Autor: Art Doherty
Email: doherty@utech.net
Datum: 3.8.1998
Forum: sci.med.diseases.lyme
LYME DISEASE - Conn's Current Therapy - 1997 - Method of Joseph J.
Burrascano, Jr., M.D.
LYME DISEASE
method of JOSEPH J. BURRASCANO, JR., M.D. East Hampton, New York
From the 1997 edition of "Conn's Current Therapy"
Latest approved methods of treatment for the practicing physician.
Edited by Robert E. Rakel, M.D.
Professor and Chariman, Department of Family Medicine
Associate Dean for Academic and Clinical Affairs
Baylor College of Medicine, Houston, Texas
W.B. Saunders Company
A Division of Harcourt Brace & Company
Philadelphia London Toronto Montreal Sydney Tokyo
LYME DISEASE
method of
JOSEPH J. BURRASCANO, JR., M.D.
East Hampton, New York
Lyme disease is an extremely complex illness that is still poorly
understood. To date, there still is no consensus on many aspects of its
management. Despite this, the diagnosis and treatment of Lyme disease
is entering a new era, replacing simplistic approaches with more modern
ones based on better knowledge, more experience, and the application of
common sense. This has resulted in an expansion of syndromes
attributable to Lyme disease, thus improving diagnosis, and new
treatment recommendations regarding both drug and dose. The existence
of seronegativity and chronic persistent infection have been confirmed,
as have relapses and treatment failures. With more careful dosing and
more prolonged treatment duration, chronic symptoms can be prevented or
eliminated in many more patients than ever before.
The diagnosis of Lyme disease is made on clinical grounds, as no
currently available test, no matter the source or type, is definitive in
confirming whether an infection with Borrelia burgdorferi is present, or
if so, whether the infection is responsible for the patient's symptoms.
Treatment is also difficult. It is impossible to know how much
medication will be necessary to control the infection, because response
to therapy is extremely variable. Also, it cannot be determined in
advance which of the many complaints will improve with further
antibiotics, and which will be permanent. There is no test available
that can be used during therapy to indicate how effective the treatment
regimen is, and there is no test for cure. That is why the entire
clinical picture must be taken into account, including a search for the
many subtleties that exist. Patient diaries that succinctly outline
symptoms over a course of therapy are vital, and as many objective
measures as possible should be followed, such as temperature graphs,
notes from physical therapists, and physical findings. This information
will help in your assessment of effectiveness of ongoing treatment and
guide you in determining optimal duration.
The concept of a "therapeutic alliance" between the caregiver and
patient has to be emphasized. This means that the patient has to become
part of the medical team and take responsibility for complying with the
recommendations given, maintaining the best possible health status,
reporting promptly any problems or new symptoms, and especially in
realizing that despite all our best efforts, success in diagnosis and
treatment is never assured.
GENERAL INFORMATION
Lyme disease is an infectious illness caused by the spirochete
Borrelia burgdorferi (Bb). Bb is transmitted by the bite of an ixodid
tick. Transmission of the organism occurs if the tick has been attached
long enough to become engorged (typically more than 24 hours), unless it
has been removed improperly, in which case transmission can occur more
rapidly. Squeezing the tick's body, irritating it with heat or
chemicals in an attempt to get it to back out, and disrupting the tick's
integrity, allowing its contents to spill into the wound, all are
examples of this. This history is important to elicit when deciding
whether to give antibiotic prophylaxis after a tick bite.
DIAGNOSIS
Because of the unreliability of serologic testing for Lyme disease,
the diagnosis is a clinical one, based upon the type and pattern of
symptoms present and their evolution over time, especially in the
setting of a previously healthy patient who has had potential tick
exposure. Erythema migrans is the sole absolute indicator of Lyme
disease, yet it is observed in fewer than 50% of cases. The other and
more common symptoms are nonspecific and protean, but they almost always
involve multiple systems and vary over time in both location and
intensity, consistent with an active, disseminated infection. A great
deal of effort must be made in ruling out similarly presenting
illnesses, for often disseminated Lyme becomes a diagnosis of
exclusion.
Another very important factor is response to treatment: presence or
absence of Jarisch-Herxheimer-like reactions, and improvement with
therapy. To simplify and clarify diagnosis a workshop was convened in
1990 and a diagnostic scheme was developed (Table 1). It is important
to note that the published reporting criteria of the Centers for Disease
Control are for surveillance, not for diagnosis.
Table 1. Lyme Disease Diagnostic Criteria
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Relative
Value
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Tick exposure in an endemic region 1
Systemic signs and symptoms consistent with Lyme
(other potential diagnoses excluded):
Single system, e.g., monoarthritis 1
Two or more systems, e.g., monoarthritis and facial 2
palsy
Erythema migrans 7
Acrodermatitis chronica atrophicans, biopsy-confirmed 7
Seropositivity 2
Seroconversion on paired sera 3
Tissue microscopy, silver stain 3
Tissue microscopy, monoclonal immunofluorescence 4
Culture positivity 5
B. burgdorferi antigen recovery (when validated) 4
B. burgdorferi DNA/RNA recovery (when validated) 4
----------------------------------------
Diagnosis
----------------------------------------
Lyme borreliosis likely 7 or above
Lyme borreliosis probable 5-6
Lyme borreliosis unlikely 4 or below
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Erythema Migrans
Erythema migrans (EM) is a raised, warm, erythemtous, centrifugally
expanding round, or oval lesion with distinct margins. Although usually
painless, mild stinging or pruritus can occur. The EM rash can begin 4
days to several weeks after the bite, lasts for several weeks, and may
or may not be associated with constitutional symptoms. Multiple lesions
are present in 10% to 20% of patients. A necrotic center may represent
a mixed infection involving other organisms besides B. burgdorferi.
Atypical lesions may have to be biopsied to aid in diagnosis.
Serologic Testing
Because Lyme serologies often given inconsistent results, you may have
to test at more than one laboratory, using different methods if
possible. Western blotting is recommended for confirmation. IgM and
IgG titers are often reported separately. In Lyme disease, elevated IgM
levels do not always indicate an early stage, for these levels may
repeatedly peak throughout the course of an active infection. False-
negative serologies are common (estimated at 30%) and false-positives
occur in up to 10% of patients. Approximately one-third of seronegative
patients will become transiently seropositive after completion of
successful treatment.
Considerable evidence suggests that in all disseminated Lyme
infections, seeding of the central nervous system occurs early (possibly
within hours after the bite), yet a recent study has shown that
antibodies to Bb can be detected in the cerebrospinal fluid (CSF) in
only 20% of such patients. Therefore, spinal taps are not routinely
recommended but are performed in patients with pronounced neurologic
manifestations, especially if they are seronegative or still
significantly symptomatic after completion of treatment. They are done
to rule out other neurologic conditions, to determine whether Bb
antigens are present, and to determine whether Bb antibodies are being
locally produced in the central nervous system. It is especially
important to look for pleocytosis and elevated protein, which correlate
with the need for more aggressive therapy, as well as the opening
pressure, which can be elevated and add to headaches, especially in
children.
TREATMENT GUIDELINES
Antibiotic Choices
Because the Lyme spirochete is rapidly distributed to all parts of the
body, including the central nervous system, shortly after B. burgdorferi
enters the bloodstream, all stages of this illness represent
disseminated disease. The antibiotic and dose chosen must be able to
penetrate all tissues in adequate concentrations to be bactericidal to
the organism, even in early infections.
There is no universally effective antibiotic for treating Lyme
disease. The antibiotic chosen and dose used will vary based on age,
weight, gastrointestinal function, blood levels achieved in light of
these factors, and on patient tolerance. For poorly understood reasons,
serum antibiotic concentrations vary widely in Lyme patients.
Therefore, whenever possible, serum antibiotic levels should be
determined to aid in arriving at therapeutic doses.
Four types of antibiotics are in general use for Lyme treatment. The
tetracyclines, including doxycycline and minocycline, are bacteriostatic
at doses commonly prescribed, and unless high blood levels are attained,
treatment failures in early and late disease are common. Tetracycline
itself does not penetrate into the CSF as well as doxycycline and
minocycline, and its use is not advised. Doxycycline can be very
effective but only if adequate blood levels are achieved either by high
oral doses (300 to 600 mg daily) or by parenteral administration.
Penicillins are bactericidal. As would be expected in managing an
infection with a gram-negative organism such as B. burgdorferi,
amoxicillin has been shown to be more effective than oral penicillin V.
Because of its short half-life and need for high levels, amoxicillin is
usually administered along with probenecid.
Cephalosporins are useful but must be of advanced generation: first-
generation drugs are not effective and second-generation drugs are
comparable to amoxicillin and doxycycline both in vitro and in vivo.
Third-generation agents are currently the most effective of the
cephalosporins because of their very low mean bactericidal
concentrations (MBCs) (0.06 for ceftriaxone) and because of excellent
tissue penetration. Also, cephalosporins have been shown to be
effective in penicillin and tetracycline failures. Cefuroxime axetil
(Ceftin), a second-generation agent, is also effective against
Staphylococcus and thus is useful in treating atypical erythema migrans
that may represent a mixed infection, containing some of the more common
skin pathogens in addition to Bb. Because it is difficult to tolerate
due to gastrointestinal (GI) side effects and is costly, cefuroxime
axetil is not used as a first-line drug.
Erythromycin has been shown to be almost ineffective. The advanced
macrolides (they are classified as azalides) such as azithromycin
(Zithromax) and clarithromycin (Biaxin) have impressively low MBCs, but
can be difficult to tolerate due to poor GI tolerance at the high doses
needed, and their excessive tendency to promote yeast overgrowth.
When choosing a third-generation cephalosporin, there are several
points to remember: cefotaxime (Claforan) and ceftriaxone (Rocephin)
both have demonstrated activity in vitro, in vivo, and in clinical
studies. Ceftriaxone is administered once daily (an advantage for home
therapy) but has 95% biliary excretion and can crystallize in the
biliary tree with resultant colic and possible cholecystitis.
Gastrointestinal excretion results in a large impact on gut flora.
Cefotaxime, which must be given at least every 12, and preferably every
8 hours, is less convenient, but as it has only 5% biliary excretion, it
never causes biliary concretions, and may have less impact on gut
flora.
Biliary complications and gastrointestinal superinfections with
ceftriaxone can be lessened if this drug is given in interrupted
courses, such as 5 days in a row each week. Table 2 contains a summary
of antibiotic choices; other agents with demonstrated in vitro efficacy
have been used successfully in treating Lyme patients and are also
listed.
Table 2. Antibiotic Choices
========================================================================
Oral Therapy
(Always check blood levels; goal is peak in midteens; trough [pre-dose]
blood level should be greater than 3 u(micro)g/mL)
Amoxicillin:
Adults: 1 gm q 8 h plus probenecid, 500 mg q 8 h
Pregnancy: 1 gm q 6 h
Children: 50 mg/kg/day divided into q 8 h doses
Doxycycline:
Adults: 100 mg tid with food
Not for children or in pregnancy
Cefuroxime axetil (Ceftin): oral alternative that may be effective in
amoxicillin and doxycycline failures; useful in erythema migrans
rashes co-infected with common skin pathogens
Adults and pregnancy: 1 gm q 12 h
Children: 125 to 500 mg q 12 h based on weight
Tetracycline: Poor response and not recommended
Erythromycin: Poor response and not recommended
Chloramphenicol: Not recommended as not proved and potentially toxic
Poorly Studied but Anecdotally Effective Alternatives
Azithromycin (Zithromax):
Adults: 500 to 1000 mg/d
Adolescents: 250 to 500 mg/d
Cannot be used in pregnancy or in younger children
Clarithromycin (Biaxin):
Adults: 250 to 500 mg q 6 h
Cannot be used in pregnancy or in younger children
Parenteral Therapy
Ceftriaxone (Rocephin): Risk of biliary sluddging can be minimized with
intermittent breaks in therapy (i.e., infuse 5 d in a row per wk)
Adults and pregnancy: 2 gm q 24 h
Children: 75 mg/kg/d up to 2 gm/d
Cefotaxime (Claforan): Comparable efficacy to ceftriaxone;no biliary
complications
Adults and pregnancy: 2 gm q 8 h
Children: 90 to 180 mg/kg/d dosed q 6 h
Doxycycline: Requires central line as it is caustic
Adults: 300 mg q 24 h, then adjust based upon blood levels
Cannot be used in pregnancy or in younger children
Penicillin G: IV penicillin G is minimally effective and not recommended
Benzathine penicillin: Useful alternative to oral therapy
Adults: 1.2 million U once to twice weekly, based upon body weight
Adolescents: 300,000 to 1.2 million U weekly
Cannot be used in pregnancy
Poorly Studied but Anecdotally Effective Alternatives
Imipenem: Similar in efficacy to cefotaxime. Must be given q 6 to 8 h
Cefuroxime: Not demonstrably better than ceftriaxone or cefotaxime
Ampicillin: More effective than penicillin G. Must be given q 6 h
========================================================================
Treatment Categories
I have found conclusively that the duration of treatment is just as
important as the choice of antibiotic. It is known that B. burgdorferi
has a very long generation time and may have periods of dormancy. This
has a major effect on the length of treatment needed for the various
stages of this illness, for the longer one is infected before adequate
treatment is begun, the longer the treatment course will have to be. In
humans, Bb seems to regenerate monthly. As antibiotics kill organisms
only during their growth phase, therapy is designed to bracket at least
one entire 4-week generation cycle. Hence the minimum treatment course
is 6 weeks; late, disseminated infections may have to be treated for
many months to be controlled. During treatment, symptoms will wax and
wane every 4 weeks, reflecting the growth period of this Borrelia,
similar to what is seen in the relapsing fevers. If the antibiotics are
working, over time these monthly flares will lessen in severity and
duration. To prevent relapses, treatment has to be continued until all
signs of active infection have cleared. The average duration of
successful therapy of advanced cases is 4 months in males, and 6 months
in hormonally active females. Treatment failures should alert the
clinician to alternative diagnoses, concurrent conditions, and the
presence of an otherwise inapparent immune deficiency.
With intravenous antibiotic therapy, a 6-week course is the minimum.
If there is a pronounced flare of symptoms during the fourth week, then
extend the course to 10 weeks to bracket the next generation cycle.
This type of clinical assessment continues, and when these monthly
reactions finally lessen in severity, then oral medications can be
substituted to the same end point as mentioned earlier. The very
occurrence of ongoing monthly cycles indicates that living organisms are
still present and that antibiotics should be continued until these
cycles no longer occur. Treatment categories are presented in Table 3.
Table 3. Treatment Categories
========================================================================
Prophylaxis of high-risk groups consist of education and preventive
measures; antibiotics not recommended
Embedded Deer Tick with No Signs or Symptoms of Lyme:
Decide to treat based on the type of tick, whether it came from an
endemic area and percent infected, how it was removed, and length of
attachment (nymphs: at least 1 day; adults: anecdotally, as little as 4
hours). The risk of transmission is greater if the tick is engorged, or
if it was removed improperly, allowing the tick's contents to spill into
the bite wound. High-risk bites are treated as follows:
Adults: Oral therapy for 14 days
Pregnancy: Amoxicillin, 1000 mg q 6 h for 6 wk
Alternative: Cefuroxime axetil, 1000 mg q 12 h for 6 wk
Young children: Oral therapy for 14 days
Erythromycin: Poor alternative with documented treatment failures
Early Localized: Single erythema migrans with no constitutional
symptoms:
Adults and children: Oral therapy for 6 weeks
Pregnancy: 1st and 2nd trimesters: IV for 21 days, then oral for 6
weeks;
3rd trimester: amoxicillin 1000 mg q 6 h for 6 weeks
Disseminated Disease: multiple lesions, constitutional symptoms,
lymphadenopathy, or any other manifestations of late disease:
Early Disseminated: Present for less than 1 year and not complicated by
immune deficiency or prior steroid treatment:
Adults: Oral therapy until no active disease for 4 weeks (4-5 months
total)
Pregnancy: As in localized disease, but duration as above. Some
experienced clinicians treat throughout pregnancy.
Children: Oral therapy with duration based upon clinical response
Parenteral Alternatives: For sicker patients and those unresponsive to
or intolerant of oral medications:
Adults and children: IV therapy for 6 weeks or until clearly
improved;
follow with oral therapy or IM benzathine penicillin until no active
disease for 4 weeks
Pregnancy: IV then oral therapy as above
Late Disseminated: present greater than 1 year, more severely ill
patients, and those with prior significant steroid therapy or any other
cause of impaired immunity:
Adults and pregnancy: extended IV therapy 6 to 10 or more weeks),
then oral or IM to same end point.
Children: IV therapy for 6 or more weeks
========================================================================
There is more to managing Lyme disease than simply prescribing
antibiotics. It is necessary for the patient to obtain adequate rest
and receive any needed physical therapy. Those who have been ill for a
prolonged period will also benefit immensely from a careful, thorough,
and aggressive graded exercise program when they are will enough to
begin. Thrush has to be controlled, and a sensible regimen of adequate
nutrition and vitamins, abstinence from smoking and alcohol, and
avoidance of caffeine is recommended. Supportive measures cannot be
ignored. Table 4 summarizes these points.
Table 4. Adjunctive Therapy
========================================================================
Recommended in All Lyme Patients:
Daily yogurt or acidophilus preparations
Multivitamins and B complex, 50 mg daily
Physical therapy and rehabilitation
Prescribe as Needed, Especially in More Severe Cases:
Analgesics and muscle relaxants
NSAIDs and remittive agents
Immune globulins and other immunotherapy if indicated
Antidepressants
Psychocsocial evaluation and possibly refer for counseling
Contraindicated:
Alcohol use
Excessive caffeine intake
Any avoidable stresses
Significant sleep deprivation
========================================================================
Unfortunately, not every Lyme patient will regain his or her former
health, and the management of refractory disease is presented in Table
5.
The ever growing number of new cases of this illness underscores the
need for better preventive measures, and the many chronically afflicted
patients who are resistant to treatment indicate that more research is
needed in this area.
Table 5. Refractory Disease
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Persistent Signs and Symptoms That Respond to Antibiotic Therapy
Patients in this group improve on antibiotics, yet relapse repeatedly
when medications are discontinued. Persistent infection, somehow
resistant to treatment, has been demonstrated in some patients in
this category. Recommended: study immune competence, search for
concurrent infections, and reconsider the diagnosis.
Options for Treatment
Longer duration, including open-ended maintenance therapy
Increased dose
Different drug
Change method of administration (oral to IV)
Supportive therapy as needed
Persistent Signs and Symptoms Not Responsive to Antibiotics
Reconsider the diagnosis
Supportive therapy based on symptoms
NSAIDs and hydroxychloroquine
Antidepressants, analgesics, and muscle relaxants
Synovectomy if the nonjoint symptoms are minimal
Psychiatric/psychometric evaluation
Long-term follow-up
Consider retreatment if condition changes
========================================================================