions from those who attempt to improve or alter antibiotic use be tolerated. Clinicians must understand the sense of urgency about the appropriate use of antibiotics.


(NB, this outbreak was also written up a few months ago in Clinical Infectious Diseases, and was a late-breaker paper at the 2008 ICAAC meeting.)

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