Are We Returning to a Pre-Antibiotic Age?

Are We Returning to a Pre-Antibiotic Age?

by David W. Sharp

WHAT'S HOT IN MEDICINE...

Rank	Paper	Citations This Period Nov-Dec 00	Rank Last Period Sep-Oct 00
1	J.G. McHutchinson, et al., "Interferon alpha-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C," New Engl. J. Med., 339(21):1485-92, 19 November 1998. [8 U.S. institutions] *139VT	32	1
2	B. Pitt, et al., "The effect of spironolactone on morbidity and mortality in patients with severe heart failure," New Engl. J. Med., 341(10):709-17, 2 September 1999. [6 institutions worldwide] *231DB	28	5
3	D.M. Eisenberg, et al., "Trends in alternative medicine use in the United States, 1990-1997: Results of a follow-up national survey," JAMA-J. Amer. Med. Assoc., 280(18):1569-75, 11 November 1998. [Beth Israel Deaconess Med. Ctr., Boston, MA; Harvard Med. Sch., Boston] *136GX	22	†
4	B. Ettinger, et al., "Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. Results from a 3-year randomized clinical trial," JAMA-J. Amer. Med. Assoc., 282(7):637-45, 18 August 1999. [11 institutions worldwide] *226QY	21	10
5	H.J.M. Barnett, et al., "Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis," New Engl. J. Med., 339(20):1415-25, 12 November 1998. [John P. Roberts Res. Inst., London, Ont., Canada; McMaster U., Hamilton, Ont., Canada; U. Western Ontario, London, Canada; U. Texas SW Med. Ctr., Dallas; U. Oxford, U.K.] *139VR	18	†
6	S. Singhal, et al., "Antitumor activity of thalidomide in refractory multiple myeloma," New Engl. J. Med., 341(21):1565-71, 18 November 1999. [U. Ark. Med. Sch., Little Rock; U. South Carolina, Columbia; Rockefeller U., New York, NY] *256GF	18	†
7	S.R. Cummings, et al., "Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures. Results from the Fracture Intervention Trial," JAMA-J. Amer. Med. Assoc., 280(24):2077-82, 23/30 December 1998. [9 U.S. institutions] *149LE	17	†
8	D.K. Chen, et al., *"Decreased susceptibility of Streptococcus pneumoniae* to fluoroquinolones in Canada,"** New Engl. J. Med., 341(4):233-9, 22 July 1999. [Mt. Sinai Hosp., Toronto, Ont., Canada; U. Toronto, Ont., Canada] *217ZL	16	†
9	B. Thurner, et al., "Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma," J. Exp. Med., 190(11):1669-78, 6 December 1999. [U. Erlangen-Nuremberg, Germany; U. Wurzburg, Germany; U. Mainz, Germany; Rockefeller U., New York, NY] *263QY	16	†
10	H.B. Rubins, et al., "Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol," New Engl. J. Med., 341(6):410-8, 5 August 1999. [11 U.S. institutions] *223UN	15	8
SOURCE: ISI’s Hot Papers Database. the Legend.

he New England Journal of Medicine is not much given to sensationalism; nor is the U.S. Centers for Disease Control. It comes as a surprise, therefore, to find at the end of the paper currently ranked at #11, from the Glycopeptide-intermediate Staphylococcus aureus Working Group (T.L. Smith, et al., New Engl. J. Med., 340: 493-501, 1999; with 15 citations this period and 81 overall), the following statement: "The emergence of S. aureus with intermediate glycopeptide resistance threatens to return us to the era before the development of antibiotics." Why the alarm?

Victory over bacterial pathogens tends to be short-lived. They acquired resistance to penicillin, when that drug was introduced in the 1940s. When the semisynthetic penicillins arrived in the 1960s it was not long before staphylococcal resistance emerged, and for the past 15 years MRSA (methicillin-resistant S. aureus) has been troubling hospital services all over the world. The major treatment for MRSA infection has been vancomycin, a glycopeptide class antibiotic. Four years ago, reduced susceptibility to vancomycin was recorded in Japan. In the summer of 1997 the first two U.S. cases were diagnosed, and paper #11 is the result.

This article is part of a continuing story of bacterial resistance. I can recall the alarm bells ringing in the 1960s when the first strains of penicillin-resistant pneumococcus (Streptococcus pneumoniae) were reported. Subsequently a new class of antibiotic, the fluoroquinolones (drugs terminating in "-ofloxacin"), began to be quite commonly used for this bacterial pneumonia. In Canada prescription of fluoroquinolones rose seven-fold between 1988 and 1997; and the prevalence of pneumococci with reduced susceptibility to fluoroquinolones has been rising too (#8).

Once a bacterium has acquired an antibiotic-resistance gene there is the potential for the gene to jump across to other species, and this has been recorded. Patient-to-patient spread of a non-responsive pathogen, within a hospital or between hospitals, is another danger with MRSA. The New Jersey and Michigan patients (#11) died. However, there was no cross-infection; nor were known vancomycin-resistance genes identified. The episodes could have been much worse.

Science Watch has been talking to Dr. James Burnie from Manchester, U.K. He and colleagues have studied MRSA causing cases of septicemia in the 1990s (Clin. Infect. Dis., 31:87-9, 2000). As it happens, the isolates from patients in the Manchester region were not vancomycin resistant, but the bacteria became so when exposed to the antibiotic in the laboratory. Burnie notes that this resistance is not picked up on routine testing; special techniques are needed. It has probably been with us, he observes, "for quite some time prior to the original observation by the Japanese." Is this intermediate pattern of resistance, he asks, the prelude to full-blooded resistance in the future? This would be the "Apocalypse Now" scenario that article #11 hints at.

Hospital cleanliness—or, rather, lack of it—is a hot topic in the U.K. these days. Perhaps greater attention to cleanliness is just as important as introducing restrictions on antibiotic prescribing both in hospitals and in the community. But that is prevention. What do we do with MRSA when it happens, now that vancomycin alone may not be enough? Combination therapy, perhaps? However, as Burnie notes there are problems with the drugs with which vancomycin might be combined—e.g., toxicity or, with ciprofloxacin, resistance (see #8). A new drug, linezolid, is being talked about as possible monotherapy. Given the proven ingenuity of S. aureus, that approach seems unwise, and Burnie agrees!

Mr. David W. Sharp, M.A. (Cambridge), is deputy editor of The Lancet, London, U.K.