Volume 2, Number 3: March
1999
Staphylococcus
resistant to vancomycin emergesGabapentin for the
Symptomatic Treatment of Painful Neuropathy in Patients With
Diabetes Mellitus Exercise training
as an adjunct to asthma management?Targeting
subclinical atherosclerosis has the potential to reduce coronary
events dramatically Staphylococcus
resistant to vancomycin emerges
Source: BMJ
1999;318:557 ( 27 February )
Researchers have reported the first three cases in the United
States of infections caused by Staphylococcus aureus
bacteria resistant to vancomycin, an antibiotic often reserved to
fight these infections when no other agent is effective.
To date, a total of four strains of S aureus intermediately
resistant to vancomycin have been documented worldwide, the first
in Japan in 1996.
Certain common factors in the US cases suggest that cellular
modification as a result of prolonged exposure to vancomycin was
probably responsible for the emergence of the recent resistant
isolates.
These strains "threaten to return us to the era before the
development of antibiotics," warn researchers at the US
Centers for Disease Control and Prevention in Atlanta, Georgia
(New England Journal of Medicine 1999;340:493-501;517-23;556-7).
S aureus, a common bacterium, is easily transmitted through
physical contact with infected people. It is a common cause of
skin infections, such as infections of surgical wounds, and also
of sepsis.
It has become resistant to a wide range of antibiotics, how-ever,
and vancomycin was considered an important "last
resort." The patients whose clinical courses were reported
in two separate articles in the New England Journal of Medicine
each had underlying conditions, including infections with
methicillin resistant strains of S aureus that were given
vancomycin intravenously for extended periods.
All three infections were eventually brought under control by
using combinations of various other antibiotics, but in each
case, the patients died anyway. Penicillin type antibiotics have
proved effective against infection with S aureus in the past.
The general overuse of antibiotics has, however, allowed the
infection to develop mutations, rendering it resistant to many of
these drugs.
The current studies suggest that the bacterium has developed an
alternative vancomycin binding pathway that diverts vancomycin
away from the usual target site.
The researchers point out that all three US patients had
histories of long term treatment with vancomycin linked with
dialysis.
Gabapentin for the
Symptomatic Treatment of Painful Neuropathy in Patients With
Diabetes Mellitus
Source:JAMA.
1998;280:1831-1836
Context.—Pain is the most disturbing symptom of diabetic
peripheral neuropathy. As many as 45% of patients with diabetes
mellitus develop peripheral neuropathies.
Objective.—To evaluate the effect of gabapentin monotherapy
on pain associated with diabetic peripheral neuropathy.
Design.—Randomized, double-blind, placebo-controlled, 8-week
trial conducted between July 1996 and March 1997.
Setting.—Outpatient clinics at 20 sites.
Patients.—The 165 patients enrolled had a 1- to 5-year
history of pain attributed to diabetic neuropathy and a minimum
40-mm pain score on the Short-Form McGill Pain Questionnaire
visual analogue scale.
Intervention.—Gabapentin (titrated from 900 to 3600 mg/d or
maximum tolerated dosage) or placebo.
Main Outcome Measures.—The primary efficacy measure was
daily pain severity as measured on an 11-point Likert scale (0,
no pain; 10, worst possible pain). Secondary measures included
sleep interference scores, the Short-Form McGill Pain
Questionnaire scores, Patient Global Impression of Change and
Clinical Global Impression of Change, the Short Form-36 Quality
of Life Questionnaire scores, and the Profile of Mood States
results.
Results.—Eighty-four patients received gabapentin and 70
(83%) completed the study; 81 received placebo and 65 (80%)
completed the study. By intent-to-treat analysis,
gabapentin-treated patients' mean daily pain score at the study
end point (baseline, 6.4; end point, 3.9; n=82) was significantly
lower (P<.001) compared with the placebo-treated patients'
end-point score (baseline, 6.5; end point, 5.1; n=80). All
secondary outcome measures of pain were significantly better in
the gabapentin group than in the placebo group. Additional
statistically significant differences favoring gabapentin
treatment were
observed in measures of quality of life (Short Form-36 Quality of
Life Questionnaire and Profile of Mood States). Adverse events
experienced significantly more frequently in the gabapentin group
were dizziness (20 [24%] in the gabapentin group vs 4 [4.9%] in
the control group; P<.001) and somnolence (19 [23%] in the
gabapentin group vs 5 [6%] in the control group; P=.003).
Confusion was also more frequent in the gabapentin group (7 [8%]
vs 1 [1.2%]; P=.06).
Conclusion.—Gabapentin monotherapy appears to be efficacious
for the treatment of pain and sleep interference associated with
diabetic peripheral neuropathy and exhibits positive effects on
mood and quality of life.
Exercise
training as an adjunct to asthma management?
Source: Thorax
1999;54:190-191 ( March )
Whether the mechanism is respiratory heat loss or increased
osmolarity due to respiratory water loss, exercise is a potent
stimulus for provoking asthma symptoms in children. For this
reason children with asthma may avoid exercise which may in turn
be detrimental to their physical and social conditioning. On this
background the efficacy of exercise training in children with
asthma has generated continued interest over the years. The use
of exercise training programmes in the clinical management of
children with asthma is at best controversial. While a number of
studies have reported an improvement in lung function, aerobic
capacity/conditioning, psychosocial behaviour, and a reduced
incidence and severity of exercise induced bronchoconstriction,
the findings in these studies have been variable and have not
addressed the clinical efficacy of such programmes. The quality
of the studies has varied and assessing the efficacy of such
programmes depends on which outcomes are assessed and how these
outcomes are measured.
It is widely recognised that suitable training regimens increase
exercise tolerance and capacity in healthy individuals, with
greater improvements usually being seen in the more sedentary
subjects.This is generally due to a greater capacity for
improvement in non-trained individuals. Improvements in exercise
capacity are usually accompanied by a number of physiological
adaptations including increased oxygen uptake (O2), reduced
ventilatory requirements, reduced cardiac frequency, and a
reduction in lactic acid production at any given work load.
Anatomical and metabolic changes such as increased mitochondrial
density, increased capillarisation of trained muscles, and
changes in muscle fibre type and density generally accompany
these physiological changes. Along with these physiological
changes in response to training, improved psychosocial outcomes
such as improved sense of self-worth and well being as well as
improved concentration and decreased stress levels have been
reported. These changes in response to appropriate modes,
duration, frequency, and intensity of exercise training
programmes should apply equally well to children with and
without asthma, provided they have no other physical limitations.
It therefore comes as no surprise when demonstrable physiological
and psychosocial improvements are observed in studies of children
with asthma following suitable exercise training regimens. The
qualitative and quantitative differences between published
studies is likely to be due, at least in part, to variations in
subject selection, both in terms of severity of disease (that is,
the amount and type of airway inflammation likely to be present
and the degree of bronchial responsiveness), medication usage,
age, and training status. Differences in the methodology used and
interpretation of the results also contribute to the reported
differences in outcome.
At rest, compromised respiratory function has been reported in
young asthmatic patients including decreased flows, increased
residual volume, increased ratio of physiological dead space to
tidal volume (VD/VT), increased alveolar-arterial oxygen tension
difference (A-aPO2), and mild arterial hypoxaemia and
desaturation. During exercise these physiological variables
return to normal and exercise tolerance is not limited by these
factors. Provided that a child's asthma is well managed and there
is no significant degree of fixed airflow obstruction, there are
few physiological reasons why they would not tolerate and,
indeed, significantly improve their aerobic capacity following an
aerobic training regimen. However, the clinical benefit of such a
training regimen to the patient may not be comparable to the
physical improvements. There is no consistent evidence that
exercise training decreases the incidence of exercise
induced bronchoconstriction or improves peak expiratory flows
(PEF). It is likely that in patients with airway pathology there
is a threshold ventilatory rate (which may be modulated by
inspired air conditions) at which exercise induced
bronchoconstriction is triggered. When patients are challenged at
or above this ventilatory threshold, exercise induced
bronchoconstriction is likely to occur regardless of the fitness
level of the subject. This would mean that exercise challenges
performed after a period of aerobic training need to be conducted
at the same relative loadsthat is, the same ventilatory
equivalentrather than at the same absolute load, and with the
same inspired air conditions. This would allow valid comparisons
of the incidence of exercise induced bronchoconstriction after a
period of exercise training. However, if exercise training allows
a patient to exercise more before reaching the threshold for
triggering exercise induced bronchoconstriction, that patient may
report an increased exercise capacity without experiencing
exercise induced
bronchoconstriction.
Two publications in this issue of Thorax describe similar
improvements in aerobic exercise capacity after swimming and
cycle ergometry training in children with asthma. The study by
Matsumoto and colleagues showed that, when asthmatic children
were assessed at the same relative work loads before and after an
aerobic training programme, the fall in FEV1 following exercise
was reduced. This occurred despite finding no change in the PC20
to histamine, which suggests minimal change in airway
structure/inflammation. The authors did not report medication
usage during the training phase and this may also have affected
the results. Interestingly, the lack of change in airway
responsiveness to histamine suggests that airway structure may be
a more important determinant of in vivo airway responsiveness to
exercise than inflammatory stimuli.
The study by Neder and colleagues reported a short term decrease
in the daily use of inhaled and oral steroids in a group of
children with severe asthma following a two month cycle ergometry
training programme, with no change in the number of positive
exercise challenges. The authors attributed the decrease in
medication usage to improved psychosocial factors related to
exercise training. The interpretation of these data requires a
cautious approach. The authors provide no evidence of longer term
treatment requirements. Also, it is possible that the reported
decrease in medication use was a "trial" effect or that
the subjects did not require the dose of inhaled steroids
initially prescribed.
Because exercise induced bronchoconstriction may itself limit the
maximum aerobic work capacity, adequate asthma control is
required during any aerobic training regimens. This may involve
an increase in preventative medication usage and/or pre-exercise
use of a bronchodilating agent. The observation that the severity
of exercise induced bronchoconstriction is reduced but airway
responsiveness to inhaled bronchoconstricting stimuli remains the
same following aerobic exercise training raises an interesting
possibility that aerobic conditioning may reduce the airway
response to specific stimuli. This hypothesis has not been
examined and warrants further investigation. From the point of
view that exercise training in children with asthma demonstrates
a beneficial effect on aerobic conditioning and psychosocial
behaviour, it warrants consideration from a general health
perspective. If aerobic conditioning
reduces the likelihood of provoking an asthma attack due to
decreased ventilatory requirements for any given task, then
increased participation in physical activity by children with
asthma is desirable. In terms of clinical management of children
with asthma, the evidence is still not strong enough to support
modifications in conventional therapeutic treatment even in well
trained children with asthma. We encourage researchers in this
field to conduct well designed studies to address the important
issue of whether exercise training programmes can improve asthma
control and decrease medication requirements in asthmatic
children.
Targeting
subclinical atherosclerosis has the potential to reduce coronary
events dramatically
Source: BMJ
1998;316:1764-1770.
A fifth of coronary deaths occur in those with no history of
ischaemic heart disease, and the absolute number of coronary
events is greater in the low risk population than in high risk
groups. Risk scores cannot predict nearly half the future
episodes of coronary heart disease. The prevention of these acute
events remains a major challenge.
Primary prevention, including health promotion in the community
and multiple risk factor screening, has generally been
disappointing a major problem has been that people have found it
difficult to change their lifestyles. On the other hand, some
trials of single risk factor screening followed by medical
treatment, rather than lifestyle changes, have shown a
significant reduction in vascular events. For example, in the
West of Scotland Coronary Prevention Study screening and treating
high serum cholesterol concentrations in 45-64 year old men led
to a 31% reduction in cardiovascular events. Such an approach,
however, is of less value in preventing events in individuals
with low risk factor levels. In those with established clinical
disease secondary prevention has proved more successful:
interventions such as antiplatelet agents can achieve a 25-33%
reduction in events.4 From a population perspective, however,
secondary prevention has a limited effect because most vascular
events occur in those without pre-existing clinical disease.
In attempting to prevent first time events a strategy which has
been largely ignored is targeting and treating individuals with
asymptomatic atherosclerosis. One difficulty is the need for an
accurate marker of subclinical disease. Measurement of the ratio
of the ankle to arm systolic pressure (ankle-brachial pressure
index) has potential. It is easily, quickly, and reproducibly
measured with a portable Doppler probe and sphygmomanometer. In
hospital the ankle-brachial pressure index has been related
inversely to the degree of atherosclerotic disease in the leg,
and a cut off point of 0.9 is over 90% sensitive and specific in
detecting angiographically defined disease. In the general
population the index has been related inversely to measures of
generalised atherosclerosis, including the prevalence of angina,
previously diagnosed myocardial infarction, and stroke.
Most importantly, a low ankle-brachial pressure index (0.9) has
been associated with a substantially increased risk of mortality
and major cardiovascular events. Population studies in Belgium,
Sweden, Scotland, and America have found a twofold to fivefold
increased relative risk of fatal and non-fatal cardiovascular
events in men and women with a low ankle-brachial pressure index.
In men and women aged 55-74 in Edinburgh much of the increased
risk associated with a low ankle-brachial pressure index occurred
independently of conventional risk factors (cigarette smoking,
hypertension, and hypercholesterolaemia), and thus measurement of
the index improved the prediction of events based on these risk
factors alone.
In adults aged under 55 the prevalence of an ankle-brachial
pressure index less than 0.9 is below 5%, but it increases
sharply in older age groups. Around 1 in 7 healthy adults aged
55-74 without clinical disease have a low index, increasing to
about 1 in 3 in those aged over 85. If such individuals with
subclinical disease and high risk of future cardiovascular events
were identified, it might be possible to reduce their risk. In
addition to control of risk factors, treatment with antiplatelet
drugs is likely to prove beneficial, as is the case in overt
cardiovascular disease.4 In asymptomatic disease, aspirin may be
as effective as in symptomatic disease because the event rate in
subjects with a low ankle-brachial pressure index is similar to
that in those with clinical disease. Assuming a 25% reduction in
major cardiovascular events,4 the five year incidence in 55-74
year olds without a history of cardiovascular disease, based on
Edinburgh data, would fall from 120 to 90/1000 treated
individuals.
If these assumptions are correct an approach that entailed simple
screening of people over 50 could potentially prevent around 60
000 major cardiovascular events in Britain over the following
five years. About 85 000 new cases of angina and intermittent
claudication would also be prevented, so about 1 in 13 treated
individuals would derive some benefit. Although more events might
be prevented by the additional use of other agents, such as
antioxidants, these benefits are more hypothetical. In due
course, however, the aspirin for asymptomatic atherosclerosis
(AAA) trial in Lanarkshire, a high risk area for coronary
mortality, will provide evidence on whether targeting subclinical
disease is effective.
