Richard Lehman’s journal review—23 March 2015

richard_lehmanNEJM 19 Mar 2015 Vol 372
1093 “All bacteria will be susceptible to common cheap antibiotics by 2050” is not a headline you will see in any newspaper. But I’d like you to think seriously whether this is not more likely than the widely-touted doomsday scenario of a post-antibiotic era in which we are all endangered by untreatable bacterial infections. Very few bacteria are pathogenic to humans, and those which are simply adapt to the environments we create for them. Staphylococcus aureus quickly became resistant to penicillin after it was widely introduced into hospitals and the community in the 1950s. Then in 1959 Beecham marketed meticillin as a beta-lactam antibiotic to deal with penicillinase-producing strains of S aureus. Its replacement, flucloxacillin, remains active against most staphylococcal infections in the UK, but not in the USA, where skin and tissue infections are now most commonly caused by meticillin-resistant staphylococci (MRSA). But this study shows that these infections respond well to treatment with either clindamycin or trimethoprim-sulfamethoxazole (co-trimoxazole) and that there is nothing to choose between these two cheap old antibiotics in terms of efficacy or safety.

1104 Mongersen sounds like a minor character from Wallander: perhaps a raincoat-wearing forensics expert who avoids company and collects beetles during his few weeks of annual leave. Actually, this is the name given to an oral SMAD7 antisense oligonucleotide which targets ileal and colonic SMAD7. Now SMAD7 is a bad thing, because it inhibits the action of the immunosuppressive cytokine transforming growth factor β1 (TGF-β1). With this clearly in mind, you can begin to see that mongersen, whether or not it collects beetles in the summer, must be a good thing, because it stops the bad thing that interferes with the good thing that stops people getting Crohn’s disease. This phase 2 trial seeks to find if it actually works for people with established Crohn’s. Yes it does, in the very short term. “The primary outcomes were clinical remission at day 15, defined as a Crohn’s Disease Activity Index (CDAI) score of less than 150, with maintenance of remission for at least 2 weeks, and the safety of mongersen treatment… The proportions of patients who reached the primary end point were 55% and 65% for the 40-mg and 160-mg mongersen groups, respectively, as compared with 10% for the placebo group (P<0.001)… Most adverse events were related to complications and symptoms of Crohn’s disease.” Wouldn’t it be wonderful to have a safe and effective treatment for Crohn’s? But don’t let’s rejoice until the longer-term phase 3 data are in.

1114 Of course the best way for humans to outwit microbes is to produce effective vaccines. Streptococcus pneumoniae was co-discovered by Louis Pasteur in 1881 and various vaccines against it have been produced in the last 50 years, one of the latest being a 13-valent polysaccharide vaccine trialled here in 84,496 adults 65 years of age or older. It protected most of them from the strains in the vaccine, but unfortunately these only accounted for 13% of community-acquired pneumonia in the study, so it had no measurable effect on that.

1168 And now for the future: can we find or create new antibiotics that will be resistant to resistance? Yes, because we already have, and we’ve hardly begun looking. This article describes a new method which allows in vitro culture of the 99% of environmental bacteria which have so far eluded capture. The first-fruit of this is the isolation of teixobactin, which appears to act by forming a complex with precursors of peptidoglycan and teichoic acids of the cell wall of gram-positive bacteria. This makes it potent against staphylococci, streptococci (including pneumococci), Clostridium difficile, Bacillus anthracis, and enterococci, including multidrug-resistant strains; and also against highly resistant Mycobacterium tuberculosis. Attempts to breed teicobaxin-resistant strains of any bacteria in the lab have so far failed.

JAMA 17 Mar 2015 Vol 313
1101 A couple of weeks ago I felt tired all the time. If I made myself do anything physical or mental, I felt awful and longed to go to bed, and when I did I slept gratefully but woke up feeling much the same. If these symptoms persist for more than six months, and are accompanied by cognitive impairment and/or orthostatic intolerance, they constitute Systemic Exertional Intolerance Disease. At the command of the Institute of Medicine, this term now supersedes Myalgic Encephalopathy and Chronic Fatigue Syndrome. Here is an open access piece arguing the logic of this re-labelling—welcome but not perfect. (Oh, and yes, I’m better now thank you.) See also the Lancet editorial.

1113 This paper is based on the DAPT trial which randomised people to receive long-term or standard duration dual antiplatelet treatment after coronary stenting. The title of the paper implies that we’ll get a full report of the trial but in fact we only get the subset of 1687 patients who received bare metal stents (BMS) rather than drug-eluting stents. Continuing a combination of aspirin and a thienopyridine (clopidogrel or pasugrel) for 30 months in these patients achieved “no statistically significant differences in rates of stent thrombosis, major adverse cardiac and cerebrovascular events, or moderate or severe bleeding. However, the BMS subset may have been underpowered to identify such differences, and further trials are suggested.” Hmm.

1122 Most of us gave up squinting down microscopes as soon as we left medical school, except for a few who opted to become pathologists. On them we place the utmost trust. Not for them the vague guesses that got us through our laboratory work in order to become proper doctors. Their word is law: and should they chance to wear raincoats and collect beetles in the summer, that but raises them in our estimation. The word “carcinoma” in their histology reports has the ring of doom. From it flows a lifetime (often curtailed) of anxiety and unpleasant further investigation, surgery and/or chemotherapy. In this study, 115 pathologists looked at 240 slides of breast biopsies. “Overall agreement between the individual pathologists’ interpretations and the expert consensus–derived reference diagnoses was 75.3%, with the highest level of concordance for invasive carcinoma and lower levels of concordance for DCIS and atypia. Further research is needed to understand the relationship of these findings with patient management.” You betcha.

JAMA Intern Med Mar 2015

OL “The main function of specialist societies is to justify what their members are used to doing” I wrote in a tweet a while back. Proof of this comes in the form of a research letter describing how specialist societies responded in print to 20 published studies which demonstrated the ineffectiveness or harm of existing practices, i.e. supported reversal of practice. “Specialist societies’ resistance to reversal was related to the importance of the reversed practice to members of the responding society.” The most important developments in UK medicine this year will be the “Choosing Wisely” campaign of the Academy of Medical Royal College and moves by NICE to embrace shared decision making. Boy, we have some work to do, even in a health system which lacks financial incentives to continue futile practices.

OL An example is the failure to stop aiming for tight glycaemic control in intensive care units. “Among patients admitted to adult ICUs in the United States, there was a slow steady adoption of tight glycemic control following publication of a clinical trial that suggested benefit, with little to no deadoption following a subsequent trial that demonstrated harm. There is an urgent need to understand and promote the deadoption of ineffective clinical practices.” An invited commentary riffs on this theme. We all need to.

The Lancet 21 Mar 2015 Vol 385
This week The Lancet publishes three papers heralding the success of combined antiviral regimens for hepatitis C. Two describe the C-WORTHY trial funded by Merck, which was a randomised, open-label phase 2 trial of grazoprevir plus elbasvir with or without ribavirin.

The third, run by Gilead, was a small proof-of-concept study in which two different three-drug regimens were given for six weeks, all including sofosbuvir and ledipasvir. These all resulted “in high cure rates for HCV infection with excellent tolerability.” So in theory we are on the threshold of a universal cure for hep C followed by its disappearance from the earth. The Lancet celebrates with an editorial titled: “Hepatitis C: only a step away from elimination?

The only slight problem is that a 12 week curative course based on sofosbuvir currently costs about £35K in the UK and between $40-100K in the USA. The Lancet editorial squirms through a disingenuous paragraph about this, fantasising that “the financial returns from reduced healthcare costs and higher economic activity might easily outweigh the expense of the medicines themselves.” But as this week’s seminar confirms, in the rich world hepatitis C is a largely asymptomatic infection typically found in drug-dependent people who are not noted for their high economic activity. And in the rest of the world it is found in millions of people living at subsistence level who may later die of cirrhosis or hepatocellular cancer, few of whom have an economic value of $1K let alone $40K. Their best hope lies in the ruling of the Indian Patent Office that sofosbuvir is not a sufficiently innovative molecule to protect it from generic copying.

The BMJ 21 Mar 2015 Vol 385
“There is compelling evidence in adults that a modest reduction in salt intake lowers blood pressure and reduces the risk of cardiovascular disease. Indeed, salt reduction is one of the most cost effective measures to prevent cardiovascular disease in both developed and developing countries.” The first author on this study is also the first author of a Cochrane review which recommends salt reduction, as opposed to other Cochrane reviews which find insufficient evidence. If looking at his references convinces you this is true, read the rest of the paper. It is all about an intervention that reduces salt intake in Chinese children. Even I think this may be a good thing, because the one thing I have against Chinese food is that it’s often too salty to enjoy properly. And that is the only valid end-point when it comes to diet.

When I first started churning these reviews out in 1998, the word “blog” had yet to be invented (it happened the following year, as an abbreviation of “weblog”), and rheumatology was a sleepy discipline that was about to wake up. The next few years saw a sudden rush of new “biological” treatments and a realization that early use of “disease-modifying” agents in rheumatoid arthritis might reduce long-term joint damage. The TACIT non-inferiority randomised controlled trial is not designed to examine the second assumption—it recruited patients with established disease—but it does call into question how much progress has actually been achieved in the era of “biological” treatment with TNF-alpha inhibitors. It found that “an alternative strategy with combinations of intensive synthetic disease modifying drugs gives non-inferior outcomes to treatment with tumour necrosis factor inhibitors. Costs are reduced substantially.” Expect a backlash. This is a multi-billion-dollar market.

Thrombolysis in acute ischaemic stroke: time for a rethink?” is a pretty challenging title, but it turns out that Brian Alper and colleagues are only questioning its use after the three-hour mark. If you like this kind of thing, this is a very well-ordered and referenced piece of argument.

Plant of the Week: Daphne acutiloba “Fragrant Cloud”

Collecting daphnes is a masochistic activity which can go on for ever, not because there are an infinite number of daphnes but because they die so easily. This is the latest to reach our killing fields. It looks wonderfully healthy because it only reached us last summer. And now it is breaking into dreamily scented pure white flowers of splendid size for a daphne.

I will let Karan Junkers, the most indefatigable daphne grower in Britain (if not the world), describe it for you: ” A wild derivative of D. acutiloba, introduced from China by Martyn Rix, the beautiful white flowers in April remind me more of D. blagayana, since they are much larger than most Daphnes. The plant however, is quite upright growing and the evergreen leaves are much larger. The scent is intoxicating. Proving to be well behaved for us, though happier in a shady site, I believe that this showy plant has a fantastic future.”

Needless to say, we have planted ours in full sun. When it dies, we will try another one in shade.