Originalia D. Hassler, L. Z611er, M. Haude, H.-D. Hufnagel, F. Heinrich, H.-G. Sonntag

Cefotaxime versus Penicillin in the Late Stage of Lyme Disease Prospective, Randomized Therapeutic Study Summary: The low responsiveness of Lyme arthritis to high dose intravenous penicillin G therapy has evoked the demand for new drugs for the treatment of late stage borreliosis. As can be deduced from in vitro susceptibility data, third generation cephalosporins are far more effective on Borrelia burgdorferi spirochetes than penicillin G. The study presented here was designed to compare cefotaxime at a dosage of 2 x 3 g/day with penicillin G at a dosage of 2 x 10 megaunits/day, for ten days in a prospective randomized trial. A total of 135 patients were included in the study. They were diagnosed to suffer from late stage Lyme borreliosis on the basis of defined clinical symptoms compatible with

stage three borreliosis manifestations of at least six months' duration and positive antibody titers against B. burgdorferi. Final outcomes were recorded after a 24 month post-treatment observation period with re-examination at three-month-intervals. Cefotaxime proved to be significantly superior to penicillin G with 87.9% versus 61.3% of treatments resulting in full or incomplete remission of symptoms (p = 0.002). Clinical remission was accompanied by declining antibody titers. Herxheimer-like reactions were observed in 20% of the patients of the penicillin group and in 40.5% of the patients of the cefotaxime group and may be interpreted as an indication of a response to therapy.

Zusammenfassung: Cefotaxim im Vergleich zu Penicillin zur Therapie der Lyme-Borreliose im Spiitstadium. Prospektive, randomisierte Studie. Die geringe Ansprechrate der Lyme-Arthritis auch bei intraven6ser und hochdosierter Gabe von Penicillin G hat das Interesse an neueren Antibiotika zur Behandlung der Lyme-Borreliose im Sp~itstadium erh6ht. Wie schon auf Grund vorliegender In-vitro-Daten zur Empfindlichkeit yon Borrelia burgdorferi erwartet werden konnte, sind Cephalosporine der dritten Generation sehr viel effektiver als Penicillin G. In der hier vorgestellten randomisierten prospektiven Untersuchung wurde deshalb Cefotaxim in einer Dosierung yon 2 x 3 g tfiglich mit Penicillin G in einer Dosierung yon 2 × 10 Mega-Einheiten verglichen. 135 Patienten, bei denen eine definierte klinische Symptomatik im Sinne einer Stadium-3-Borreliose ffir mindestens sechs Monate bestanden hatte und bei de-

nen Antik6rper gegen 13. burgdorferi nachweisbar waren, wurden in die Studie aufgenommen. Die Patienten wurden 24 Monate nachbeobachtet und im Abstand von drei Monaten reevaluiert. Die mit Cefotaxim behandelten Patienten zeigten ein signifikant besseres Therapieergebnis. WS~rend in der Penicillin-Gruppe nut 61,3% der Patienten eine Voll- oder Teilremission ihrer Beschwerden zeigten, konnte dies bei der Cefotaxim-Gruppe bei 87,9% der Patienten erreicht werden (p = 0,002). Parallel zum klinischen Effekt war ein Absinken der Antik6rpertiter im Immunfluoreszenztest zu beobachten. Herxheimer-artige Reaktionen waren bei 20% der Patienten der Penicillin-Gruppe und bei 40,5% der Patienten der Cefotaxim-Gruppe zu beobachten. Diese Reaktion kann als Hinweis auf ein Ansprechen der Therapie gewertet werden.

Introduction Penicillin G has for long been the standard therapeutic regimen for Lyme borreliosis. Intravenous high dose therapy has been found to be effective in stage two neurologic abnormalities but failed to be sufficiently effective in stage three arthritis. Non-responders of penicillin G treatment were reported in 50% of stage three cases [1, 2]. Recent in vitro susceptibility data [3-5] revealed that Borrelia burgdorferi is only moderately susceptible to penicillin G but highly susceptible to third generation cephalosporins. An MICg0 value of 0.12 rag/1 was reported for cefotaxime. In vitro data contributed by Luft et al. [6] emphasize the necessity to achieve bactericidal concentrations for a sufficient period of time. Moreover, high penetration into tissues and cerebrospinal fluid is required with regard to the CNS manifestations and the persistence of spirochetes 24 / 16

in bradytrophic tissues. There are sufficient data available which prove the superiority of third generation cephalosporins in this respect. In spite of these facts, there is a lack of controlled prospective clinical studies which clearly" document the superiority of third generation cephalosporins and other antibiotics to penicillin G in the late stage of Lyme borreliosis. This is probably due to the difficulties in defining the clinical diagnosis of late Lyme borretiosis, which is characterized Received: 10 May 1989/Revision accepted: 18 December 1989 Dr. med. D. Hassler, Dr. reed. L. ZOller, can. reed. Martina Haude, Prof. Dr. med. 14.-6;. Sonntag, Hygiene-Institut der Universitat Heidelberg, D-6900 Heidelberg, FR Germany; can. rer. hum. H, -D. Hufnagel, Digital Equipment GmbH, D-6072 Dreieich; Prof. Dr. reed. F. Heinrich, Med. Klinik des Krankenhauses Ftirst-Stirum-Stiftung, D-7520 Bruchsal.

Infection 18 (1990) No. 1 © MMV Medizin Verlag GmbH Miinchen, Miinchen 1990

D. Hassler et al.: Cefotaxime in Late Lyme borreliosis

Table 1: Distribution of main diagnostic criteria and additional symptoms in the study population.

Entlnesio- ~ a d a e h e Sweating

~;::

~:i!i

Recurrent arthritis

(n = 18)

*

3

4

8

10

5

3

4

1

Peripheral neuropathy

(n = 30)

21

5

7

15

9

14

2

4

1

Arthritis and neuropathy

(n = 14)

*

3

3

7

8

7

3

4

3

ACA/LABC

(n = 2)

2

1

1

-

1

-

-

-

1

Arthritis and ACA

(n = 2)

*

-

1

2

~ i~ i ~

i~ ~ % ~

~~ I ~ E ~

~ ! ~~i~~ i ~ ~ ] ~ ! ~ ' ~

~ii~

.

.

............ •.............. ' . . . . . . . . . . . . . . . . . . . . . .

ii ¸

.

.

.

~................ ~ ° ~ " ~ ~ ~

!

i~i~i~i~

............

~ !!:~

~

, .............

Recurrent arthritis

(n = 16)

*

1

5

7

4

4

2

4

1

Peripheral neuropathy

(n = 29)

20

4

4

13

12

13

2

4

2

Arthritis and neuropathy

(n = 20)

*

4

5

7

8

9

1

4

2

ACA/LABC

(n = 1)

1

-

1

-

1

Arthritis and ACA

(n = 3)

*

1

1

-

-

by multiple symptoms that are rarely pathognomonic. A p a r t f r o m case history reports on the t r e a t m e n t of rheumatological or neurological late complications and several reports on the failure of the r e c o m m e n d e d treatment [7-14], there has so far b e e n only one prospective study of the t r e a t m e n t of the chronic stage, presented by Dattwyler [15] in which ceftriaxone was c o m p a r e d with penicillin. W e describe here a prospective r a n d o m i z e d trial which was p e r f o r m e d to evaluate the therapeutic effects of cefotaxime versus penicillin G in cases that were diagnosed as L y m e borreliosis on the basis of defined clinical symptoms belonging to the stage three L y m e borreliosis complex and positive antibody titers against B. burgdorferi.

Patients and Methods

Study population and study design: A total of 135 patients, living in an endemic area of Lyme borreliosis, who met the clinical definition of late stage Lyme disease were included in the study. Mean age was 50.5 (13-81) years. Patients who presented with at least one main symptom (Table 1) which had persisted for at least six months, and in whom IgG antibodies to B. burgdorferi with a titer of at least 1:256 in the immunofluorescence test and 200 standard units in the enzyme immunoassay could be detected, were included in the study. In accordance with the presumed stage of the disease, IgM antibodies were not detectable in most cases. Patients who had previously received antibiotic therapy with drugs effective against B. burgdorferi, or who had rheumatoid or neurological diseases of different etiology (e. g. rheumatoid arthritis), other infectious diseases, a positive TPHA (MHA-TP) test or a positive rheumatoid factor were excluded from the study.

1

-

. -

.

. -

.

Included patients were prospectively randomized by means of a random numbers table and treated either with penicillin G in a dose of 2 × 10 megaunits/day (n = 66) or with 2 x 3 g of cefotaxime/day (n = 69) for at least eight (- ten) days. Doses were administered as infusions. Four patients with a history of penicillin allergy had to be excluded. All patients in the penicillin group received the same dosage, whereas the dose was reduced to 2 x 2 g in three patients of less than 50 kg body weight in the cefotaxime group. 30 min prior to the first infusion each patient was given 80 mg of triamcinolone acetonide intravenously for prevention of Herxheimer reactions [16-18]. Symptoms were similarly distributed in both groups. Main symptoms (Table 1) were recurrent oligoarthritis which in most cases concerned large joints, peripheral neuropathy concomitant with paresis, painful dysaesthesia, paraesthesia and lightening pseudoradicular pain, and the characteristic skin manifestations of stage three borreliosis (Acrodermatitis chronica atrophicans, Lymphadenosis cutis benigna dispersa). Most of the patients suffered from additional symptoms compatible with Lyme borreliosis. Aside from persistent arthralgia, chronic headache, sweating and fatigue a relatively high number of patients suffered from cardiac symptoms like tachycardia, tacharrhythmia, premature ventricular beats and conduction disturbances (e. g. atrioventricular block). The latter are so far not generally accepted as clinical manifestations of stage three borreliosis. Results of treatment were assessed after 3, 6, 9, 12, 18 and 24 months, the antibody titers being monitored simultaneously. The success of therapy was recorded according to clinical criteria as "full remisson", "incomplete remission" or "ineffective". If symptoms disappeared within three to six months after treatment and patients remained symptom-free throughout the whole follow-up period, they were classified as "full remission". Patients who had originally presented with arthritis and who after treatment continued to have persistent arthralgia without signs of inflamma-

Infection 18 (1990) No. 1 © MMV Medizin Verlag GmbH Mfinchen, Mfinchen 1990

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D. I-Iassler et al.: Cefotaxime in Late Lyme borreliosis

tion were assessed as "partial response". In patients presenting with neurological symptoms, only the classifications as "full remission" and "ineffective" were accepted. Clinical courses in which only the frequency of the complaints could be positively influenced were recorded as ineffective.

Cefotaxime versus Penicillin G in late Lyme borreliosis 70 6O 5O

Results

4O

The two groups were identical in terms of age distribution (average age of the penicillin group 50.0 (15-81) years; average age of the cefotaxime group 51.0 (13-81) years). They were also virtually identical as regards the existing concomitant disorders. Before the seventh day, treatment had to be discontinued because of poor tolerance in four patients (6%) of the penicillin group and in three patients (4.3%) of the cefotaxime group. After the full observation period 66.7% (n = 44) of the patients of the cefotaxime group versus 40.3% (n = 25) of the patients of the penicillin group fulfilled the criteria of full remission. 21.2% (n = 14) cases of the cefotaxime group versus 20.9% (n = 13) cases of the penicillin group were classified as incomplete remissions (Figure 1). The results are statistically significant as proved by the chisquare-test with p = 0.002. The distribution of treatment outcomes corresponding to the initial classification of symptoms is shown in Table 2. Late relapses were observed in four patients who had been symptom-free for a post-treatment observation period of 12 to 24 months (penicillin group n = 1, cefotaxime group n = 3). Some of these relapses may have been reinfections. Serious complications were observed in four cases: A shock reaction occurred on the sixth day in one patient of the penicillin group but this subsided completely after symptomatic therapy. Antibiotic-associated colitis was observed in another case which necessitated admission to

30 20 10 0 :otaxime D=86

full rem.

partial r.

3 n=62

no response

Effect of Therapy Figure 1" Final outcome of treatment in the two study groups.

hospital. In the cefotaxime group, a severe systemic allergy of the immediate hypersensitive type, which was also immediately reversible, occurred and another patient developed antibiotic-associated colitis in which the Ctostridium difficile toxin A was detectable. Less serious side effects such as diarrhoea occurred with similar frequency in both groups and were spontaneously reversible (penicillin group n = 6; cefotaxime group n = 9). Herxheimer-like reactions were frequently observed despite prophylaxis (Figure 2). They were characterized by distinct vasoconstriction as revealed by rising blood pressure, paleness, chills and Raynaud's phenomenon within 6 and 18 h after onset of therapy followed by vasodilatation with hypotonia, headache and flush persisting for 24 to 48 h. Moreover, exacerbation and worsening of joint complaints, myalgia, and mild pyrexia were observed.

Table 2: Final outcome of treatment, differentiated according to the initial clinical manifestations.

Recurrent arthritis

(n = t8)

4 (22%)

Peripheral neuropathy

(n = 30)

20 (66%)

Arthritis and neuropathy

(n = 14)

-

ACA/LABC

(n = 2)

Arthritis and ACA

Arthritis and neuropathy

7 (39%)

1 (5%)

8 (27%)

2 (7%)

6 (43%)

1 (7%)

1 (50%)

1 (50%)

-

(n = 2)

-

2 (100%)

-

(n = 20)

9 (45%)

4 (20%)

1 (5%)

7 (50%)

6 (30%)

ACA/LABC

(n = i)

1 (100%)

Arthritis and ACA

(n = 3)

1 (33%)

26 / 18

6 (33%)

......

2 (67%)

Infection 18 (1990) No, 1 © MMV Medizin Verlag GmbH Miinchen, Mtinchen 1990

D. Hassler et al.: Cefotaxime in Late Lyme borreliosis darisch-Herxheimer-Reactions 30

t'tl1

2O

El.

m severe

.13

• mild

• distinct E

lo

t-

Penicillin

Cefotaxime

Figure 2: Distribution of Herxheimer-like reactions in the two study groups.

The post-treatment antibody kinetics have been evaluated and published elsewhere [19]. In brief, a significant response of antibody titers could be demonstrated in patients who were successfully treated as compared to those in whom success of treatment was classified as ineffective or in spontaneous courses of untreated patients. Discussion

This study provides significant evidence that cefotaxime is superior to penicillin G in the treatment of late stage Lyme borreliosis. The data are consistent with the findings published by Dattwyler [15] and strongly confirm what has been expected from the in vitro data cited above. Besides a low MIC90 value, the advantages of cefotaxime are probably due to its favourable pharmacokinetic properties. Cefotaxime reaches high tissue concentrations that exceed the MIC for B. burgdorferi for the whole time of dose application intervals. Moreover, cefotaxime penetrates well through inflamed meninges but there is also some diffusion through healthy meninges [20]. These properties are particularly important in CNS manifestations of borreliosis, which in most cases are accompanied by meningeal inflammation. However, according to recent reports, this is not a constant feature of CNS borreliosis which may explain why B. burgdorferi spirochetes could be recovered from CSF in spite of previous antibiotic therapy [21]. In contrast, penicillin G reaches only subinhibitory concentrations in the CSF of borreliosis patients, as was communicated by Pfister [21]. Various pathophysiological features of stage three borreliosis can be suggested as a possible reason for the much lower efficacy of the standard therapy with penicillin G at this stage as compared with stages one and two. The concept of reduced tissue permeability in

stage three borreliosis is borne out by the finding that vasculitic processes are an important feature of pathophysiological processes at this stage. Thus, Duray [22] detected microangiopathy with trophic disorders in cartilage biopsies in Lyme arthritis. Meyer [23] and Camponovo [24] found perivascular plasmacellular infiltrates and epineural vasculitis with vascular occlusions in biopsies of peripheral nerves. This pathophysiological concept was confirmed by Schaible [25] in an animal model. The resulting trophic disorders may prevent effective antibiotic tissue levels from being reached in tissues with poor capillary beds. The diagnosis of the late stage of Lyme disease presents considerable problems owing to the absence of symptoms or laboratory parameters with 100% specificity. In practice, a number of differential diagnoses must be excluded. Even the serological finding of a positive antibody titer against B. burgdorferi is a prerequisite but not a proof for the clinical diagnosis of borreliosis. Consequently the problem of clear clinical definition of stage three Lyme borreliosis has so far not been satisfactorily solved and this must be considered in interpreting the data provided by this study. On the other hand, restricting the view only to pathognomonic symptoms like acrodermatitis would of course improve the validity of a drug evaluation, but it would also mean ignoring all the other manifestations of late Lyme borreliosis and the fact that patients presenting with such symptoms may benefit from antibiotic treatment. The latter is another major finding of this work and confirms the data of others [26-28]. The term "occult Lyme borreliosis" was introduced by Lipschitz et al. [28] in order to designate clinical manifestations compatible with the symptoms of Lyme borreliosis in seropositive subjects living or working in an endemic area. The authors report significant beneficial effects of antibiotic treatment in these patients which is considered as further evidence for the etiologic role of B. burgdorferi for the symptoms found. In a double blind placebo-controlled study Caperton et al. [26] found intravenous ceftriaxone to be effective in patients with chronic arthritis and a positive antibody titer against B. burgdorferi although the clinical manifestations alone were not clearly indicative for Lyme borreliosis. Surprisingly, even cardiac symptoms that were frequently recorded as minor symptoms could often be influenced by the antibiotic treatment. This may indicate that these manifestations are etiologically linked to B. burgdorferi infection. Our finding that antibody titers can be influenced as well by antibiotic treatment provides further evidence for the etiologic role ofB. burgdorferi infection in the clinical manifestations that could be successfully treated. The observation that Herxheimer-like reactions often occurred in patients who responded well to therapy can be interpreted both as an indication of the presence of live borreliae and of an indication of the response to treatment. This finding corresponds well to similar observations by others, although the frequency of its occurrence was surprisingly high.

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D. Hassler et al.: Cefotaxime in Late Lyme borreliosis

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