Treatment of Lyme disease

INTRODUCTION — Lyme disease is the most common tick-borne disease in the United States, Canada, and Europe. It is a spirochetal infection caused by seven or more species in the spirochete family Borreliaceae. The taxonomy of these spirochetes is undergoing revision, and the genus name may be represented as either Borrelia or Borreliella. In either case, the abbreviation for the genus is "B" and stands for both terminologies in the discussion below.

In North America, infection is caused primarily by B. burgdorferi sensu stricto (hereafter called B. burgdorferi) and, less commonly, in a region of the upper Midwest, by B. mayonii. In Europe and Asia, infection is caused primarily by either B. afzelii or B. garinii, less commonly by B. burgdorferi, and even less commonly by B. spielmanii, B. lusitaniae, B. valaisiana, or B. bavariensis.

Lyme disease primarily affects the skin, joints, nervous system, and heart. There is a broad spectrum of manifestations, and the severity of disease is due, in part, to differences in the infecting species.

This topic will review the treatment of Lyme disease in adults and children. The microbiology, epidemiology, clinical manifestations, and diagnosis of Lyme disease are discussed elsewhere:

●(See "Microbiology of Lyme disease".)

●(See "Epidemiology of Lyme disease".)

●(See "Immunopathogenesis of Lyme disease".)

●(See "Prevention of Lyme disease".)

●(See "Evaluation of a tick bite for possible Lyme disease".)

●(See "Clinical manifestations of Lyme disease in adults".)

●(See "Lyme disease: Clinical manifestations in children".)

●(See "Diagnosis of Lyme disease".)

The treatment of other tick-borne diseases is also presented in separate topic reviews. (See "Treatment of Rocky Mountain spotted fever" and "Human ehrlichiosis and anaplasmosis" and "Southern tick-associated rash illness (STARI)" and "Babesiosis: Clinical manifestations and diagnosis" and "Borrelia miyamotoi infection".)

PROPHYLAXIS AFTER A TICK BITE — Antibiotic prophylaxis following a tick bite by an Ixodes tick is indicated in some cases. This issue is discussed in detail elsewhere. (See "Evaluation of a tick bite for possible Lyme disease", section on 'Efficacy and rationale'.)

EARLY LOCALIZED DISEASE (SINGLE ERYTHEMA MIGRANS) — Lyme disease can involve the skin, joints, nervous system, and heart. The clinical manifestations can generally be divided into three phases: early localized, early disseminated, and late disease (table 1).

A skin lesion called erythema migrans (EM) is the primary manifestation of early (also called early localized) Lyme disease. Although some patients who present with early localized disease probably have some degree of dissemination [1], they can be successfully treated with a 10-day course of doxycycline or a 14-day course of amoxicillin or cefuroxime.

This section will discuss the treatment of patients who present with single EM. The approach to treatment in patients with multiple EM (those with early disseminated disease) is discussed below. (See 'Multiple erythema migrans lesions' below.)

Indications — All patients with EM should be treated for Lyme disease. The goal of therapy is to shorten the duration of the signs and symptoms of early disease and to prevent progression to later stages of Lyme disease [2,3]. (See 'Response to therapy' below and 'Clinical trials' below.)

In patients with EM, the decision to initiate treatment is generally made on clinical grounds alone when a characteristic lesion is present in a patient who lives in or has recently traveled to an endemic area. Serologies are often negative during this stage of the disease. (See "Clinical manifestations of Lyme disease in adults" and "Lyme disease: Clinical manifestations in children" and "Diagnosis of Lyme disease".)

Antimicrobial therapy

Preferred regimens — Doxycycline, amoxicillin, or cefuroxime should be used for treatment of patients with EM (table 2) [4]. The dose and duration for early localized disease are as follows:

●Doxycycline – 100 mg orally twice daily for adults; 4.4 mg/kg per day in two divided doses (maximum 100 mg per dose) for children. The duration of therapy is 10 days.

●Amoxicillin – 500 mg orally three times daily for adults; 50 mg/kg per day in three divided doses (maximum 500 mg per dose) for children. The duration of therapy is 14 days.

●Cefuroxime axetil – 500 mg orally twice daily for adults; 30 mg/kg per day in two divided doses (maximum 500 mg per dose) for children. The duration of therapy is 14 days.

For nonpregnant adults and older children with Lyme disease, we suggest doxycycline rather than one of the other oral agents because it is also effective against some of the coinfecting agents (eg, Anaplasma phagocytophilum, which causes human granulocytic anaplasmosis); in addition, of the oral agents, doxycycline also has the best penetration into the central nervous system. However, clinical trial data suggest that all of these agents have equivalent efficacy for the treatment of early Lyme disease in those without neurologic manifestations when treatment is initiated, and beta-lactams are generally preferred in pregnant persons. (See 'Clinical trials' below and 'Pregnancy' below.)

The approach to treatment of young children varies. We generally prefer to treat young children with cutaneous disease with amoxicillin as long as there is no concern for neurologic involvement. However, others may prefer doxycycline since the American Academy of Pediatrics supports the use of doxycycline for children <8 years of age if it is administered for ≤21 days [5]. Additional information on the management of young children is found below. (See 'Children <8 years old' below.)

Although most of the trials of therapy for EM used a treatment duration of 21 days [2,3,6-10], subsequent trials of doxycycline have shown that 10 to 14 days of therapy are as effective as more prolonged therapy in most patients [11-14]. For EM in the United States, the best data about the relationship between treatment duration and efficacy come from a randomized double-blind trial in which 180 patients with EM were assigned to one of three treatment groups: 10 days of doxycycline; one dose of intravenous ceftriaxone followed by 10 days of doxycycline; or 20 days of doxycycline [12]. Efficacy was assessed at 20 days and at 3, 12, and 30 months. There was no significant difference in outcomes among the groups at any of the follow-up time points. One of 61 patients who received 10 days of doxycycline developed Lyme meningitis at day 18 and was successfully treated with two weeks of IV ceftriaxone.

The duration of therapy for EM has also been evaluated in Europe, where most cases of EM are caused by B. afzelii, which does not usually disseminate (in contrast to B. burgdorferi infection in the United States). A trial evaluated the efficacy of 10 versus 15 days of oral doxycycline in 225 patients in Slovenia who had a single EM lesion [11]. Twelve months after enrollment, 85 of 91 patients (93 percent) who received 15 days of therapy had a complete response without sequelae, compared with 79 of 86 patients (91 percent) who received 10 days of therapy. At six months, the frequency of non-specific symptoms was similar in the two groups. Another trial in Slovenia compared 7 days of oral doxycycline with 14 days and found similar findings [15]. These results show that for patients in Europe with a solitary EM lesion, a 10-day regimen of oral doxycycline is as effective as longer regimens; although 7-day regimens were effective in one study, we continue to use 10-day regimens until larger studies from different locales are performed.

Alternative agents — Azithromycin is an alternative agent for patients with early localized disease. The dose is 500 mg once daily for adults, or 10 mg/kg once daily (maximum 500 mg per dose) for children; guidelines suggest a duration of 7 days (range 5 to 10 days) (table 2) [4]. Another alternative is clarithromycin; the dose is 500 mg twice daily for adults and 15 mg/kg per day divided twice daily (maximum 500 mg per dose) for children; the duration of treatment for clarithromycin is 14 to 21 days. Patients treated with a macrolide should be followed closely for evidence of an inadequate response, such as persistent objective findings of Lyme disease, relapse after apparent clinical response, or evolution into a later stage of Lyme disease [4].

In the United States, macrolides are generally felt to be less effective than amoxicillin (and presumably the other first-line drugs), based upon findings from a randomized trial, which demonstrated improved resolution of symptoms and reduced risk of relapse in patients treated with amoxicillin compared with those treated with azithromycin [8]. In addition, some strains of B. burgdorferi exhibit resistance to macrolides in vitro [16,17]. However, other studies, mostly from Europe, have shown equivalence between azithromycin and other antibiotics for the treatment of EM [18-21]. (See 'Clinical trials' below.)

If the diagnosis is uncertain — Antibiotics such as first-generation cephalosporins (eg, cephalexin), quinolones, and vancomycin should not be used because they are either not active against B. burgdorferi or not clinically proven to be effective for treatment [4,22,23]. Thus, when there is uncertainty about whether a rash is cellulitis or EM, antibiotics that are active against both should be used; the choice of agent depends upon local resistance patterns and the patient’s risk factors for a specific organism. As an example, amoxicillin-clavulanate or cefuroxime would provide coverage for Lyme disease as well as for either methicillin-susceptible Staphylococcus aureus (MSSA) or group A streptococci; doxycycline would provide similar coverage (though perhaps not as good for some group A streptococci) and would also be effective against methicillin-resistant S. aureus (MRSA). (See "Acute cellulitis and erysipelas in adults: Treatment".)

Response to therapy — Oral therapy for early Lyme disease is generally well tolerated. The majority of patients with early Lyme disease who receive appropriate antibiotic therapy have complete resolution of the signs and symptoms of infection within 20 days [8]. In one trial, EM and its associated symptoms resolved in a mean of five to six days [3]; however, patients who are more systemically ill at the beginning of treatment may take longer to recover [7]. Almost all patients who have a satisfactory response to antibiotic therapy do well over the long term. Among 201 patients in two randomized treatment trials who had a satisfactory outcome at one month and were evaluable at one year post-treatment, 190 (95 percent) continued to have a satisfactory outcome [2,7].

Although most patients respond to antibiotic therapy, those with persistent objective findings, particularly high fever, may be coinfected with other tick-borne infections transmitted by Ixodes ticks. Investigation for coinfection with these agents is warranted if the initial antimicrobial does not have activity against these pathogens. (See 'Possible coinfection' below.)

In addition, some patients may experience a Jarisch-Herxheimer reaction. (See 'Jarisch-Herxheimer reaction' below.)

On occasion, patients may have subjective symptoms, such as headache, musculoskeletal pain, arthralgia, or fatigue, that persist for weeks to months after appropriate treatment [2,3,6,8,24]. These subjective findings are not due to ongoing active Lyme disease and often resolve spontaneously (usually within six months) without further antibiotic therapy [6]. More prolonged subjective symptoms after appropriate antibiotic therapy have been called the post-treatment Lyme disease syndrome. (See "Clinical manifestations of Lyme disease in adults", section on 'Post-treatment Lyme disease syndrome and chronic Lyme disease' and 'Persistent symptoms after treatment' below.)

A more detailed discussion of patients with persistent symptoms after treatment is presented below. (See 'Persistent symptoms after treatment' below.)

Clinical trials — A number of randomized clinical trials have demonstrated the efficacy of antimicrobial therapy in patients with EM [2,3,6-10]. Different antibiotic regimens were used in these trials, and the criteria used to define treatment success and failure varied.

The following observations illustrate the range of findings:

●In a prospective trial, 72 adults with EM were randomly assigned to treatment with amoxicillin with probenecid (500 mg three times daily) or doxycycline (100 mg twice daily) each for 21 days [6]. The regimens were equally effective, and none of the patients experienced progression of disease.

●A randomized multicenter trial of 232 patients with EM compared treatment with cefuroxime axetil (500 mg twice daily) to doxycycline (100 mg three times daily) [7]. Each regimen was given for 20 days and was equally effective (clinical success in 90 versus 95 percent, respectively). Similar efficacy was noted in another randomized trial that compared these drugs [2]. The only major complication at one month post-treatment was Lyme arthritis in one patient who was treated with cefuroxime axetil; there were no other cases of Lyme arthritis at later follow-up.

●A randomized multicenter trial of 246 adult patients with EM found that amoxicillin (500 mg three times daily for 20 days) was superior to azithromycin (500 mg once daily for seven days) in producing complete resolution of signs and symptoms of infection at the end of therapy (88 versus 76 percent, respectively) [8].

●A randomized trial from Europe of 88 patients with EM showed that azithromycin (500 mg twice daily on day 1, followed by 500 mg daily for four days) and doxycycline (100 mg twice daily for 14 days) resulted in similar outcomes (96 versus 83 percent clinical success, respectively, which was a non-significant difference) [18]. EM in Europe is usually caused by B. afzelii, which does not usually disseminate. Therefore, doxycycline and azithromycin may give equivalent results in that setting.

EARLY DISSEMINATED DISEASE — This section will review the general approach to treatment in patients with early disseminated Lyme disease characterized by cutaneous, neurologic, and/or cardiac manifestations.

For most manifestations of early disseminated Lyme disease, oral therapy, preferably doxycycline, is sufficient. In an open-label controlled trial, 140 patients with acute disseminated Lyme disease without meningitis (95 percent of the patients had multiple EM) were randomly assigned to receive either oral doxycycline (100 mg twice daily for 21 days) or ceftriaxone (2 g once daily intravenously [IV] or intramuscularly for 14 days) [10]. Disseminated disease was considered present if the patient had at least one of the following findings: more than one erythema migrans (EM) lesion, carditis manifested by heart block, neurologic abnormalities (facial nerve palsy or radiculitis of less than three months' duration), or acute large-joint arthritis. The rate of clinical cure was the same in both groups (88 and 85 percent, respectively), while treatment failure occurred in one patient in each group. Persistent symptoms at the last follow-up, usually mild arthralgias, were less common with doxycycline (14 versus 27 percent), but this difference was not statistically significant.

Multiple erythema migrans lesions — Spirochetal dissemination often occurs during the first days or weeks of infection while the initial erythema migrans (EM) lesion is still present. This may result in multiple EM lesions. The approach to treatment in patients with multiple EM is the same as that for single EM [4] and is described above. (See 'Early localized disease (single erythema migrans)' above.)

Early clinical trials used 21 days of doxycycline for treatment of early disseminated disease [10]; however, guidelines support shorter courses in patients with multiple EM [4,5,25]. Although there are no clinical trials that have specifically evaluated the duration of treatment for patients with multiple EM, the shortened course is reasonable since many patients who present with early localized disease probably have some degree of dissemination [1], yet they are successfully treated with a 10-day course of doxycycline or a 14-day course of amoxicillin or cefuroxime. In addition, patients with other forms of early disseminated disease (eg, meningitis, carditis) do well with 14 days of antibiotics. (See 'Acute neurologic manifestations' below and 'Carditis' below.)

Acute neurologic manifestations — The most common manifestations of acute neurologic Lyme disease include meningitis, cranial neuropathy (particularly facial nerve palsy), and sensory or motor radiculoneuropathy, alone or in combination. (See "Nervous system Lyme disease".)

On rare occasion, a patient may present with parenchymal involvement (encephalitis or myelitis). This is typically considered a manifestation of late disease and is discussed below. (See 'Late neurologic findings' below.)

Treatment regimens — Treatment regimens for patients with acute neurologic manifestations are based on small case series from the United States [26], as well as randomized and prospective open-label trials, most of which were conducted in Europe [27-34]. For patients with acute neurologic disease, treatment typically consists of one of the following regimens for 14 to 21 days (table 2):

●Oral doxycycline (in adults, 100 mg orally twice daily; in children, 4.4 mg/kg per day in two divided doses, maximum 100 mg per dose)

●Ceftriaxone (in adults, 2 g IV once daily; in children, 50 to 75 mg/kg IV once daily, maximum dose 2 g) or

●Cefotaxime (in adults, 2 g IV every eight hours; in children, 150 to 200 mg/kg IV per day divided in three doses, maximum dose 6 g per day)

Approach for most patients

●Preferred regimen – For most patients with acute neurologic Lyme disease, we suggest oral doxycycline. IV therapy is reasonable for those with neurologic manifestations who require hospitalization, but such patients can usually be transitioned to oral doxycycline upon discharge. For pregnant women, the decision to use doxycycline or an alternative agent must be individualized. (See 'Pregnancy' below.)

Doxycycline has >98 percent oral bioavailability, making oral dosing equivalent to IV dosing. In addition, doxycycline has moderately good penetration into the cerebrospinal fluid (CSF) [35]. Several studies have supported the use of oral doxycycline for acute neurologic disease [27,28,32-34,36,37]. As an example, in a prospective, nonrandomized study of 29 patients in Sweden with Lyme facial nerve palsy and meningitis, treatment with oral doxycycline (200 to 400 mg daily) for 9 to 17 days was associated with clinical recovery in 26 patients (90 percent) within six months [28]. Post-treatment CSF examination showed a marked improvement in cell and protein levels compared with pretreatment levels in all patients. In addition, two small randomized, controlled trials of patients with meningitis found a 10- to 14-day course of oral doxycycline was associated with excellent outcomes that were equivalent to outcomes in patients treated with penicillin IV [27,36]. Although the strains prevalent in Europe and the United States are different, there are no data in vitro or in vivo that suggest differences in susceptibility to doxycycline [38,39].

●Patients who cannot take doxycycline – For most patients with acute neurologic disease who cannot take doxycycline, we prefer IV therapy rather than oral amoxicillin or cefuroxime, given the lack of data with these agents (table 2). In the United States, early studies supporting the efficacy of IV therapy include one study that found high-dose IV penicillin G was associated with more rapid resolution of neurologic symptoms (eg, headache, stiff neck, and radicular pain) in 12 patients compared with historical controls treated with prednisone alone [26]. Other studies have found that ceftriaxone and cefotaxime were as effective as penicillin G or doxycycline [31,32,37], and the two cephalosporins had equal efficacy [29].

The one exception is patients with isolated facial nerve palsy. For patients with isolated facial nerve palsy who cannot take doxycycline and are without evidence of other concurrent central nervous system (CNS) involvement (eg, meningitis), oral amoxicillin and cefuroxime are likely effective alternatives (table 2). Treatment of isolated facial nerve palsy is primarily recommended to prevent additional complications of disseminated Lyme disease since antibiotic therapy may not have a major impact on the outcome of the facial palsy itself. Most patients with Lyme facial palsy recover spontaneously; in one study, the median time to recovery was 26 days (range 1 to 270 days) [40], although the prognosis is worse for patients with bilateral facial palsy.

●Response to treatment – There are no diagnostic tests that can either determine clearance of infection or predict the success of therapy in patients with acute neurologic Lyme disease. Resolution of neurologic manifestations is sometimes delayed, and persistence of signs, such as facial palsy, is not necessarily indicative of treatment failure. It may take up to seven or eight weeks for full recovery of motor function.

Role of corticosteroids for facial palsy — For patients with known Lyme disease-associated facial palsy (eg, those with objective clinical or serologic evidence of Lyme disease), glucocorticoids are not indicated [4]. Data from retrospective studies have found no benefit when glucocorticoids were administered in this setting [40,41], and some reports suggest patients may have worse outcomes [42,43].

However, corticosteroids are recommended for the treatment of idiopathic facial nerve palsy and should not be delayed pending evaluation for those without clear evidence of Lyme disease. (See "Bell's palsy: Treatment and prognosis in adults".)

Carditis — Because of the potential for life-threatening complications of Lyme carditis, patients with serious disease should be hospitalized, monitored with cardiac telemetry, and treated with IV antibiotics (table 2) [4]. This includes those who are symptomatic (eg, syncope, dyspnea, or chest pain), have second- or third-degree atrioventricular (AV) block, have a markedly prolonged PR interval (≥300 milliseconds), or have other arrhythmias (eg, bundle branch blocks). As with other manifestations of Lyme disease, the goal of therapy is to shorten the duration of cardiac manifestations and to prevent later complications of Lyme disease [4]. (See "Lyme carditis".)

Antibiotics — No comparative trials have been performed to identify the optimal antibiotic regimen for Lyme carditis or to confirm that outcomes are improved with initial treatment with IV antibiotics compared with oral antibiotics. Supportive data come from case reports and small case series [44,45].

Symptomatic patients/patients at risk for high-degree AV block — For hospitalized patients, we initiate IV therapy; the drug of choice is typically ceftriaxone (2 g IV once daily in adults; 50 to 75 mg/kg IV, maximum 2 g, once daily in children), but reasonable alternatives include IV cefotaxime and penicillin G (table 2).

IV antibiotics should be continued until the patient begins to improve (eg, high-grade atrioventricular [AV] block has resolved and the PR interval has become less than 300 milliseconds). The patient may then be switched to oral therapy to complete a 14- to 21-day course [4,25]. Appropriate oral antibiotics include doxycycline, amoxicillin, and cefuroxime (table 2).

Although IV therapy is typically preferred, doxycycline (oral or IV) is reasonable for patients who have a history of a severe reaction to beta-lactam antibiotics.

Patients with asymptomatic low-grade first-degree heart block — Patients without cardiac symptoms but with early disseminated disease and first-degree AV block with a PR interval <300 milliseconds who are not admitted to the hospital can be treated initially with doxycycline, amoxicillin, or cefuroxime axetil for 14 to 21 days (table 2) [4]. We suggest doxycycline for nonpregnant patients rather than amoxicillin or cefuroxime since it also has better CNS penetration and is active against several potential coinfecting pathogens. (See 'Possible coinfection' below.)

Telemetry and pacemakers — Hospitalized patients require close monitoring with cardiac telemetry [4]. After the PR interval is <300 milliseconds, monitoring with telemetry is usually continued for an additional 24 to 48 hours.

Some patients with severe and/or symptomatic AV block may require a temporary pacemaker; the indications for pacing are the same as in other causes of heart block [46]. AV block caused by Lyme disease is usually short-lived, so a permanent pacemaker is generally not needed. (See "Temporary cardiac pacing", section on 'Indications' and "Lyme carditis", section on 'Atrioventricular conduction abnormalities'.)

LATE DISEASE — Arthritis and, in rare instances, subtle neurologic findings are the major manifestations of late Lyme disease in the United States. In Europe and Asia, late cutaneous manifestations are the major manifestations of late disease rather than arthritis. (See "Clinical manifestations of Lyme disease in adults", section on 'Late disease'.)

Arthritis — In the United States, untreated patients with Lyme disease often develop frank arthritis, which is usually manifested as marked swelling and pain in either one or a few large joints, especially the knee. Younger children may present with a septic arthritis-like presentation. Patients may have persistent fatigue between attacks. Lyme arthritis differs from the migratory musculoskeletal pains that occur in the first weeks to months of Lyme disease, which can present as pain in the joints, muscles, tendons, bursae, and bone, usually in one or a few locations at a time. (See "Musculoskeletal manifestations of Lyme disease" and "Lyme disease: Clinical manifestations in children", section on 'Arthritis'.)

All patients with Lyme arthritis should be treated to accelerate resolution of arthritis and to prevent arthritis recurrence and other damage [47]. Although studies of the natural history of Lyme arthritis have demonstrated eventual resolution in most patients, even in the absence of antibiotic therapy, patients with untreated Lyme arthritis can have recurrent, intermittent attacks or persistent knee swelling, which can last for several years [48].

Our approach to treatment is as follows:

●Initial therapy – Most patients with Lyme arthritis should receive initial therapy with an oral regimen for 28 days (table 2).

•For nonpregnant adults and children ≥8 years of age, we generally suggest doxycycline rather than other oral agents. Doxycycline is effective in treating arthritis [47] and has good central nervous system (CNS) penetration, which may theoretically reduce the development of neurologic sequelae, although late neurologic disease is very rare.

•Amoxicillin or cefuroxime can also be used [4]; we typically prefer amoxicillin rather than cefuroxime since there are no studies specifically evaluating cefuroxime for this indication. Beta-lactams are generally used for treatment of arthritis in children <8 years of age and pregnant women. (See 'Children <8 years old' below and 'Pregnancy' below.)

For patients who are hospitalized, intravenous (IV) ceftriaxone or IV cefuroxime can be used as part of an initial treatment regimen if there is uncertainty about whether an acute arthritis is due to B. burgdorferi or a bacterial pathogen. Patients can then be transitioned to oral therapy if the diagnosis of Lyme arthritis is confirmed (table 2). Detailed discussions of regimen selection for bacterial arthritis are presented elsewhere. (See "Septic arthritis in adults" and "Bacterial arthritis: Treatment and outcome in infants and children".)

IV ceftriaxone is also reasonable on the rare occasion a patient presents with late neurologic disease in addition to arthritis. (See 'Late neurologic findings' below.)

Treatment of Lyme arthritis is based upon case series and small randomized controlled trials. [31,49,50]. The use of oral therapy was supported by a randomized trial that addressed the comparative efficacy of 30 days of therapy with doxycycline (200 mg once daily) or amoxicillin (500 mg every six hours plus probenecid) in 38 patients with Lyme arthritis [47]. In this study, arthritis resolved in 90 percent of patients within one to three months after study entry. However, neurologic manifestations were later recognized in five patients, four of whom had received the amoxicillin regimen. In addition, there was a trend toward more adverse events (allergic reactions, gastrointestinal intolerance) in those who received amoxicillin.

Although a randomized trial of oral versus IV therapy has not been conducted in such patients, the efficacy of antimicrobial therapy for Lyme arthritis was initially demonstrated in a randomized trial in which 40 patients were assigned to 2.4 million units of intramuscular benzathine penicillin weekly for three weeks or placebo [49]. Seven of the penicillin-treated patients (35 percent) had complete resolution of arthritis soon after the injections and remained well at a mean follow-up of 33 months. In contrast, all 20 placebo-treated patients continued to have attacks of arthritis during the trial. Subsequent studies have found IV cefotaxime and ceftriaxone resulted in greater improvement in symptoms compared with IV penicillin G [31,50].

●Patients with persistent joint inflammation after oral antibiotic therapy – Some patients have persistent joint inflammation after initial treatment with an oral regimen. Our approach to management depends primarily upon the degree of improvement:

•Arthritis mostly resolved – If the arthritis has almost resolved after one month of therapy we typically observe without additional treatment. Most patients respond to a single course of oral therapy [47], although it may take several months to achieve a complete clinical response [30,51].

•Partial response to treatment – If the patient had a partial response to treatment (eg, 50 percent improvement), we typically try a second course of oral therapy. Some experts prefer to go to intravenous therapy at this point; however, we prefer oral therapy as there is evidence that some patients will respond to a second course of oral treatment [51]. If there is an incomplete response after the second course of oral treatment, then IV therapy should be administered.

•Minimal response to treatment – If there was no or minimal response to an initial course of oral antibiotics (eg, severe joint swelling with minimal reduction of the joint effusion), we suggest a two- to four-week course of IV antibiotics (eg, ceftriaxone) for most patients (table 2). Although oral therapy is the preferred initial treatment, patients who have minimal or no response to oral antibiotics typically have considerable improvement with IV therapy [51-53]. However, in patients who presented with mild arthritis, some providers would administer a second course of oral therapy before initiating IV treatment, even if there was a minimal response.

On occasion, some patients can have a persistent inflammatory, proliferative synovitis that may even worsen in the post-infectious period, despite treatment with oral and IV antibiotic therapy. In this setting, the use of disease-modifying antirheumatic drugs (eg, methotrexate) or arthroscopic synovectomy may be helpful [51-53]. (See "Diagnosis of Lyme disease", section on 'Post-infectious arthritis' and "Musculoskeletal manifestations of Lyme disease", section on 'Post-infectious Lyme arthritis'.)

Post-infectious arthritis occurs primarily in adults and teenagers and is quite unusual in young children. In addition, it appears to occur more often in patients who were infected with the highly inflammatory OspC type A (RST1) strain of B. burgdorferi [54]. These strains appear to be more common in New England than in other locations, which may account for differences in the frequency of this complication in different geographic regions.

●Adjunctive therapies – Adjunctive measures for treatment of Lyme arthritis, such as nonsteroidal anti-inflammatory drugs, may be beneficial. In addition, patients with Lyme arthritis should reduce high levels of activity and high impact on affected joints. After the resolution of joint inflammation, physical therapy is often beneficial in helping to increase tendon flexibility and increase quadriceps strength. If joint swelling causes a patient to limp, crutch walking is recommended, and lessening weight bearing on a swollen knee may help to prevent rupture of a Baker cyst. (See "Overview of joint protection".)

Joint aspiration may be required to treat intensely swollen joints, but inflamed joints often become just as swollen again within 24 hours. Intra-articular glucocorticoid injection is not generally recommended during the infection, as there is some evidence that this may delay the resolution of Lyme arthritis [31].

Late neurologic findings — The clinical manifestations of late neurologic Lyme disease include confluent mononeuropathy multiplex, a subtle sensory axonal peripheral neuropathy, encephalomyelitis, and possibly a subtle encephalopathy. With appropriate antibiotic therapy for early Lyme disease, late neurologic findings have almost disappeared; however, these manifestations of late Lyme disease are rare even in untreated patients. (See "Nervous system Lyme disease", section on 'Clinical manifestations'.)

●Preferred treatment – For patients with late neurologic disease, we suggest IV therapy with ceftriaxone for 28 days (table 2) [4,55], although guidelines give a range of 14 to 28 days duration [4]. It can be difficult to determine the efficacy of antibiotic therapy during treatment, as improvement may not begin until several months after treatment [56].

Treatment recommendations for patients with late neurologic manifestations of Lyme disease acquired in the United States are based upon limited data from small studies. The following observations illustrate the range of findings:

•In a randomized trial, 23 patients with late Lyme disease with arthritis or neurologic findings were randomly assigned to IV penicillin G (20 million units per day for 10 days) or ceftriaxone (4 g per day for 14 days) [31]. Among the 13 patients who received ceftriaxone, only one did not respond (ongoing fatigue and memory problems); in contrast, 5 of the 10 patients who received penicillin G failed therapy. In a subsequent phase of the study that compared 2 g to 4 g of ceftriaxone for 14 days, the outcomes were similar in both groups, as 13 percent of patients had persistent symptoms.

•An uncontrolled study evaluated 27 patients with Lyme encephalopathy and/or polyneuropathy [57]. The administration of ceftriaxone (2 g/day for two weeks) led to improvement in 17 (63 percent), improvement followed by relapse in 6 (22 percent), and no response in 4 (15 percent). The cerebrospinal fluid (CSF) findings generally improved after antibiotic therapy regardless of the clinical response, whereas objective neurologic tests improved primarily in patients with symptomatic improvement.

The same researchers subsequently performed another uncontrolled study in which 18 consecutive patients with Lyme encephalopathy were treated with IV ceftriaxone (2 g once daily for 30 days) [56]. The mean duration of encephalopathy was 24 months and the mean interval between erythema migrans (EM) and the development of encephalopathy was 72 months. At six months following treatment, 14 of the 15 patients (93 percent) had improvement in symptoms. In addition, verbal memory scores were significantly higher and CSF protein levels were significantly lower in the 10 patients who had follow-up analysis.

•Ceftriaxone therapy given for two to four weeks may also be effective in children with late neurologic Lyme disease. This was illustrated in an observational study of five such children; gradual improvement in symptoms occurred in all four of the children in whom follow-up information was available [58].

●Alternative regimens – In some cases (eg, patients with severe allergy to beta-lactams) treatment with oral doxycycline is reasonable. In one European study there was no difference in outcomes between patients treated with oral versus IV therapy for any neurologic manifestation [33].

CUTANEOUS MANIFESTATIONS OF EURASIAN LYME DISEASE — Borrelial lymphocytoma (BL) and acrodermatitis chronica atrophicans are cutaneous manifestations of Lyme disease seen in Europe and parts of Asia. BL is a subacute manifestation found primarily on the earlobe or nipple of the breast [59]. Acrodermatitis chronica atrophicans is a late manifestation of Lyme disease and may appear years following primary infection. These conditions are not usually seen in patients who develop infection in the United States. (See "Clinical manifestations of Lyme disease in adults", section on 'Borrelial lymphocytoma' and "Clinical manifestations of Lyme disease in adults", section on 'Acrodermatitis chronica atrophicans'.)

Both conditions can be treated with oral therapy (doxycycline, amoxicillin, cefuroxime) (table 2).

●For patients with BL, the duration of therapy is 14 days. The lymphocytoma reportedly lasts from two weeks to two months following initiation of therapy.

●Patients with acrodermatitis chronica atrophicans are typically treated for 21 to 28 days [4]. In observational studies, oral or parenteral antibiotics appeared to result in improvement in pain and swelling, diminution of fibrous nodules, and gradual fading of the lesion over two to six months [4,60,61]. Areas of atrophy usually persist, and the progression of associated neuropathy is probably halted.

ADDITIONAL CONSIDERATIONS

Children <8 years old — All of the preferred agents for treatment of Lyme disease can be used in children <8 years of age. Our approach to regimen selection depends upon the clinical manifestation.

●Acute neurologic disease – We suggest doxycycline instead of a beta-lactam for those with evidence of acute neurologic disease given the efficacy of doxycycline for this indication and the risks associated with intravenous (IV) therapy (table 2). (See 'Approach for most patients' above.)

Doxycycline had previously been contraindicated in young children because of the risk of dental staining; however, the American Academy of Pediatrics now supports the use of doxycycline in young children if it is administered for ≤21 days since the risk is low when short courses are used [5].

●Other manifestations of Lyme disease – For other manifestations of Lyme disease (eg, erythema migrans [EM], carditis, arthritis) we prefer a beta-lactam (table 2). For those without neurologic disease, there is no clear evidence that treatment outcomes are better in those who receive oral therapy with doxycycline rather than a beta-lactam [62], and although studies support the safety of doxycycline in young children [63,64], they are based on small numbers of patients.

For those with early disease who cannot take a beta-lactam, we prefer doxycycline rather than an alternative agent (eg, azithromycin for EM). In addition, doxycycline should be used for those with early disease who have coinfection with A. phagocytophilum. (See 'Possible coinfection' below.)

Young children with arthritis who cannot take a beta-lactam should be managed in consultation with an expert in infectious diseases since studies have not evaluated the safety of doxycycline when the duration of treatment is >21 days (which is required for treatment of Lyme arthritis). (See 'Arthritis' above.)

Pregnancy — Women who develop Lyme disease during pregnancy should be treated according to their disease manifestations (table 2). In general, doxycycline is avoided during pregnancy when an equally effective beta-lactam (eg, amoxicillin, cefuroxime) can be used.

The decision to use doxycycline during pregnancy when either a beta-lactam is contraindicated (eg, because of allergy) or the alternative is an IV regimen must be decided on a case-by-case basis. Although most tetracyclines are contraindicated in pregnancy because of the risk of hepatotoxicity in the mother and adverse effects on fetal bone and teeth [65-67], these events are extremely rare with short courses of doxycycline. Observational studies support the relative safety of doxycycline compared with older tetracyclines both in pregnancy and in young children [63,64,68,69]. As an example, in a systematic review, there was no correlation between the use of doxycycline during pregnancy and teratogenic effects or dental staining in children [62,68]. However, data are limited and insufficient to conclude that there is no risk. Additional discussions of the use of doxycycline during pregnancy are presented elsewhere. (See "Tetracyclines", section on 'Pregnant or breastfeeding women' and "Prenatal care: Patient education, health promotion, and safety of commonly used drugs", section on 'Antibiotics'.)

There is no evidence that Lyme disease during pregnancy causes harm to the developing fetus. These issues are discussed in detail separately. (See "Clinical manifestations of Lyme disease in adults", section on 'Pregnancy and breast feeding'.)

Jarisch-Herxheimer reaction — Up to 15 percent of patients with early Lyme disease, particularly those with multiple EM lesions, experience a transient worsening of symptoms during the first 24 hours of therapy, consistent with a Jarisch-Herxheimer reaction, which is due to the host immune response to antigens released by dying organisms [3,7,70]. Antimicrobial treatment should be continued. Nonsteroidal anti-inflammatory agents may provide symptomatic relief until the symptoms of the Jarisch-Herxheimer reaction remit, usually within 24 to 48 hours.

Possible coinfection — Patients with Lyme disease in endemic areas may be coinfected with the other infectious agents transmitted by Ixodes ticks. These include A. phagocytophilum, which causes human granulocytic anaplasmosis (HGA, previously called human granulocytic ehrlichiosis), Powassan virus, Babesia microti, and Borrelia miyamotoi in the United States. B. miyamotoi is also seen in Europe, as is tick-borne encephalitis (TBE) virus. (See "Clinical manifestations of Lyme disease in adults", section on 'Coinfection with other tick-borne pathogens'.)

All of the preferred oral agents used to treat Lyme disease can be used to treat B. miyamotoi. By contrast, only doxycycline is effective against A. phagocytophilum. None of the antibiotics used for Lyme disease are effective alone for the treatment of B. microti, and no agents are effective for treatment of Powassan virus or TBE virus. (See "Borrelia miyamotoi infection" and "Human ehrlichiosis and anaplasmosis" and "Babesiosis: Clinical manifestations and diagnosis" and "Arthropod-borne encephalitides", section on 'Tick-borne encephalitis virus'.)

Reinfection — Reinfection is almost always identified by the development of a new EM rash in a patient with a history of previous EM that was successfully treated with antibiotics [71,72]. (See "Clinical manifestations of Lyme disease in adults", section on 'Reinfection'.)

If a diagnosis of reinfection has been established, patients should be treated with the same antibiotic regimen as would be recommended for a primary infection. The specific regimen depends upon the clinical presentation (table 2).

Reports of reinfection in patients who had early disseminated disease or whose infection was present for six to eight weeks prior to treatment are uncommon. Reinfection has not been reported after Lyme arthritis, which is usually associated with high antibody titers that may be protective.

Additional information on the diagnosis of reinfection is discussed separately. (See "Diagnosis of Lyme disease", section on 'Reinfection'.)

Asymptomatic seropositive individuals — Testing for Lyme disease is not warranted in asymptomatic patients. (See "Diagnosis of Lyme disease", section on 'When Lyme testing is not warranted'.)

However, if testing is performed, and the immune globulin (Ig) G serologic tests are positive, the question then arises as to whether treatment is warranted. Approximately 10 percent of individuals infected with B. burgdorferi have asymptomatic IgG seroconversion by enzyme-linked immunosorbent assay (ELISA) and Western blot [73].

Assuming that a positive ELISA has been corroborated by confirmatory testing (ie, the ELISA is a true positive), a clinical evaluation should be performed to rule out subtle manifestations of Lyme disease.

●For patients with clinical features compatible with Lyme disease, we treat with the regimen most appropriate for those findings (table 2).

●If no symptoms or only constitutional symptoms are uncovered, the decision to treat must be determined on a case-by-case basis since the potential benefit of treatment in such patients has not been established. As an example, for asymptomatic patients who do not have a high risk of exposure (eg, those from an area with no Lyme disease), a positive result is more likely to be a false positive, and the risk of treatment is usually not warranted. By contrast, for asymptomatic patients with a history of high-risk exposures, some experts would administer a single 14- to 28-day course of oral doxycycline or amoxicillin to prevent the potential development of late sequelae of Lyme disease. Even in these patients, there is no consensus on this approach, and some experts would not treat any asymptomatic patient based on positive serologic testing alone.

Persistent symptoms after treatment

Evaluation — In cases of apparent refractory symptoms, such as headache and fatigue, after a course of appropriate therapy, re-evaluation, rather than immediate or reflexive retreatment, is the proper next step [74]. Reasons for persistent symptoms include:

●Slow response to therapy – Most patients with early disease have complete resolution of the signs and symptoms of infection within 20 days [3,8]. In contrast, the response to therapy is often slower in patients with later stage disease, and some patients with arthritis may require a second course of treatment. (See 'Response to therapy' above and 'Arthritis' above.)

In a trial of patients with early Lyme disease, mild subjective symptoms were noted after treatment in almost one-half of patients and correlated significantly with the severity of the initial illness [3]. Extending antibiotic therapy from 10 to 20 days had no effect on the frequency of these symptoms [3], which typically resolve within six months [6].

●Treatment failure – Microbiologic treatment failure does occur, but it is extremely rare. No strains of B. burgdorferi that are resistant to the primary antibiotics recommended for therapy have been described [17,75]. Poor absorption or noncompliance with treatment is a more likely explanation for treatment failure than intrinsic resistance of the organism. When the term "treatment failure" is used, it usually refers to symptoms that have persisted or recurred.

●Alternative diagnosis – In patients with persistent symptoms after treatment of Lyme disease, it is possible the initial diagnosis of Lyme disease was incorrect [74,76-82]. The frequency with which this might occur was illustrated in a review of 209 patients with a presumptive diagnosis of Lyme disease: only 44 (21 percent) met criteria for active Lyme disease, 40 (19 percent) had prior but not active Lyme disease, and 125 (60 percent) had no evidence of either current or prior Lyme disease [77].

●Coinfection with another pathogen – Patients with early Lyme disease may be coinfected with another agent transmitted by Ixodes ticks, such as Babesia spp or A. phagocytophilum, which cause babesiosis and HGA, respectively. (See 'Possible coinfection' above.)

However, coinfection would not be an explanation for lack of response in patients with late Lyme disease, such as Lyme arthritis.

●Sequelae of Lyme disease – Some patients may develop sequelae of Lyme disease. As an example, some patients may develop post-treatment Lyme disease syndrome. Such patients have subjective symptoms, such as headache, musculoskeletal pain, arthralgia, lethargy, cognitive complaints, and/or fatigue, that persist for months after appropriate treatment (table 3) [2,3,6,8,24,83]. (See "Clinical manifestations of Lyme disease in adults", section on 'Post-treatment Lyme disease syndrome and chronic Lyme disease'.)

Another syndrome is a persistent, inflammatory, proliferative synovitis that may persist for months or several years after antibiotic therapy. This complication results from an excessive, dysregulated immune response during the infection which persists in the post-infectious period [84]. This response is characterized by exceptionally high interferon gamma levels with inadequate levels of the anti-inflammatory cytokine IL-10. The consequences of this excessive pro-inflammatory response include vascular damage, autoimmune and cytotoxic processes, and fibroblast proliferation and fibrosis in synovial tissue. This lesion is similar with that seen in other forms of chronic inflammatory arthritis, including rheumatoid arthritis. Patients who fail to respond to a course of oral and IV therapy may benefit from disease-modifying antirheumatic drugs. (See "Musculoskeletal manifestations of Lyme disease", section on 'Post-infectious Lyme arthritis'.)

In patients with previous neurologic involvement, mild but permanent tissue damage may also occur. As an example, in one study of 84 children with confirmed Lyme neuroborreliosis, persistent facial nerve palsy and motor or sensory deficits were seen in 13 and 14 percent, respectively; however, these symptoms were mild and did not affect activities of daily living [85]. (See "Nervous system Lyme disease".)

Role of additional antibiotics — Further antibiotic therapy for Lyme disease should not be given unless there are objective findings of active disease. This is most often seen in patients with Lyme arthritis. (See 'Arthritis' above and "Musculoskeletal manifestations of Lyme disease", section on 'Management of Lyme arthritis'.)

For patients with post-treatment Lyme disease syndrome, their nonspecific symptoms are difficult to treat. However, randomized controlled trials of repeat antimicrobial therapy in such patients have not shown a sustained benefit of prolonged antimicrobial therapy [86-91].

The largest trial evaluated 280 patients in Europe with persistent symptoms attributed to Lyme disease (eg, musculoskeletal pain, neuropsychological disorders, cognitive disorders) [91]. All patients received two weeks of IV ceftriaxone and were then randomized to receive 12 weeks of doxycycline, clarithromycin plus hydroxychloroquine, or placebo. Prior to entering the study, patients received a median of 40 days of antibiotic therapy. All groups described improved quality of life at the end of treatment (as assessed by the RAND-26 Health Status Inventory); however, there was no additional benefit among those who received prolonged antimicrobial therapy. In addition, approximately 50 percent of patients experienced adverse events and most were drug-related. Although the majority of drug reactions were not severe, four serious allergic reactions occurred among patients who received ceftriaxone.

These findings support those described in two parallel multicenter controlled trials that were performed in a total of 129 patients with clinical evidence of Lyme disease and persistent subjective symptoms [86]. The symptoms began within six months of the original treatment for acute Lyme disease and lasted for at least 6 months but less than 12 years by the time of study entry. One trial was conducted in 78 seropositive patients and one in 51 seronegative patients who had clinician-observed EM lesions. Treatment with IV ceftriaxone (2 g once daily for 30 days) followed by oral doxycycline (100 mg orally twice daily for 60 days) was compared with treatment with placebo (also identically administered IV then orally). The two trials were terminated early after an interim analysis in the first 107 patients showed similar outcomes in the two groups. As an example, improvement in physical and mental component scales was seen in 37 percent of seropositive patients receiving antibiotics and 40 percent receiving placebo, no change in 29 and 26 percent, and worsening in 34 percent in both groups.

Another trial included 55 patients with Lyme disease and severe fatigue for at least six months after appropriate antibiotic therapy; the patients were randomly assigned to 28 days of therapy with IV ceftriaxone (2 g once daily) or placebo [88]. Treated patients had a modest improvement in fatigue compared with those given placebo, but there was no difference in cognitive function or a laboratory measure of persistent infection. The authors concluded that IV therapy was not indicated for post-Lyme disease fatigue symptoms.

This was also illustrated in a trial in which 37 patients with post-treatment neurocognitive findings and 20 controls were randomly assigned to 10 weeks of IV ceftriaxone or placebo [89]. Short-term cognitive improvement was noted at week 12, but was not sustained at week 24 in patients who received ceftriaxone. In addition, 26 percent of those who received ceftriaxone experienced serious adverse effects, most commonly related to the peripherally inserted central IV catheter.

Other reports of serious adverse effects in patients receiving prolonged courses of antibiotics for presumed Lyme disease have included anaphylaxis [88], severe or fatal catheter-associated bloodstream infections [88,92,93], and severe or fatal Clostridioides difficile colitis [93,94].

Role of alternative therapies — Certain nonpharmacologic interventions (eg, cognitive behavioral therapy, tai chi, yoga, acupuncture) may have a role in the management of symptoms associated with post-treatment Lyme disease syndrome [95]; however, clinicians must evaluate the potential risks and benefits of these treatments. One study reported on the use of alternative therapies that were offered to patients who felt they had ongoing infection with B. burgdorferi (eg, oxygen and reactive oxygen therapy; energy- and radiation-based therapies; nutritional therapy; chelation and heavy metal therapy; and biologic and pharmacologic therapies); these therapies did not show benefit and, in some settings, were harmful [96].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Tick-borne infections (Lyme disease, ehrlichiosis, anaplasmosis, babesiosis, and Rocky Mountain spotted fever)".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Lyme disease (The Basics)")

●Beyond the Basics topics (see "Patient education: Lyme disease treatment (Beyond the Basics)" and "Patient education: Lyme disease symptoms and diagnosis (Beyond the Basics)" and "Patient education: Lyme disease prevention (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Stages of disease – Lyme disease can involve the skin, joints, nervous system, and heart. The clinical manifestations can generally be divided into three phases: early localized, early disseminated, and late disease (table 1). Treatment depends upon the stage of disease and the specific manifestation. (See 'Introduction' above.)

●Early localized disease – For patients who present with a single erythema migrans (EM) lesion (the primary manifestation of early localized Lyme disease), treatment with oral therapy is appropriate to reduce the duration of symptoms and prevent progression to later stages of Lyme disease. Intravenous (IV) therapy is not required for treatment of EM. (See 'Early localized disease (single erythema migrans)' above.)

•For most patients, we suggest doxycycline for 10 days rather than other oral antibiotic regimens (table 2) (Grade 2C). Doxycycline is also effective against some of the potentially coinfecting pathogens, such as A. phagocytophilum. (See 'Preferred regimens' above.)

•Other suitable oral regimens are amoxicillin or cefuroxime for 14 days (table 2). Macrolides (eg, azithromycin) are an alternative for patients with early Lyme disease who cannot take doxycycline, amoxicillin, or cefuroxime. (See 'Preferred regimens' above and 'Alternative agents' above.)

●Early disseminated disease – Early disseminated Lyme disease is characterized by multiple EM lesions, and/or neurologic or cardiac manifestations.

•For most patients with multiple EM, we suggest doxycycline for 10 days rather than a longer duration of treatment or other antibiotic regimens (table 2) (Grade 2C). Either amoxicillin or cefuroxime for 14 days are good alternatives. This approach parallels treatment of early localized disease. (See 'Multiple erythema migrans lesions' above.)

•For patients with acute neurologic Lyme disease manifesting with meningitis, cranial neuropathy (particularly facial nerve palsy), and/or sensory or motor radiculoneuropathy, we suggest oral doxycycline rather than IV therapy (table 2) (Grade 2C). The duration of treatment is 14 to 21 days. When doxycycline should be avoided, we typically use IV ceftriaxone except for isolated facial nerve palsy, which can be treated with oral amoxicillin or cefuroxime. (See 'Acute neurologic manifestations' above.)

•Patients with Lyme carditis who are symptomatic, are at risk for symptoms (eg, a prolonged PR interval of ≥300 milliseconds), or who have evidence of other arrhythmias should be hospitalized and monitored with cardiac telemetry. For such patients, we suggest IV antibiotics (eg, ceftriaxone) rather than oral therapy (table 2) (Grade 2C). IV antibiotics should be continued until the patient begins to improve; the patient may then be switched to oral therapy to complete a 14- to 21-day course. For asymptomatic patients with mild carditis, such as those with atrioventricular (AV) block with a PR interval <300 milliseconds, oral therapy (eg, doxycycline) can be used for the entire course of treatment. (See 'Carditis' above.)

•Patients with severe and/or symptomatic AV block may require a temporary pacemaker in addition to antimicrobial therapy. However, AV block caused by Lyme disease is usually short-lived, so a permanent pacemaker is generally not needed. (See 'Telemetry and pacemakers' above.)

●Arthritis – Arthritis is the major manifestation of late Lyme disease in the United States.

•All patients with Lyme arthritis should be treated to accelerate resolution of arthritis and to prevent recurrence and other damage. For most patients, we suggest initial therapy with oral doxycycline rather than other oral agents (Grade 2C). Antibiotics should be administered for 28 days. Patients typically respond to therapy within one to three months.

•For patients with moderate to severe joint inflammation who had minimal improvement with the initial course, we suggest a second course of treatment with IV therapy (Grade 2C). The duration of treatment is 14 to 28 days. A second course of treatment should also be administered to those with a partial response after initial oral therapy; however, in such patients, oral therapy is usually sufficient. (See 'Arthritis' above.)

•For patients who have persistent, inflammatory, proliferative synovitis despite treatment with oral and IV antibiotic therapy, the use of disease-modifying antirheumatic drugs (eg, methotrexate) or arthroscopic synovectomy may be helpful. This is discussed in a separate topic review. (See "Musculoskeletal manifestations of Lyme disease", section on 'Post-infectious Lyme arthritis'.)

●Cutaneous manifestations of Eurasian Lyme disease – In Europe and parts of Asia, borrelial lymphocytoma is a subacute manifestation of Lyme disease that typically occurs months after infection. Acrodermatitis chronica atrophicans is a manifestation of late Lyme disease and may appear years following primary infection. Both conditions can be treated with oral therapy (doxycycline, amoxicillin, cefuroxime). (See 'Cutaneous manifestations of Eurasian Lyme disease' above.)

●Children – The approach to treatment for children is generally the same as that for adults; however, for children <8 years of age, we prefer a beta-lactam, rather than doxycycline, in certain settings. As examples:

•For children with acute neurologic disease, we suggest doxycycline rather than a beta-lactam (Grade 2C). Doxycycline should also be used for those with early disease who have evidence of coinfection with A. phagocytophilum. Doxycycline had previously been contraindicated in children <8 years of age, but the risk of adverse events (eg, dental staining) is felt to be low if it is administered for ≤21 days.

•For children <8 years of age with other manifestations of Lyme disease (eg, EM, carditis, arthritis), we prefer a beta-lactam (eg, amoxicillin). Although studies support the safety of doxycycline in young children, they are based on small numbers of patients.

●Pregnant and lactating patients – For pregnant and lactating patients, tetracyclines are generally avoided in favor of a beta-lactam antibiotic (eg, amoxicillin, cefuroxime). However, in the setting of acute neurologic disease or contraindications to a beta-lactam, the decision to use doxycycline must be decided on a case-by-case basis. Although most tetracyclines are contraindicated in pregnancy because of the risk of hepatotoxicity in the mother and potential adverse effects on fetal bone and teeth, limited data suggest these events are extremely rare with doxycycline when short courses are used.

●Persistent symptoms after treatment – In cases of apparent refractory symptoms after a course of appropriate therapy, re-evaluation, rather than immediate or reflexive retreatment, is the proper next step. For patients without objective findings of active Lyme disease (eg, arthritis), we suggest against further antibiotic therapy for Lyme disease (Grade 2B). Randomized trials of treatment in these patient groups have not demonstrated a benefit. (See 'Persistent symptoms after treatment' above.)