Standard care

ILADS Guideliness
Guidelines for the management of Lyme disease (PDF)
November 1st, 2006
Joseph J. Burrascano Jr, MD:
Diagnostic Hints and Treatment Guidelines for Lyme and Other Tick Borne Illnesses (PDF)
October, 2008  NEW UPDATES

National Guideline Clearinghouse:
Summary of ILADS Treatment Guidelines for Lyme Disease

Treatment Considerations

Since Lyme disease can become persistent, recurrent, and refractory even in the face of antibiotic therapy, evaluation and treatment must be prompt and aggressive.

Prompt Use of Antibiotics

Although no well designed studies have been carried out, the available data support the prompt use of antibiotics to prevent chronic Lyme disease. Antibiotic therapy may need to be initiated upon suspicion of the diagnosis, even without definitive proof. Neither the optimal antibiotic dose nor the duration of therapy has been standardized, but limited data suggest a benefit from increased dosages and longer treatment, comparable to the data on tuberculosis and leprosy which are caused by similarly slow-growing pathogens.

Choosing an Antibiotic

In acute Lyme disease, the choice of antibiotics should be tailored to the individual and take into account the severity of the disease as well as the patient’s age, ability to tolerate side effects, clinical features, allergy profile, comorbidities, prior exposure, epidemiologic setting, and cost.

Conversely, persistent and refractory Lyme disease treatment is more likely to include intravenous and/or intramuscular antibiotics. The choices depend in part on the patient’s response to antibiotic therapy and on the success of antibiotics in treating other Lyme disease patients.

Therapy usually starts with oral antibiotics, and some experts recommend high dosages. The choice of antibiotic therapy is guided by weighing the greater activity of intravenous antibiotics in the central nervous system against the lower cost and easy administration of oral antibiotics for B. burgdorferi.

Oral Antibiotic Options

For many Lyme disease patients, there is no clear advantage of parenteral therapy. Along with cost considerations and pressure to treat patients with Lyme disease with the least intervention, there is growing interest in the use of oral therapy.

First-line drug therapies for Lyme disease may include (in alphabetical order): oral amoxicillin, azithromycin, cefuroxime, clarithromycin, doxycycline, and tetracycline. These antibiotics have similar favorable results in comparative trials of early Lyme disease.

Intravenous Antibiotic Options

It is common practice to consider intravenous antibiotics upon failure of oral medications in patients with persistent, recurrent, or refractory Lyme disease, and as the first line of therapy for certain conditions, (i.e., encephalitis, meningitis, optic neuritis, joint effusions, and heart block).

Ideally, the intravenous antibiotic should be selected on the basis of in vitro sensitivity testing or clinical experience. Intravenous antibiotics are also justified by concern for penetration into the central nervous system.

Until recently, ceftriaxone, cefotaxime, and penicillin were the only intravenous antibiotics routinely studied for use in Lyme disease. Intravenous imipenem, azithromycin, and doxycycline have an adequate antispirochetal spectrum of activity and may represent suitable alternative therapies. However, the latter two drugs are often considered for intravenous use only if they are not tolerated orally.

Intramuscular Antibiotic Options

Intramuscular benzathine penicillin (1.2 to 2.4 million units per week) is sometimes effective in patients who do not respond to oral and intravenous antibiotics. If intramuscular benzathine penicillin is used, long-term therapy may be necessary due to the low serum concentration of this form of penicillin. Benzathine penicillin has mainly been used in patients who have had multiple relapses while receiving oral or intravenous antibiotic therapy or who are intolerant of oral or intravenous antibiotics.

Combination Antibiotic Treatment

Combination therapy with two or more antibiotics is now increasingly used for refractory Lyme disease and has also been given as initial therapy for some chronic presentations.

This approach is already used for another tick-borne illness, babesiosis. Oral amoxicillin, cefuroxime, or (more recently) cefdinir combined with a macrolide (azithromycin or clarithromycin) are examples of combination regimens that have proven successful in clinical practice, although controlled clinical trials are lacking in persistent, recurrent, and refractory Lyme disease.

Combination therapy in patients with Lyme disease raises the risk of adverse events. This risk must be weighed against the improved response to combination therapy in Lyme disease patients failing single agents.

Sequential Treatment

Clinicians increasingly use the sequence of an intravenous antibiotic followed by an oral or intramuscular antibiotic. In two recent case series that employed combination therapy and sequential therapy, most patients were successfully treated. A logical and attractive sequence would be to use intravenous therapy first (e.g., intravenous ceftriaxone), at least until disease progression is arrested and then follow with oral therapy for persistent and recurrent Lyme disease.


Increasingly, clinicians recommend that certain drugs used for Lyme disease be given at higher daily doses: for example, 3,000–6,000 mg of amoxicillin, 300–400 mg doxycycline, and 500–600 mg of azithromycin. Some clinicians prescribe antibiotics using blood levels to guide higher doses. Close monitoring of complete blood counts and chemistries are also required with this approach.

With higher doses, there may be an increase in adverse events in general and gastrointestinal problems in particular. Acidophilus has reportedly reduced the incidence of Clostridium difficile colitis and non-C. difficile antibiotic-related diarrhea.

Serious adverse effects of antibiotics, however, were less common than previous estimates. In a recent clinical trial of chronic Lyme disease, the overall serious adverse event rate was 3% after three months of antibiotics, including 1 month of intravenous antibiotics. Clinicians who have experience with higher dose antibiotic therapy must balance the benefit of higher drug levels achieved with this therapy against the modest risk of gastrointestinal and other side effects.

Duration of Therapy

Because of the disappointing long-term outcome with shorter courses of antibiotics, the practice of stopping antibiotics to allow for a delayed recovery is no longer recommended for patients with persistent, recurrent, and refractory Lyme disease. Reports show failure rates of 30–62% within 3 years of short-course treatment using antibiotics thought to be effective for Lyme disease. Conversely for neurologic complications of Lyme disease, doubling the length of intravenous ceftriaxone treatment from 2 to 4 weeks improved the success rate from 66 to 80%.

The management of chronic Lyme disease must be individualized, since patients will vary according to severity of presentation and response to previous treatment.

Concurrent risk factors (i.e., coinfections, previous treatment failures, frequent relapses, neurologic involvement, or previous use of corticosteroids) or evidence of unusually severe Lyme disease should lead to the initiation of prolonged and/or intravenous antibiotic treatment. Physicians should always assess the patient’s response to treatment before deciding on appropriate duration of therapy (i.e., weeks versus months).

Empiric Treatment

The importance of establishing the diagnosis of Lyme disease is heightened in light of increasing concern about antibiotic overuse. After an appropriate history, physical examination, and laboratory testing are completed, empiric antimicrobial therapy should be initiated on the basis of clinical clues, the severity of the patient’s acute illness, underlying disease, and the likelihood of B. burgdorferi infection. The International Lyme and Associated Diseases Society (ILADS) working group recommends that empiric treatment be considered routine for patients with a likely diagnosis of Lyme disease.

Persistent Lyme Disease

Persistent Lyme disease is more resistant to treatment and more likely to produce a relapse. Although persistent Lyme disease may resolve without additional therapy, many experts believe that this condition should be treated with repeated and prolonged antibiotics. Physicians should extend the duration of antibiotics to prevent or delay recurrent and refractory Lyme disease.

Recurrent Lyme Disease

Despite previous antibiotic treatment, Lyme disease has a propensity for relapse and requires careful follow-up for years. The data suggest that failure to eradicate the organism may be the reason for a recurrence of symptoms. Early and aggressive treatment with antibiotics is indicated for recurrent Lyme disease. The ultimate impact from retreating each episode of recurrent Lyme disease is currently unclear.

Refractory Lyme Disease

Refractory Lyme disease is a devastating condition that usually affects patients with persistent symptomatology and long-term disability. Prompt and aggressive institution of antibiotic therapy may be essential to prevent refractory disease. Increasing evidence shows that antibiotics have a beneficial effect on the course of refractory Lyme disease even in cases where the patient is intolerant of antibiotics or when a previous regimen has failed. Several months of therapy are often required to produce clear evidence of improvement. During this time, symptomatic treatment may be combined with antibiotic treatment.

Treatment Failure

When patients fail to respond or their conditions deteriorate after initiation of empiric therapy, a number of possibilities should be considered other than Jarisch-Herxheimer reaction. These include adverse events that limit treatment, allergic history to medication, inappropriate or inadequate dosing regimen, compliance problems, incorrect medication, immune sequelae, and sequestering of the organism (e.g., in the central nervous system). An alternative diagnosis or coinfection should also be considered.

Symptomatic Treatment

Although there may be a potential role for symptomatic treatment in chronic Lyme disease, this approach has little support due to the strong possibility of persistent infection. Owing to the potential hazard of immunosuppression and the poor outcome in one study, steroid therapy is not recommended. Surgical synovectomy is associated with significant morbidity and does not address neurologic presentations; it should be reserved for knee pain failing antibiotic treatment. Intra-articular steroid injection may be useful as a temporizing procedure in patients with persistent knee pain but this runs the risk of masking persistent infection.

Symptomatic therapy (particularly anti-inflammatory medications, tricyclic antidepressants, selective serotonin re-uptake inhibitors, and hydroxychloroquine) may be useful in concert with antibiotics and in individuals failing antibiotics.

Hyperbaric oxygen therapy (HBOT) is under study but is not recommended for routine therapeutic use. Other treatments, including cholestyramine (CSM), antifungal therapy, and antiviral agents require further study.

Since patients are becoming more interested in alternative therapies (e.g., traditional Chinese medicine, anti-oxidants, hyperthermia, bee venom, naturopathy and homeopathy), physicians should be prepared to address questions regarding these topics.


The outcome of treating fibromyalgia secondary to Lyme disease with nonantibiotic regimens has been poor. The most encouraging clinical trial showed success in only one of 15 patients and only modest improvement in 6 of 15 individuals with fibromyalgia despite 2 years of treatment.

Antibiotic therapy has been much more effective than supportive therapy in symptomatic patients with fibromyalgia secondary to Lyme disease.

Fibromyalgia treatment alone without antibiotics raises the risk of conversion to refractory chronic Lyme disease and/or exacerbation of an undiagnosed persistent infection and is not recommended. Increasingly, clinicians do not feel comfortable treating fibromyalgia in Lyme disease without antibiotics.

Decision to Stop Antibiotics

Several studies of patients with Lyme disease have recommended that antibiotics be discontinued after 30 days of treatment. Complicating the decision to stop antibiotics is the fact that some patients present with disease recurrence after the resolution of their initial Lyme disease symptoms. This is consistent with incomplete antibiotic therapy. Although the optimal time to discontinue antibiotics is unknown, it appears to be dependent on the extent of symptomatology, the patient’s previous response to antibiotics, and the overall response to therapy (see below).

Rather than an arbitrary 30-day treatment course, the patient’s clinical response should guide duration of therapy. Patients must therefore be carefully evaluated for persistent infection before a decision is made to withhold therapy.

The decision to discontinue antibiotics should be made in consultation with the patient and should take into account such factors as the frequency and duration of persistent infection, frequency of recurrence, probability of refractory Lyme disease, gains with antibiotics, the importance to the patient of discontinuing antibiotics, and potential for careful follow-up.

The ideal approach would be to continue therapy for Lyme disease until the Lyme spirochete is eradicated. Unfortunately there is currently no test available to determine this point. Therefore, the clinician must rely on the factors outlined above to decide on the length of antibiotic therapy for chronic Lyme disease.

Alternative Antibiotics

There is compelling evidence that Lyme disease can result in serious and potentially refractory illness. Use of alternative antibiotics to treat early Lyme disease with erythema migrans is generally not indicated unless coinfection is suspected.

The ILADS Working Group believes that the risk of alternative antibiotics is acceptable in selected Lyme disease patients presenting with chronic Lyme disease. Alternative antibiotics include less commonly used oral antibiotics (cefixime, cefdinir, metronidazole) and intravenous antibiotics (imipenem, azithromycin). The role of alternative antibiotics in low-risk patients is less certain and there is less consensus among the guideline developers as to whether the potential benefits outweigh the risks.

Therapy for Coinfection

Therapy for polymicrobial infection in Lyme disease is a rapidly changing area of clinical practice. Uncomplicated Lyme disease may be managed without addressing coinfection by means of standard oral or parenteral antibiotic therapy. Some but not all experts recommend therapy for subclinical or chronic coinfection with Ehrlichia, Babesia, or Bartonella on the basis of their belief that responses are more prompt with this approach.

The dose, duration, and type of treatment for coinfections have not been defined. Published reports of coinfection are limited to a small number of patients treated in open-label, nonrandomized studies. Doxycycline has been indicated for Ehrlichia. A recently published randomized trial determined that treatment of severe Babesia microti with the combination of atovaquone and azithromycin was as effective as the use of standard oral therapy with clindamycin and quinine.

The decision to use alternative antibiotics should be based on the individual case, including a careful assessment of the patient’s risk factors and personal preferences. Patients managed in this way must be carefully selected and considered reliable for follow-up. Further controlled studies are needed to address the optimal antimicrobial agents for coinfections and the optimal duration of therapy.


Evidence-based guidelines for the management of Lyme disease. Expert Rev Antiinfect Ther 2004;2(1 Suppl):S1-13. [66 references]


GUIDELINE DEVELOPER(S): International Lyme and Associated Diseases Society — Disease Specific Society

SOURCE(S) OF FUNDING: International Lyme and Associated Diseases Society


COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE: Working Group Members: Daniel Cameron, MD, MPH, Internal Medicine and Epidemiology, Mt. Kisco, New York; Andrea Gaito, MD, Rheumatology, Basking Ridge, New Jersey; Nick Harris, PhD, Immunology, Pal Alto, California; Gregory Bach, DO, Family and Integrative Medicine, Colmar, Pennsylvania; Sabra Bellovin, MD, Family Practice, Portsmouth, Virginia; Kenneth Bock, MD, Family Practice, Rhineback, New York; Steven Bock, MD, Family Practice, Rhineback, New York; Joseph Burrascano, MD, Internal Medicine, East Hampton, New York; Constance Dickey, RN, Registered Nurse, Hampden, Maine; Richard Horowitz, MD, Internal Medicine, Hyde Park, New York; Steven Phillips, MD, Internal Medicine, Ridgefield, Connecticut; Laurence Meer-Scherrer, MD, Internal Medicine, Flamatt, Switzerland; Bernard Raxlen, MD; Psychiatry, Greenwich, Connecticut; Virginia Sherr, MD, Psychiatry, Holland, Pennsylvania; Harold Smith, MD, Emergency Medicine, Danville, Pennsylvania; Pat Smith, President, Lyme Disease Association, Inc., Jackson, New Jersey; Raphael Stricker, MD, Hematology and Immunotherapy, San Francisco, California


GUIDELINE STATUS: This is the current release of the guideline.