Antibiotic therapy is the mainstay of treatment.
Postexposure prophylaxis with a single dose of doxycycline is recommended for significant exposures under the following circumstances:
An engorged Ixodes scapularis tick is removed after at least an estimated 36 hours of attachment.
Prophylaxis is started within 72 hours of tick removal.
Borrelia burgdorferi prevalence in local ticks is known to be greater than 20%.
Doxycycline is not contraindicated (contraindications include children <8 years of age, pregnancy, or lactation).
Patients who cannot take doxycycline are started on treatment if early symptoms develop.
Amoxicillin or cefuroxime for 14 to 21 days. Doxycycline for 10 to 21 days.
Pregnant or lactating patients should be treated in the same way, except doxycycline should be avoided.
Macrolides are not recommended for first-line treatment, but reserved for patients who are intolerant to all 3 first-line antibiotics.
When erythema migrans cannot be distinguished from community-acquired cellulitis, cefuroxime or amoxicillin/clavulanate, effective for both conditions, is recommended.
Patients with Lyme disease and cardiac complications, but without high-grade heart block, are treated with oral antibiotics.  Hospitalization, intravenous antibiotics, and continuous monitoring are required for patients with chest pain, syncope, dyspnea, second- or third-degree AV block, or first-degree block with PR interval 300 milliseconds or longer. Temporary pacemaker is recommended for patients with advanced AV block.  
Treatment depends on the type and extent of infection: 
Patients with Lyme arthritis are treated with oral antibiotics including doxycycline, amoxicillin, or cefuroxime for 28 days; nonsteroidal anti-inflammatory drugs (NSAIDs) may be used adjunctively for symptom relief.
Patients with recurrent or persistent joint swelling should receive an additional 4 weeks of oral (preferred) or 2 to 4 weeks of parenteral therapy.
Arthroscopic synovectomy has been used successfully in patients with antibiotic-refractory Lyme arthritis. Anecdotal use of intraarticular injections of corticosteroids, systemic administation of nonsteroidal anti-inflammatory drugs (NSAIDs), or disease-modifying antirheumatic drugs (DMARDs) such as hydroxychloroquine have also been reported to help patients with antibiotic-refractory Lyme arthritis. These treatments should be initiated only under specialist supervision.
Neurologic Lyme disease (neuroborreliosis)
Although parenteral antibiotics are generally used for patients with neurologic complications, oral doxycycline has been shown to be equally effective.
Patients with early neurologic Lyme disease confined to the meninges, cranial nerves, nerve roots, or peripheral nerves (Bannwarth syndrome) can be treated with a 2-week course of either an oral antibiotic (doxycycline) or an intravenous antibiotic (ceftriaxone, cefotaxime, or penicillin G).  However, based on available small studies, patients with early neuroborreliosis with manifestations such as myelitis, encephalitis, and vasculitis require intravenous antibiotic for 2 weeks. 
For late Lyme disease with peripheral neuropathy and acrodermatitis chronica atrophicans (ACA), the European Federation of Neurological Societies (EFNS) guideline recommends treatment with either oral doxycycline or IV ceftriaxone.  However, if these patients have CNS manifestations, such as myelitis, encephalitis, and vasculitis, they should be treated with IV ceftriaxone.
The treatment of facial palsies is controversial. There are no definitive data to support whether they need to be treated as neurologic complications or acute Lyme disease without CNS manifestation.  The authors of this monograph treat isolated facial palsies in patients with Lyme disease as early neuroborreliosis with cranial nerve involvement.
Treatment decisions for patients with both joint and neurologic involvement are based on an individual patient's circumstances under specialist supervision.