In vitro, B. burgdorferi is sensitive to several antibiotics
(20,25). This assumption is complicated, however, because of
the long incubation times needed to determine minimum
inhibitory concentrations (MIC), as the borrelia have doubling
times of 20-24 hrs. With these limitations, the results of a
few studies show minimum bactericidal concentrations (MBC) to
penicillin of 8ug/ml, ampicillin: 2ug/ml, tetracycline: 1-2ug/ml,
doxycycline: 2ug/ml, ceftriaxone: 0.5ug/ml, cefotaxime: 0.5ug/ml,
cefuroxime: 1-2ug/ml, cefixime: 8ug/ml,erythromycin: 0.5ug/ml,
clarithromycin: 0.5ug/ml, azithromycin: 0.5ug/ml,
and ciprofloxacin: 4ug/ml.
At the time of the first rash, any one of several antibiotics
appear to be effective, if given for 2 weeks, according to several
published studies. However, a number of patients so treated
developed subsequent symptoms of arthralgias, fatigue, and
paresthesias, with positive Western blots, who were then
successfully treated with longer courses of antibiotics (8, 10).
The recommendation at this time, therefore, is that tetracycline,
doxycycline, or amoxicillin be used for 1 month if ECM is the
only symptom of Lyme Disease.
Once any other symptoms appear, the treatment of Lyme Disease
for only 2-4 weeks is associated with frequent failures and
relapses (8, 10). Our initial experience suggested that a 3 month course of tetracycline was associated with a higher success rate(8).
In patients with symptoms present for more than six months, the
treatment course may need to be more prolonged, or a retreatment
course of varying length may be needed. In patients with symptoms
for more than a year, 12-18 months may be needed for complete resolution of symptoms. The rationale for a longer treatment course is based on extensive observations (8,10), plus the analogy to the longer treatment courses required for tuberculosis, leprosy, Q fever, and certain fungal diseases.
With Lyme Disease, the slow growth rate and metabolic activity of the borrelia would seem to correlate with the need for longer treatment periods.
Once treatment is initiated for patients beyond the earliest
signs of infection, their symptoms frequently increase during
the first several days, or even for the first several weeks of
therapy. For patients with preexisting symptoms of more than a
few months, relief of any of their symptoms may not occur until
after 4-6 weeks of therapy (8, 10). Typically, there are short
periods of relief, followed by relapsing or migrating symptoms;
with continued therapy there are longer symptom-free periods.
Some arthralgias may require 3 months or more to resolve, and
fatigue may be the last symptom to disappear.
The preference for tetracycline evolved because of the large
number of failures that were noted in patients who had been
on ampicillin and doxycycline. Patients generally had some
response to doxycycline, but it was uaually not complete, nor
long-lasting. Tetracycline may be more effective than
doxycycline simply because of the greater dose, i.e., 100mg
of doxycycline twice daily is not equivalent to 500mg of
tetracycline three times daily; also, doxycycline is highly
protein-bound, compared to tetracycline, which could limit the
availability of free drug to diffuse into tissues and cells.
Some physicians use doxycycline at doses of 300-400mg daily to
try to achieve a successful result. A strict comparison
between doxycycline and tetracycline has not yet been
made. Minocycline has also been used by some physicians, with
varying success, but faces the same issues of dosage and
protein binding.
Of the beta lactams used for the treatment of Lyme Disease, the
most efficacious appears to be ceftriaxone. In limited comparitive trials, cefotaxime appears to be equally efficacious, and high-dose
IV penicillin may also be effective.
In early Lyme Disease, oral amoxicillin is as effective as doxycycline. In later disease, many failures are noted, despite the use of up to 3 grams of amoxicillin daily, with probenicid. Cefixime would also not appear to be
effective therapy. Cefuroxime axetil has been evaluated only in
the treatment of early Lyme Disease, and appears comparable to
doxycycline. Limited reports of its use in later Lyme Disease have
not shown it to be efficacious.
The role of the newer macrolides in the treatment of Lyme
Disease needs further assessment. Erythromycin has been regarded
as ineffective, despite its good in vitro sensitivities.
Azithromycin has been reported to be less effective in the
treatment of early Lyme Disease than amoxicillin (21). Some
physicians use clarithromycin and azithromycin in higher dosages
and for longer periods of time, but there have been no reports of
greater success with these drugs than with the tetracyclines or
beta-lactams. In our experience, all macrolides are effective
when combined with a lysosomotropic agent, especially
hydroxychloroquine(see below)(10).
In evaluating the possible factors, it would appear that
antibiotics that can achieve intracellular concentrations and activity are the most efficacious drugs. The results of studies in Klempner's laboratory using a tissue culture model of borrelia infection demonstrated that ceftriaxone was incapable of eradicating intracellular organisms (17); similar experiments in Raoult's laboratory using an endothelial cell model
demonstrated that tetracycline and erythromycin were effective,
but beta lactam antibiotics were not (3). These results are in line with our experience that the tetracyclines and macrolides achieve the greatest success.
In contrast to beta lactams, antibiotics of the tetracycline and macrolide classes are capable of good intracellular penetration. Experience with the macrolide antibiotics has been disappointing, however, when compared with
its in vitro activities against the Lyme borreliae, and with the established efficacy of macrolides against other intracellular parasites such as chlamydia, legionella, mycobacterium-avium intracellulare, and toxoplasma. If, though, the Lyme borreliae reside in intracellular vesicles that are acidic, the macrolides' activity would be sharply decreased at the lower pH.
This is in contrast to the tetracyclines, which are active at acid pH; even
so, the activity of doxycycline was shown to be further increased by increasing the pH. In a tissue culture model of ehrlichia infection, the use of lysosomotropic agents such as amantidine, NH4Cl, and chloroquine increased the killing of intracellular organisms by doxycycline (22).
Based on those studies, and the hypothesis that late Lyme Disease symptoms are due to persisting intracellular infection, we have been successfully treating patients using the combination of a macrolide and hydroxychloroquine (10).
As regards "CNS" disease, there is no evidence that ceftriaxone
is more successful than either the tetracyclines or the combination of macrolide and hydroxychloroquine; if our presumption that the pathogenesis of the disease involves the localization of the borrelia to the endothelial cells of the blood vessels serving the nervous system or to glial or neural
cells is correct, then one would not need to have a drug that can cross the blood-brain barrier to be effective. Indeed, the tetracyclines can cross the blood-brain barrier to some extent, and were used when initially introduced into clinical medicine for the treatment of meningitis, with some success.
Macrolide antibiotics do not cross the blood-brain barrier, but have been
effective in treating other CNS infections (e.g., toxoplasmosis), and in our experience have been effective in reversing the neuropsychiatric symptoms and signs (eg SPECT scans) of Lyme Disease (10). With regard to the issue of bactericidal vs bacteristatic effects, any such effect in vivo has not been demonstrated.
Finally, there have been no reports showing any change in antibiotic resistance patterns during the course of treatment. Ultimately, the determination of efficacy of therapy depends on the clinical response.
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Ada la forgis says: | 2010-07-16 10:48:46 |
| Very good information, short and easy to understand! | ||
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