This document addresses the use of parenteral antibiotics (i.e., intravenous and intramuscular) for the treatment of Lyme disease.

Medically Necessary:

A course of up to 4 weeks of intravenous (IV) antibiotic therapy, usually with ceftriaxone (Rocephin^®₎, cefotaxime (Claforan^®₎ or Penicillin G is considered medically necessary for individuals with Lyme disease meeting ANY of the following criteria:

• Myocarditis associated with second- or third-degree atrioventricular block, or with first-degree heart block when the PR interval is prolonged to 30 milliseconds or greater; or
• Persistent or recurrent joint swelling (i.e., arthritis) after an initial 1 month trial of oral antibiotics; or
• Acute or chronic  neurological disease affecting the central or peripheral nervous system, including ANY of the following:
  • Meningitis
  • Any neurologic syndrome with cerebrospinal fluid (CSF) pleocytosis
  • Peripheral neurologic syndromes with normal CSF (including radiculopathy, diffuse neuropathy, mononeuropathy multiplex, or cranial neuropathy) if severe or following treatment failure with oral antibiotic therapy
  • Encephalomyelitis
  • Encephalopathy

Investigational and Not Medically Necessary: 

Intravenous (IV) antibiotic therapy for individuals with Lyme disease is considered investigational and not medically necessary when criteria are not met.

Other indications for intravenous (IV) antibiotic therapy for Lyme disease are considered investigational and not medically necessary, including, but not limited to any of the following:

• Prophylactic treatment of individuals who have reported a tick bite but have no clinical findings suggestive of Lyme disease; or
• Treatment of individuals with vague systemic symptoms without serologic or cerebrospinal fluid (CSF) studies confirming Lyme disease; or
• Treatment of chronic fatigue syndrome or fibromyalgia attributed to Lyme disease; or
• Initial treatment of Lyme arthritis without coexisting neurological symptoms; or
• Treatment of persistent Lyme-associated arthritis after 2 prior courses of antibiotic therapy; or
• Treatment of "post-Lyme disease" syndrome; or
• Repeat or prolonged courses (greater than 4 weeks) of intravenous antibiotics. 

Intramuscular antibiotics as a treatment of any aspect of Lyme disease are considered investigational and not medically necessary.

A diagnosis of Lyme disease (LD) requires appropriate epidemiologic data, supporting clinical observation (including exposure to ixodid ticks in an endemic area), and supporting laboratory findings.  However, over-diagnosis and over-treatment of LD is common (Am College of Rheumatology, 1993; Hu, 1993; Steere, 1993).  Intravenous antibiotic therapy in individuals with presumed LD may be inappropriately recommended in the following situations: an incorrect diagnosis; prolonged or repeated courses of IV antibiotics; and use of IV antibiotics when oral antibiotics are adequate.  An incorrect diagnosis of LD includes those individuals with positive serologies without characteristic signs or symptoms of LD, or those with non-specific symptoms, but with no known exposure to ticks in an endemic area, or those without supporting serologic evidence.  In 1993, the American College of Rheumatology published a position paper on IV antibiotic treatment for LD, which concluded that:

Empiric treatment of patients with nonspecific chronic fatigue or myalgia on the basis of positive serologic results alone will result in many more instances of antibiotic toxicity than cures of atypically symptomatic true Lyme disease.  In patients whose only evidence for Lyme disease is a positive immunologic test, the risks for empiric IV antibiotic treatment outweigh the benefits (Am College of Rheumatology, 1993). 

Published literature suggests that IV antibiotic therapy should be limited to those individuals with objective and laboratory evidence of neuroborreliosis, those individuals with carditis and some degree of heart block, and in those with well-documented severe Lyme arthritis that does not respond to initial oral antibiotic therapy (Pachner, 1995; Rahn, 1991; Sigal, 1992 and 1995; Steere, 1997).  Multiple randomized controlled studies, as well as reviews, of long-term antibiotic treatment for Lyme disease have failed to show a sustained positive therapeutic effect (Dattwyler, 1997; Fallon, 2007; Halperin, 2007a; Oksi, 2007; Wormser, 2006).

Practice guidelines regarding the treatment of Lyme disease have been issued by the Infectious Diseases Society of America (2006).  These guidelines included the following recommendations for IV antibiotics.  Note that none of the recommendations suggest longer than a 1-month course of IV antibiotics:

• Meningitis or radiculopathy; 14–28 days
• Second- or third-degree atrioventricular block, or with first-degree heart block when the PR interval is prolonged to 30 milliseconds or greater; 14–21 days
• Recurrent arthritis after oral regimen; 14–28 days
• CNS or peripheral nervous system disease; 14–28 days

In addition, these guidelines recommend symptomatic treatment for symptoms that persist after appropriate antibiotic therapy.  For example, individuals with persistent arthritis may be treated with anti-inflammatory agents or arthroscopic synovectomy.  These guidelines do not identify any role for intramuscular antibiotics.

In 2007, the American Academy of Neurology published a practice parameter that specifies that "prolonged courses of antibiotics do not improve the outcome of post-Lyme syndrome, are potentially associated with adverse events, and are therefore not recommended (Level A recommendation)."

Lyme disease (LD) is a multisystem inflammatory disease caused by the spirochete Borrelia burgdorferi and transmitted by the bite of an infected ixodid tick endemic to Northeastern, North Central, and Pacific coastal regions of the United States.  The disease is characterized by stages, beginning with localized infection of the skin (erythema migrans), followed by dissemination to many sites.  Manifestations of early disseminated disease may include lymphocytic meningitis, facial palsy, painful radiculoneuritis, atrioventricular nodal block, or migratory musculoskeletal pain.  Months to years later, the disease may be manifested by intermittent oligoarthritis, particularly involving the knee joint, chronic encephalopathy, spinal pain, or distal paresthesias.  While most manifestations of LD can be adequately treated with oral antibiotics, intravenous (IV) antibiotics are indicated in some individuals with neurologic involvement or atrioventricular heart block.  However, over-diagnosis and over-treatment of LD is common due to its nonspecific symptoms, a lack of standardization of serologic tests, and difficulties in interpreting serologic test results.  In particular, individuals with chronic fatigue syndrome or fibromyalgia are commonly misdiagnosed as possibly having LD and undergo inappropriate IV antibiotic therapy. 

Risk factors in contracting Lyme disease center on people's exposure to outside environments in areas where Lyme disease occurs.  Such activities include working in areas surrounding tick-infested woods and overgrown brush and in outside occupations.  Additionally, people who spend time outside or participate in leisure activities such as hunting, fishing, hiking, or camping are at high risk for Lyme disease.  Any of these activities bring these participants into areas where ticks may be present.

The following paragraphs describe the various manifestations of LD that may prompt therapy with IV antibiotics.

Neurologic Manifestations of Lyme Disease (Neuroborreliosis) 

Lymphocytic meningitis, characterized by head and neck pain, may occur during the acute disseminated stage of the disease.  Analysis of the cerebrospinal fluid (CSF) is indispensable for the diagnosis of Lyme meningitis.  If the individual has LD, the CSF will show a lymphocytic pleocytosis (presence of too many cells) with increased levels of protein.  Intrathecal production of antibodies directed at spirochetal antigens is typically present.  A normal CSF analysis is strong evidence against Lyme meningitis.  Treatment with a 2- to 4-week course of IV antibiotics, typically ceftriaxone or cefotaxime, is recommended.

Cranial neuritis, most frequently Bell's palsy, may present early in the course of disseminated LD, occasionally prior to the development of antibodies, such that an LD etiology may be difficult to rule in or out.  While Bell's palsy typically resolves spontaneously with or without treatment with oral antibiotics, some physicians have recommended a lumbar puncture and a course of IV antibiotics if pleocytosis in the CSF is identified, primarily as a prophylactic measure to prevent further neurologic symptoms.

A subacute encephalopathy may occur months to years after disease onset, characterized by subtle disturbances in memory, mood, sleep, or cognition accompanied by fatigue.  These symptoms may occur in the absence of abnormalities in the electroencephalogram (EEG), magnetic resonance imaging (MRI), or CSF.  In addition, the symptoms are nonspecific and overlap with fibromyalgia and chronic fatigue syndrome.  Thus diagnosis of Lyme encephalopathy may be difficult and may be best diagnosed with a mental status exam or neuropsychological testing.  However, treatment with IV antibiotics is generally not indicated unless CSF abnormalities are identified. 

Much rarer, but of greater concern, is the development of encephalomyelitis, characterized by spastic paraparesis, ataxias, cognitive impairment, bladder dysfunction, and cranial neuropathy.  CSF examination reveals a pleocytosis and an elevation in protein.  Selective synthesis of anti-spirochetal antigens can also be identified.  A course of IV antibiotics with 3 to 4 weeks of ceftriaxone is suggested when CSF abnormalities are identified. 

A variety of peripheral nervous system manifestations of LD have also been identified.  Symptoms of peripheral neuropathy include paresthesias, or radicular pain with only minimal sensory signs.  Individuals typically exhibit electromyographic (EMG) or nerve conduction velocity abnormalities.  CSF abnormalities are usually seen only in those individuals with a coexistent encephalopathy.

Cardiac Manifestations of Lyme Disease

Lyme carditis may appear during the early dissemination stage of the disease; symptoms include atrioventricular heart block, tachyarrhythmias, and myopericarditis.  Antibiotics are typically given, although no evidence proves that this therapy hastens the resolution of symptoms.  Both oral and IV regimens have been advocated.  Intravenous regimens are typically used in individuals with a high degree atrioventricular block or a PR interval on the electrocardiogram (EKG) of greater than 0.3 second.  Individuals with milder forms of carditis may be treated with oral antibiotics.   

Lyme Arthritis 

Lyme arthritis is a late manifestation of infection and is characterized by an elevated IgG response to B. burgdorferi and intermittent attacks of oligoarticular arthritis, primarily in the large joints such as the knee.  Individuals with Lyme arthritis may be successfully treated with a 30-day course of oral doxycycline or amoxicillin, but care must be taken to exclude simultaneous central nervous system (CNS) involvement, requiring IV antibiotic treatment.  In the small subset of individuals who do not respond to oral antibiotics, an additional 30-day course of oral or IV antibiotics may be recommended.

Fibromyalgia and Chronic Fatigue Syndrome 

Fibromyalgia and chronic fatigue syndrome are the diseases most commonly confused with LD.  Fibromyalgia is characterized by musculoskeletal complaints, multiple trigger points, difficulty in sleeping, generalized fatigue, headache, or neck pain.  The joint pain associated with fibromyalgia is typically diffuse, in contrast to Lyme arthritis, which is characterized by marked joint swelling in one or a few joints at a time, with few systemic symptoms.  Chronic fatigue syndrome is characterized by multiple subjective complaints, such as overwhelming fatigue, difficulty in concentration, and diffuse muscle and joint pain.  In contrast to LD, both of the above conditions lack joint inflammation, have normal neurological test results, or have test results suggesting anxiety or depression.  Neither fibromyalgia nor chronic fatigue syndrome has been shown to respond to antibiotic therapy.

Arthritis: inflammation of the joints

Carditis: inflammation of the heart

Chronic Fatigue Syndrome: a condition of prolonged and severe tiredness or weariness (fatigue) that is not relieved by rest and is not directly caused by other conditions

Fibromyalgia: a common condition characterized by widespread pain in joints, muscles, tendons, and other soft tissues

Lyme Disease: Lyme disease is transmitted through the bite of the deer tick (Ixodes scapularis) infected with the bacteria Borrelia burgdorferi, which is the actual cause of the disease

Neurological Involvement: when a condition involves the nervous system

PR interval: a portion of an electrocardiogram that measures the distance in time (in seconds) from the beginning of the P wave to the beginning of the R wave; the normal PR interval duration range is from 0.12 sec - 0.20 sec; longer PR intervals may indicate electrical conductions problems within the heart

Prophylactic Antibiotic Therapy: using antibiotic medications in order to prevent infection when no infection exists

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met: 

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above, when criteria are not met, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

When services also may be Investigational and Not Medically Necessary: 

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Peer Reviewed Publications:

1. Dattwyler RJ, Luft BJ, Kunkel MJ, et al.  Ceftriaxone compared with doxycycline for the treatment of acute disseminated Lyme disease.  N Engl J Med. 1997; 337(5):289–294.
2. Fallon BA, Keilp JG, Corbera KM, et al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology. 2007; 70(13):992-1003.
3. Halperin JJ.  Prolonged Lyme disease treatment: enough is enough. Neurology. 2008; 70(13):986-987.
4. Hsu VM, Patella SJ, Sigal LH.  "Chronic Lyme disease" as the incorrect diagnosis in patients with fibromyalgia.  Arthritis Rheum. 1993; 36(11):1493–1500.
5. Oksi J, Nikoskelainen J, Hiekkanen H, et al.  Duration of antibiotic treatment in disseminated Lyme borreliosis: a double-blind, randomized, placebo-controlled, multicenter clinical study. Eur J Clin Microbiol Infect Dis. 2007; 26(8):571-581.
6. Pachner AR.  Early disseminated Lyme disease: Lyme meningitis.  Am J Med. 1995; 98(4A):30S–43S.
7. Sigal LH.  Early disseminated Lyme disease: cardiac manifestations. Am J Med. 1995; 98(4A):25S–29S.
8. Steere AC.  Diagnosis and treatment of Lyme arthritis.  Med Clin North Am. 1997; 81(1):179–194.
9. Steere AC, Taylor E, McHugh GL, et al.  The overdiagnosis of Lyme disease.  JAMA. 1993; 269(14): 1812–1826.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American College of Rheumatology.  Appropriateness of parenteral antibiotic treatment for patients with presumed Lyme disease. A joint statement of the American College of Rheumatology and the Council of the Infectious Diseases Society of America.  Ann Intern Med. 1993; 119(6):518.
2. Fallon BA, Keilp JG, Corbera KM, et al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology. 2008; 70(13):992-1003.
3. Feder HM Jr, Johnson BJ, O'Connell S, et al. Ad Hoc International Lyme Disease Group. A critical appraisal of "chronic Lyme disease". N Engl J Med. 2007; 357(14):1422-1430.
4. Halperin JJ, Shapiro ED, Logigian E, et al; Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of  Neurology. Neurology. 2007a; 69(1):91-102.
5. Mygland A, Ljøstad U, Fingerle V, et al.; European Federation of Neurological Societies. EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis. Eur J Neurol. 2010; 17(1):8-16, e1-4.
6. Wormser GP, Dattwyler RJ, Shapiro ED, et al.  The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America .  Clin Infect Dis. 2006; 43:1089-1134.

1. American College of Physicians-American Society of Internal Medicine. Lyme Disease: A patient's guide. Available at: http://www.acponline.org/lyme/patient/diagnosis.htm . Accessed on December 10, 2010.
2. Centers for Disease Control and Prevention.  Lyme disease Home Page. Available at: http://www.cdc.gov/ncidod/dvbid/lyme/.  Accessed on December 10, 2010.

Antibiotic Therapy
Intravenous Antibiotic Therapy
Lyme Disease