Lyme Disease: Current Therapies and Prevention

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Lyme Disease: Current Therapies and Prevention

[infect Med 18(8):388-395, 2001. © 2001 Cliggott Publishing Co.,

Division of SCP/Cliggott Communications, Inc.]

C. Eppes, MD, AI duPont Hospital for Children, Wilmington,

Del, and Jefferson Medical College, Philadelphia

Abstract and Introduction

Abstract

Sound management of Lyme disease (LD) rests with accurate

identification of disease manifestations coupled with evidence-based

approaches to therapy. Early disease usually responds very well to

appropriate antibiotics. Patients with neurologic disease and

arthritis may pose difficulties in management but ultimately have a

good prognosis in most cases. A tetracycline (usually doxycycline) is

the agent of choice for early LD not involving the CNS. Amoxicillin

is recommended for children younger than 8 years. For CNS

involvement, third-generation cephalosporins can be used. Lyme

arthritis usually responds to a 4-week course of oral antibiotics,

but following this with parenteral therapy may be considered if the

arthritis does not resolve. Methods of prevention include personal

protection methods, prophylactic antibiotics following a tick bite,

and the LD vaccine.

Introduction

Lyme disease (LD) is, by far, the most common vector-borne disease in

the United States. It is among the top 10 notifiable diseases in both

sexes and in all age groups.[1] Most states have reported cases of LD

(Figure), and it is a major public health problem in southern New

England, the mid-Atlantic states, and parts of the upper Midwest. The

actual number of cases may be much larger than reported.[2]

Figure. Distribution of cases of Lyme disease by county, 1982-1998.

LD is caused by spirochetes belonging to the genus Borrelia. Several

species can produce disease. In the United States, Borrelia

burgdorferi sensu stricto is responsible for virtually all cases,

while in Europe, LD is also caused by Borrelia garinii and Borrelia

afzelli. There are clinical differences in the disease

manifestations, particularly with respect to neurologic involvement,

between infections caused by these species. Furthermore, within

species, there is considerable genetic diversity, which has led to

concerns about diagnostic testing and vaccine development. Like other

spirochetes, these organisms can cause persistent infection with

symptoms that may persist or recur over a long period. A prominent

host inflammatory response accounts for many of the manifestations of

LD.

The reservoir of B burgdorferi in nature is the white-footed mouse.

The usual vector of LD is the deer tick, Ixodes scapularis, which

acquires the spirochete by feeding on the mouse. Human disease

results when there is prolonged (24 to 48 hours) attachment of the

tick to the skin, during which time bacteria may pass into the dermis.

Clinical Manifestations

Following inoculation of B burgdorferi into skin, the characteristic

skin lesion, erythema migrans (EM), appears in the majority of cases

(early localized LD). EM is an annular erythematous lesion that

typically enlarges over several days; it may resolve spontaneously or

as a result of antibiotic treatment, and many patients then exhibit

no further disease manifestations. If the spirochete gains access to

the systemic circulation, infection may occur in a variety of

tissues, resulting in joint, cardiac, ocular, and central and

peripheral nervous system involvement. Even without treatment, early

disseminated disease may resolve; however, it may also progress and

result in significant morbidity (and occasional- ly death, from third-

degree heart block). Persistent infection in the joints, eyes, or CNS

can result in late clinical manifestations. Table 1 lists the main

clinical manifestations according to the stage of disease.

Diagnosis

Tick exposure in an area where LD is endemic is generally considered

a prerequisite for the diagnosis of LD, although many patients do not

recall a tick bite. Clinical recognition of EM is sufficient for

diagnosis of early LD. When other compatible disease manifestations

are observed but EM is lacking, diagnosis may be facilitated by

laboratory tests. In most instances, the clinician will use serologic

testing, typically an enzyme-linked immunosorbent assay (ELISA) for

antibodies to B burgdorferi. The current recommendations call for the

use of Western immunoblotting (a more specific assay) to confirm any

positive or equivocal ELISA results; interpretive criteria for

Western blots are published and usually accompany reports of

laboratory results.[3] The reliability of the urine antigen detection

assay for LD is highly questionable.[4] A discussion of the use of

polymerase chain reaction technology for diagnosis of LD is beyond

the scope of this article.

Treatment: Antibiotics

A variety of antibiotics show good in vitro activity against B

burgdorferi. These include several third-generation cephalosporins

and the macrolides (minimum inhibitory concentrations [MICs] are

generally 0.1 µg/ mL or less and minimum bactericidal concentrations

[MBCs] are generally 0.5 µg/mL or less).[5-7] Tetracyclines,

particularly doxycycline, are very active (MIC90, 0.25 µg/mL) but

have somewhat higher MBCs.[5,7] The MIC for amoxicillin is also low

(0.03 µg/mL or less),[5] but bactericidal activity (MBC, 0.8 to 2

µg/mL) is reduced; the MBCs for penicillin are even higher.[7] The

MBC for cefuroxime axetil is 1 µg/mL.[7] Quinolones are less active

than other antibiotics in vitro.

Many studies of antibiotic therapy for LD have been performed over

the last 2 decades, in both the United States and Europe. Most of

these trials have involved adult patients and have focused on

specific clini- cal manifestations, such as EM and aseptic

meningitis. Most of the current published recommendations derive from

the available literature and from expert opinion. The most important

considerations in antibiotic selection for a given situation are the

clinical manifestations and organ system involvement. For example,

more aggressive therapy with parenteral antibiotics is recommended

for CNS involvement or third-degree heart block, while early

localized disease usually responds well to a course of oral therapy.

Recommendations for treatment of LD, based on the clinical situation,

are summarized in Table 2.

Oral Agents

For early disease not involving the CNS, a tetracycline is the agent

of choice. Advantages of tetracyclines include their good in vitro

activity against B burgdorferi and their long- established track

record in clinical trials and in practice. Doxycycline is often

considered the best drug in this class based on its excellent

bioavailability, ease of dosing (twice daily), and better

tolerability than other tetracyclines. Because it is lipophil- ic,

doxycycline also has reasonably good CNS penetration (up to 26% of

plasma levels[8]). Two studies from Europe involving patients with

early neuroborreliosis have shown the efficacy of doxycycline to be

comparable to that of parenteral penicillin G[9] or ceftriaxone[10];

similar studies have not been performed in the United States.

Doxycycline also compared favorably with parenteral ceftriaxone for

early disseminated LD, not involving the CNS.[11] A retrospective

study suggested that tetracycline, given for a mean of 4 months, was

successful in treating chronic infection.[12] Situations in which CNS

involvement is possible, such as in the patient with early

disseminated disease, are better served by doxycycline therapy than

by alternative oral antibiotics that do not attain adequate CNS

levels (if CNS infection is established, parenteral therapy is

recommended -- see below).

Another advantage of doxycycline is that it is considered the agent

of choice for treating human granulocytic ehrlichiosis, which is

transmitted by deer ticks and may occur simultaneously with early LD.

Disadvantages of the tetracyclines include the potential hazards to

the fetus and young child, photosensitivity reactions (significant,

since early LD is usually treated in the warmer months), and

esophageal burns. Although tetracyclines are usually avoided in the

young child, up to 2 weeks of doxycycline therapy can be given safely

without risking dental staining.

Of the oral b-lactam antibiotics, amoxicillin and cefuroxime axetil

have been the most extensively studied in LD clinical trials. The

combination of amoxicillin with probenecid demonstrated efficacy

comparable to that of doxycycline in a trial of adult patients with

early LD[13] and in adults with Lyme arthritis.[14] However, in the

latter study, subsequent neurologic involvement appeared more

frequently in patients who received amoxicillin. Based on its in

vitro activity and on limited published studies, amoxicillin is

considered the oral agent of choice for children younger than 8

years. One recent prospective study appears to support the efficacy

of amoxicillin in treating early LD in that population.[15]

Probenecid can be used to raise serum levels of amoxicillin, but

whether that is advantageous is unclear; in actual practice, this is

generally omitted.

Cefuroxime axetil has been compared with doxycycline in adults with

early LD and appears to have equal efficacy with fewer adverse

reactions.[16,17] A pediatric trial showed the efficacy and safety of

cefuroxime axetil to be comparable with those of amoxicillin.[15]

Cefuroxime axetil is more expensive than doxycycline or amoxicillin.

Oral third-generation cephalosporins have been less well studied.

Erythromycin is active in vitro but has not been found to perform

well in clinical practice.[18] It is generally considered a second-

or third-line agent. Clarithromycin has been evaluated in one

noncomparative pilot study, which found efficacy similar to that

reported for other agents in early LD.[19] Azithromycin would appear

to be an attractive agent, based on its ease of administration (once

daily), long half-life, and intracellular penetration (B burgdorferi

can survive intracellularly). In early LD, its efficacy has been

shown in some studies to be comparable to that of

amoxicillin/probenecid and doxycycline[20,21]; however, another trial

demonstrated amoxicillin to be more effective than azithromycin in

resolving acute manifestations and preventing additional symptoms.

[22] A potential drawback to the use of macrolides is their

relatively poor penetration into the CNS. None of the macrolides are

approved by the FDA for treating LD.

Parenteral Agents

The parenteral agents that have been evaluated most extensively are

pen-icillin G and the third-generation cephalosporins cefotaxime and

ceftriaxone. The latter agents have better in vitro activity against

B burgdorferi, attain higher serum concentrations, and have superior

penetration into the CNS. Studies comparing the efficacy of these

agents have generally favored the cephalosporins for early

disseminated and late LD. For patients with CNS involvement, they are

considered the agents of choice. The ease of once-daily dosing has

made ceftriaxone a suitable agent for outpatient intravenous therapy.

While it is relatively safe, the prolonged use of ceftriaxone in the

treatment of LD (including patients with unsubstantiated diagnoses)

has been reported to result in biliary complications.[23] The

literature generally does not support the use of ceftriaxone for

courses longer than 4 weeks.[24] If parenteral penicillin G is used,

it must be dosed every 4 hours, which is a disadvantage. Doxycycline

can also be used intravenously but offers relatively little advantage

over the highly bioavailable oral form of the drug.

Treatment: Other Issues and Controversies

Cranial Neuritis

Standard recommendations over the years have called for oral

antibiotic therapy for patients with isolated cranial neuritis.

Peripheral facial nerve palsy (PFNP) is, by far, the most common and

well studied of the LD-associated cranial neuropathies. In areas

where LD is endemic, LD is probably the most common identifiable

cause of PFNP (particularly if the palsy is bilateral).[25] Recent

studies have shown that many, if not most, cases of PFNP will be

associated with concomitant CNS inflammation. Among both adult[26]

and pediatric[27] patients with PFNP, cerebrospinal fluid (CSF)

abnormalities, including the presence of lymphocytic pleocytosis,

antibody to B burgdorferi, and borrelial DNA, are frequently observed.

From a treatment perspective, it is not absolutely clear whether all

such patients require parenteral antibiotic therapy. In fact, a

retrospective European study of patients who had had PFNP in the era

before LD was recognized and treated with antibiotics found no

pattern of neurologic or other sequelae attributable to LD, even

though a number of these patients probably had LD-associated PFNP.

[28] However, the potential exists for significant CNS sequelae in

some patients with PFNP, just as with Lyme meningitis. Experts are

divided on the issue of whether all cases of LD-associated PFNP

should have a CSF evaluation.[24] Clearly, however, the clinician

practicing in an area where LD is endemic should evaluate patients

with PFNP carefully, including LD serology, and perform lumbar

puncture if there are any symptoms or signs suggesting CNS

involvement. Oral doxycycline can be used to treat such patients,[9]

but if CSF abnormalities are discovered, parenteral ceftriaxone would

offer the best chance for eradication of CNS infection.

Lyme Arthritis: Oral Versus Parenteral Therapy

Early literature on LD suggested the need for parenteral antibiotics

for arthritis. Experience and the results of clinical trials[14] have

shown that about 90% of cases of Lyme arthritis respond to a 4-week

course of oral antibiotics. Some patients may continue to have joint

swelling and other symptoms at the completion of treatment, but most

of these resolve with time and can be treated symptomatically with

NSAIDs. Those whose symptoms do not resolve may be given a second

course of oral antibiotic or a course of intravenous antibiotic; few

published data guide the decision to use parenteral therapy in this

situation, so the approach must be individualized. However, if there

is evidence of concomitant CNS involvement, parenteral therapy with

ceftriaxone may offer a better cure rate.[29] A small minority of

patients have antibiotic treatment- resistant arthritis. Such

patients usually have the HLA-DR4 haplotype. (This genetic marker is

found in about 20% of the general population, and testing for it is

rarely needed in clinical practice.)

Duration of Therapy

An older study from Europe suggested that a 10-day course of oral

antibiotics for early LD could result not only in a poor clinical

response but also in the ability to cultivate B burgdorferi from

affected tissues in some such patients.[30] Treatment of Lyme

meningitis for only 10 days has been associated with a high rate of

residual symptoms.[31,32] On the other hand, many cases of LD

undoubtedly resolve spontaneously. There is little question that

antibiotic therapy can hasten clinical resolution and prevent the

occurrence of late complications, but no studies have clearly defined

the optimum duration of treatment. Further, surveys of physicians'

practices suggest that there is no consensus among practitioners.

[33,34] Most standard recommendations give a minimum duration of

treatment, for any disease manifestation, of 2 weeks. Uncomplicated

early disease is generally treated for 2 to 4 weeks with an oral

antibiotic. Because arthritis can be slow to resolve, a 4-week course

is usually recommended for Lyme arthritis. Lyme meningitis should be

treated with a minimum of 2 weeks of intravenous ceftriaxone;

treatment may be extended for 1 to 2 weeks depending on the response

of the patient.

Chronic neurologic disease is not only challenging to diagnose but

frequently is difficult to manage. Likewise, the appropriate

management of patients who have persistent symptoms (for example,

cognitive impairment, musculoskeletal pain) following treatment for

LD has been controversial. Difficulties in accurate diagnosis

of " chronic Lyme disease, " as it is often called, have been

associated with prolonged and often inappropriate therapy, sometimes

with significant adverse drug reactions.[23,24]

Overtreatment is undoubtedly common.[33] Some experts argue that more

than 2 months of treatment is seldom needed, while others question

whether chronic CNS disease actually exists as a separate diagnostic

entity.[24] Oral doxycycline, given for 1 to 11 months, was reported

to be efficacious in one uncontrolled study of patients with chronic

LD.[11] A recent placebo-controlled study involving adult patients

with persistent symptoms and a history of LD was unable to

demonstrate any benefit from a 30-day course of intravenous

ceftriaxone followed by a 60-day course of oral doxycycline.[35]

One truism is found throughout the literature, as well as in clinical

experience: timely and accurate diagnosis and appropriate treatment

have a clear influence on response to therapy, need for additional

antibiotics, and ultimate prognosis.

Treatment in Pregnant Women

Transmission of B burgdorferi from mother to fetus has been described

but appears to be extremely uncommon.[36] Pregnant women should be

treated in accordance with treatment recommendations for nonpregnant

adults, with the exception that tetracyclines should be avoided

because of their effect on fetal bones and teeth.

Adjunctive Therapy

In addition to antibiotic therapy for the infection, some patients

may benefit from supplementary therapies. NSAIDs are often used to

treat constitutional symptoms as well as arthritis. Topical eye care

is often required for patients who are unable to oppose their eyelids

because of facial palsy. Increased intracranial pressure associated

with acute CNS disease may respond to acetazol- amide. Synovectomy

may be necessary in a small minority of patients with arthritis

refractory to antibiotic therapy.[37]

Treatment Cost

Costs of antibiotics and costs of treatment failures must both be

factored into a cost-effectiveness analysis. Oral doxycycline given

for 3 weeks was compared with intravenous ceftriaxone administered at

home for 2 weeks in a model that evaluated multiple possible

scenarios.[38] Doxycycline proved to be considerably more cost-

effective. Another study evaluated several testing/treatment

strategies using doxycycline given orally for 30 days.[39] In this

study, for patients with only constitutional symptoms, the no test/no

treatment approach was the most cost-effective. When an EM rash was

present, empiric therapy without testing was the best strategy. For

patients with constitutional symptoms and a history of tick bite and

rash, the most cost-effective approach was serologic testing, with

treatment provided only for those with positive results. Prolonged

intravenous treatment of LD can be a very costly proposition, in

addition to posing hazards of adverse drug reactions. The costs of

prevention are discussed below.

Prevention

Tick Avoidance

Until recently, the emphasis on the prevention of LD has focused on

efforts to reduce the likelihood of tick attachment. Avoidance of

tick-infested areas is often recommended, but evidence suggests that

many people acquire infection in their home environment. Maintenance

of this environment, especially removal of leaf litter (larval deer

ticks attach to leaves), can reduce the risk of acquiring LD at home.

Personal protective measures are also widely recommended; these

include wearing light-colored clothing, wearing long sleeves and long

pants, tucking pants legs into socks, and application of DEET or

other tick repellents to skin or clothing. Unfortunately, none of

these measures has been demonstrated to reliably prevent LD in case-

control studies. Tick checks to identify and remove Ixodes ticks make

sense but may not be practiced routinely by at-risk individuals. If a

deer tick is found, it should be grasped with forceps or tweezers

close to the mouth parts and pulled directly outward. If the

attachment is less than 24 hours, infection usually does not follow.

Antibiotic Prophylaxis Following Tick Attachment

In a study of antibiotic prophylaxis in an area where LD is endemic

(Connecticut), it was reported that the risk of acquiring LD from a

given deer tick attachment was 1.2%.[40] In this study, no efficacy

of prophylaxis could be established. A meta-analysis of several

studies comparing antibiotic prophylaxis with placebo also concluded

that antibiotics were not significantly effective in preventing

clinical LD.[41] This paper and others note that in the groups that

received antibiotics, significant adverse effects from the

antibiotics occurred with a frequency similar to that of early LD in

the groups that did not receive antibiotic prophylaxis.

A recent study done in an area of New York where LD is hyperendemic

compared a single 200-mg oral dose of doxycycline with placebo in

subjects 12 years and older who had documented I scapularis

attachments.[42] EM developed in 0.4% of doxycycline recipients,

compared with 3.2% in the placebo group. No extracutaneous

manifestations of LD occurred in any subject, and there were no

asymptomatic seroconversions. Nausea and vomiting were common in

doxycycline recipients. The relevance of the efficacy demonstrated in

this study to areas with lower infection rates is unknown.

The cost-effectiveness of prophylaxis has been studied, with the

authors suggesting that antibiotics would be clearly justified only

if the risk of infection after a tick bite were 3.6% or more[43];

this level of risk may apply in a few communities. In the New York

study, a minimum of 40 deer tick attachments would have needed to be

treated to prevent 1 case of EM,[42] calling into question the cost-

effectiveness of prophylaxis. Most authorities have recommended that

for most instances of tick attachment, the patient should be advised

to be vigi-lant about rashes and constitutional symptoms and to seek

medical care if they occur, and that antibiotics should not be given

prophylactically.

However, prophylaxis would be reasonable in certain situations. If

the tick is engorged with blood, indicating more prolonged attachment

and higher risk of disease, prophylaxis would be more likely to be

beneficial.[44] Other circumstances in which prophylactic antibiotics

might be considered include multiple simultaneous tick attachments,

presence of neurologic conditions or arthritis, and when there is a

previous history of LD. If a course of antibiotic prophylaxis is

deemed necessary, it should be given promptly; single-dose

doxycycline would be reasonable for older children and adults, but

safety and efficacy of a regimen for younger children and pregnant

women has not been established.

Vaccination

Most efforts to develop an LD vaccine have focused on the outer

surface protein A (ospA) of B burgdorferi. This protein is expressed

by organisms residing in the tick vector but is largely replaced by

the expression of ospC after the spirochete enters the human host.

OspA vaccines are believed to work in this unique fashion: after

immunization, the human responds with production of IgG antibody,

which is ingested by the tick during its blood meal; antibody to ospA

is lethal to the spirochete within the tick, so viable organisms nev-

er reach the human. Recombinant ospA vaccines are produced in an

Escherichia coli vector, purified and, in the case of the currently

available vaccine, combined with an aluminum hydroxide adjuvant.

Two studies involving intramuscularly administered ospA vaccines,

which were simultaneously reported, demonstrated impressive efficacy

in preventing LD.[45,46] As a result of the pivotal trial of the ospA

vaccine manufactured by Kline Beecham (now GlaxoKline)

(Philadelphia), that product (LYMErix) was licensed in late 1998 for

use in adults aged 15 to 70 years. In that trial, 10,936 volunteers

aged 15 to 70 years were randomized to receive either placebo or 30-

µg doses of ospA at 0, 1, and 12 months.[45] After the first 2

immunizations, cases of clinical LD occurred in 43 placebo recipients

and in 22 vaccine recipients (vaccine ef- ficacy, 49%). After the

third dose, vaccine efficacy rose to 76%; the response was age-

dependent, with some diminution of efficacy in older persons. Also,

after the third dose, asymptomatic seroconversion (indicating

infection with B burgdorferi during the study period) occurred in 15

controls but in no vaccine recipients.

Antibody responses to ospA were also measured in a subset of

volunteers. The vaccine was shown to be immunogenic, with a

significant anamnestic response following the third dose. Further

analysis of these data demonstrated that cases of LD in vaccine

recipients occurred mainly in those whose geometric mean titer (GMT)

was below 400 ELISA units/mL and that a GMT of 1400 ELISA units/mL or

greater was associated with a high likelihood of protection in the

next LD season.[47]

No further field efficacy trials have been conducted with this

vaccine, but several studies have been done based on this immunologic

correlate of protection. The results of accelerated vaccination

schedules at 0, 1, and 6 months[48] and 0, 1, and 2 months[49]

demonstrate immunoge- nicity similar to that of the 0-, 1-, and 12-

month regimen, in terms of both the GMT and the proportion of

subjects attaining titers of 1400 ELISA units/mL or greater after the

third dose. It is probable that the accelerated schedules will

provide comparable protection, but as of this writing, only the

original dosing has FDA approval.

OspA antibody titers also have been measured longitudinally in

cohorts of subjects in an effort to define duration of immunity.

Declining titers over time have suggested the need for periodic

boosters, perhaps with the first booster immunization 2 years after

the primary series, but there is no firm recommendation (or FDA

approval) concerning booster doses.

The ospA vaccines have proved to be well tolerated. In all studies,

injection site pain has been the most common adverse reaction (24% in

the pivotal study). Hypersensitivity reactions are rare. No pattern

of significant adverse events, including arthritis, has been

associated with the vaccine in clinical trials, in postmarketing

experience involving over a million doses, or in analysis of cases

reported to the federal Vaccine Adverse Event Reporting System; this

information is available on the FDA Web site (www.FDA.gov). The lack

of association with arthritis is important, since ospA may play a

pathogenic role in treatment-resistant Lyme arthritis seen in natural

infection with B burgdorferi. There is no clinical or laboratory

evidence that ospA alone can induce significant arthritis.

The cost of vaccinating against LD has been addressed.[50] Results

depend on the assumptions made. In areas where LD is highly endemic,

vaccination would appear cost-effective, while in other areas, the

cost would be harder to justify.

The CDC's Advisory Council on Immunization Practices has recommended

that LD vaccine be considered for persons aged 15 to 70 years who

reside, work, or recreate in areas of high or moderate risk of

exposure to infected ticks.[51] Both geographic location and a

person's activities and behaviors relating to tick exposure are

important determinants of risk of infection. Pediatric studies have

been completed and show favorable safety and immunogenicity, but FDA

approval for use in children younger than 15 years is still pending.

In patients who have been vaccinated, the ospA antibody can cause the

ELISA result to be positive. The Western blot will also have a 31-

kilodalton band corresponding to ospA antibody, but theoretically no

other bands should appear in the absence of natural infection with B

burgdorferi. Hence, the Western blot is the critical serologic test

in immunized persons in whom LD is suspected. However, some Western

blot tests have given unusual patterns of reactivity related only to

vaccination.[52] This phenomenon requires further study and may incur

the need for alternative serologic methods.

Sidebar

Drugs Mentioned in This Article

Acetazolamide Generic

Amoxicillin Amoxil, generic

Azithromycin Zithromax

Cefotaxime Claforan, generic

Ceftriaxone Rocephin

Cefuroxime axetil Ceftin

Clarithromycin Biaxin

Doxycycline Vibramycin, generic

Erythromycin Ery-Tab, generic

Penicillin Generic

Probenecid Generic

Tetracycline Achromycin, generic

Table 1. Major clinical manifestations of Lyme disease

Disease stage Timing after tick bite Clinical manifestations

Early localized 3 - 30 d Erythema migrans (EM) -- single; variable

constitutional symptoms: myalgia, arthralgia, fever, headache,

fatigue; regional lymphadenopathy

Early disseminated 1 - 12 wk EM -- single or multiple; constitutional

symptoms; neck pain; meningitis; cranial neuritis (eg, facial palsy);

radiculoneuritis; carditis (variable heart block); eye involvement

Late disease <= 2 mo Arthritis; chronic CNS involvement

Table 2. Antibiotics useful for treating Lyme disease, based on

clinical situation*

Clinical manifestation Usual treatment[†] Alternative agents[†]

Early localized disease Doxycycline (PO)

Amoxicillin

Cefuroxime axetil Macrolides (erythromycin, clarithromycin,

azithromycin)

Early disseminated disease

No CNS involvement, no more than first-degree heart block Doxycycline

(PO)

Amoxicillin axetil

Cefuroxime Macrolides

With CNS involvement, symptomatic carditis, PR interval > 0.3 s, or

second- or third-degree heart block Ceftriaxone (IV) Penicillin G (IV)

Doxycycline (IV or PO)

Late disease

Arthritis Doxycycline (PO)

Amoxicillin Ceftriaxone (IV)[‡]

Penicillin G (IV)[‡]

CNS involvement Ceftriaxone (IV) Penicillin G (IV)

Doxycycline (IV or PO)

* See text for details and for duration of treatment. Agents of

choice are given in italics.

[†] Dosage:

Doxycycline: 100 mg bid (pediatric: 2 - 4 mg/kg/d divided bid)

Amoxicillin: 500 mg tid (pediatric: 50 mg/kg/d divided tid)

Cefuroxime axetil: 500 mg bid (pediatric: 20 - 30 mg/kg/d divided

bid)

Erythromycin: 250 mg qid (pediatric: no data)

Clarithromycin: 500 mg bid (pediatric: no data)

Azithromycin: 500 mg on day 1 and 250 mg qd (pediatric: no data)

Ceftriaxone: 2 g qd (pediatric: 100 mg/kg/d)

Penicillin G: 20 million units/d divided q4 - 6h (pediatric:

200,000 - 400,000 units/kg/d divided q4 - 6h)

[‡] For severe or refractory cases.

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Dr Eppes is associate director of infectious diseases at the AI

duPont Hospital for Children, Wilmington, Del, and clinical associate

professor of pediatrics at Jefferson Medical College, Philadelphia.