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The following paper was prepared to
support an external appeal for a Lyme patient who was refused coverage because
the insurance company stated that the dosage administered was greater than that
recommended by IDSA guidelines and therefore was not medically appropriate or
necessary. The writer, Carolyn Cramoy,
M. S. is not a medical doctor or pharmacologist and the information and
opinions expressed should not be interpreted as medical advice. Rather, this is a review of the scientific
literature pertaining to the case in question and the treating physicians'
decision to use antibiotic levels greater than those recommended by the IDSA
for the initial treatment of uncomplicated Lyme disease. References are provided. The Use of Cefotaxime in Treating CNS Lyme Disease by
Carolyn Cramoy, M. S. Antibiotics
are accepted as mandatory in active Lyme disease treatment. However, the ideal antibiotics, their
dosage, route of administration and duration of therapy have not been
established. Treatment failures occur
with all regimens tested to date (1, 2). There is no IV antibiotic that currently has FDA approval for the
treatment of Lyme disease. Ceftin is
the only oral antibiotic so approved and that approval is only for the
treatment of early Lyme disease.
Persistent infection has been proven repeatedly through the culturing of
live spirochetes from the blood or tissue of previously antibiotic treated
patients, as well as by DNA detection by PCR.
Because there is no test, other than the extremely difficult procedure
of culturing of live spirochetes from blood or tissue, which can 100% reliably
detect the presence of active Borrelia
burgdorferi (Bb)
infection in the body or prove its eradication from the body, the final
diagnosis of and treatment decisions for persistent Lyme infection remain with
the experienced clinician directly involved in the treatment of the
patient. When the Lyme bacteria have
established themselves in the central nervous system, effective treatment
becomes an urgent and complex challenge. Guidance
on appropriate treatment of difficult-to-treat, antibiotic responsive,
neurological Lyme disease can be gleaned from the extensive medical literature
available on Lyme disease, and other spirochetal illnesses, as well as that
available on other bacterial infections of the central nervous system. Bacterial eradication from the cerebrospinal
fluid (CSF) is the definition of bacteriologic cure or response in meningitis (3).
The same definition can be valuable in Lyme disease but must be taken a step
further and demand eradication of both spirochetal and cystic forms of the
bacteria from intra and extracellular spaces within the body as well. Successful
treatment of a central nervous system (CNS) infection will be dependent on
adequate CSF penetration by the chosen antibiotic, with the goal of achieving
greater than minimum bactericidal concentration (MBC) levels for as long as
necessary to assure destruction of the bacteria in question (4). Much
research and clinical experience supports the need for sustained high levels of
CSF concentration in treating Lyme disease.
Though
early reports claimed that Lyme disease will resolve by itself if left
untreated, it has been found that, even over a period of years, the immune system
is often unable to clear the infection. Bb DNA has been shown to persist
in untreated patients for up to 7 years after onset of arthritis (49). In infections where the host defenses
contribute minimally to cure, bactericidal drug concentrations must be achieved
in the infected tissue (5). Bb's slow rate of replication,
proven access to intracellular and extracellular "privileged sites",
immune system evasion tactics, and conversion to cystic forms when exposed to
antibiotics or CSF, all add to the challenge of selecting the proper
antibiotic, adequate dosage and length of treatment. The large body of evidence proving continuing Bb infection
in a small percentage of patients following antibiotic treatment underscores
the need for truly bactericidal results in treating Lyme disease. The ability to eradicate Bb infection
in an individual patient is likely dependent on bacterial load, infecting
strain, bacterial penetration of privileged sites and the ability of
antibiotics to penetrate those privileged sites, and the ability of cyst forms
to survive exposure to antibiotics (61).
The formation of Bb cysts in vitro upon exposure to
antibiotics, which can later revert to active spirochetes when antibiotic
levels drop, may help to explain the observed need for repeated courses of
antibiotics in order to achieve total eradication of the infection (6). The experiences of clinicians in Lyme
endemic areas, as well as the work of many researchers support this idea. The presence of these cystic forms in blood
of Lyme disease patients has also been demonstrated. The
third generation cephalosporins, cefotaxime and ceftriaxone, members of the
beta-lactam group of antibiotics, are recommended for the treatment of Lyme
disease because of their efficient penetration into CSF, and because of Bb's
in vitro sensitivity to both substances. Cefotaxime has been shown to
achieve access to the vitreous humor, a proven "hiding place" for the
Lyme spirochete (7).
Cephalosporins are widely used in clinical situations because they cover
a large range of bacteria and they offer a lower frequency of toxicity than
other antibiotics (8). According to clinical studies, cefotaxime is one
of the safer third generation cephalosporins (9,10,11,12,13,14). The
dosage used and length of treatment is dependent on the bacteria involved and
the location of the infection. Ceftriaxone
is often recommended for home infusion situations because it can be delivered
in a convenient once-a-day dose.
However, the advantages of cefotaxime over ceftriaxone are numerous and
it should be carefully considered as the firstline of treatment in CNS Lyme
disease. Most patients find the small
(approx 3''x6''x1"), quiet portable electronic pumps now available for
multiple daily dosing or continuous infusion to be only minimally intrusive as
they recover and are able to resume activities outside the home. These pumps are generally worn all day in an
inconspicuous waist pack. Another
option is the non-electronic "Homepump" automatic delivery system if
a multiple dose schedule is chosen.
These small (approx 3" diameter), silent, pre-filled and
calibrated, elastic pumps fit in a waist pack, remain totally sterile and are
easily hooked-up no matter where the patient might be. They are especially
popular with teen-agers who don't want their therapy to be noticed by their
peers. Cefotaxime
has a lesser degree of protein binding in the serum and therefore a higher
potential for concentration in the CNS.
Studies have found the percent penetration of cefotaxime and ceftriaxone
into the CSF in humans with meningitis to be 27% and 16% respectively (38). Additionally, 95% of cefotaxime elimination
is renal, eliminating the possibility of liver toxicity and the gall bladder
damage so often seen with long-term ceftriaxone use, especially in young
women. The major metabolite of
cefotaxime, desacetyl-cefotaxime has antibacterial activity at about 1/4 that
of cefotaxime and can make significant contributions to the maintenance of bactericidal
levels in the CNS. The short half-life
of cefotaxime (approx. 1 hour) and desacetyl-cefotaxime (approx. 1.5 hours)
makes maintenance of high levels in the CNS practical without the likelihood of
undesirable accumulation (39). Beta-lactam
antibiotics work by preventing the proper formation of the bacterial cell wall
during cell division. Therefore, they
are only bactericidal when cells are actively dividing. Borrelia burgdorferi has a very slow
reproduction rate of 7 to 22 hours. Beta-lactam
antibiotic effectiveness against bacteria is dependent on the presence of
adequate drug levels through multiple cell divisions. While increases in the concentration of these drugs above a
certain point have little effect on kill rate, the constant maintenance of
adequate concentrations over the entire treatment time is extremely important
in achieving eradication of the infecting bacteria (15). When Bb was
incubated for 5 days in Pen G, severe cytolysis of the bacteria only occurred
at levels 75% to 300% above the MBC.
Allowing levels to cycle below optimum will allow for regrowth of the
bacteria, as there is either no, or short, post antibiotic effect (PAE) for
most beta-lactams both in vivo and in vitro (16, 15). Research has shown that the CSF levels need
to exceed the minimum bactericidal concentration (MBC) by 10 to 30-fold to
obtain maximum bactericidal activity in experimental models of meningitis. This may be in part due to the slower growth
rate of bacteria in CSF than in broth (18). Given Bb's very slow reproduction rate even under ideal
conditions, this point is especially important in designing a treatment
schedule for persistent CNS Lyme disease. The
minimum inhibitory concentration (MIC) of cefotaxime against Bb was
shown by Hunfield, et al to be 0.15 mg/L (19). Given that the MBC's for ceftriaxone against Bb are
usually 2 to 8 times the MIC, it is reasonable to predict that the MBC for
cefotaxime is in the range of 0.30-1.2 mg/L and that a therapeutic CSF
concentration would be 3 to 12 mg/L.
Studies of CSF concentrations of cefotaxime in meningitis indicate that
levels vary tremendously from individual to individual, but it is reasonable to
expect that effective therapeutic levels can be achieved through high-dose
continuous infusion. The median CSF
levels and (range) in children given 300 mg/kg/day in 3 divided doses, were
4.7(1.4-12.4), 3.3(<0.5-7.1), 1(<0.5-23.7) and 2.2(<0.5-7.8) at 2, 4,
6 and 8 hours after dose (20).
In a discussion of the clinical use of antibiotics, Mills lists a
cefotaxime level in CSF (with inflamed meninges) of 0.3-27 mg/L for dosages of
30-150mg/kg/day, however he offers no details or reference for this information
(21). Experience has shown that both cefotaxime and ceftriaxone given
at the IDSA recommended dosage for neurologic Lyme often result in treatment
failure, incomplete resolution of symptoms, or subsequent relapse even when
given for treatment periods of many months (22, 23, 24, 25, 26). It has been shown that retreatment increases
the number of patients cured (27, 28). Though
lower than traditional doses of cefotaxime have been found to be effective
against organisms outside of the CNS, the necessity of increasing the dose in
the treatment of meningitis and endocarditis has been shown (29,30). Additionally, a higher dose may be necessary
for resistant bacteria, and in treating immunocompromised patients (29). Studies of the immune competency of Lyme
disease patients have shown a reduction of killer T-cell activity, and the
actual invasion and killing of human B and T lymphocytes by Bb (31). Additionally, Bb's ability to elude
the immune system by various methods, in fact, compromises the patient's immune
system with reference to its ability to find, identify and eliminate that
specific bacteria. The
manufacturer of Claforan (cefotaxime), Hoechst Marion Roussel Pharmaceuticals,
Inc., states that 12 gm/day in adults, or 200 mg/kg/day in children, is the
recommended dosage for treatment of serious infections. However, in clinical settings, it is now
fairly common for dosing to be given at 300 mg/kg/day in both adults and
children (20, 32, 33, 34). The
Canadian Pediatric Society recommends cefotaxime 300mg/kg/day plus
vancomycin 60 mg/kg/day for the empirical treatment of suspected bacterial
meningitis (34). It is
interesting to note that an early study of Lyme treatment used ceftriaxone at a
dosage of 4 gm per day, but this dosage was subsequently reduced due to the
manufacturer's warnings of toxicity (35). Given cefotaxime's safety record and the number of documented
Lyme disease treatment failures, it is puzzling that it continues to be
recommended only in doses equivalent to the reduced ceftriaxone levels. Pulse
therapy with high doses of cefotaxime being given 2 to 4 days per week at a
dose of 10 to 12 gm/day has been reported in anecdotal accounts to be effective
in some patients. However, this is a
confusing finding in light of all the research showing the importance of
maintaining levels well above the MBC to assure maximum effectiveness of
beta-lactam treatment. A possible mechanism
of effectiveness would be that gaps in antibiotic exposure help to preserve the
spirochete in its cell wall form and thus maintain its vulnerability to the
cell wall inhibiting action of the cefotaxime.
Without further knowledge of the dynamics of cyst formation in Bb only
speculation is possible. When
300 mg/kg/day doses are used, the upper limit of dosing is set at 24
gm/day. The dose for a 120 pound adult
would be 16 gm/day. In that same 120
pound adult; 12 gm/day is equivalent to 220 mg/kg/day. 10 gm/day is equivalent to 180 gm/day. 8 gm/day is equivalent to 145 gm/day 6 gm/day is equivalent to 110 gm/day The
experience of clinicians in Lyme endemic areas indicates: - that long-term antibiotic therapy is sometimes necessary in
treating Lyme disease, - that testing for co-infection with other tick-borne illnesses
should be performed - that in the absence of clear objective evidence of Lyme a
thorough differential diagnosis is necessary, including infectious,
auto-immune, and neurological conditions with similar clinical presentations,
and if indicated, psychological/psychiatric evaluation, - that complications are possible with oral or parenteral
antibiotics and careful monitoring is the best way to assure safety - that gradual but continuous resolution of minor symptoms may
be acceptable after stopping antibiotics, - that worsening of symptoms after stopping antibiotics likely
indicates failure to eradicate the infection and retreatment should be
considered - that the choice of antibiotics used in retreatment should be
carefully determined based on the patient's clinical presentation and responses
to past therapy - that multiple retreatments may be necessary and can lead to
cure (27, 28, 36, 37, 62). MIC's
and MBC's are useful in guiding clinical decisions on antimicrobial usage,
however, it must be recognized that they may or may not be analogous to the
clinical situation, and results must be interpreted accordingly. Treatment of
most serious (bacterial) infections requires parenteral administration of
antimicrobial agents. When toxicity is not a limiting factor, an increase of
the dose may result in a sufficient concentration of free drug to be effective
(22). There has never been a study that proves that currently
recommended short-course (two to four weeks) therapy results in a bacteriologic
cure in Lyme disease (41). Clinical improvement is the best and most
comprehensive guide to the adequacy of therapy, but it often is difficult to
monitor objectively, especially in critically ill patients with multisystemic
disease. Clinical improvement may be
very slow for infections requiring long-term therapy (for example, endocarditis
and osteomyelitis) (22).
Although agreement among multiple double blinded, placebo controlled
clinical trials would be the gold standard, there are many sources of valid
scientific evidence for clinical decision-making. In the absence of well-designed, double-blind studies, the
strength of evidence available to clinicians in making treatment decisions for
individual patients can be divided into 3 levels: 1.
Evidence obtained from at least one properly randomized controlled
trial. 2.
Evidence from at least one well-designed, clinical trial without
randomization, from cohort or case-controlled analytic studies preferably from
more than one center, from multiple time series or from dramatic results in
uncontrolled experiments. 3.
Evidence from opinions of respected authorities on the basis of clinical
experience, descriptive studies or reports of expert committees. (19) The
information provided in this paper supports the medical appropriateness of high
dose cefotaxime treatment in difficult cases of chronic or relapsing antibiotic
responsive Lyme disease. Prepared
by: Carolyn
C. Cramoy, M. S., Nutrition Consultant Lyme
Disease Advocate 10
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