What alternative treatments (in clinical trials, off-label) are available for lyme disease (i.e. other than doxycycline)?

Comment by InpharmD Researcher

Lyme disease is a tick-borne bacterial infection found throughout the northern hemisphere. The progression of Lyme disease typically consists of an early localized phase which can potentially progress into a multisystem disease that can affect the nervous system, cardiac system, CNS, and musculoskeletal. The choice in treatment varies by the presence and progression of disease, typically involving the use of antibiotics.

Background

Lyme disease is a tick-borne bacterial infection caused by Borrelia burgdorferi, transmitted via hard-backed Ixodes ticks. In the United States, Lyme disease is predominant in the northeast and upper midwestern section. The incidence rate is approximately 40 per 100,000 people where Lyme disease is common, occurring during late spring, summer, and early fall. Lyme disease is tested via a 2-step approach to first identify serum antibodies to B. burgdorferi followed by a Western blot to confirm findings for both IgM and IgG antibodies. Lyme disease at the early stage is most commonly presented as a rash (erythema migrans) that occurs one to two weeks later at the site of tick bite, which can be accompanied by a low-grade fever. Disease progression to late-stage Lyme disease can lead to muscle pain, neurologic, and cardiac complications presenting as a number of symptoms (e.g., malaise, fever, muscle pain, chest pain, palpitations, dyspnea, arthritis). The central nervous system may also be involved (e.g., encephalopathy, meningitis, cranial nerve neuropathy). A vaccine is currently not available for prevention of Lyme disease and mainly focuses on tick repellent and removal. The early cases of Lyme disease respond promptly to oral antibiotic therapy. Yet, some patients may require additional treatment or experience post-treatment Lyme disease with persistent systems untreatable with antibiotics. [1], [2], [3], [4]

The Infectious Disease Society of America (IDSA) has published a comprehensive 2020 guidelines on the management of Lyme disease, the tick-borne infection. Upon removal of an identified high-risk tick bite (identified Ixodes ssp. Vector species; occurred in a highly endemic area; attached for > 36 hours), antibiotic prophylaxis of oral doxycycline within 72 hours of removal is recommended over observation. Doxycycline is dosed at 200 mg single oral for adults and 4.4 mg/kg (up to a max 200 mg) for children. Patients with equivocal or low risk (or cannot be identified as high risk with certainty) are recommended to undergo wait and watch method. [5]

Patients with confirmed erythema migrans are recommended to receive oral antibiotics with doxycycline, amoxicillin, or cefuroxime axetil as the first-line or azithromycin as the second-line with treatment lasting either 10 days for doxycycline, 14 days for amoxicillin or cefuroxime, or 5-10 days (7 days preferred in the United States) for azithromycin. [5]

Patients with acute neurological manifestations of Lyme disease without parenchymal involvement of the brain or spinal cord are recommended to receive intravenous (IV) ceftriaxone, cefotaxime, penicillin G, or oral doxycycline for 14 to 21 days, although oral may be considered based on patient factors and tolerance. Lyme disease associated with parenchymal involvement of brain or spinal cord should receive IV over oral antibiotics. [5]

No recommendations are made regarding corticosteroid use as an adjunct to antibiotics if facial nerve palsy is involved. Patients with severe cardiac complications due to Lyme disease (e.g., arrhythmia, myopericarditis) are recommended to be hospitalized with ECG monitoring. Lyme carditis may be treated with oral antibiotics using doxycycline, amoxicillin, cefuroxime axetil, or azithromycin in the outpatient setting; or IV ceftriaxone if hospitalized (which can be switched to oral once clinical improvement is observed) for 14 to 21 days. Patients with diagnosis of Lyme arthritis are recommended to receive oral antibiotics for 28 days with a follow-up of 2- to 4-week course of IV ceftriaxone should there be no or minimal improvement. Patients diagnosed with borrelial lymphocytoma are recommended to receive oral antibiotics for 14 days. Patients with acrodermatitis chronia atrophicans are recommended to receive oral antibiotics for 21 to 28 days. [5]

If a patient presents with certain acute disorders related to Lyme disease (e.g., meningitis, painful radiculoneuritis, spinal cord inflammation, etc.), then testing for Lyme disease is recommended. Patients with certain psychiatric or neurological conditions (e.g., Parkinson’s disease, dementia) are recommended against routine testing. [5]

References:

[1] Ross Russell AL, Dryden MS, Pinto AA, Lovett JK. Lyme disease: diagnosis and management. Pract Neurol. 2018;18(6):455-464. doi:10.1136/practneurol-2018-001998
[2] Schoen RT. Lyme disease: diagnosis and treatment. Curr Opin Rheumatol. 2020;32(3):247-254. doi:10.1097/BOR.0000000000000698
[3] Van Hout MC. The Controversies, Challenges and Complexities of Lyme Disease: A Narrative Review. J Pharm Pharm Sci. 2018;21(1):429-436. doi:10.18433/jpps30254
[4] Skar GL, Simonsen KA. Lyme Disease. [Updated 2021 Jul 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK431066/
[5] Lantos PM, Rumbaugh J, Bockenstedt LK, et al. Clinical practice guidelines by the infectious diseases society of america (Idsa), american academy of neurology (Aan), and american college of rheumatology (Acr): 2020 guidelines for the prevention, diagnosis and treatment of lyme disease. Clinical Infectious Diseases. 2021;72(1):e1-e48. doi:10.1093/cid/ciaa1215

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What is Lyme disease?

Please see Table 1 for your response.


 

Oral Doxycycline Compared to Intravenous Ceftriaxone in the Treatment of Lyme Neuroborreliosis: A Multicenter, Equivalence, Randomized, Open-label Trial

Design

Multicentre, open-label, randomized study

N= 210

Objective

To evaluate the efficacy of oral doxycycline in comparison to ceftriaxone in the treatment of Lyme neuroborreliosis (LNB)

Study Groups

Doxycycline (n= 104)

Ceftriaxone (n= 106)

Inclusion Criteria

Production of B. burgdorferi specific antibodies in cerebrospinal fluid (CSF) or serum; or B. burgdorferi DNA in the CSF; or an erythema migrans during the past three months

Exclusion Criteria

LNB as unlikely diagnosis, alternative diagnosis

Methods

Eligible patients were randomized (1:1) ratio to receive either oral doxycycline 100 mg BID for four weeks, or intravenous (IV) ceftriaxone 2 g once daily for three weeks. The participants described their subjective condition with a visual analogue scale (VAS) from 0 to 10 (0 = normal; 10 = worst) before the treatment and 4 and 12 months after the treatment.

Duration

Between Sep 14, 2012 and Dec 28, 2017

Outcome Measures

Primary: change in the VAS score at 12 months

Secondary: difference between ceftriaxone and doxycycline groups in leukocyte count, protein, lactate, and CXCL13 concentrations in the CSF specimens collected after three weeks of treatment.

Baseline  Characteristics

mITT population

Doxycycline (n= 94)

Ceftriaxone (n= 93)

 

Age, years

54 ± 15 59 ± 14  

Female

37 (39%) 30 (32%)  

Number of coexisting diseases, median (IQR)

1 (0-3) 1 (0-3)  

Recalled tick bites during the past year

One tick bite

Several tick bites

 

16 (17%)

19 (20%)

 

18 (19%)

19 (20%) 

 

EM during the past year

Solitary

Multiple

 

22 (23%)

3 (3%)  

 

27 (29%)

3 (3%)

 

Number of symptoms, median (IQR)

4 (3-6) 4 (3-5.5)  

Duration of symptoms in weeks, median (IQR)

4 (3.0-10.3) 6 (3.5-11.0)  

Symptoms relieved partly before recruitment to the study

26 (28%) 29 (31%)  

Possible late LNB with symptoms for more than 6 months

9 (10%) 8 (9%)  

Certainty of LNB

Definite LNB

Possible LNB

 

51 (54%)

43 (46%)

 

48 (52%)

45 (48%)

 

Glucocorticoid therapy for facial nerve palsy

31 (33%) 35 (38%)  

VAS at the beginning

5.0 ± 2.4 5.1 ± 2.3  

Results

Per-protocol

Doxycycline (n= 82)

Ceftriaxone (n= 84)

Mean difference (95% CI)

Mean change in the VAS score at 12 months

-3.9 ± 2.5 -3.8 ± 2.4 0.17 (-0.59, –0.92) 

Median VAS scores at 12 months

0 (IQR 0–1.8) 1 (IQR 0–2.0) p= 0.343

Modified intention-to-treat

Doxycycline (n= 94) Ceftriaxone (n= 93)  

Leukocytes /mm3 , median (IQR)

37 (4-103)

(n= 92)

24 (2-93)

(n= 91)

 

Protein level g/L, median (IQR)

654 (436-1168)

(n= 90)

613 (423-1055)

(n= 90)

 

Lactate level mmol/L, median (IQR)

1.9 (1.5-2.2)

(n= 72)

1.8 (1.6-2.2)

(n= 77)

 

CXCL13 concentration pg/mL, median (IQR)

249 (<7.8-3132)

(n= 84)

392 (<7.8-4349)

(n= 88)

 

Positive B. burgdorferi PCR, n (%)

12 (14%)

(n= 83)

12 (14%)

(n= 85)

 

The mean change in the VAS score (-3.9 doxycycline group vs. -3.8 ceftriaxone group; mean difference 0.17; 95% CI, -0.59 – 0.92) is within the prespecified equivalence margins of -1 to 1 units. Participants in both groups improved equally.

Adverse Events

Common Adverse Events: 5 (4.8%; rash, nausea, solar eczema) vs. 9 (8.5%; rash, rise in liver enzyme levels, diarrhea, Clostridioides difficile infection, superficial thrombophlebitis due to the IV cannula)

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: 7 (2 doxycycline vs. 5 ceftriaxone)

Study Author Conclusions

Oral doxycycline is equally effective as intravenous ceftriaxone in the treatment of LNB.

InpharmD Researcher Critique

The study used a subjective VAS score as a measure of primary treatment outcome, which may vary greatly between patients. Given that presenting symptoms at the beginning and the residual symptoms at the end of the follow-up were collected from medical records retrospectively, there may be some inaccuracy involved with reported symptoms. 



References:

Kortela E, Kanerva MJ, Puustinen J, et al. Oral doxycycline compared to intravenous ceftriaxone in the treatment of lyme neuroborreliosis: a multicenter, equivalence, randomized, open-label Trial. Clin Infect Dis. 2021;72(8):1323-1331. doi:10.1093/cid/ciaa217