Medical Policy


Subject: Parenteral Antibiotics for the Treatment of Lyme Disease
Document #: MED.00013 Publish Date:    03/29/2018
Status: Reviewed Last Review Date:    02/27/2018



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


Position Statement

Medically Necessary:

A course of up to 4 weeks of intravenous (IV) antibiotic therapy is considered medically necessary for individuals with Lyme disease meeting ANY of the following criteria:

And antibiotic used is:

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, including when the following IV drugs are used:

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:

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 (American 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.  

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, or 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; Kaplan, 2003; Krupp, 2003; Oksi, 2007; Wormser, 2006).

In contrast to this body of data is a longitudinal cohort study of 158 subjects with significant neuropsychiatric symptoms of at least 3 months duration and laboratory-confirmed Lyme disease (Stricker, 2011).  Subjects were treated with long-term IV ceftriaxone.  The dose, frequency, and length of treatment were not standardized, but were left to the discretion of the treating physician.  Subjects were categorized into five groups based on length of treatment: (1) 1-4 weeks (n=32); (2) 5-8 weeks (n=33); (3) 9-12 weeks (n=28); (4) 13-24 weeks (n=37); and (5) 25-52 weeks (n=28).  Symptom outcomes were measured by a questionnaire developed by the investigators that evaluated three major categories including pain, neurologic function, and general symptoms.  Primary outcomes were improvement in fatigue, cognition, myalgia, and arthralgia using the measurement tool.  Baseline measures indicated significant variation in the degree of symptom severity, but the authors note that this variation reflected real-world presentation of Lyme neuroborreliosis.  The results show that arthralgias were significantly improved during the 1-4 week treatment period, (p=0.04) but that no significant improvements were noted in any of the other time periods.  Both myalgias and fatigue were significantly improved during the 5-8, 13-14, and 25-52 week periods (p=0.03, p=0.01, and p=0.01, respectively).  Cognition was only significantly improved in the 25-52 week timeframe (p=0.02).  No data were provided regarding the impact of the different dosing or treatment protocols.  These results are very interesting, and provide some data to indicate that longer-length treatment has differential impact on various symptom categories.  However, the uncontrolled nature of this study, as well as the lack of standardization with regard to treatment protocol and dosing, the use of an unvalidated outcome tool, and finally, the small sample size of each group do not allow wider generalization of these results.

Practice guidelines regarding the treatment of Lyme disease have been issued by the Infectious Diseases Society of America (IDSA, 2006). These guidelines include recommendations for the use of the following IV antibiotics; ceftriaxone, cefotaxime, and Penicillin G.  The recommended courses of treatment are:

The guidelines state:

Macrolide antibiotics are not recommended as first-line therapy for early Lyme disease, because those macrolides that have been compared with other antimicrobials in clinical trials have been found to be less effective (E-I).  When used, they should be reserved for patients who are intolerant of, or should not take, amoxicillin, doxycycline, and cefuroxime axetil.

Thus, treatment with macrolide drugs, including azithromycin, may be warranted in some individuals who are allergic or intolerant to amoxicillin, doxycycline, or cefuroxime axetil.

The IDSA guidelines also identify several treatment methods that are specifically not recommended, including the use of carbapenems, first-generation cephalosporins, fluconazole, or fluoroquinolones and treatment with IV antibiotics longer than 1 month.  

The 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).” 

A recent biostatistical review published by Delong and colleagues concludes that the results of the four NIH-sponsored randomized controlled trials most frequently cited to demonstrate the ineffectiveness of long-term antibiotic therapy for Lyme disease are significantly flawed, and that the conclusions drawn by their authors are unfounded (2012).  The authors evaluate the methodology and results used by Fallon (2008), Kaplan (2003), Klempner (2001), and Krupp (2003) in a systematic manner.  Overall, Delong indicates that none of the trials were designed to demonstrate non-inferiority of long-term antibiotic therapy.  Furthermore, the studies had methodological flaws such as inadequate power due to small sample sizes, insufficient data on drop-outs, inappropriate combination of data, and use of an end point marker not widely recognized by the clinical community.  In one case, they assert that the conclusions by Fallon et al. stating that the positive finding regarding improvement in fatigue measures was biased due to unblinding, was unsubstantiated.  Delong concludes that, “the inability of these trials to demonstrate a statistically significant finding provides neither proof of the absence of a clinically meaningful treatment effect nor evidence that patients with persistent symptoms suffer from a post-infectious syndrome.”  While many of Delong’s points are technically correct, the authors offer no evidence that repeated or long-term antibiotics are actually effective in ameliorating symptoms experienced by individuals after completion of currently recommended (IDSA) antibiotic therapy of Lyme disease.  The evidence of improved net health outcomes from long-term antibiotic therapy for the treatment of Lyme disease remains insufficient.  Additional evidence from well-designed, properly conducted and analyzed trials is needed to understand the balance of benefits and harms from long-term antibiotic therapy before such a strategy can be considered medically necessary.

In 2012, Fallon and colleagues published an article reappraising the available clinical trial data addressing what they term “post-treatment Lyme disease syndrome.”  As with the DeLong article, Fallon discusses a list of methodological flaws in the Klempner report (2002), including failure to control for pre-treatment disease severity and utilization of appropriate statistical analyses.  They also extensively address criticisms of the Krupp study (2003), including the finding that only one of the three primary outcome measures showed improvement.  In defense of their position, they state that the study was “adequately powered to test only one of the three primary outcome measures: the only clinical measure on which patients were enrolled (i.e., fatigue) and on which they were definitively impaired.”  Next they address the concern that inadvertent unmasking may have skewed the results to show favorable outcomes.  Among their several comments, they point out that since there was no significant difference between the treatment groups with respect to adverse effects, the higher correct guess rate in the ceftriaxone group may have also been due to the beneficial impact of the drug rather than unmasking.  Also, they note that at 6 months, among subjects who thought they were receiving active treatment, those who were actually receiving active treatment reported a higher responder rate than those in the placebo group.  In other words, even among those who believed that they had been given an active drug, the higher responder rate still persisted among those who had in fact received an active drug rather than placebo.  It is also stated that subjects who were IgG Western blot positive were 6 times more likely to show improvement in fatigue if given ceftriaxone than if they were given placebo.  It is argued that if the higher responder rate in response to ceftriaxone were primarily due to “correct guessing”, then there shouldn’t be a biologically homogenous subgroup that had a higher response rate compared to the placebo group.  Another criticism they address is that the magnitude of the effect found was small.  They conclude that, “based on currently accepted methods for the analysis of clinical trial data, the effect size for improvement in fatigue in the STOP-LD study was moderate to large, and would be considered clinically meaningful.”  Lastly, they address the study by Fallon (2008).  One criticism of the findings of this study was that improvement in cognitive function was a “regression to the mean.”  In the review by Fallon, they point out that the slope of the curve in Figure 2 actually increases away from the mean following cessation of treatment in the active group.  It is also noted that a planned analysis on secondary outcomes showed an interaction effect at week 12 favoring active vs. placebo treatment based on baseline impairment, indicating that individuals with more severe impairment had a greater benefit from active treatment.  This commentary is followed by recommendations for the planning and evaluation of clinical trials addressing chronic Lyme disease. They conclude by stating that their points support the contention that extended IV antibiotic therapy provides significant benefit.

In response to these articles by DeLong and Fallon, Klempner (2013) published an article addressing their comments.  Regarding the DeLong paper, Klempner states that their assumptions were questionable, and identified potential bias in that the authors are all long-time supporters of alternative treatments for Lyme disease.  In this discussion, they indicate that DeLong states that the symptoms of chronic Lyme disease are of the same severity as multiple sclerosis or congestive heart failure based on trial subjects’ reported symptoms.  While this may be true for the study subjects, it is not clear if this is true of all individuals with chronic Lyme disease.  Furthermore, it is argued that the subjects with severe symptoms in the available prospective trials have an “unconvincing history of having had Lyme disease.”  As evidence of this, Klempner points to lack of credible evidence of Lyme infection as the reason most trials had difficulty recruiting participants.  They also address the claim by DeLong that the clinical improvement criteria used in the 2001 Klempner study was unrealistic, stating that Delong’s proposal of accepting a lower power to detect smaller treatment effects, as is done in similar trials with non-infective conditions, is not appropriate for the trial in question.  Klempner states that such a proposal indicates a lack of understanding of the treatment effects of antibiotic therapy in infectious diseases, which are much greater on average than those seen in trials with non-infective conditions.  It is pointed out that 36% of placebo group subjects met the supposedly “unrealistic” standard, which is very similar to the 40% rate seen in the experimental group, and also close to the 32% of experimental subjects who had a decline in outcomes.  Even with the proposed lower threshold, Klempner states that “it is highly unlikely that there could have been a sufficiently large effect in this small subgroup to have substantially changed the results.”  They also criticize Delong’s focus on global assessment scales without consideration of potential drawbacks of long-term IV antibiotic therapy including adverse events, indicating that if a larger population of 800 subjects were used, as proposed by De Long, that the 1.6% and 7.3% adverse event rates reported by Klempner and Krupp, respectively, would have resulted in between 13-58 individuals adversely affected.  In addressing the Delong comments regarding the Krupp study, Klempner mentioned that they did not address the fact that the placebo group had an almost 33% loss to follow-up rate, which is much greater than a widely accepted 20% at which trials are considered invalidated, and intent-to-treat and on-study analyses are jeopardized.  Addressing the Krupp study directly, Klempner stated that 69% of the experimental group had a > 0.7 point reduction in fatigue scores at 6 months.  However, the mean total score was still greater than 4.4, indicating persistent fatigue was still present and trial inclusion criteria was still being met.  It is also pointed out that Krupp may have underestimated the placebo effect.  At 6 months, 68% of the placebo group believed that they were on active therapy vs. 69% of the experimental group, hinting at a significant placebo effect or the presence of some other factor that allowed subjects to guess they had received active treatment.  Also called into question is the clinical significance of a 22% reduction in fatigue severity index.  At the 6 week point, the intensity between groups was not statistically significant, nor did antibiotic treatment have a significant effect on perceived health status.  Klempner points out that DeLong does not mention that in the Krupp study a main hypothesis for chronic Lyme disease is persistent CNS B. burgdorferi infection.  Yet they attempt to discount the lack of cognitive improvement in the experimental group by indicating that it was not an entry criterion.  However, Krupp stated that affected subjects clearly “showed slower mental speed than…healthy controls” on objective measures prior to treatment.  Nor was there any data demonstrating clearance of infectious antigens from CFS, partly due to the fact that few subjects had detectible antigen prior to treatment.  Addressing the Fallon study, it was noted by Klempner that fatigue measures decreased by 15% in both the experimental and placebo groups.  This outcome refutes Delong’s assertion of benefit after 10 weeks of treatment with IV antibiotics.  Fallon cites a 0.7 point decrease in fatigue score in 66.7% of experimental subjects vs. only 25% in placebo subjects (p=0.05).  Klempner states that this is misleading, as it comes from a post-hoc analysis and was not statistically corrected for the multiple other post-hoc comparisons conducted.  It is also highlighted that DeLong did not address discrepancies between the Krupp and Fallon studies with regard to time points of improvement.  In the Krupp study, differential improvement was most evident at 6 months but not at 1 month after entry.  In contrast, in the Fallon study, treatment effect on cognition was most evident 2 weeks after the end of treatment, but not 3 months later.  This indicates a contradictory treatment effect for cognition and fatigue, with the former improving during treatment, but not persisting, and the latter having a benefit initially indistinguishable from placebo but superior at 6 months.  Another contradiction between studies is that post-hoc analyses revealed a larger treatment effect for fatigue in subjects with less pain in the Krupp study, whereas in the study by Fallon study post-hoc analyses showed an interaction effect favoring antibiotic treatment vs. placebo as a function of baseline severity of the subjects’ symptoms.  Fallon found in an ad-hoc analysis that subjects with worse baseline pain and physical functioning who received antibiotics were improved at week 12, and this was sustained at week 24.  However, no data is presented regarding analgesic or non-inflammatory agent use at any time point.  It is widely acknowledged that the use of such drugs can confound the assessment of pain and physical functioning.  Finally, Klempner stated that in all the prospective NIH trials discussed, none of the subjects had either microbial or molecular evidence of resistant infection, nor did they have CSF evidence of inflammation.  Treatment with ceftriaxone is intended to treat CNS infections, due to its ability to cross the blood-brain barrier.  Thus, in the Klempner study, which had the fewest subjects previously treated with ceftriaxone, one would have expected the greatest benefit of ceftriaxone on CNS infection.  This was not the case, despite the longest treatment used in any of the discussed studies.  The authors of this review conclude with the following:

Moreover, to justify intensive retreatment with antibiotics, an additional criterion needs to be met-that retreatment both resolves the infection and relieves the symptoms. Those who argue that antibiotics cannot fully eradicate Borrelia burgdorferi from animals or patients never provide evidence for why, if this were true, longer courses of antibiotic therapy would overcome this limitation.


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 (IDSA, 2006).

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: A disease caused by the bacteria Borrelia burgdorferi, which is transmitted through the bite of the deer tick (Ixodes scapularis).

Neurological involvement: When a medical 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 conduction problems within the heart.

Prophylactic antibiotic therapy: The use of 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:




Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour


Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); each additional hour


Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); additional sequential infusion of a new drug/substance, up to 1 hour


Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); concurrent infusion




Injection, azithromycin, 500 mg


Injection, ceftriaxone sodium, per 250 mg


Injection, cefotaxime sodium, per gm


Injection, penicillin G potassium, up to 600,000 units [IV]


Home infusion therapy, antibiotic, antiviral, or antifungal therapy; administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment, per diem


Home infusion therapy, antibiotic, antiviral, or antifungal therapy; once every 3 hours


Home infusion therapy, antibiotic, antiviral, or antifungal therapy; once every 24 hours


Home infusion therapy, antibiotic, antiviral, or antifungal therapy, once every 12 hours 


Home infusion therapy, antibiotic, antiviral, or antifungal therapy, once every 8 hours 


Home infusion therapy, antibiotic, antiviral, or antifungal therapy, once every 6 hours 


Home infusion therapy, antibiotic, antiviral, or antifungal therapy, once every 4 hours

ICD-10 Diagnosis



Lyme disease

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 are Investigational and Not Medically Necessary:




Therapeutic, prophylactic or diagnostic injection (specify substance or drug); subcutaneous or intramuscular [when specified as intramuscular antibiotic injection]




Injection, penicillin G benzathine and penicillin G procaine, 100,000 units [IM]


Injection, penicillin G benzathine, 100,000 units [IM]


Injection, cefazolin sodium, 500 mg


Injection, cilastatin sodium; imipenem, per 250 mg


Injection, doripenem, 10 mg


Injection, ertapenem sodium, 500 mg


Injection, fluconazole, 200 mg


Injection, levofloxacin, 250 mg


Injection, meropenem, 100 mg


Injection, moxifloxacin, 100 mg


Injection, penicillin G procaine, aqueous, up to 600,000 units [IM]

ICD-10 Diagnosis



Lyme disease


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. Delong AK, Blossom B, Maloney EL, Phillips SE. Antibiotic retreatment of Lyme disease in patients with persistent symptoms: a biostatistical review of randomized, placebo-controlled, clinical trials. Contemp Clin Trials. 2012; 33(6):1132-1142.
  3. 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.
  4. Fallon BA, Petkova E, Keilp JG, Britton CB. A reappraisal of the U.S. clinical trials of post-treatment Lyme disease syndrome. Open Neurol J. 2012; 6:79-87.
  5. Halperin JJ. Prolonged Lyme disease treatment: enough is enough. Neurology. 2008; 70(13):986-987.
  6. Hsu VM, Patella SJ, Sigal LH. “Chronic Lyme disease” as the incorrect diagnosis in patients with fibromyalgia. Arthritis Rheum. 1993; 36(11):1493-1500.
  7. Kaplan RF, Trevino RP, Johnson GM, et al. Cognitive function in post-treatment Lyme disease: do additional antibiotics help? Neurology. 2003; 60(12):1916-1922.
  8. Klempner MS, Baker PJ, Shapiro ED, et al. Treatment trials for post-Lyme disease symptoms revisited. Am J Med. 2013; 126(8):665-669.
  9. 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. 2001; 345(2):85-92.
  10. Krupp LB, Hyman LG, Grimson R, et al. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology 2003; 60(12):1923-1930.
  11. 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.
  12. Pachner AR. Early disseminated Lyme disease: Lyme meningitis. Am J Med. 1995; 98(4A):30S-43S.
  13. Sigal LH. Early disseminated Lyme disease: cardiac manifestations. Am J Med. 1995; 98(4A):25S-29S.
  14. Steere AC. Diagnosis and treatment of Lyme arthritis. Med Clin North Am. 1997; 81(1):179-194.
  15. Steere AC, Taylor E, McHugh GL, Logigian EL. The overdiagnosis of Lyme disease.  JAMA. 1993; 269(14):1812-1816.
  16. Stricker RB, Delong AK, Green CL, et al. Benefit of intravenous antibiotic therapy in patients referred for treatment of neurologic Lyme disease. Int J Gen Med. 2011; 4:639-646.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. 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.
  2. 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.
  3. 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.
  4. 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(9):1089-1134.
Websites for Additional Information
  1. Centers for Disease Control and Prevention. Lyme disease Home Page. Available at: Accessed on October 29, 2017.
  2. Centers for Disease Control and Prevention. Post-Treatment Lyme Disease Syndrome.  Available at: Accessed on October 29, 2017.


Antibiotic Therapy
Intravenous Antibiotic Therapy
Lyme Disease


Document History






Medical Policy & Technology Assessment Committee (MPTAC) review. The document header wording updated from “Current Effective Date” to “Publish Date.” Updated References section.



MPTAC review. Updated Reference section.



MPTAC review. Added a minor language revision in the position statement. Removed ICD-9 codes from Coding section.



MPTAC review. Updated Rationale and Reference sections.



MPTAC review. Updated Rationale and Reference sections.



MPTAC review. Deleted the term “vague” from the not medically necessary section. Updated Rationale, Background and Reference sections.



MPTAC review. Added use of azithromycin to medically necessary position statement. Added use of carbapenems, first-generation cephalosporins, Fluconazole, and fluoroquinolones to investigational and not medically necessary section. Updated Rationale, Background and Coding sections.



MPTAC review. Updated Coding and Reference sections.



MPTAC review.



MPTAC review. Updated medically necessary criteria regarding myocarditis. Updated Reference section.



Updated Coding section with 01/01/2009 CPT changes; removed 90765, 90766, 90767, 90768, 90772 deleted 12/31/2008.



MPTAC review. Clarified type of Penicillin in medically necessary section. Added criteria for the diagnosis of acute or chronic neurological Lyme disease to medically necessary section.



MPTAC review. Added cefotaxime and drug brand names to medically necessary statement. Added investigational and not medically necessary statement for when criteria are not met. The phrase “investigational/not medically necessary” was clarified to read “investigational and not medically necessary.” Updated Rationale, Coding and Reference sections.



MPTAC review. Coding updated; removed CPT 90780, 90781, 90782 and HCPCS G0347, G0348, G0349, G0350 deleted 12/31/2005.



MPTAC review. Revised document title to “Parenteral Antibiotics for the Treatment of Lyme Disease”. Removed position language regarding the use of oral antibiotics and laboratory testing; elaborated on the definition of neurological involvement in Medically Necessary section; added treatment of persistent arthritis after 2 prior courses of antibiotic therapy and treatment of “post-Lyme disease” syndrome as not medically necessary.



MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.

Pre-Merger Organizations

Last Review Date

Document Number


Anthem, Inc.



Lyme Disease Treatment

WellPoint Health Networks, Inc.



Lyme Disease (Lyme Borreliosis)