Studies on late uncomplicated Lyme

General or non-medical topics with information and discussion related to Lyme disease and other tick-borne diseases.
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Re: Studies on late uncomplicated Lyme

Post by X-member » Mon 8 Apr 2013 23:50

CO wrote:
perhaps the above is useful in meantime
Yes it is!

Thank you, CO!

Sophsky
Posts: 15
Joined: Sun 31 Mar 2013 16:49

Re: Studies on late uncomplicated Lyme

Post by Sophsky » Tue 9 Apr 2013 21:17

Carina wrote:I didn't find the full text to this:
5: Dattwyler RJ et al, Treatment of late Lyme disease, Lancet (1988), 1: 1191-4
I have the pdf of this I can send you if you PM your email address? or unformatted difficult to read text is shown below.

TREATMENT OF LATE LYME
BORRELIOSIS—RANDOMISED COMPARISON
OF CEFTRIAXONE AND PENICILLIN
RAYMOND J. DATTWYLER
DAVID J. VOLKMAN
JOHN J. HALPERIN
BENJAMIN J. LUFT
Departments of Internal Medicine, Pathology, and Neurology,
School of Medicine, State University of New York, Stony Brook,
NY, USA
Summary 23 patients with clinically active late Lyme
disease were randomly assigned to
intravenous treatment with either penicillin or ceftriaxone.
Of the 10 treated with penicillin, 5 were judged treatment
failures; of the 13 who received ceftriaxone, only 1 did not
respond. An additional 31 patients were subsequently
treated with ceftriaxone 4 g/day (n = 17) or 2 g/day (n = 14);
successs rates in both groups were comparable to those in
the cohort randomised to ceftriaxone. Patients unresponsive
to ceftriaxone were more likely to have received
corticosteroid treatment.
Introduction
LYME borreliosis is caused by infection with the tickbome spirochaete Borrelia burgdorferi. 1-3 Although the
disorder typically begins with local cutaneous lesions, early
dissemination is common and leads to multisystem disease,
including involvement of the heart, nervous system, and
joints.4-12 Oral antibiotics usually, 13.14 but not invariably /5
eradicate early, apparently localised infections; treatment
failures may be due to inapparent early dissemination. Late
illness is more refractory to therapy. Intravenous penicillin,
the standard treatment for late Lyme borreliosis,16 has not
been universally successful:16-19 failure rates as high as
50%16 or more19 have been reported. Clearly, alternative
therapies are needed.
To be effective in the treatment of Lyme borreliosis, an
antibiotic should have good tissue penetration into the sites
commonly infected by B burgdorferi. Since the nervous
system is often involved in late disease ’11,920,-22 and since
antibiotic penetration into this site is limited, it is necessary
to achieve adequate microbicidal concentrations in nervous
tissue. We previously showed that ceftriaxone is effective in
the treatment of late Lyme borreliosis in patients with
neurological or rheumatological disease who had not
responded to high-dose penicillin. 18 We have now compared
ceftriaxone (4 g/day) and penicillin (24 million units/day) in
patients with late disease in a randomised study.
Patients and Methods
Enrolment of patients started in July, 1986, and finished in
February, 1987. All patients had been referred to the Lyme Disease
Service at University Hospital, State University of New York at
Stony Brook. Those who had objective evidence of late Lyme
borreliosis were offered admission to the randomised trial.
Diagnostic criteria included: (a) a well-documented, physicianobserved rash consistent with erythema migrans and/or evidence of
specific immunological reactivity to B burgdorferi and (b) objective
evidence of involvement of two or more organ systems (central and
peripheral nervous systems, cardiovascular system, or
musculoskeletal system). Patients were randomised to treatment by
use of a computer-generated pseudorandom number-if the two
digit integer was odd, the patient received penicillin; if it was even,
ceftriaxone.
Specific antibody reactivity to B burgdorferi was measured with a
standard enzyme-linked immunosorbent assay (ELISA).23 Serum
samples were diluted 1 in 500 and run in duplicate; optical densities1192
were compared with those of concurrently processed negative
controls. Only values > 3 SD above the mean of negative controls
were considered positive. T-cell immunity was measured24 by
determining the specific lymphoproliferative response to whole
B burgdorfen; the response was considered positive if the
stimulation index was > 5 and the number of counts in Borreliastimulated cultures was > 5000 disintegrations/min. Neurological
abnormalities were assessed by clinical examination and nerve
conduction studies25 in all patients, and by magnetic resonance
imaging (MRI) of the brain in 4.21
23 patients entered the initial study (table I, group I). 10 were
randomised to receive penicillin (4 million units intravenously eveiy y
4 h for 10 days), and 13 to receive ceftriaxone (2 g intravenously
every 12 h for 14 days). All patients in this group have now been
followed for at least 9 months. Patients were considered treatment
failures if, at the end of 3 months after treatment, they had persistent
(a) objective evidence of arthritis, (b) symptoms, confirmed by
neurophysiological testing, of peripheral neuropathy, or (c)
encephalopathy. Patients who did not respond to one treatment arm
were offered treatment with the other regimen. 4 of the 5 patients
unresponsive to penicillin were subsequently treated with
ceftriaxone. The patient who did not respond to ceftriaxone
declined retreatment.
After 23 patients had been treated, we reviewed the rate of
response to the two treatment arms and found that the difference
between penicillin and ceftriaxone had achieved statistical
significance. We then prospectively treated an additional 31 patients
who met the same admission criteria (group II) with ceftriaxone.
Neurological evaluation in this group was more limited-30 were
examined by a neurologist, 25 with symptoms of peripheral
neuropathy underwent neurophysiological testing, and 3 with
encephalopathy had MRI scans of the brain. The initial patients in
this group received 4 g/day (17 patients). However, in April, 1987,
the manufacturers raised questions about the possibility of sideeffects at this dose level, so all subsequent patients received 2 g!day
(14 patients). All patients in group II have now been followed for at
least 6 months.
Fisher’s exact test or Student’s t test was used for statistical
comparisons.
Results
The four subgroups (tables I and II) were well matched in
terms of age, sex, and frequency of involvement of different
organ systems. Most patients had received oral antibiotics
early in the course of their infection-tetracycline (21
patients), penicillin (16), amoxycillin (1), cefadroxil (1), and
cephalothin (1). The patients in the non-randomised study
(group II) resembled those in the randomised group (group
I), and there were no significant demographic differences
between those treated with 2 g/day and those receiving 4
g/day. Ceftriaxone was generally well tolerated. Although
none of our patients experienced serious side-effects, mild to
moderate diarrhoea developed in about half of those
receiving 4 g/day and in about 10% of those treated with 2
g/day. A skin rash requiring discontinuation of therapy
developed in 2 after 8-10 days. Within the first 3 days of
treatment, 13 patients noted mild worsening of their joint
pains, malaise, headaches, and/or mild fever; these
symptoms suggested a mild Jarisch-Herxheimer reaction. 1
of these patients received penicillin, 3 ceftriaxone 2 g/day,
and 9 ceftriaxone 4 g/day (differences not statistically
significant).
Randomised Study
We initially compared the rates of response to penicillin
and ceftriaxone. Mean duration of disease was slightly
longer in the penicillin-treated patients, but the difference
was not statistically significant. Disease duration in patients
who did not respond to penicillin (from onset 28-8 [SD 22-1]
TABLE I-CLINICAL CHARACTERISTICS
*Not significant.
months, systemic symptoms 22-4 [SD 15-5] months) was
indistinguishable from that in the ceftriaxone-treated group.
Arthritis, which was always of a relapsing oligoarticular
type, recurred with variable frequency (weekly to once every
other month). Of the 7 patients receiving penicillin who had
arthritis, the knee was involved in 7, and the hip, shoulder,
and wrist in 1 each. In the ceftriaxone group, 9 had arthritis
(knee 9, shoulder 2, wrist 2, hip 1, elbow 1). Mean duration
of arthritis was 33 months (range 4-84) in the penicillintreated group, and 42 months (range 2-120) in the
ceftriaxone group. Initially no patients in the randomised
trial had erosive changes on radiographic examination or
pannus formation. Neuropathy, manifested clinically as
intermittent paraesthesias, with mild abnormalities on
neurological examination, was confirmed by
neurophysiological tests in 4 of the penicillin-treated
patients, and in 9 of those randomised to ceftriaxone. The
encephalopathy was generally mild; it interfered with the
patient’s daily activities and was apparent on mental status
tests, but seldom caused a profound confusional state.
After treatment, half the patients randomised to penicillin
continued to have arthritis, fatigue, and memory difficulties
(table II). 1 of the 4 who had neurophysiological evidence of
a peripheral neuropathy before penicillin treatment did not
improve. 1 who was treated with intravenous penicillin
when he initially presented with cardiac conduction
abnormalities first got arthritis 2 months after completion of
antibiotic treatment. Another, who initially had active
arthritis but no erosive changes, progressed to erosive
arthritis of both hips after completion of penicillin
treatment. In contrast, none of the patients randomised to
ceftriaxone had any objective evidence of persistent disease
activity, although 1 described persistent fatigue and memory
difficulty and 3 had mild arthralgias. All ceftriaxone-treated
patients in this study had significant improvement in their
peripheral neuropathy (subjective assessment and nerve
TABLE II-RESPONSE TO ANTIMICROBIAL THERAPY1193
conduction studies) and resolution of their arthritis. Even in
the patient with persistent fatigue and memory difficulty,
the abnormalities present on the initial MRI scan (white
matter hyper-resonant plaques) disappeared on a follow-up
scan carried out 5 months after treatment. In all patients,
improvement was gradual. Patients generally noted little
change during treatment, but symptoms began to improve
over the ensuing weeks. There was objective evidence of
improvement (improved nerve conduction, resolution of
arthritis) within the 6-month follow-up period.
Of the 4 penicillin non-responders who were retreated
with ceftriaxone, all symptoms resolved in 3; erosive
arthritis of the hip had developed in the fourth but all
evidence of active disease (neuropathy, headaches,
arthralgias, fatigue) disappeared.
Ceftriaxone 2 g vs 4 g
The character and distribution of arthritis in groups I and
II were similar. The response rate of patients in the
non-randomised cohort resembled that in the group I
ceftriaxone-treated patients (table II). 3 of the 31 group II
patients had persistent neuropathy, and 2 had persistent
encephalopathy. In 3, arthritis did not improve; the arthritis
was of a relapsing/remitting type in 1, whereas in the others
it was unremitting and associated with synovial hypertrophy
and persistent pain. The rates of response to the two doses of
ceftriaxone were similar (table n). Overall, 5 of 44 patients
treated with ceftriaxone did not respond to treatment. The
non-responders (table III) were slightly older than the
responders, and had disease of slightly longer duration,
although these differences were not statistically significant.
TABLE III-COMPARISON OF CEFTRIAXONE RESPONDERS
AND NON-RESPONDERS
*Not significant; tp = 0-007, Fisher exact test.
TCN = tetracycline; PCN = penicillin.
5 of the 44 ceftriaxone-treated patients had previously
received systemic (2) or intra-articular (3) corticosteroids. 3
of these patients did not respond to antibiotic treatment (4
g/day in all 3). Their disease was no more severe than in
patients not receiving steroids--comparable duration of
illness (3 years in 2, 6 years in 1), and severity of joint
involvement. The association of previous steroid treatment
with lack of response to ceftriaxone was significant
(p = 0-007, Fisher exact test).
Discussion
We have previously shown that ceftriaxone can be
effective in treating patients with late Lyme disease who
have not responded to high doses of parenteral penicillin; 8
other third-generation cephalosporins may be similarly
effective.26.27 In this study we have established that
ceftriaxone is better than intravenous penicillin as primary
therapy for late Lyme borreliosis: about 90% of patients
treated with ceftriaxone responded whereas half of those
treated with penicillin had persistent evidence of disease
activity. In patients who responded, both rheumatological
and neurological abnormalities improved. Recovery tended
to be gradual, and took place slowly over several months
following treatment.
Of the 44 patients treated with ceftriaxone, 5 were deemed
to be treatment failures. 1 of the non-responders had active
neurological and rheumatological manifestations for over 5
years before receiving ceftriaxone; in contrast to the 3 other
patients whose arthritis did not respond, she did not have
pronounced pannus formation and her arthritis resolved
after therapy whereas her neurological manifestations
persisted. Another ceftriaxone non-responder had
persistent symptoms (arthralgias, memory deficit, and
fatigue), although by all objective criteria (including repeat
MRI scan of the brain) he had improved. The remaining 3
patients had had chronic arthritis for more than 3 years
before diagnosis and treatment; all had synovial
proliferation at the time of entry into the study, but none had
erosive arthritis. All had persistent arthritis after treatment.
Erosive changes or pannus formation appeared to diminish
the likelihood of complete recovery after antimicrobial
therapy; in patients without these changes, arthritis usually
resolved. Once mechanical derangement has occurred, any
medical therapy would be expected to be less effective.
Several properties of ceftriaxone may contribute to its
superiority in the treatment of B burgdorferi infections.
In-vitro studies have shown that B burgdorferi is much more
susceptible to this agent28-30 than to penicillin. Comparisons
of ceftriaxone and penicillin in animals have shown that
ceftriaxone is far better in eradicating the infection than
penicillin.28,30 Moreover, ceftriaxone crosses the blood/brain
barrier and readily attains microbicidal concentrations
within the nervous system. In-vitro studies indicate that
prolonged exposure of B burgdorferi to a beta-lactam
antibiotic is necessary for effective killing.29 Ceftriaxone,
with its long half-life, provides the necessary sustained
minimum inhibitory concentrations of antibiotic in the
brain, synovial fluid, and other tissues whereas considerably
greater concentrations of penicillin are necessary to inhibit
the growth of this organism.28-30
Our study also suggests that the use of glucocorticosteroids may be detrimental in the treatment of the
late arthritic manifestations of Lyme borreliosis. 3 of the
5 patients unresponsive to ceftriaxone had been treated with
corticosteroids; this observation accords with the findings of
an earlier report" that patients who had been given steroids
were less likely to improve after intravenous penicillin. In
that study it was felt that the higher failure rate in the steroid
group might have reflected the fact that only patients with
more severe arthritis received corticosteroids. However, in
our study the pre-treatment severity and extent of joint
involvement in the steroid-treated and non-steroid-treated
patients were comparable. The association of steroid use
with an increased failure rate or worsening of disease is
understandable in view of the well-known effects of these
agents on the inflammatory and immune responses. Many
patients with acute and chronic infections will improve
initially after receiving corticosteroids, but most will
relapse.31,32 In view of the strong association between the use
of steroids and the lack of response to antibiotic therapy, we
believe that glucocorticoids should not be used in the
treatment of Lyme borreliosis. Whether glucocorticoids can1194
be used safely once the patient is receiving high-dose
antibiotics remains to be established.
The best strategy for the treatment of Lyme borreliosis is
prompt administration of oral antibiotics at the time of initial
infection. If the symptoms of late Lyme borreliosis develop,
prompt treatment will usually lead to excellent recovery. On
the basis of these results, we believe that ceftriaxone is the
treatment of choice for late Lyme disease.

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Posts: 9887
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Re: Studies on late uncomplicated Lyme

Post by X-member » Tue 9 Apr 2013 21:32

Very interesting, thank you, Sophsky!

Edit to add:

Like this for example:
The association of steroid use
with an increased failure rate or worsening of disease is
understandable in view of the well-known effects of these
agents on the inflammatory and immune responses. Many
patients with acute and chronic infections will improve
initially after receiving corticosteroids, but most will
relapse.

X-member
Posts: 9887
Joined: Mon 30 Jul 2007 18:18

Re: Studies on late uncomplicated Lyme

Post by X-member » Tue 31 Mar 2015 16:25

Bump!

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