Blue Cross of Idaho Logo

Express Sign-on

Thank you for registering with Blue Cross of Idaho

If you are an Individual or Family Member, please register here.

If you are a Medicare Advantage or Medicare Supplement member, please register here.

MP 5.01.08

Intravenous Antibiotic Therapy and Associated Diagnostic Testing for Lyme Disease

Medical Policy



Prescription Drugs

Original Policy Date

Last Review Status/Date
Reviewed with literature search/1:2015



Return to Medical Policy Index


Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.


Lyme disease 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 Lyme disease can be adequately treated with oral antibiotics, intravenous (IV) antibiotics are indicated in some patients with neurologic involvement or atrioventricular heart block. However, overdiagnosis and overtreatment of Lyme disease are common due to its nonspecific symptoms, a lack of standardization of serologic tests, and difficulties in interpreting serologic test results. In particular, patients with chronic fatigue syndrome or fibromyalgia are commonly misdiagnosed as possibly having Lyme disease and undergo inappropriate IV antibiotic therapy. The purpose of this policy is to provide diagnostic criteria for the appropriate use of IV antibiotic therapy. The following paragraphs describe the various manifestations of Lyme disease that may prompt therapy with IV antibiotics and the various laboratory tests that are used to support the diagnosis of Lyme disease.

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 patient has Lyme disease, the CSF will show a lymphocytic pleocytosis (lymphocyte count greater than normal) 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 palsy, may present early in the course of disseminated Lyme disease, occasionally prior to the development of antibodies, such that a Lyme disease etiology may be difficult to rule in or out. While Bell 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 neuropsychologic 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 antispirochetal antibodies 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 Lyme disease have also been identified. Symptoms of peripheral neuropathy include paresthesias, or radicular pain with only minimal sensory signs. Patients typically exhibit electromyographic (EMG) or nerve conduction velocity abnormalities. CSF abnormalities are usually seen only in those patients 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 patients with a high-degree atrioventricular block or a PR interval on the electrocardiogram of greater than 0.3 second. Patients 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 immunoglobulin G (IgG) response to B burgdorferi and intermittent attacks of oligoarticular arthritis, primarily in the large joints such as the knee. Patients 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 patients 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 Lyme disease. 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 Lyme disease, both of the above conditions lack joint inflammation, have normal neurologic test results, or have test results suggesting anxiety or depression. Neither fibromyalgia nor chronic fatigue syndrome has been shown to respond to antibiotic therapy.

Serologic Tests

The antibody response to infection with B burgdorferi follows a typical pattern. During the first few weeks after the initial onset of infection, there is no antibody production. The specific immunoglobulin M (IgM) response characteristic of acute infection peaks between the third and sixth week. The specific IgG response develops only after months and includes antibodies to a variety of spirochetal antigens. IgG antibodies produced in response to Lyme disease may persist for months or years. Thus detection of IgG antibodies only indicates exposure, either past or present. In Lyme disease endemic areas, underlying asymptomatic seropositivity may range up to 5% to 10%. Thus, as with any laboratory test, interpretation of serologic tests requires close correlation with the patient’s signs and symptoms. For example, patients with vague symptoms of Lyme disease, chronic fatigue syndrome, or fibromyalgia may undergo multiple serologic tests over many weeks to months in an effort to establish the diagnosis of Lyme disease. Inevitably, in this setting of repeat testing, one enzyme-linked immunosorbent assay (ELISA) or test, whether IgG or IgM, may be reported as weakly positive or indeterminate. These results most likely represent false-positive test results in the uninfected patient who has had long-standing symptoms from a different condition and previously negative test results.

Currently, the Centers for Disease Control and Prevention (CDC) recommend a 2-step method for the serologic diagnosis of Lyme disease:

ELISA for Borrelia burgdorferi Antibodies

This test is a screening serologic test for Lyme disease. ELISA tests are available to detect IgM or IgG antibodies or to detect both antibody types together. More recently developed tests using recombinant or synthetic antigens have improved diagnostic sensitivity. For example, the U.S. Food and Drug Administration (FDA)‒approved C6 ELISA is highly sensitive to infection and is under study as an indicator of antibiotic therapy efficacy. A positive or indeterminate ELISA test result alone is inadequate serologic evidence of Lyme disease. All of these tests must be confirmed with an immunoblot test. In addition, results must be correlated with the clinical picture.

(Western) Immunoblot

This test is used to confirm the serologic diagnosis of Lyme disease in patients with positive or indeterminate ELISA tests. In contrast to the standard ELISA test, the immunoblot investigates the specific antibody response to the different antigens of B burgdorferi. Typically, several clinically significant antigens are tested. According to CDC criteria, the test result is considered positive if 2 of the 3 most common IgM antibody bands to spirochetal antigens are present, or 5 of the 10 most frequent IgG antibody bands are present. Because the CDC criteria were developed for surveillance, they are conservative and may miss true Lyme disease cases. Some support the use of more liberal criteria for a positive result in clinical diagnosis; however, alternative criteria have not been well validated. Criteria for interpreting immunoblot results are different in Europe than in the United States due to differences in prevalent Borrelia species causing disease.

Other tests include the following.

Polymerase Chain Reaction

In contrast to the above 2 serologic tests, which only indirectly assess prior or present exposure to B burgdorferi, polymerase chain reaction (PCR) directly tests for the presence of the spirochete. Because PCR technology involves amplification of DNA from a portion of B burgdorferi, there is a high risk of exogenous contamination, resulting in false-positive results. Positive results in the absence of clear clinical indicators or positive serology are not definitive for diagnosis. In addition, the test cannot distinguish between live spirochetes or fragments of dead ones. The PCR technique has been studied using a variety of specimens. PCR has the best detection rates for skin biopsies from patients with erythema migrans (but may not be indicated with recent history of tick bite or exposure) and for synovial tissue (and synovial fluid, to a lesser extent) from patients with Lyme arthritis. CSF may be positive by PCR during the first 2 weeks of infection, but thereafter the detection rate is low. PCR is not recommended for urine or blood specimens. However, PCR-based direct detection of B burgdorferi in the blood may be useful for documenting Lyme carditis when results of serologic studies are equivocal.

Borrelia PCR also provides information on which of the 3 major species pathogenic for humans has been found in the specimen tested (genotyping).

T-Cell Proliferative Assay

T-lymphocyte proliferation assays are not recommended as diagnostic tests; they are difficult to perform and standardize, and their sensitivity is not well characterized.

Evaluation of CSF

Aside from the standard evaluation of CSF for pleocytosis, protein levels, and glucose levels, various tests are available to determine whether anti-B burgdorferi antibodies are being selectively produced within the CNS. Techniques include a variety of immunoassays. For example, intrathecal antibody production can be detected by the CSF/serum index of B burgdorferi antibodies. CSF and serum samples diluted to match the total IgG concentration in CSF are run in parallel in an IgG ELISA. Excess Borrelia-specific antibody in CSF indicates a positive result. As noted, PCR can also be used to detect the spirochete in the CSF, most successfully within the first 2 weeks of infection.

Evaluation of the Chemoattractant CXCL13

CXCL13 is a B lymphocyte chemoattractant and has been reported to be elevated in acute neuroborreliosis and a potential marker for successful treatment.

Treatment of Lyme Disease

As noted above, treatment with IV antibiotics is generally indicated only in patients with symptoms and laboratory findings consistent with CNS or peripheral neurologic involvement and in a small subset of patients with heart block or documented Lyme arthritis who have not responded to oral antibiotics. Typical IV therapy consists of a 2- to 4-week course of ceftriaxone or cefotaxime, both third-generation cephalosporins, or penicillin or chloramphenicol. No data suggest that prolonged or repeated courses of IV antibiotics are effective. Lack of effect should suggest an incorrect diagnosis or slow resolution of symptoms, which is commonly seen in Lyme disease. In addition, some symptoms may persist after treatment, such as Lyme arthritis; this phenomenon may be related to various self-sustaining inflammatory mechanisms rather than persistent infection.


Treatment of Lyme disease consists of oral antibiotics, except for the following indications:

I. A 2- to 4-week course of IV antibiotic therapy may be considered medically necessary in patients with neuroborreliosis with objective neurologic complications of documented Lyme disease (see the following for methods of documentation).

Objective neurologic findings include:

  • Lymphocytic meningitis with documented cerebrospinal fluid (CSF) abnormalities
  • Cranial neuropathy, other than uncomplicated cranial nerve palsy, with documented CSF abnormalities
  • Encephalitis or encephalomyelitis with documented CSF abnormalities
  • Radiculopathy
  • Polyneuropathy

Lyme disease may be documented either on the basis of serologic testing or by clinical findings of erythema migrans in early infection. Documentation of CSF abnormalities is required for suspected CNS infection, as indicated above.

Serologic documentation of infection requires:

  • Positive or indeterminate enzyme-linked immunosorbent assay (ELISA), AND
  • Positive immunoblot blot by CDC criteria.

Documented CSF abnormalities include ALL of the following:

  • Pleocytosis;
  • Evidence of intrathecal production of Borrelia burgdorferi antibodies in CSF; and
  • Increased protein levels.

Polymerase chain reaction (PCR)‒based direct detection of B burgdorferi in CSF samples may be considered medically necessary and may replace serologic documentation of infection in patients with a short duration of neurologic symptoms (<14 days) during the window between exposure and production of detectable antibodies.

II. A single 2- to 4-week course of IV antibiotics may be considered medically necessary in patients with Lyme carditis, as evidenced by positive serologic findings (defined above) and associated with a high degree of atrioventricular block or a PR interval of greater than 0.3 second. Documentation of Lyme carditis may include PCR-based direct detection of B burgdorferi in the blood when results of serologic studies are equivocal.

III. A single 2- to 4-week course of IV antibiotic therapy may be considered medically necessary in the small subset of patients with well-documented Lyme arthritis who have such severe arthritis that it requires the rapid response associated with IV antibiotics. Documentation of Lyme arthritis may include PCR-based direct detection of B burgdorferi in the synovial tissue or fluid when results of serologic studies are equivocal.

IV. Intravenous antibiotic therapy is considered not medically necessary in the following situations:

  • Patients with symptoms consistent with chronic fatigue syndrome or fibromyalgia, in the absence of objective clinical or laboratory evidence for Lyme disease;
  • Patients with seronegative Lyme disease in the absence of CSF antibodies;
  • Initial therapy in patients with Lyme arthritis without coexisting neurologic symptoms;
  • Cranial nerve palsy (eg, Bell palsy) without clinical evidence of meningitis;
  • Antibiotic-refractory Lyme arthritis (unresponsive to 2 courses of oral antibiotics or to 1 course of oral and 1 course of intravenous antibiotic therapy);
  • Patients with vague systemic symptoms without supporting serologic or CSF studies;
  • Patients with a positive ELISA test, unconfirmed by an immunoblot or Western blot test (see definition above);
  • Patients with an isolated positive serologic test in the setting of multiple negative serologic studies;
  • Patients with chronic (≥6 months) subjective symptoms (“post-Lyme syndrome”) after receiving recommended treatment regimens for documented Lyme disease.

V. Repeat or prolonged courses (eg, >4 weeks) of IV antibiotic therapy are considered not medically necessary.

VI. Repeat PCR-based direct detection of B burgdorferi is considered investigational in the following situations:

  • as a justification for continuation of IV antibiotics beyond 1 month in patients with persistent symptoms
  • as a technique to follow therapeutic response

VII. PCR-based direct detection of B burgdorferi in urine samples is considered investigational in all clinical situations.

VIII. Genotyping or phenotyping of B burgdorferi is considered investigational.

IX. Other diagnostic testing is considered investigational including but not limited to C6 peptide ELISA or determination of levels of the B lymphocyte chemoattractant CXCL13 for diagnosis or monitoring treatment.

Policy Guidelines  

Benefit Application
BlueCard/National Account Issues  

The diagnostic performance of PCR-based technology to identify B. burgdorferi is subject to false-positive results unless strict measures are instituted to prevent cross contamination between samples. As laboratory performance is variable, plans may want to assess the diagnostic performance of local laboratories.


This policy was originally created in 1998 and was updated regularly with searches of the MEDLINE database. The most recent literature search was performed for the period of December 2013 through December 18, 2014. The following is a summary of the key literature to date.

Direct Detection of Borrelia burgdorferi with Polymerase Chain Reaction (PCR) Technology

While diagnosis of Lyme disease is generally based on the clinical picture and demonstration of specific antibodies, polymerase chain reaction (PCR)‒based technology can detect the spirochete in the central nervous system (CSF) in cases of neuroborreliosis, in the synovial fluid of cases of Lyme arthritis, and rarely in skin biopsy specimens of those with atypical dermatologic manifestations.(1,2) However, a PCR-based test is generally considered a second tier test, performed only when the results of serologic tests and clinical evaluation are equivocal. For example, while PCR-based tests can identify organisms in skin biopsy specimens of patients with dermatologic manifestations (ie, erythema migrans), this diagnosis is typically made clinically and antibiotic therapy is started empirically. A skin biopsy is rarely necessary. Similarly, diagnosis of Lyme arthritis is based on clinical and serologic studies without the need for synovial tissue or fluid. Finally, intrathecal antibody production is considered a more sensitive test than PCR-based CSF detection in patients with suspected neuroborreliosis, but a PCR-based technique may be useful in patients with a short duration of disease (ie, <14 days) during the window between exposure and the emergence of detectable levels of antibodies in the CSF.(3) However, it should be noted that that the test cannot distinguish between live and dead organisms. PCR-based detection is typically not performed in the urine due to the variable presence of endogenous polymerase inhibitors that have an impact on the test's sensitivity.

PCR-based technology has been used as one step in the genotypic analysis of Borreliaburgdorferi.B burgdorferi was originally characterized as a single species (B burgdorferi sensu lato), but genotypic analysis has revealed that this group represents 3 distinct species and genomic groups. Of these, the following have been isolated from patients with Lyme disease: B burgdorferi sensu stricto, B garinii, and B afzelii. The prevalence of these different genospecies may vary among populations and may be associated with different clinical manifestations.(4) However, no data were found in the published literature regarding whether or how knowledge of the genotype or phenotype of B burgdorferi could be used to improve patient management and outcomes. In the U.S., B burgdorferi sensu stricto is the only human pathogenic species, but in Europe, all 3 species cause infection. Recently, a new human pathogenic species, B spielmanii, was found in a small number of European patients; therefore, criteria for interpreting immunoblot results are different in Europe than in the U.S.(5)

Chemokine CXCL13 and Other Diagnostic Tests

CXCL13 is a B lymphocyte chemoattractant that has been reported to be elevated in acute neuroborreliosis(6); thus it is a potential marker for successful treatment. However, data are limited. Additional research is necessary to determine diagnostic and treatment utility.

Other diagnostic testing strategies, such as enzyme immunoassay (EIA) using the C6 peptide, have not demonstrated improvements in specificity over the 2-tiered testing approach of ELISA followed by the Western blot.(2,7) Branda et al reported on the use of whole-cell sonicate EIA (ELISA) followed by C6 EIA and found the specificity and positive predictive values were comparable to the 2-tiered ELISA-Western blot approach (99.5% vs 98.4%, and 70% vs 66%, both respectively).(7) Additional research is necessary to determine the validity and interpretation of study results and the value of using the 2-tiered EIA approach over the current standard of EIA (ELISA) followed by Western blot.

Role of Intravenous Antibiotics

A diagnosis of Lyme disease requires appropriate epidemiologic data, supporting clinical observation (including exposure to ixodid ticks in an endemic area), and supporting laboratory findings. However, overdiagnosis and overtreatment of Lyme disease is common.(8-10) Intravenous antibiotic therapy in patients with presumed Lyme disease would be inappropriate in the following situations: an incorrect diagnosis; a history of prolonged or repeated courses of IV antibiotics; and use of intravenous (IV) antibiotics when oral antibiotics are adequate. An incorrect diagnosis of Lyme disease includes those patients with positive serologies without characteristic signs or symptoms of Lyme disease, or those with nonspecific symptoms and no known exposure to ticks in an endemic area, or those without supporting serologic evidence.

The evidence generally does not support persistent B burgdorferi infection in patients with well-documented infection who have received recommended antibiotic therapy.(11) Blinded, randomized controlled trials (RCTs) of extended antibiotic therapy versus placebo in such patients have shown no consistent differences in outcomes (summarized in the Table). Moreover, prolonged exposure to antibiotics carries a high risk of side effects, including pseudomembranous colitis and the accumulation of ceftriaxone calcium salts in the gall bladder.(12)

While morphologic variants of B burgdorferi have been thought to be related to persistent Lyme disease symptoms, a 2013 systematic review by Lantos et al found no evidence to support this.(13) The reviewers found no pathogenic relationship between morphologic variants of B burgdorferi and persistent symptoms of Lyme disease. Additionally, no literature was identified that would support a role for treatment of B burgdorferi morphologic variants.

Table. Summary of Randomized Controlled Trials of Prolonged Antibiotic Therapy in Patients With Well-Documented, Previously Treated Lyme Disease



Patient Description

Experimental Treatment

Control Treatment


Klempner et al 2001(14)



(1) Positive for IgG Abs to B burgdorferi; persistent symptoms that interfered with patient function

(2) Negative for IgG Abs to B burgdorferi; else, as above

IV ceftriaxone daily for 30 d, oral doxycycline for 60 d

IV and oral placebos

No significant difference in quality-of-life outcomes for (1) and (2). Studies terminated after interim analysis indicated that it was highly unlikely that a significant difference in treatment efficacy would be observed

Kaplan et al (2003)(15)


Same trial as Klempner et al 2001(14)

Both treatment and control arms showed similar and not significantly different decreases in Medical Outcomes Study cognitive, pain, and role functioning scales; and improved mood as assessed with the Beck Depression Inventory and Minnesota Multiphasic Personality Inventory

Krupp et al (2003)(1)


Patients with persistent severe fatigue of duration ≥6 mo

IV ceftriaxone daily for 28 d

IV placebo

Ceftriaxone treatment arm showed no significant improvement in primary outcome of laboratory measure of persistent infection. Significant improvement in the secondary outcome of disabling fatigue; no significant treatment effect on cognitive function; no difference in change in SF-36 scores. Patients in ceftriaxone group were significantly more likely to correctly identify their treatment assignment.

Oksi et al (2007)(17)


Consecutive patients treated with standard antibiotic regimen for 21 d

Amoxicillin twice daily for 100 d starting immediately after standard regimen

Placebo twice daily for 100 d starting immediately after standard regimen

Both treatment and control arms showed similar and not significantly different decreases in patient and investigator visual analog scale (VAS) outcomes (VAS evaluation of symptoms, range, 0-100; 0=no symptoms) at 12 mo. B burgdorferi-specific antibodies declined similarly in both groups over 12 mo.

Fallon et al (2008)(17)


Patients with documented objective memory impairment

IV ceftriaxone daily for 70 d

IV placebo daily for 70 d

Primary outcome of cognitive function across 6 domains was similarly improved in both groups at week 24 and was not significantly different between groups; improvement between groups was marginally significantly different at week 12 (p=0.05). Exploratory subgroup analyses suggested significantly better improvement in ceftriaxone-treated patients with more severe baseline pain and physical functioning

Cameron (2008)(19)


Patients with symptoms of arthralgia, cardiac or neurologic involvement with or without fatigue after previous successful antibiotic treatment of Lyme disease; study conducted in a primary care internal medicine practice (52 assigned, 31 evaluable)

Oral amoxicillin 3 g daily for 3 mo (34 assigned, 17 evaluable)

Oral placebo daily for 3 mo

  • 44% of enrolled patients not evaluable at 6 mo; 17 of them had poorer baseline quality of life and were lost due to treatment failure
  • SF-36 improvements for antibiotic vs placebo arm were significant (46% vs 18%, p=0.007), but text not clear if analysis of all or only evaluable patients;
  • SF-36 physical component improvement not significantly different between treatment arms for evaluable patients (8.5 vs 7);
  • SF-36 mental component significantly improved in antibiotic arm for evaluable patients (14.4 vs 6.2, p=0.04)

Ongoing and Unpublished Clinical Trials

An online search of on December 20, 2014, identified no RCTs that addressed prolonged or repeated courses of intravenous antibiotics. Two RCTs were identified that will compare the effectiveness of oral doxycycline with intravenous ceftriaxone. One study will focus on patients with Lyme neuroborreliosis but has not yet begun recruiting patients (NCT01635530). The other study focused on patients with multiple erythema migrans and is expected to be completed October 2015 (NCT01163994). Another RCT, Persistent Lyme Empiric Antibiotic Study Europe (PLEASE), will compare outcomes after 12 weeks of treatment with 2 oral antibiotics (doxycycline or clarithromycin and
hydroxychloroquine) or placebo after initial intravenous ceftriaxone (NCT01207739). This study was expected to be completed in June 2014 but is still ongoing.

Summary of Evidence

Lyme disease is a multisystem inflammatory disease caused by Borrelia burgdorferi and transmitted by the bite of an infected ixodid tick. Oral antibiotics usually are adequate for treatment of Lyme disease, but in some cases, a 2- to 4-week course of intravenous (IV) antibiotics may be appropriate such as in cases of Lyme arthritis, carditis or objective neurologic complications. Evidence has not shown a benefit to prolonged (>4 weeks) or repeat courses of IV antibiotics. Therefore, repeat or prolonged courses of antibiotic therapy are considered not medically necessary.

Diagnostic testing for Lyme disease is challenging and can potentially lead to overdiagnosis and overtreatment. Diagnostic testing may not be necessary when a diagnosis can be made clinically in patients with a recent tick bite or exposure and the presence of the characteristic rash of erythema migrans. When laboratory studies are needed, serologic testing using the 2-step ELISA followed by Western blot is the recommended first approach. Polymerase chain reaction (PCR), may be considered medically necessary as a second approach in patients with a short duration of neurologic symptoms (<14 days) or uncertainty in serologic testing. Other uses for PCR-based testing are considered investigational. Genotyping or phenotyping of B burgdorferi is considered investigational. Additional research is necessary to determine diagnostic and treatment utility of the CXCL13, and its use is considered investigational. Other diagnostic testing approaches, such as C6 peptide, also warrant additional research and therefore, are considered investigational.

Practice Guidelines and Position Statements

In 1993, the American College of Rheumatology published a position paper on IV antibiotic treatment for Lyme disease, 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….”(10) Other studies have also supported the use of oral, not IV, antibiotics in patients with Lyme disease without neurologic involvement.(20-22)

Practice guidelines regarding the treatment of Lyme disease and including discussion of supportive evidence have been issued by the Infectious Diseases Society of America (IDSA).(23) The IDSA also endorsed the American Academy of Neurology evidence-based practice parameter for the treatment of nervous system Lyme disease.(11) The IDSA guidelines recommend IV antibiotics only in the following situations (Note: none of the recommendations suggest longer than a 1-month course of IV antibiotics):

  • Early neurologic disease
    • Meningitis or radiculopathy: 14 to 28 days
  • Cardiac disease
    • Acute onset of varying degrees of intermittent atrioventricular heart block, sometimes in association with clinical evidence of myopericarditis: 14 to 21 days
  • Late disease
    • Persistent or recurrent arthritis after initial oral regimen: 14 to 28 days (a second, 4-week oral regimen may also be used)
    • CNS or peripheral nervous system disease: 14 to 28 days

In the particular case of cranial nerve palsy associated with Lyme disease (most commonly Bell palsy, also known as 7th nerve palsy) and without clinical evidence of meningitis, the evidence indicates that oral antibiotic therapy is satisfactory.(11,23) Cranial nerve palsy may, in fact, resolve without treatment, but treatment should be administered to avoid late complications of Lyme disease.

In addition, guidelines recommend symptomatic treatment for symptoms that persist after appropriate antibiotic therapy. For example, in a small number of patients with known prior infection, arthritis may persist despite negative B burgdorferi DNA by PCR in synovial fluid or tissue. Such persistent arthritis is termed “antibiotic-refractory Lyme arthritis,” defined as “persistent synovitis for at least 2 months after completion of a course of intravenous ceftriaxone (or after completion of two 4-week courses of an oral antibiotic for patients unable to tolerate cephalosporins), in conjunction with negative results of PCR.”(23) Symptomatic treatment, rather than additional antibiotic treatment, is recommended.(23)

In November 2006, the Connecticut Attorney General initiated an antitrust investigation to determine whether the Infectious Diseases Society of America violated antitrust laws in the promulgation of their 2006 Lyme disease guidelines for assessing and treating Lyme disease. The investigation ended with an agreement under which the guidelines remained in effect while the Society convened a Review Panel to determine whether or not the 2006 guidelines were based on sound medical/scientific evidence or required revision. The final report of the Review Panel details the methodology, results, and conclusions of the review.(24) According to the report, “After multiple meetings, a public hearing, and extensive review of research and other information, the Review Panel concluded that the recommendations contained in the 2006 guidelines were medically and scientifically justified on the basis of all of the available evidence and that no changes to the guidelines were necessary.” The 2006 guidelines were reaffirmed in 2010.

The European Federation of Neurological Societies (EFNS) guidelines on Lyme neuroborreliosis are similar to the IDSA guidelines and recommend a 14-day course of oral or intravenous antibiotics in definite or possible acute Lyme neuroborreliosis.(25) In patients with late Lyme neuroborreliosis, a 3-week course of intravenous antibiotics is recommended. The EFNS guidelines indicate antibiotic use for post-Lyme disease syndrome has shown no effect.

Similar recommendations can be found in the British Infection Association’s (BIA) position statement on Lyme disease, which indicates intravenous antibiotics may be appropriate in Lyme carditis, meningitis, or arthritis for periods of 14 to 21 days.(26) Late neuroborreliosis can be treated with intravenous antibiotics for 14 to 28 days. The BIA’s position statement also notes the use of long-term antibiotics can be harmful.

US Preventive Services Task Force Recommendations
The US Preventive Services Task Force has not addressed intravenous antibiotic therapy and associated diagnostic testing for Lyme disease.

Medicare National Coverage

There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.


  1. Steere AC. Lyme disease. N Engl J Med. Jul 12 2001;345(2):115-125. PMID 11450660
  2. Critical Needs and Gaps in Understanding: Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report 2011; Accessed November 20, 2014.
  3. Situm M, Poje G, Grahovac B, et al. Diagnosis of Lyme borreliosis by polymerase chain reaction. Clin Dermatol. Mar-Apr 2002;20(2):147-155. PMID 11973049
  4. Oksi J, Marjamaki M, Nikoskelainen J, et al. Borrelia burgdorferi detected by culture and PCR in clinical relapse of disseminated Lyme borreliosis. Ann Med. Jun 1999;31(3):225-232. PMID 10442678
  5. Wilske B, Fingerle V, Schulte-Spechtel U. Microbiological and serological diagnosis of Lyme borreliosis. FEMS Immunol Med Microbiol. Feb 2007;49(1):13-21. PMID 17266710
  6. Hytonen J, Kortela E, Waris M, et al. CXCL13 and neopterin concentrations in cerebrospinal fluid of patients with Lyme neuroborreliosis and other diseases that cause neuroinflammation. J Neuroinflammation. 2014;11:103. PMID 24920219
  7. Branda JA, Linskey K, Kim YA, et al. Two-tiered antibody testing for Lyme disease with use of 2 enzyme immunoassays, a whole-cell sonicate enzyme immunoassay followed by a VlsE C6 peptide enzyme immunoassay. Clin Infect Dis. Sep 2011;53(6):541-547. PMID 21865190
  8. Hsu VM, Patella SJ, Sigal LH. "Chronic Lyme disease" as the incorrect diagnosis in patients with fibromyalgia. Arthritis Rheum. Nov 1993;36(11):1493-1500. PMID 8240427
  9. Steere AC, Taylor E, McHugh GL, et al. The overdiagnosis of Lyme disease. JAMA. Apr 14 1993;269(14):1812-1816. PMID 8459513
  10. 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. Sep 15 1993;119(6):518. PMID 8357119
  11. Halperin JJ, Shapiro ED, Logigian E, et al. 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. Jul 3 2007;69(1):91-102. PMID 17522387
  12. Nau R, Christen HJ, Eiffert H. Lyme disease--current state of knowledge. Dtsch Arztebl Int. Jan 2009;106(5):72-81; quiz 82, I. PMID 19562015
  13. Lantos PM, Auwaerter PG, Wormser GP. A Systematic Review of Borrelia burgdorferi Morphologic Variants Does Not Support a Role in Chronic Lyme Disease. Clin Infect Dis. Dec 12 2013. PMID 24336823
  14. Klempner MS, Hu LT, Evans J, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med. Jul 12 2001;345(2):85-92.PMID 11450676
  15. Kaplan RF, Trevino RP, Johnson GM, et al. Cognitive function in post-treatment Lyme disease: do additional antibiotics help? Neurology. Jun 24 2003;60(12):1916-1922. PMID 12821733
  16. Krupp LB, Hyman LG, Grimson R, et al. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology. Jun 24 2003;60(12):1923-1930. PMID 12821734
  17. 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. Aug 2007;26(8):571-581. PMID 17587070
  18. Fallon BA, Keilp JG, Corbera KM, et al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology. Mar 25 2008;70(13):992-1003. PMID 17928580
  19. Cameron D. Severity of Lyme disease with persistent symptoms. Insights from a double-blind placebo-controlled clinical trial. Minerva Med. Oct 2008;99(5):489-496. PMID 18971914
  20. Dattwyler RJ, Luft BJ, Kunkel MJ, et al. Ceftriaxone compared with doxycycline for the treatment of acute disseminated Lyme disease. N Engl J Med. Jul 31 1997;337(5):289-294. PMID 9233865
  21. Eckman MH, Steere AC, Kalish RA, et al. Cost effectiveness of oral as compared with intravenous antibiotic therapy for patients with early Lyme disease or Lyme arthritis. N Engl J Med. Jul 31 1997;337(5):357-363. PMID 9233874
  22. Wormser GP, Ramanathan R, Nowakowski J, et al. Duration of antibiotic therapy for early Lyme disease. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. May 6 2003;138(9):697-704. PMID 12729423
  23. 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 [Practice Guideline]. 2006; 2006/10/10:1089-1134. Available at: Accessed November 20, 2014.
  24. Lantos PM, Charini WA, Medoff G, et al. Final report of the Lyme disease review panel of the Infectious Diseases Society of America. Clin Infect Dis. Jul 1 2010;51(1):1-5. PMID 20504239
  25. Mygland A, Ljostad U, Fingerle V, et al. EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis. Eur J Neurol. Jan 2010;17(1):8-16, e11-14. PMID 19930447
  26. British Infection A. The epidemiology, prevention, investigation and treatment of Lyme borreliosis in United Kingdom patients: a position statement by the British Infection Association. J Infect. May 2011;62(5):329-338. PMID 21421007







Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); intravenous push, single or initial substance/drug



Borrelia burgdorferi (Lyme disease) confirmatory test (e.g., Western blot or immunoblot)



Infectious agent detection by nucleic acid; Borrelia burgodorferi, direct probe technique



Infectious agent detection by nucleic acid; Borrelia burgdorferi, amplified probe technique (describes PCR technique)



Infectious agent detection by nucleic acid; Borrelia burgodorferi; quantification

ICD-9 Procedure


Injection of antibiotic

ICD-9 Diagnosis


Lymphocytic meningitis



Lyme disease



Other causes of encephalitis



Unspecified cause of encephalitis



Trigeminal nerve disorder, unspecified



Bell’s palsy



Facial nerve disorder, unspecified



Disorders of olfactory (1st) cranial nerve


352.2 – 352.6

Disorders of other cranial nerves, code range



Unspecified disorder of cranial nerves



Unspecified hereditary and idiopathic peripheral neuropathy (includes polyneuropathy)



Other disorders of optic nerve


378.51 – 378.54

Paralytic strabismus code range



Disorders of acoustic nerve



Atrioventricular block, unspecified



Other ill-defined heart diseases (includes Lyme carditis)


No Code


ICD-10-CM (effective 10/1/15)


Lyme disease code range

ICD-10-PCS (effective 10/1/15)


ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for the initiation of this therapy and there are no ICD procedure codes for laboratory tests.



Administration, peripheral vein, percutaneous, anti-infective

Type of Service



Place of Service




Intravenous Antibiotic Therapy for Lyme Disease
Lyme Disease, Intravenous Antibiotic Therapy

Policy History




01/30/98 Add to Prescription Drug section New policy
10/08/02 Replace policy Policy reviewed with literature search; policy statement unchanged regarding IV antibiotic therapy; additional policy statements on PCR technique, updated rationale and references
12/17/03 Replace policy Policy updated with literature search; policy statement unchanged
04/1/05 Replace policy Policy updated with literature search; policy statement unchanged
12/14/05 Replace policy – coding update only CPT coding updated
04/25/06 Replace policy – error correction only Corrected last sentence in Policy Guidelines to delete 87476 and read: “Therefore, codes 87475 and 87477 would be considered investigational.”
06/14/07 Replace policy Policy updated with literature search. Policy statements updated; uncomplicated cranial nerve palsy (e.g., Bell’s palsy) not considered a medically necessary indication for intravenous antibiotics. Reference numbers 18-20 added
07/10/08 Replace policy Policy updated with literature search. Rationale and references reorganized and revised extensively. Policy statements unchanged
07/09/09 Replace policy Policy updated with literature search; no new references added; minor wording changes to text. Policy statements unchanged
12/09/10 Replace policy Policy updated with literature search; references 13 and 14 added, references 11 and 12 updated. Policy statement added, “Determination of levels of the B lymphocyte chemoattractant CXCL13 for diagnosis or monitoring treatment is considered investigational.” Otherwise, no change to policy statements
12/08/11 Replace policy Policy updated with literature search; references 2, 6, 23 and 24 added, reference 21 updated. Added “Other diagnostic testing” is considered investigational “including but not limited to C6 peptide ELISA” to the CXCL13 policy statement. Otherwise, no change to policy statements
9/13/12 Replace policy Policy updated with literature search; policy statements unchanged. Policy Guidelines paragraph removed to reduce confusion with the policy statements.
1/09/14 Replace policy Policy updated with literature search through December 18, 2013; Reference 12 added. Policy statements unchanged.
4/10/14 Replace policy Policy statements renumbered to put the “not medically necessary” situations into their own numbered section (IV) and change the numbers of the subsequent sections.
1/15/15 Replace policy Policy updated with literature review through December 18, 2014; Reference 6 added. Policy statements unchanged.


Resource Center

Find a Provider Find a Pharmacy Medicare Medicare Formulary