Saturday, August 19, 2006

New developments in staphylococcal infections

This week’s NEJM reports a study from the S. aureus Endocarditis and Bacteremia Study Group showing non-inferiority of daptomycin (Cubicin) compared with “standard” therapy (vancomycin or an antistaphylococcal penicillin for MRSA or MSSA, respectively, both initially combined with low dose gentamicin) in patients with Staphylococcus aureus bacteremia and right sided endocarditis. Acquired resistance to daptomycin occurred leading to treatment failure, counterbalanced by increased renal toxicity causing treatment interruption in the standard therapy group, also contributing to treatment failure.

In the same issue is a
report from Moran and colleagues on the microbiology and clinical characteristics of skin and soft tissue infections (classified as abscess, wound infection or cellulitis) presenting to emergency departments across a wide swath of the U.S. The majority of isolates were MRSA which possessed characteristics unique to community associated MRSA (CA-MRSA) including expression of the Panton-Valentine leukocidin toxin (PVL) and the characteristic sensitivity pattern.

editorial in the same issue makes these points about the two studies:

1) When oral antibiotic therapy is indicated, trimethoprim-sulfamethoxazole (TMP-SMX) may be a reasonable choice for CA-MRSA but it is not effective against streptococci. Clindamycin is effective against streptococci but CA-MRSA may exhibit inducible clindamycin resistance. (This Mayo Clinic Proceedings
review suggests combining TMP-SMX or a tetracycline with a beta lactam such as cephalexin to get around the problem).
2) Abscesses should be incised and drained and, given somewhat variable sensitivity patterns, culture data should guide therapy.
3) Daptomycin is an alternative to older standard therapy for bacteremia. Emergence of resistance during treatment is a problem. Patients who appear to fail treatment should be evaluated for acquired resistance to daptomycin in addition to sequestered foci of infection. (Daptomycin is not recommended for treatment of pneumonia).

DB weighs in with a discussion of how the problem is handled at his institution.

Friday, August 18, 2006

The restructuring of an embattled medical journal

In the wake of the fracas a few months ago over its leadership, the Canadian Medical Association Journal (CMAJ) is reorganizing. Changes include a strengthening of the Joint Oversight Committee responsible for mediating disputes between the editors and the journal owners. It remains to be seen how the changes will play out but contrary to popular speculation, and no doubt to the disappointment of some, the sky hasn’t fallen at CMAJ.

As debate unfolded in the weeks following the dispute at CMAJ “editorial independence” became a tired mantra. Dr. Jerome Kassirer, a member of the CMAJ editorial board and a critic of the publisher during the dispute, is quoted in the August 15 CMAJ article: "You want an editor who is not intimidated by anything. ... It's critical to have an editor who is beholden to nobody." My translation: an editor who is accountable to nobody. Editorial independence is not an absolute value. There must be a healthy tension between independence and accountability, which is what the people screaming about editorial independence don’t seem to get.

Background: previous notes from Dr. RW on this topic here and here.

Wednesday, August 16, 2006

Cool neurology sites

Educational web sites covering everything from molecular mechanisms to optical illusions are linked and reviewed here. Via Life Sciences Education.

Changing trends in hospital acquired bacteremia

According to this report form Archives of Internal Medicine the pendulum is beginning to swing back toward gram negatives.

Tuesday, August 15, 2006

NCCAM chelation study site tour—part IV

The Born Preventive Health Care Clinic in Grand Rapids Michigan and its Crossroad Healing Arts branch in Goshen Indiana are NCCAM chelation study sites. The clinics feature craniosacral therapy for autism, chelation, and Nambudripad’s Allergy Elimination Technique. The clinics offer lecithin infusions in combination with chelation which they claim have been shown to reduce plaques that cause various forms of vascular disease.

In explaining the Nambudripad’s Allergy Elimination Technique the web page offers an interesting theory of allergic diseases: “… blocked energy flow is the first step in a chain of events which can develop into an allergic response.” The section on autism and related developmental disorders attributes the increased incidence as to “excessive vaccination in infants.”

How close are we to an influenza pandemic?

This review from Baylor University Medical Center Proceedings discusses the World Health Organization’s statement: we’re at stage 3 of 6 along the progression.

Monday, August 14, 2006

Complementary and alternative medicine viewed from the perspective of medical ethics

Present day promotion and research on complementary and alternative medicine (CAM) is often unethical. Dr. Wallace Sampson, Clinical Professor of Medicine (Emeritus), Stanford University, in a Medscape General Medicine video editorial focuses on two little discussed issues relating to CAM: informed consent and the ethics of clinical research.

Physicians have a duty to inform the patient if a treatment under discussion is not scientifically validated. Dr. Sampson points out:
An ethical dilemma occurs when patients have unrealistic expectations for an ineffective remedy. The practitioner who fails to inform realistically, or leads the patient on, compounds the dilemma. Failure to inform realistically is sometimes rationalized as either choosing not to remove hope or as nonjudgmental patient support.
However, uncritical support amounts to abetting ill-informed, counterproductive, and harmful decisions.

Concerning clinical trials Dr. Sampson points out that subjecting research participants to methods of “negligible plausibility” violates the Belmont and Helsinki declarations. By this standard much of current NCCAM sponsored research would be unethical.

Are statins beneficial in heart failure?

Although the body of evidence is small it suggests numerous beneficial effects and no harm, according to a review in American Heart Journal.

Wednesday, August 09, 2006

Type 1.5 diabetes---a clinical vignette

In the summer 2006 edition of Clinical Diabetes is a case study of atypical diabetes along with a brief topic review. I previously posted on type 1.5 diabetes here.

What test for suspected aortic dissection?

Transesophageal echocardiography, computerized tomography and magnetic resonance imaging performed equally well in the evaluation of patients with suspected aortic dissection in this meta-analysis published in Archives of Internal Medicine.

Monday, August 07, 2006

Pulling old antibiotics off the shelf

Gram negative infections in hospitalized patients are re-emerging, along with multiple antibiotic resistance. Options for dealing with such infections are limited because, with the exception of tygecycline the antibiotic pipeline is running dry. Tygecycline is a welcome addition to the formulary and may be an option for some, but certainly not all multiply resistant gram negative infections.

The June issue of Clinical Medicine and Research contains a review of the use of polymyxins for such multiply resistant gram negative infections. Polymyxins are polypeptide cationic antibiotics. The commercially available parenteral polymyxins, colistin (polymyxin E) and polymyxin B, were used extensively for a number of years before falling out of favor in the 1960s due to concerns about toxicity and the emergence of newer agents. The toxicity is primarily renal and neuromuscular (similar to aminoglycosides) and, the article cites more recent literature to suggest that this toxicity is less severe, or more manageable than reported decades ago.

We’ve been there before with polymyxins. This paper provides a memory jog back to my days as a Vanderbilt medical student. When I was doing my senior elective in infectious disease the VA hospital was in the throes of a severe epidemic of Serratia marcescens resistant to all commercially available antibiotics. It was 1974. Our big guns for gram negative infections were gentamicin and carbenicillin. The ID folks were able to get amikacin for some patients but it was investigational (then known as BBK8) and difficult to obtain. The polymyxins, which had already fallen into disuse by that time, were not effective against Serratia. Synergy against Serratia, however, was known to occur between the polymyxins and sulfamethoxazole/trimethoprim. The combination of sulfamethoxazole, trimethoprim and polymyxin E (STP) proved clinically effective against the infection. The Serratia epidemic and the use of STP were reported here in Antimicrob. Agents and Chemother. in 1976.

Saturday, August 05, 2006

NCCAM chelation study site tour part III

This is the third in a series of posts in which I will examine some of the study sites for the National Center for Complementary and Alternative Medicine (NCCAM) sponsored Trail to Assess Chelation Therapy (TACT). The purpose is to address questions about the quality of the research based on conditions at the study sites. The vast majority of sites are private clinics at remote locations across the U.S., raising questions about supervision, and many are alternative or holistic medicine clinics, raising questions about scientific qualifications and investigator bias.

The next study site we will examine on our tour is Wellness Works in Brandon Florida. The mission of Wellness Works is, in part, “to offer our patients an evaluation, treatment, and education based on the holistic model of body-mind-spirit.” Services offered include the assessment of hormone status via saliva testing, intravenous vitamin therapy to treat neurologic dysfunction and immune deficiency, and chelation therapy for atherosclerosis.

The chelation page of the Wellness Works web site describes chelation thusly: “Chelation therapy is also thought by many doctors to be effective in reducing plaque in the arteries. By softening ‘hardening’ of the arteries, this process makes them capable of carrying much more oxygen and nutrients to all the organs of the body.”

Because this seems to be a recurring misconception among TACT investigators, a comment on the pathophysiology of atherosclerosis is in order here. Although reducing the lipid content of atherosclerotic plaques would be expected to reduce the risk of coronary events, reduction of plaque size to enable more blood flow would not. In fact, highly stenotic plaques appear to be an uncommon cause of acute coronary syndrome compared to plaques producing milder degrees of stenosis. Moreover, softening of plaques is not beneficial, as softer plaques are more prone to rupture and cause acute coronary syndrome (Ayala TH-Cardiol. Clin.-1-Feb-2006;24(1):19-35).

Background: Part I; Part II.

Medscape Roundtable

The first installment of Roundtable Discussion is posted at Medscape. The topic is physician obesity. Be sure to stop by the discussion page and “weigh in” with your opinion!

Friday, August 04, 2006

The fox is guarding the henhouse of science and public trust

And the National Council for Complementary and Alternative Medicine (NCCAM) doesn’t seem to mind. In researching for my posts on the NCCAM chelation study sites (Trial for the Assessment of Chelation Therapy, TACT) I’m becoming convinced that the NCCAM is entrusting chelation research to promoters of unscientific health claims who have a vested interest in the results. This is particularly concerning because the blinding of the investigators is faulty. According to the study protocol the chelation solution must be mixed at the individual study sites. Patients randomized to the EDTA arm have ascorbic acid injected into the chelation solution at the local study site. Those assigned to placebo have placebo ascorbic acid injected into the mixture. The problem is, the ascorbic acid solution is yellow, while the placebo ascorbic acid is colorless. The work around for this problem is to wrap the ascorbic acid and placebo syringes in tinted translucent tape. It is claimed that the ascorbic acid does not cause a yellow puff when injected into the infusion bag. It would seem easy enough, though, to waste and inspect a few drops of solution before or after injecting the infusion bag.

For insightful and humorous commentary on chelation and the NCCAM check out this week’s Friday dose of woo by Orac.

Thursday, August 03, 2006

NCCAM chelation study site tour part II

The Trial to Assess Chelation Therapy (TACT) is a National Center for Complementary and Alternative Medicine (NCCAM) sponsored study to evaluate chelation therapy for patients with coronary artery disease. The study is conducted at multiple sites across the U.S., almost 100 of which are private clinics, with only 12 academic medical centers participating. Although this selection of study sites facilitates enrollment of large numbers of patients and has the purported advantage of simulating “real world” conditions, the approach has problems. Some authorities have expressed the view that investigation of chelation therapy should be restricted to academic centers. Supervision and credentialing of investigators at multiple non-academic sites is compromised and leaves research vulnerable to fraud, fabrication and faulty methodology, as illustrated recently by the Aventis sponsored Ketek trial.

After perusal of the TACT web site I became concerned that many of the study sites are clinics which are engaged in the practice and promotion of unscientific methods. Disclaimer: The profiles of NCCAM study sites in this and subsequent posts are not intended as criticisms of the clinics in question or their staffs. Although I disagree with the health claims to be discussed here I do not question the sincerity of the providers and respect their right to compete in the marketplace of ideas. The observations made are with the sole intention of raising questions about the quality of the research.

The first stop on our tour is Tequesta Family Practice, Tequesta Florida. Among the alternative practices featured there are heavy metal analysis for chronic fatigue, intravenous infusion of vitamins and minerals for chronic fatigue, evaluation and treatment of “dysbiosis”, evaluation of colonic “ecology” by various culturing techniques, intravenous colchicine infusion for spinal disk herniation and, of course, chelation therapy.

The clinic’s uncritical promotion of chelation raises questions about the objectivity and scientific qualification of the investigators. Chelation therapy is touted by the clinic as “one of the premier anti-aging therapies” and as useful for scleroderma, Alzheimer’s disease, rheumatoid arthritis, multiple sclerosis and porphyria.

Worse, the comments about how chelation therapy “works” reflect a misunderstanding of the pathophysiology of coronary heart disease: “… literally strip calcium out of the artery plaques that cause the clogging of the blood vessels that cause heart attacks and strokes. It can ‘soften’ the ‘hardening’ of the arteries caused by atherosclerosis, reversing the disease process.” I won’t go into a detailed explanation of the mechanisms of coronary atherosclerosis---look it up in any standard text or review---just suffice it to say that “soft” coronary plaques are much more rupture prone than “hard” plaques, and that a treatment to “soften” atherosclerotic plaques would be the wrong treatment. From the promotional comments about chelation therapy it is clear that the investigator(s) there believe that its effectiveness has already been proven.

In summary, consider these questions: Are the site investigators biased in favor of the treatment? Could such bias compromise the scientific integrity of the study, particularly given that the blinding of the investigators is faulty? Do the site investigators understand the pathophysiology of coronary heart disease and is such an understanding important for research on a treatment modality?

Part I
General criticisms of NCCAM here, here, and here.

Wednesday, August 02, 2006

A magical mystery tour of NCCAM chelation study sites---part 1

On first learning of the National Center for Complementary and Alternative Medicine’s Trial to Assess Chelation Therapy (TACT) I was optimistic that it would settle the chelation controversy once and for all. But examination of the TACT web pages raises concerns about the quality of the study. The scientific integrity of many of the research sites is questionable. Only 12 of the 110 study sites are located in academic medical centers. Worse, a substantial number appear to be engaged in dubious practices, making pseudoscientific and even fraudulent health claims. This is the first in a series of posts in which I will profile some of the questionable NCCAM study sites involved in TACT.

What is important about a study site? The investigators must be knowledgeable in the scientific underpinnings of the question being studied. Skills in the methodology of clinical research are important. The investigators must be honest, and conflicts of interest must be addressed. As you read my descriptions of the study sites in the posts that follow, keep these points in mind.

Can the overall study quality be any better than that of the individual sites? An argument could be made that because the study is double blinded, it would be shielded from bias that may exist at individual sites. A close reading of the TACT protocol, however, reveals that the blinding is not secure. First of all, the chelation mixture is not stable and therefore must be mixed at the local site. The ascorbic acid which must be injected into the mixture is yellow in color and highly viscous. The work around for this problem is to cover ascorbic acid, chelation mixture and placebo syringes and bags with tinted translucent tape and to add concentrated dextrose solution to the placebo syringe to make it as viscous as the ascorbic acid.

At the very least, the study conditions which I will point out raise serious questions about the validity of the trial.

Tuesday, August 01, 2006

Good housekeeping and mortality in mechanically ventilated patients

Six simple interventions have been demonstrated to improve outcomes in mechanical ventilation: daily interruptions in sedation, stress ulcer prophylaxis, DVT prophylaxis, elevation of the head of the bed, aggressive glycemic control and spontaneous breathing trials. The first four of these comprise the ventilator bundle. But as basic as they seem their rate of implementation is variable across clinical settings and low overall.

In this report from the American Journal of Medical Quality cases involving mechanical ventilation were reviewed from 38 academic medical centers. Compliance with the six practices was determined and a logistic regression model was used to estimate the effect of each measure on mortality. Compliance rates varied among institutions and were poor in general. Of the six measures, sedation interruption and glycemic control were associated with reductions in mortality.

This is all about the elusive goal of putting evidence into practice. The authors discuss barriers and potential solutions.