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. 2016 Dec 8;12(12):CD006978.
doi: 10.1002/14651858.CD006978.pub2.

Antibiotics for the neurological complications of Lyme disease

Diego Cadavid  1 , Paul G Auwaerter  2 , Jeffrey Rumbaugh  3 , Harald Gelderblom  4
Affiliations

Antibiotics for the neurological complications of Lyme disease

Diego Cadavid et al. Cochrane Database Syst Rev. .

Abstract

Background: Various central nervous system-penetrant antibiotics are bactericidal in vitro and in vivo against the causative agent of Lyme neuroborreliosis (LNB), Borrelia burgdorferi. These antibiotics are routinely used clinically to treat LNB, but their relative efficacy is not clear.

Objectives: To assess the effects of antibiotics for the treatment of LNB.

Search methods: On 25 October 2016 we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. We searched clinical trial registers on 26 October 2016. We reviewed the bibliographies of the randomized trials identified and contacted the authors and known experts in the field to identify additional published or unpublished data. There were no language restrictions when searching for studies.

Selection criteria: Randomized clinical trials of antibiotic treatment of LNB in adults and children that compared any antibiotic treatment, including combinations of treatments, versus any other treatment, placebo, or no treatment. We excluded studies of entities considered as post-Lyme syndrome.

Data collection and analysis: We used standard methodological procedures expected by Cochrane.

Main results: We identified seven randomized studies involving 450 European participants with LNB for inclusion in this systematic review. We found no trials conducted in the United States. Marked heterogeneity among these studies prevented meta-analysis. None of the studies included a placebo control on the initial antibiotic treatment, and only one was blinded. None were delayed-start studies. All were active comparator studies, and most were not adequately powered for non-inferiority comparison. The trials investigated four antibiotics: penicillin G and ceftriaxone in four studies, doxycycline in three studies, and cefotaxime in two studies. One study tested a three-month course of oral amoxicillin versus placebo following initial treatment with intravenous ceftriaxone. One study was limited to children. The trials measured efficacy using heterogeneous physician- or patient-reported outcomes, or both. In some cases cerebrospinal fluid analysis was included as an indirect biomarker of disease and outcome. None of the studies reported on our proposed primary outcome, 'Improvement in a measure of overall disability in the long term (three or more months).' None of the trials revealed any between-group differences in symptom resolution in response to active treatment. In general, treatment was tolerated well. The quality of adverse event reporting, however, was low.

Authors' conclusions: There is mostly low- to very low-quality clinical evidence from a limited number of mostly small, heterogeneous trials with diverse outcome measures, comparing the relative efficacy of central nervous system-penetrant antibiotics for the treatment of LNB. The few existing randomized studies have limited power and lack consistent and well-defined entry criteria and efficacy endpoints. It is not possible to draw firm conclusions on the relative efficacy of accepted antibiotic drug regimens for the treatment of LNB. The majority of people are reported to have good outcomes, and symptoms resolve by 12 months regardless of the antibiotic used. A minority of participants did not improve sufficiently, and some were retreated. These randomized studies provide some evidence that doxycycline, penicillin G, ceftriaxone, and cefotaxime are efficacious in the treatment of European LNB. No evidence of additional efficacy was observed when, in one study, an initial antibiotic treatment with intravenous ceftriaxone was followed by additional longer treatment with oral amoxicillin. There is a lack of evidence identified through our high-quality search strategy on the efficacy of antibiotics for treatment of LNB in the United States.

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Conflict of interest statement

D Cadavid was a full‐time paid employee of Biogen during most of the preparatory time for this review. He is currently a full‐time employee of Fulcrum Therapeutics. Neither Biogen nor Fulcrum Therapeutics is involved in research on LNB. D Cadavid's work on this review is not related to his employment with Biogen or Fulcrum Therapeutics.

PG Auwaerter has served as a medical‐legal expert witness regarding Lyme disease; has been reimbursed for travel expenses related to an update of the Lyme Disease Guideline by the Infectious Diseases Society of America, the American Academy of Neurology, and the American College of Rheumatology (IDSA/AAN/ACR); and has been given honoraria for CME courses regarding Lyme disease.

J Rumbaugh has been reimbursed for travel expenses related to an update of the Lyme Disease Guideline (IDSA/AAN/ACR).

H Gelderblom: none known.

Figures

1
1
Study flow diagram.
2
2
1.1
1.1. Analysis
Comparison 1 Oral amoxicillin versus placebo after previous treatment with ceftriaxone for disseminated Lyme disease, Outcome 1 Symptoms (patient‐rated VAS, scale 0 to 100, higher worse) in all participants (definite and possible Lyme disease).
1.2
1.2. Analysis
Comparison 1 Oral amoxicillin versus placebo after previous treatment with ceftriaxone for disseminated Lyme disease, Outcome 2 Symptoms (investigator‐rated VAS, scale 0 to 100 higher worse) in all participants (definite and possible Lyme disease).
1.3
1.3. Analysis
Comparison 1 Oral amoxicillin versus placebo after previous treatment with ceftriaxone for disseminated Lyme disease, Outcome 3 Improvement of symptoms (excellent or good on investigator VAS) (12 months) in participants with definite Lyme disease.
1.4
1.4. Analysis
Comparison 1 Oral amoxicillin versus placebo after previous treatment with ceftriaxone for disseminated Lyme disease, Outcome 4 Adverse events (12 months) in all participants (definite and possible Lyme disease).
2.1
2.1. Analysis
Comparison 2 Oral doxycycline versus intravenous ceftriaxone for Lyme neuroborreliosis (acute and chronic), Outcome 1 Mean reduction in clinical score (4 months).
2.2
2.2. Analysis
Comparison 2 Oral doxycycline versus intravenous ceftriaxone for Lyme neuroborreliosis (acute and chronic), Outcome 2 Resolution of symptoms.
2.3
2.3. Analysis
Comparison 2 Oral doxycycline versus intravenous ceftriaxone for Lyme neuroborreliosis (acute and chronic), Outcome 3 All adverse events.
2.4
2.4. Analysis
Comparison 2 Oral doxycycline versus intravenous ceftriaxone for Lyme neuroborreliosis (acute and chronic), Outcome 4 Adverse events leading to discontinuation.
2.5
2.5. Analysis
Comparison 2 Oral doxycycline versus intravenous ceftriaxone for Lyme neuroborreliosis (acute and chronic), Outcome 5 Serious adverse events.
3.1
3.1. Analysis
Comparison 3 Intravenous penicillin G versus oral doxycycline for Lyme neuroborreliosis (acute and chronic), Outcome 1 Improvement of symptoms.
3.2
3.2. Analysis
Comparison 3 Intravenous penicillin G versus oral doxycycline for Lyme neuroborreliosis (acute and chronic), Outcome 2 Resolution of symptoms.
3.3
3.3. Analysis
Comparison 3 Intravenous penicillin G versus oral doxycycline for Lyme neuroborreliosis (acute and chronic), Outcome 3 Resolution of CSF pleocytosis at 1 year.
3.4
3.4. Analysis
Comparison 3 Intravenous penicillin G versus oral doxycycline for Lyme neuroborreliosis (acute and chronic), Outcome 4 All adverse events.
4.1
4.1. Analysis
Comparison 4 Intravenous doxycycline versus intravenous penicillin G for Lyme neuroborreliosis (acute and chronic), Outcome 1 Improvement of symptoms ("partial remission").
4.2
4.2. Analysis
Comparison 4 Intravenous doxycycline versus intravenous penicillin G for Lyme neuroborreliosis (acute and chronic), Outcome 2 Resolution of symptoms ("full remission").
4.3
4.3. Analysis
Comparison 4 Intravenous doxycycline versus intravenous penicillin G for Lyme neuroborreliosis (acute and chronic), Outcome 3 Serious adverse events.
5.1
5.1. Analysis
Comparison 5 Intravenous cefotaxime versus intravenous penicillin G for acute Lyme neuroborreliosis, Outcome 1 Resolution of symptoms (mean 7.7 months' follow‐up).
5.2
5.2. Analysis
Comparison 5 Intravenous cefotaxime versus intravenous penicillin G for acute Lyme neuroborreliosis, Outcome 2 Resolution of CSF pleocytosis.
5.3
5.3. Analysis
Comparison 5 Intravenous cefotaxime versus intravenous penicillin G for acute Lyme neuroborreliosis, Outcome 3 All adverse events (at 2 weeks).
6.1
6.1. Analysis
Comparison 6 Intravenous ceftriaxone versus intravenous cefotaxime for acute Lyme neuroborreliosis, Outcome 1 Resolution of symptoms (mean 8.1 months' follow‐up).
6.2
6.2. Analysis
Comparison 6 Intravenous ceftriaxone versus intravenous cefotaxime for acute Lyme neuroborreliosis, Outcome 2 Resolution of CSF pleocytosis.
6.3
6.3. Analysis
Comparison 6 Intravenous ceftriaxone versus intravenous cefotaxime for acute Lyme neuroborreliosis, Outcome 3 All adverse events.
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Update of

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