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Practice Guidelines for the Treatment of Lyme Disease

GUIDELINESFROMTHEINFECTIOUSDISEASESSOCIETYOFAMERICA

Gary P. Wormser,1 Robert B. Nadelman,1 Raymond J. Dattwyler,2 David T. Dennis,6 Eugene D. Shapiro,7 Allen C. Steere,9 Thomas J. Rush,5 Daniel W. Rahn,10 Patricia K. Coyle,3 David H. Persing,11 Durland Fish,8 andBenjamin J. Luft4

1DivisionofInfectiousDiseases,DepartmentofMedicine,NewYorkMedicalCollege,Valhalla, 2DivisionofAllergy,ImmunologyandLymeDisease,DepartmentofMedicine, 3DepartmentofNeurology,and 4DepartmentofMedicine,HealthSciencesCenter,StateUniversityofNewYorkatStonyBrook,and 5privatepractice,BriarcliffManor,NewYork; 6DivisionofVector-BorneInfectiousDiseases,NationalCenterforInfectiousDiseases,CentersforDiseaseControlandPrevention,FortCollins,Colorado;Departmentsof 7Pediatricsand 8EpidemiologyandPublicHealth,YaleUniversitySchoolofMedicine,NewHaven,Connecticut; 9TuftsUniversitySchoolofMedicine,NewEnglandMedicalCenter,Boston,Massachusetts; 10OfficeofMedicalManagement,MedicalCollegeofGeorgia,Augusta;and 11DiagnosticsDevelopment,CorixaCorporation,andInfectiousDiseaseResearchInstitute,SeattleLifeSciencesCenter,Seattle,Washington Reprintsorcorrespondence:Dr.GaryP.Wormser,Room209SE,MacyPavilion,WestchesterMedicalCenter,Valhalla,NY10595.

Executive Summary

Tick bites and prophylaxis. The best currently availablemethod for preventing infectionwith Borrelia burgdorferi is toavoid vector tick exposure.If exposure to Ixodes scapularisor Ixodes pacificus ticks isunavoidable, measures recommended toreduce the risk ofinfection include using bothprotective clothing and tickrepellents, checking the entirebody for ticks daily,and promptly removing attachedticks, before transmission ofB. burgdorferi can occur (A-III[see tables 1 and2 for recommendation categories,indicated in parentheses throughoutthis text]).

Table 1. Categories indicating thestrength of each recommendationfor or against use.

Table 2. Gradesindicating the quality ofevidence on which recommendationsare based.

Routine use ofeither antimicrobial prophylaxis (E-I)or serological tests (D-III)after a tick biteis not recommended. Someexperts recommend antibiotic therapyfor patients bitten byI. scapularis ticks that areestimated to have beenattached for >48 h(on the basis ofthe degree of engorgementof the tick withblood), in conjunction withepidemiological information regarding theprevalence of tick-transmitted infection(C-III). However, accurate determinationsof species of tickand degree of engorgementare not routinely possible,and data are insufficientto demonstrate efficacy ofantimicrobial therapy in thissetting.

Persons who remove attachedticks should be monitoredclosely for signs andsymptoms of tick-borne diseasesfor up to 30days and specifically forthe occurrence of askin lesion at thesite of the tickbite (which may suggestLyme disease) or atemperature >38°C (which maysuggest human granulocytic ehrlichiosis[HGE] or babesiosis). Personswho develop a skinlesion or other illnesswithin 1 month afterremoving an attached tickshould promptly seek medicalattention for assessment ofthe possibility of havingacquired a tick-borne disease(A-II).

Health care practitioners, particularlythose in areas whereLyme disease is endemic,should become familiar withits clinical manifestations, recommendedpractices for testing forit, and therapy forthe disease, as wellas for HGE andbabesiosis (A-III).

Testing of ticksfor tick-borne infectious organismsis not recommended, exceptin research studies (D-III).

Priorvaccination with the recentlylicensed recombinant outer-surface proteinA (OspA) vaccine preparationreduces the risk ofdeveloping Lyme disease associatedwith tick bites butshould not alter theabove recommendations (A-I).

Early Lyme disease. Administration ofdoxycycline (100 mg twicedaily) or amoxicillin (500mg 3 times daily)for 1421 days isrecommended for treatment ofearly localized or earlydisseminated Lyme disease associatedwith erythema migrans, inthe absence of neurologicalinvolvement or third-degree atrioventricularheart block (A-I). Inprospective studies, these agentshave been shown tobe effective in treatingerythema migrans and associatedsymptoms. Doxycycline has theadvantage of being efficaciousfor treatment of HGE,which may occur simultaneouslywith early Lyme disease.Doxycycline is relatively contraindicatedduring pregnancy or lactationand for children aged<8 years.

Because of itshigher cost, cefuroxime axetil(500 mg orally twicedaily), which is aseffective as doxycycline inthe treatment of erythemamigrans (A-I), should bereserved as an alternativeagent for those patientswho can take neitherdoxycycline nor amoxicillin. Forchildren, we recommend amoxicillinat a dosage of50 mg/kg/d, divided into3 doses per day(maximum, 500 mg/dose), ordoxycycline (for those aged8 years) at adosage of 12 mg/kgtwice per day (maximum,100 mg/dose) (B-II). Cefuroximeaxetil, at a dosageof 30 mg/kg/d, dividedinto 2 doses daily(maximum, 500 mg/dose), isan acceptable alternative agent(B-III).

Macrolide antibiotics are notrecommended as first-line therapyfor early Lyme disease(E-I). When used, theyshould be reserved forpatients who are intolerantof amoxicillin, doxycycline, andcefuroxime axetil. Possible regimensfor adults are asfollows: azithromycin, 500 mgorally daily for 710days; erythromycin, 500 mgorally 4 times dailyfor 1421 days; andclarithromycin, 500 mg orallytwice daily for 1421days. Possible dosages forchildren are the following:azithromycin, 10 mg/kg/d (maximum,500 mg/d); erythromycin, 12.5mg/kg 4 times daily(maximum, 500 mg/dose); andclarithromycin, 7.5 mg/kg twicedaily (maximum, 500 mg/dose).Patients treated with macrolidesshould be closely followed.

Ceftriaxone(2 g iv daily),although effective, is notsuperior to oral agentsand is not recommendedas a first-line agentfor treatment of Lymedisease in the absenceof neurological involvement orthird-degree atrioventricular heart block(E-I).

The use of ceftriaxone(2 g once dailyiv for 1428 days)in early Lyme diseaseis recommended for acuteneurological disease manifested bymeningitis or radiculopathy (B-II).Intravenous penicillin G ata dosage of 1824million units daily, dividedinto doses given every4 h (for patientswith normal renal function),may be a satisfactoryalternative (B-II). Cefotaxime (2g iv every 8h) may also bea satisfactory alternative (B-II).For adult patients whoare intolerant of bothpenicillin and cephalosporins, doxycycline(200400 mg/d) in 2divided doses given orally(or iv if thepatient is unable totake oral medications) for1428 days may beadequate (B-II).

For children, werecommend ceftriaxone (75100 mg/kg/d)in a single dailyiv dose (maximum, 2g) (B-II) or cefotaxime(150200 mg/kg/d) divided into3 or 4 ivdoses (maximum, 6 g/d)(B-III) for 1428 days.An alternative is ivpenicillin G (200,000400,000 units/kg/d;maximum, 1824 million units/d)divided into doses givenevery 4 h forthose with normal renalfunction (B-II).

Patients with first-or second-degree atrioventricular heartblock associated with earlyLyme disease should betreated with the sameantimicrobial regimens as patientswith erythema migrans withoutcarditis (see paragraphs 1and 2 of therecommendations in this section,above) (B-III). We recommendthat patients with third-degreeatrioventricular heart block betreated with parenteral antibioticssuch as ceftriaxone (seeparagraphs 5 and 6of the recommendations inthis section, above) inthe hospital, although thereare no clinical trialsto support this recommendation(B-III). A temporary pacemakermay also be required.

Althoughantibiotic treatment does nothasten the resolution ofseventh-cranial-nerve palsy associated withB. burgdorferi infection, antibiotics shouldbe given to preventfurther sequelae (B-II). Therewas disagreement among panelmembers on the neurologicalevaluation of patients withseventh-cranial-nerve palsy. Some membersperform a CSF examinationon all patients withseventh-cranial-nerve palsy, whereas othersreserve lumbar puncture forpatients for whom thereis strong clinical suspicionof CNS involvement (e.g.,severe headache or nuchalrigidity). Patients whose CSFexaminations yield normal findingsmay be treated withthe same regimens usedfor patients with erythemamigrans (B-III), whereas patientsfor whom there isclinical and laboratory evidenceof CNS involvement shouldbe treated with regimenseffective against meningitis (seeparagraphs 5 and 6of the recommendations inthis section, above) (B-II).

Treatmentfor pregnant patients canbe identical to thatfor nonpregnant patients withthe same disease manifestation,except that tetracyclines shouldbe avoided (B-III).

Lyme arthritis. Lyme arthritisusually can be treatedsuccessfully with antimicrobial agentsadministered orally or intravenously.Administration of doxycycline (100mg twice daily orally)or amoxicillin (500 mg3 times daily), ineach instance for 28days, is recommended forpatients without clinically evidentneurological disease (B-II). Forchildren, we recommend administrationof doxycycline (12 mg/kgtwice per day; maximum,100 mg/dose), which canbe given to patientsaged 8 years, oramoxicillin (50 mg/kg/d, dividedinto 3 doses perday; maximum, 500 mg/dose)for 28 days (B-II).

Oraltherapy is easier toadminister than iv antibiotics,is associated with fewerserious complications, and isconsiderably less expensive. Itsdisadvantage is that somepatients treated with oralagents have subsequently manifestedovert neuroborreliosis, which mayrequire iv therapy forsuccessful treatment. Further controlledtrials are needed tocompare oral with ivtherapy.

Neurological evaluation, including lumbarpuncture, should be donefor patients if thereis a strong clinicalsuspicion of neurological involvement.Patients with both arthritisand objective evidence ofneurological disease should receiveiv ceftriaxone (2 gonce daily for 1428days) (A-II). Alternative therapiesinclude iv cefotaxime (2g iv every 8h) (B-III) or ivpenicillin G (1824 millionunits daily, divided intodoses given every 4h for patients withnormal renal function) (B-II).Because of low bloodlevels, the long-acting benzathinepreparation of penicillin isnot recommended (D-III). Forchildren, we recommend administrationof ceftriaxone (75100 mg/kg/din a single dailyiv dose; maximum, 2g) (B-III) or cefotaxime(150200 mg/kg/d divided into3 or 4 ivdoses; maximum, 6 g/d)(B-III) for 1428 days.An alternative is ivpenicillin G (200,000400,000 units/kg/d;maximum, 1824 million units/d),divided into doses givenevery 4 h forthose with normal renalfunction (B-III).

For patients whohave persistent or recurrentjoint swelling after recommendedcourses of antibiotic therapy,we recommend repeat treatmentwith another 4-week courseof oral antibiotics orwith a 2- to4-week course of ivceftriaxone (B-III). Clinicians shouldconsider waiting several monthsbefore initiating repeat treatmentwith antimicrobial agents becauseof the anticipated slowresolution of inflammation aftertreatment. If patients havepersistent arthritis despite 2courses of oral therapyor one course ofiv therapy, symptomatic treatmentwith nonsteroidal anti-inflammatory agentsis recommended; intra-articular steroidsmay also be ofbenefit (B-III). If persistentsynovitis is associated withsignificant pain or ifit limits function, arthroscopicsynovectomy can reduce theperiod of joint inflammation(B-II).

Late neuroborreliosis affecting the CNS or peripheral nervous system. For patients with lateneurological disease affecting theCNS or peripheral nervoussystem, treatment with ceftriaxone(2 g once aday iv for 24weeks) is recommended (B-II).Alternative parenteral therapy mayinclude administration of cefotaxime(2 g iv every8 h) (B-II) oriv penicillin G (1824million units daily, dividedinto doses given every4 h for patientswith normal renal function)(B-II). Response to treatmentis usually slow andmay be incomplete. However,unless relapse is shownby reliable objective measures,repeat treatment is notrecommended. For children, a1428-day course of treatmentwith ceftriaxone (75100 mg/kg/din a single dailyiv dose; maximum, 2g) is recommended (B-II).An alternative is cefotaxime(150200 mg/kg/d iv, dividedinto 3 or 4doses; maximum, 6 g/d)(B-II). Another alternative isiv penicillin G (200,000400,000units/kg/d, divided into dosesgiven every 4 hfor those with normalrenal function; maximum, 1824million units/d) (B-II).

Chronic Lyme disease or postLyme disease syndrome. After anepisode of Lyme diseasethat is treated appropriately,some persons have avariety of subjective complaints(such as myalgia, arthralgia,or fatigue). Some ofthese patients have beenclassified as having “chronicLyme disease” or “postLymedisease syndrome,” which arepoorly defined entities. Thesepatients appear to bea heterogeneous group. AlthoughEuropean patients rarely havebeen reported to haveresidual infection with B. burgdorferi,this has yet tobe convincingly demonstrated eitherin a large seriesof appropriately treated Europeanpatients or in astudy of North Americanpatients.

Randomized controlled studies oftreatment of patients whoremain unwell after standardcourses of antibiotic therapyfor Lyme disease arein progress. To date,there are no convincingpublished data that repeatedor prolonged courses ofeither oral or ivantimicrobial therapy are effectivefor such patients. Theconsensus of the InfectiousDiseases Society of America(IDSA) expert-panel members isthat there is insufficientevidence to regard “chronicLyme disease” as aseparate diagnostic entity.

Objective

The objectiveof these practice guidelinesis to provide cliniciansand other health carepractitioners with recommendations formanagement of cases inwhich either Lyme diseasehas been diagnosed orthe patient was bittenby an Ixodes tickin North America (tables1 and 2) [1].Lyme disease is endemicin several regions ofthe United States, particularlyareas of the Northeast,Upper Midwest, and Northwest[2]. It is themost frequent vector-borne diseasein the United States.Adults and children ofboth sexes can beaffected. These patients areevaluated and treated bygeneral practitioners, pediatricians, andinternists, as well asby infectious disease specialists,dermatologists, rheumatologists, neurologists, orthopedists,obstetricians, and ophthalmologists. Becausethe genospecies of B. burgdorferithat cause Lyme diseasein North America aredifferent from those thatcause Lyme borreliosis inEurasia, recommendations were based,whenever possible, on studiesconducted in the UnitedStates.

In the treatment ofthis disease, as inall infectious diseases, basicmedical and scientific principlesshould be considered. Inselecting an antibiotic, thereshould be evidence ofactivity in vitro, evidenceof penetration into theinfected sites, and clinicalstudies to support thetreatment regimen. The readeris referred to othersources for information ondiagnostic aspects of Lymedisease [39].

Prevention of Tick Bites

The best currentlyavailable method for preventinginfection with B. burgdorferi andother Ixodes-transmitted infections isto avoid tick-infested areas[10]. If exposure toI. scapularis or I. pacificus ticksis unavoidable, a numberof measures may helpto decrease the riskthat ticks will attachand subsequently transmit infection.The use of protectiveclothing (shirt tucked intopants and pants tuckedinto socks) may interferewith attachment by ticksby increasing the timerequired for ticks tofind exposed skin, thusfacilitating their recognition andremoval. By wearing light-coloredclothing (to provide abackground with which thetick contrasts), persons inareas of endemicity mayalso be more likelyto see (and remove)ticks before they haveattached.

Daily inspections of theentire body to locate(and remove) ticks alsoprovide an opportunity toprevent transmission of tick-borneinfections [11, 12]. Attachedticks should be removedpromptly with fine-toothed forceps,if possible [13]. Tickand insect repellents appliedto the skin andclothing provide additional protection[10, 14, 15].

Tick Bites and Prophylaxis

Primary Management Options

For patientswho remove attached ticks,we considered the followingmanagement options: (1) treatingall such persons; (2)treating only persons believedto be at highrisk (e.g., those removinga nymphal or adultvector tick [I. scapularis orI. pacificus] after 48 hof attachment); (3) treatingonly persons who developerythema migrans or otherclinical signs and symptomsof tick-borne infection; and(4) treating all personswho seroconvert from negativityto positivity (optimally witha 4-fold increase intiter) for serum antibodiesto B. burgdorferi (acute andfollow-up blood specimens fromall persons who arebitten would need tobe collected and testedfor antibodies in pairedspecimens).

Outcome

The panel weighed boththe risks and theconsequences of developing Lymedisease (including the riskof late complications) forpersons bitten by vectorticks (I. scapularis or I. pacificus)against the cost andadverse effects of prophylacticantimicrobials. The effect ofthe different strategies onquality of life wasconsidered. In addition, weconsidered the effect ofthe recent licensing ofa recombinant OspA vaccinefor prevention of Lymedisease [16]. The principaldesired outcome is preventionof Lyme disease. Anotherdesired outcome is theprevention of other Ixodes-borneillnesses, including babesiosis andHGE. Concurrent infection anddisease with these organismshave been described [1719].

Evidence

Option 1: treating with antimicrobials all persons who remove vector ticks (I.scapularis or I. pacificus) that have become attached. Although somepractitioners routinely treat patientsthat have been bittenby I. scapularis [20], severalprospective, randomized double-blind clinicaltrials involving persons whowere bitten by I. scapularisticks and then weretreated with placebo, penicillin,tetracycline, or amoxicillin eachled to conclusions thatroutine antimicrobial prophylaxis isnot warranted [2123]. Ameta-analysis of these studies(in which >600 personswere enrolled) did notindicate that antimicrobial prophylaxisis effective (pooled OR,0.0; 95% CI, 0.01.5;P = .12) [24].The authors of themeta-analysis estimated that ifamoxicillin rather than doxycyclinewere used (to enablesmall children and pregnantor lactating women toreceive prophylaxis), 8 casesof drug-associated rash, including1 severe life-threatening reaction,would occur for every10 cases of earlyLyme disease that wereprevented [24].

In addition, 3cases of minor amoxicillin-relatedadverse effects (e.g., diarrhea)would occur for everycase of Lyme diseasethat was prevented. In2 studies of prophylaxisfor tick bites inwhich adverse effects ofthe antimicrobials used forprophylaxis were reported, therisk of acquiring Lymedisease after a tickbite was no differentthan the risk ofdeveloping adverse effects fromthe prophylactic antibiotics [21,22].

One cost-effectiveness analysis concludedthat a 2-week courseof doxycycline is indicatedwhen the probability ofinfection with B. burgdorferi aftera tick bite is.036 and should beconsidered when the theoreticalprobability ranges from .01to .035 [25]. Manyexperts, however, disagree withkey assumptions in themodel. Furthermore, doxycycline isrelatively contraindicated for womenwho are either pregnantor breast-feeding, as wellas for children aged<8 years.

Some practitioners prescribea 10-to-14-day course ofamoxicillin for pregnant womenwho have been bittenby I. scapularis, because casereports have suggested thatadverse outcomes for thefetus may be associatedwith pregnancies complicated byLyme borreliosis [26]. Increasingdata from clinical andepidemiological studies, however, suggestthat favorable outcomes canbe expected when pregnantwomen with Lyme borreliosisare treated with standardantibiotic regimens [2729].

In additionto B. burgdorferi, other potentialpathogens may be presentin I. scapularis ticks [30,31]. Babesiosis and HGEcan occur independently ortogether with Lyme disease[17, 18, 32]. Administrationof doxycycline is effectivein the treatment ofpatients with HGE [33]but is not recommendedas therapy for babesiosis.There are no publishedclinical data regarding theefficacy of prophylaxis withdoxycycline against either ofthese infections.

Option 2: treating with antimicrobials only persons believed to be at high risk (e.g., those who have removed a nymphal or adult vector tick [I. scapularis or I. pacificus] after 48 h of attachment). Entomologicalstudies have shown thatB. burgdorferi is rarely transmittedby I. scapularis within thefirst 48 h ofattachment to laboratory animals[11, 12]. This “graceperiod” is required forspirochetes to migrate fromthe gut into thesalivary glands of infectedticks once feeding commences[34]. Thus, ticks thathave been attached for<48 h theoretically cannottransmit B. burgdorferi infection. However,this is not truefor HGE or babesiosis,since the organisms thatcause these diseases arealready present in thesalivary glands before feeding(D. Fish, unpublished data,and [35]).

The option oftreating selectively persons with”high-risk” tick bites toprevent Lyme disease assumesthat the species, stage,degree of engorgement, andinfection status of thetick, as well asthe probability of transmissionof infection, can bereadily ascertained. This israrely true. Many differenttick species bite humans,and some “ticks” removedfrom humans are actuallyspiders, scabs, lice, ordirt and thus poseno risk of Lymedisease [36, 37]. Methodsfor determining the infectionstatus of ticks removedfrom patients are experimentaland are not standardized.One study found thatpatients who removed partiallyengorged ticks that werecalculated to have beenattached for 72 hwere significantly more likelyto develop B. burgdorferi infectionthan were patients whoremoved ticks that hadbeen attached for anestimated duration of <72h (P = .008)[37]. However, even ifthe risk of Lymedisease is increased withpartially engorged ticks, nostudy has demonstrated thatantimicrobials are effective inreducing the risk ofinfection after a tickbite.

Option 3: treating with antimicrobials only persons who develop erythema migrans or other clinical manifestations of Lyme disease or other tick-transmitted diseases. The great majority ofpersons with B. burgdorferi infectionpresent with erythema migrans[16, 3840]. Since primaryerythema migrans lesions occurat the site ofa tick bite [4144],a person who removesa tick would belikely to detect andto seek care fora rash that subsequentlydevelops at that location.Patients who develop feverin the absence oferythema migrans after anIxodes tick bite shouldbe evaluated for HGEand/or babesiosis in areaswhere these infections areendemic [33, 45, 46].

Ina placebo-treated population observedprospectively in a large,multicenter vaccine trial, somevolunteers developed serological evidenceof asymptomatic B. burgdorferi infection[16]. Whether antibiotic therapyis beneficial for suchpatients is unknown, aquestion in need offurther study. (See nextparagraph [option 4] forcaveats concerning serological diagnosis.)

Option 4: treating with antimicrobials all persons who seroconvert from negativity to positivity for serum antibodies to B. burgdorferi when acute and follow-up serum samples are tested simultaneously. Althoughassessment of acute- andconvalescent-phase serologies is astandard means of identifyingindividuals with a varietyof infectious diseases, theutility of this approachfor identifying infection withB. burgdorferi following a tickbite is unknown. Presentserological assays for Lymedisease have substantial limitations[37], and their useis not recommended forscreening of persons lackingobjective manifestations of Lymedisease [3, 4, 6,7].

Recommendations

The best currently availablemethod for preventing infectionwith B. burgdorferi and otherIxodes-transmitted infections is toavoid vector tick exposure.If exposure to I. scapularisor I. pacificus ticks isunavoidable, measures recommended toreduce the risk ofinfection include using bothprotective clothing and tickrepellents, checking the entirebody for ticks daily,and promptly removing attachedticks before transmission ofB. burgdorferi can occur (A-III).

Routineuse of either antimicrobialprophylaxis (E-I) or serologicaltests (D-III) after atick bite is notrecommended. Some experts recommendantibiotic therapy for patientsbitten by I. scapularis ticksthat are estimated tohave been attached for>48 h (on thebasis of the degreeof engorgement of thetick with blood), inconjunction with epidemiological informationregarding the prevalence oftick-transmitted diseases (C-III). However,accurate determinations of tickspecies and degree ofengorgement are not routinelypossible, and data areinsufficient to demonstrate efficacyof antimicrobials in thissetting.

Persons who remove attachedticks should be monitoredclosely for signs andsymptoms of tick-borne diseasesfor up to 30days and specifically forthe occurrence of askin lesion at thesite of the tickbite (which may suggestLyme disease) or atemperature >38°C (which maysuggest HGE or babesiosis).Persons who develop askin lesion or otherillness within 1 monthafter removing an attachedtick should promptly seekmedical attention for assessmentof the possibility ofhaving acquired a tick-bornedisease (A-II).

Health care practitioners,particularly those in areaswhere Lyme disease isendemic, should become familiarwith the clinical manifestationsof and recommended practicesfor testing and therapyfor Lyme disease, aswell as for HGEand babesiosis (A-III).

Testing ofticks for tick-borne infectiousorganisms is not recommended,except in research studies(D-III).

Prior vaccination with therecently licensed recombinant OspAvaccine preparation reduces therisk of developing Lymedisease associated with tickbites but should notalter the above recommendations(A-I).

Early Lyme Disease

Primary Management Options

We considered the followingmanagement options for earlyLyme disease: oral antimicrobialtherapy for early localizedinfection (i.e., solitary erythemamigrans) and oral versusiv therapy for casesof early disseminated infection(i.e., patients presenting withmultiple erythema migrans lesions,carditis, cranial-nerve palsy, meningitis,or acute radiculopathy). Borreliallymphocytoma was not addressedbecause of its rarityin North America (itsprimary causative organism, Borrelia afzelii,is an exclusively Eurasiangenospecies).

Outcome

The panel weighed boththe risks and theconsequences of developing latecomplications of Lyme diseaseand the possible adverseeffects of antimicrobial therapy.The desired outcome isto resolve the symptomsand signs of earlyLyme disease and toprevent late complications.

Evidence

At least7 randomized prospective trialshave addressed the treatmentof early Lyme diseasein the United States[4753]. All studies usederythema migrans as thedisease-defining criterion. Six studiesrecruited patients with eitherlocalized or disseminated earlyLyme disease [4752], whereas1 study required disseminatedearly disease for enrollment[53]. Differing criteria wereused to define treatmentsuccess and failure inthe various studies. Moststudies defined “failure” bythe occurrence of objectiveclinical manifestations, but subjectivesymptoms were considered evidenceof treatment failure insome studies.

The etiology ofresidual patient complaints aftertreatment may include aninflammatory response, unrelated toactive infection, or alternativedisease processes. Failure rateswere not considered inthe context of backgroundcomplaints in an otherwise”healthy” population. For example,in a recent randomtelephone survey collecting self-reportedhealth information, the prevalenceof chronic joint symptomsin adults ranged from12.3% to 22.7% [54].In a study ofadult members in ahealth maintenance organization inSeattle, 20% reported fatigueof at least 6months’ duration that interferedwith normal activities [55].Twelve percent of acontrol group of childrenwithout Lyme disease inanother study mentioned fatigueas a symptom [56].In rheumatology practice, aprevalence of 15%20% forfibromyalgia is common [57].Nearly 85% of thegeneral population may experienceat least 1 somaticsymptom in a 6-weekperiod, and 81% ofhealthy university students andhospital staff members describedat least 1 suchsymptom over a 3-dayinterval [58, 59]. Thus,the occurrence of arthralgia,myalgia, and fatigue aftertreatment for early Lymedisease must be evaluatedin the context ofbackground complaints for asignificant proportion of patients.

Inaddition, the possibility ofcoinfection with other pathogenssuch as Babesia microti andthe Ehrlichia species thatcauses HGE was notconsidered in any ofthe treatment studies ofearly Lyme disease. Ina separate study inan area in whichbabesiosis is endemic, mostpatients who had residualcomplaints after treatment forearly Lyme disease hadevidence of coinfection withB. microti [17]. Specific treatmentwith antiparasitic agents directedagainst this microorganism waseffective in diminishing symptomsin 1 study [60].

Thefirst randomized clinical trialof treatment of erythemamigrans compared erythromycin, tetracycline,and penicillin at dosagesof 250 mg 4times daily for 10days and included 112adult patients [47]. Signsand symptoms after treatmentwere considered to beeither “minor” (headache, fatigue,supraventricular tachycardia, arthralgias, briefarthritis of <2 weeks’duration, or isolated facialpalsy) or “major” (meningitis,meningoencephalitis, carditis, or recurrentattacks of arthritis). Approximately15% of patients hadtransient intensification of symptomsduring the first 24h of therapy, consistentwith a Jarisch-Herxheimer reaction.Erythema migrans and itsassociated symptoms resolved significantlyfaster in patients treatedwith penicillin or tetracyclinethan in patients treatedwith erythromycin (P <.05). In addition, treatmentwith tetracycline or penicillinwas associated with alower rate of occurrenceof “major” manifestations bythese criteria, compared withthe occurrence rate associatedwith erythromycin.

Overall, “minor” posttreatmentsigns and symptoms occurredin 45% of patients.Extending therapy to 20days with tetracycline ina subsequent study bythe same investigators hadno effect on thefrequency of posttreatment symptoms[47]. The results ofthese studies supported thefindings of an earlieropen trial of oralpenicillin therapy [61]. Itcould be concluded thaterythema migrans was responsiveto antibiotic treatment butoptimal therapy was notdefined.

Subsequent small studies foundthat doxycycline and amoxicillin(plus probenecid), which arethe tetracycline and -lactampreparations most commonly prescribedin current clinical practicefor patients with erythemamigrans, were effective therapies,and that the efficaciesof each drug regimenwere similar [48, 49].

Amulticenter study that comparedcefuroxime axetil (500 mgtwice daily for 20days) with doxycycline (100mg 3 times dailyfor 20 days) in123 patients with erythemamigrans demonstrated satisfactory outcomesfor 90% of patientsfollowed for 1 yearafter treatment [50]. Seventy-onepercent of patients inthe cefuroxime group and76% in the doxycyclinegroup were completely cured,whereas 19% and 16%of patients, respectively, hadpersistent subjective complaints buttheir conditions improved. Althoughtreatment was considered tohave failed for 10%of patients, most ofthese patients did nothave objective evidence ofcontinuing active infection.

A secondmulticenter study, in which232 patients with erythemamigrans were randomized toreceive either cefuroxime ordoxycycline for 20 days,confirmed that the 2drugs had comparable efficacy[51]. Consistent with earlierreports, a Jarisch-Herxheimerlike reactionoccurred during the first24 h of therapyin 12% of patientsin each treatment group.

Amulticenter, double-blind, randomized prospectivetrial compared azithromycin (500mg once daily for7 days) with amoxicillin(500 mg 3 timesdaily for 20 days)in the treatment ofpatients with erythema migrans[52]. Amoxicillin was foundto be significantly moreeffective than azithromycin inresolving the acute manifestationsof erythema migrans completelyand in preventing relapsewithin a 6-month period.Of 217 evaluable patients,only 4% of thosetreated with amoxicillin relapsed,compared with 16% ofthose treated with azithromycin(P = .005). Ahigher symptom score beforetreatment correlated with persistentsymptoms after treatment.

Only 1study has specifically addressedthe treatment of acutedisseminated nonneurological Lyme disease.This prospective, randomized multicentertrial revealed that inthe absence of clinicallyapparent CNS involvement, oraldoxycycline (100 mg twicedaily for 3 weeks)was similar in efficacyto iv ceftriaxone (2g daily for 2weeks) [53].

In most ofthe controlled trials, patientsassigned to be treatedwith either doxycycline oramoxicillin received therapy for3 weeks. However, similarsuccess rates have beenreported in studies inwhich 14-day treatment courseswith these antibiotics wereused [62, 63]. Althoughnone of the prospectivestudies included pregnant patients,there are no datato suggest that thesepatients should be treateddifferently from other patientswith Lyme disease, exceptthat tetracycline therapy shouldbe avoided [64].

Several conclusionscan be drawn fromthese trials. Doxycycline, amoxicillin,and cefuroxime axetil areefficacious in the treatmentof early Lyme disease.Most patients respond promptlyand completely. Some individualshave persistent subjective complaintsdespite therapy that otherwiseappears curative. Less than10% of infected individualsfail to respond toantibiotic therapy, as evidencedby objective manifestations ofpersistent infection, and repeattreatment is rarely required.In general, patients whoare more systemically ill(e.g., febrile with significantconstitutional complaints) at thetime of diagnosis takelonger to have acomplete response to therapy.Coinfection with other tick-borneinfections or inadequately recognizedCNS infection at thetime of institution ofantibiotic therapy may bethe explanation for antibioticfailures in some circumstances.

Despiteexcellent activity against B. burgdorferiin vitro [65], themacrolides that have beenstudied systematically, namely, erythromycin[47] and azithromycin [52]in the United Statesand roxithromycin [66] inEurope, are less effectivethan other therapeutic agents(reviewed in [67]). Clarithromycinhas not been studiedin a controlled trial[68].

All antimicrobials effective inearly Lyme disease areassociated with a lowfrequency of serious adverseeffects. Drug-induced rashes occurwith both amoxicillin [52]and cefuroxime [50, 51].Doxycycline may cause photosensitivity[50, 51], which maybe problematic since earlyLyme disease occurs mostcommonly during the summermonths. Individuals treated withdoxycycline are advised toavoid exposure to thesun while receiving therapy.In addition, doxycycline isrelatively contraindicated for childrenaged <8 years andfor women who arepregnant or breast-feeding.

Cefuroxime axetilis much more expensivethan doxycycline or amoxicillin;therefore, its administration isnot recommended as first-linetherapy (table 3).

Table 3. Recommended antimicrobial regimensfor treatment of patientswith Lyme disease.

In contrastto the second-generation cephalosporincefuroxime and certain third-generationcephalosporins (e.g., ceftriaxone), first-generationcephalosporins such as cephalexinare inactive in vitroagainst B. burgdorferi and areineffective clinically [69, 70].

Availableevidence regarding treatment ofacute neurological Lyme diseasein the United Statesis based on smallcase series. Patients withLyme meningitis or acuteradiculopathy respond to ivpenicillin [71], although ceftriaxoneis more widely usedfor this indication becauseof its convenient once-dailydosing [72]. European trialshave found iv penicillinto be as effectiveas cefotaxime or ceftriaxone[73, 74] and cefotaximeto be as effectiveas ceftriaxone [75]. Doxycyclineadministered orally or ivhas also been usedsuccessfully in Europe [7679],but experience with thisagent for the treatmentof patients with meningitisdue to Lyme diseasein the United Statesis limited.

Cranial-nerve palsy hasbeen treated satisfactorily withoral antibiotics [38, 80].There was disagreement amongpanel members, however, onthe neurological evaluation ofpatients with seventh-cranial-nerve palsy.Some members perform alumbar puncture for allindividuals with Lyme diseaseassociatedseventh-cranial-nerve palsy. Others reservelumbar puncture for thosepatients for whom thereis strong clinical evidenceof CNS involvement (e.g.,severe headache or nuchalrigidity).

Patients whose CSF examinationsyield normal findings maybe treated with thesame regimens used forpatients with erythema migrans,whereas those with clinicaland laboratory evidence ofCNS involvement should betreated with regimens effectiveagainst meningitis. Since thefrequency and rate ofrecovery of seventh-cranial-nerve palsyin patients treated withantibiotics appear to bethe same as inuntreated patients, the principalgoal of therapy isto prevent the developmentof later clinical manifestations[80].

No studies have specificallyaddressed the treatment ofcarditis. Cardiac involvement inNorth American Lyme diseaseprimarily manifests as atrioventricularheart block and usuallyoccurs within the firstseveral weeks of infection,often in conjunction witherythema migrans [81]. First-and second-degree atrioventricular heartblocks resolve during therapywith oral antibiotics. Becauseof the potential forlife-threatening complications, patients withthird-degree atrioventricular heart blockshould be closely monitoredin the hospital. Mostpanel members treat suchpatients with iv ceftriaxone,although there is noevidence that parenteral therapyis more effective thanoral therapy. Insertion ofa temporary pacemaker maybe necessary for patientswith third-degree heart blockin some circumstances.

Recommendations

Administration ofdoxycycline (100 mg twicedaily) or amoxicillin (500mg 3 times daily)for 1421 days isrecommended for treatment ofearly localized or earlydisseminated Lyme disease associatedwith erythema migrans, inthe absence of neurologicalinvolvement or third-degree atrioventricularheart block (tables 3and 4) (A-I). Inprospective studies, these agentshave been shown tobe effective in thetreatment of erythema migransand associated symptoms.

Table 4. Recommended therapyfor patients with Lymedisease.

Doxycycline has the advantageof being efficacious fortreatment of HGE, whichmay occur simultaneously withearly Lyme disease. Doxycyclineis relatively contraindicated duringpregnancy or lactation andfor children aged <8years. Because of itshigher cost, cefuroxime axetil,which is as effectiveas doxycycline in thetreatment of erythema migrans(A-I), should be reservedas an alternative agentfor those patients whocan take neither doxycyclinenor amoxicillin. For children,amoxicillin or doxycycline (forthose aged 8 years)is recommended (tables 3and 4) (B-II). Cefuroximeaxetil is an acceptablealternative agent (B-III).

Administration ofmacrolide antibiotics is notrecommended as first-line therapyfor early Lyme disease(E-I). When used, theyshould be reserved forpatients who are intolerantof amoxicillin, doxycycline, andcefuroxime axetil (table 4). Patientstreated with macrolides shouldbe closely followed.

Ceftriaxone (2g iv daily), althougheffective, is not superiorto oral agents andis therefore not recommendedfor treatment of Lymedisease in the absenceof neurological involvement orthird-degree atrioventricular heart block(E-I).

The use of ceftriaxone(2 g once dailyiv for 1428 days)in early Lyme diseaseis recommended for acuteneurological disease manifested bymeningitis or radiculopathy (tables3 and 4) (B-II).Parenteral therapy with penicillinG or cefotaxime maybe a satisfactory alternative(B-II). For adult patientswho are intolerant ofboth penicillin and cephalosporins,doxycycline (200400 mg/d in2 divided doses orally[or iv if thepatient is unable totake oral medications]) for1428 days may beadequate (B-II).

For children, ivceftriaxone (B-II) or cefotaxime(B-III) is recommended (tables3 and 4); penicillinG given iv isan alternative (B-II).

Patients withfirst- or second-degree atrioventricularheart block associated withearly Lyme disease shouldbe treated in thesame manner as patientswith erythema migrans withoutcarditis (tables 3 and4) (B-III). We recommendthat patients with third-degreeatrioventricular heart block betreated with parenteral antibioticssuch as ceftriaxone (table 3)in the hospital, althoughthere are no clinicaltrial data to supportthis recommendation (B-III). Atemporary pacemaker may alsobe required.

Although antibiotic treatmentdoes not hasten theresolution of seventh-cranial-nerve palsyassociated with B. burgdorferi infection,antibiotics should be givento prevent further sequelae(B-II). There was disagreementamong panel members onthe neurological evaluation ofpatients with seventh-cranial-nerve palsy.Some members perform aCSF examination of allpatients with seventh-cranial-nerve palsy,whereas others reserve lumbarpuncture for those inwhom there is strongclinical evidence of CNSinvolvement (e.g., severe headacheor nuchal rigidity).

Patients whoseCSF examinations yield normalfindings may be treatedwith the same regimensused for patients witherythema migrans (B-III). Thosewith clinical and laboratoryevidence of CNS involvementshould be treated withregimens effective against meningitis(tables 3 and 4)(B-II).

Treatment for pregnant patientscan be identical tothat for nonpregnant patientswith the same diseasemanifestation, except that tetracyclinesshould be avoided (B-III).

Late Lyme Disease

Options

Thepanel considered various oraland parenteral antimicrobial regimensfor treatment of thelate manifestations of Lymedisease. Late manifestations includearthritis (oligoarticular), encephalopathy (characterizedprimarily by memory deficit,irritability, and somnolence), andneuropathy (manifested primarily bydistal paresthesias or radicularpain). Acrodermatitis chronica atrophicanswas not addressed becauseof its rarity inNorth America (its primarycausative organism, B. afzelii, isan exclusively Eurasian genospecies).Because of the lackof evaluable data onophthalmologic complications, which arevery rare, the panelwas unable to makerecommendations concerning keratitis andother possible ocular manifestationsof Lyme disease.

The responseto treatment of latemanifestations is typically slow,and improvement or resolutionof symptoms may takeweeks or months. However,appropriate antibiotic treatment resultsin eventual recovery inmost patients.

Outcome

The panel comparedthe risks and consequencesof ineffective treatment oflate Lyme disease withthe problems resulting fromadverse effects of antimicrobialtherapies. The desired outcomeis to treat effectivelythe late complications ofLyme disease while minimizingthe adverse effects ofantibiotic therapy. It hasnot been shown noris it anticipated thatB. burgdorferi will develop resistanceto antibiotics, but theindiscriminate use of antibioticsexacerbates the problem ofantibiotic-resistant community-acquired infections withother bacteria.

Evidence

The first studyof antibiotic treatment inpatients with Lyme arthritiswas initiated in 1980[82]. The regimens testedwere those used forthe treatment of tertiarysyphilis, and the studydesign was a double-blind,placebo-controlled trial. The patientshad intermittent or chronicLyme arthritis primarily affectingthe knees, and allpatients were subsequently shownto be seropositive forantibodies to B. burgdorferi. Inthe first phase ofthe study, 40 patientswere randomized to receiveim benzathine penicillin G(7.2 million units) orplacebo. In the secondphase, 20 patients weretreated with iv penicillinG (20 million unitsper day for 10days). Of the 20patients who received imbenzathine penicillin, 7 (35%)had complete resolution ofjoint involvement soon aftertreatment, compared with noneof 20 patients whowere given placebo (P< 0.02). Of the20 patients treated thefollowing year with ivpenicillin G, 11 (55%)had complete resolution ofthe arthritis soon aftertreatment. It was concludedthat parenteral penicillin wasoften effective in thetreatment of Lyme arthritis,but a number ofpatients failed to respond.

Subsequently,a series of studieswas begun to testthe efficacy of ivceftriaxone in the treatmentof late Lyme disease.In comparison with penicillin,the advantages of ceftriaxoneare its excellent CSFpenetration and long serumhalf-life, which permits once-a-daydosing for outpatient management.In 1987, a caseseries of 7 patientswith Lyme arthritis orchronic neuroborreliosis, who wererefractory to oral oriv penicillin therapy, werethen treated with ivceftriaxone (2 or 4g/d for 2 weeks)[83]. All 5 patientswho had arthritis respondedto ceftriaxone therapy, andfor 5 of the6 patients with limbparesthesias, a reduction insymptoms and improvement ofnerve-conduction study findings werenoted.

In a follow-up study,23 patients with Lymearthritis or late neuroborreliosiswere randomly assigned toreceive penicillin (20 millionunits per day ivfor 10 days) orceftriaxone (4 g/d ivfor 14 days) [84].Of the 13 patientswho received ceftriaxone, nonehad objective evidence ofpersistent disease after treatment,although 3 had mildarthralgias and 1 complainedof fatigue and memorydifficulty. In contrast, 5of the 10 patientswho received iv penicillincontinued to have fatigue,memory deficit, or recurrentoligoarthritis. For 4 ofthese 5 patients, symptomsresolved after repeat treatmentwith ceftriaxone.

In a subsequentstudy, 31 patients withLyme arthritis or chronicneuroborreliosis were randomly assignedto receive 2 or4 g/d of ceftriaxonefor 2 weeks [84].After treatment, 3 ofthe 31 patients hadpersistent encephalopathy, 2 hadpersistent neuropathy, and 3had no diminishment oftheir arthritis. The overallfrequency of persistent symptomsamong patients was 13%,which was similar inboth treatment groups. Inan open-label, randomized, multicenterstudy, 143 evaluable patientswith manifestations of lateLyme disease, primarily Lymearthritis, were treated withiv ceftriaxone (2 g/dfor either 2 or4 weeks) [85]. In76% of those treatedfor 2 weeks and70% of those treatedfor 4 weeks, symptomsresolved after treatment (theP value was notsignificant). The most commonpersistent symptoms were arthralgia,pain, weakness, malaise, andfatigue.

The principal conclusions ofthese 2 studies werethat the efficacy ofiv ceftriaxone at adosage of 2 g/dwas equivalent to thatat a dosage of4 g/d, and a2-week course was asefficacious as a 4-weekcourse for the treatmentof late Lyme disease.However, some patients hadpersistent symptoms despite ceftriaxonetreatment.

At the same timethat studies were beingcarried out to assessparenteral antibiotic regimens, oraltherapy was also foundto be effective inthe treatment of patientswith Lyme arthritis. In1983 and 1984, 14children with Lyme arthritiswere treated orally witheither phenoxymethyl penicillin ortetracycline for 1030 days[86]. Thirteen experienced nofurther attacks of arthritisat follow-up at 424months after treatment, whereas1 patient’s symptoms didnot resolve until aftera 10-day course ofiv penicillin.

From 1986 through1991, 48 adult andpediatric patients with Lymearthritis were randomly assignedto receive either doxycycline(100 mg orally twicea day) or amoxicillinand probenecid (500 mgof each 4 timesa day), in eachinstance for 30 days[87]. Eighteen of the20 evaluable patients treatedwith doxycycline and 16of the 18 evaluablepatients who completed theamoxicillin regimen had resolutionof arthritis within 13months after enrollment inthe study. However, neuroborreliosislater developed in 5patients, 4 of whomwere treated with theamoxicillin/probenecid regimen. The concomitantuse of probenecid withamoxicillin may be inadvisable,because probenecid may impairpenetration of -lactam antibioticsinto brain parenchyma [72,88].

In retrospect, it wasnoted that all 5patients reported subtle distalparesthesias or memory impairmentat the time ofenrollment. It was concludedthat patients with Lymearthritis can usually betreated successfully with oralantibiotics, but practitioners mustbe aware of subtleneurological symptoms that mayrequire treatment with ivantibiotics.

In a cost-effectiveness analysis,iv therapy was foundto be no morecost-effective than oral therapyfor patients with Lymearthritis; iv therapy wasmore likely to resultin serious complications andwas substantially more expensive[89]. Therefore, the authorsconcluded that oral antibioticsare to be preferredin the initial treatmentof Lyme arthritis inthe absence of concomitantneurological involvement.

Not all patientswith Lyme arthritis respondto antibiotic therapy. In1 treatment trial, noneof the 16 patientswith Lyme arthritis whowere treated with ivceftriaxone (2 g dailyfor 2 weeks) hadresolution of arthritis within3 months after completionof therapy [87]. Thatstudy’s enrollment requirement ofcontinuous joint swelling forat least 3 monthsdespite treatment with otherrecommended parenteral or oralantibiotic regimens differed fromrequirements in previous studies.

These16 patients were alsofound to have distinctiveimmunogenetic and immune markers,including a high frequencyof human leukocyte antigenDR4specificity and of antibodyreactivity with OspA ofthe spirochete. More recentdata based on PCRtesting of serial jointfluid samples suggest thatarthritis may persist ina small number ofpatients despite eradication ofthe spirochete [90]. Theobservation that there areepitopes of OspA thatcross-react with human leukocytefunctionassociated antigen-1 [91] suggeststhat immune phenomena mightexplain the persistent jointinflammation in these cases.

Arthroscopicsynovectomy has been usedsuccessfully in the treatmentof patients whose arthritispersists despite antibiotic therapy.Of 20 patients whounderwent this procedure forrefractory chronic Lyme arthritisof the knee, 16(80%) had resolution ofjoint inflammation during thefirst month following surgeryor soon thereafter [92].The remaining 4 patients(20%) had persistent orrecurrent synovitis.

Patients with lateLyme disease associated withprominent neurological features alsorespond to antibiotic therapy.In trials conducted from1987 through 1989, 27adult patients with Lymeencephalopathy, polyneuropathy, or bothwere treated with ivceftriaxone (2 g/d for2 weeks) [93]. Inaddition to clinical signsand symptoms, outcome measuresincluded CSF analyses andneuropsychological tests of memory.Response to therapy wasusually gradual and didnot begin until severalmonths after treatment. Whenresponse was measured 6months after treatment, 17patients (63%) had uncomplicatedimprovement, 6 (22%) hadimprovement but then relapsed,and 4 (15%) hadno change in theircondition.

In a subsequent study,the same investigators treated18 adult patients withLyme encephalopathy with ivceftriaxone (2 g/d for30 days) [94]. Ofthe 18 patients, 16had abnormal verbal orvisual memory scores onneuropsychological tests and 16had CSF abnormalities, mostcommonly production of intrathecalantibody to B. burgdorferi oran elevated total proteinlevel. As determined 6months after treatment, 14(93%) of the 15patients examined had diminishedsymptoms, and verbal memoryscores for the 15patients were significantly improved(P < .01). Thetotal CSF protein valueswere significantly less forthe 10 patients whohad follow-up analyses (P< .05). At 1224months, all patients’ conditionswere back to normalor improved (1 ofthe 18 patients wasgiven repeat treatment after8 months).

It was concludedthat Lyme encephalopathy maybe associated with activeinfection of the nervoussystem and that theinfection in most patientscan be treated successfullywith a 30-day courseof iv ceftriaxone. Whethera 30-day course issuperior to 14 daysof treatment is unclear.Although the data aremuch more limited, theconditions of children withneurocognitive abnormalities attributed toLyme disease also appearto improve after 24weeks of iv ceftriaxone[95].

The third-generation cephalosporin cefotaximehas been tested inEurope and has beenfound to be effectivein the treatment oflate Lyme disease [96].Although cefotaxime has tobe administered 34 timesdaily (compared with oncedaily administration of ceftriaxone),it does not causethe biliary complications thathave been associated withceftriaxone therapy [97].

Recommendations

Lyme arthritis. Lyme arthritiscan usually be treatedsuccessfully with antimicrobial agentsadministered orally or iv(tables 3 and 4).Administration of doxycycline oramoxicillin, in each instancefor 28 days, isrecommended for patients withoutclinical evidence of neurologicaldisease (B-II). For children,doxycycline (for those aged8 years) or amoxicillinis recommended (tables 3and 4) (B-II). Oraltherapy is easier toadminister than iv antibiotics,is associated with fewerserious complications, and isconsiderably less expensive. Itsdisadvantage is that somepatients treated with oralagents have subsequently manifestedovert neuroborreliosis, which mayrequire iv therapy forsuccessful treatment. Further controlledtrials are needed tocompare oral with ivtherapy.

Neurological evaluation, including lumbarpuncture, should be donefor patients for whomthere is a strongclinical suspicion of neurologicalinvolvement. Patients with arthritisand objective evidence ofneurological disease should receiveparenteral therapy with ceftriaxone(tables 3 and 4)(A-II). Alternative parenteral agentsinclude cefotaxime (B-III) andpenicillin G (B-II). Thelong-acting benzathine preparation ofpenicillin achieves only lowlevels in the bloodand therefore is notrecommended (D-III). For children,ceftriaxone iv (B-III) orcefotaxime (B-III) is recommended(tables 3 and 4);penicillin G administered ivis an alternative (B-III).

Forpatients who have persistentor recurrent joint swellingafter recommended courses ofantibiotic therapy, we recommendrepeat treatment with another4-week course of oralantibiotics or with a2- to 4-week courseof ceftriaxone iv (tables3 and 4) (B-III).Clinicians should consider waitingseveral months before initiatingrepeat treatment with antimicrobialagents, because of theanticipated slow resolution ofinflammation after treatment. Ifpatients have persistent arthritisdespite 2 courses oforal therapy or 1course of iv therapy,symptomatic treatment with nonsteroidalanti-inflammatory agents is recommended;intra-articular steroids may alsobe of benefit (B-III).If persistent synovitis isassociated with significant painor if it limitsfunction, arthroscopic synovectomy canreduce the period ofjoint inflammation (B-II).

Late neuroborreliosis affecting the CNS or the peripheral nervous system. For patientswith late neurological diseaseaffecting the CNS orperipheral nervous system, treatmentwith ceftriaxone (2 gonce a day ivfor 24 weeks) isrecommended (tables 3 and4) (B-II). Alternative parenteraltherapy may include administrationof cefotaxime (B-II) orpenicillin G (B-II). Responseto treatment is usuallyslow and may beincomplete. However, unless relapseis shown by reliableobjective measures, repeat treatmentis not recommended. Forchildren, treatment with ceftriaxoneis recommended (tables 3and 4) (B-II). Cefotaximeor penicillin G administerediv are alternatives (B-II).

Chronic Lyme Disease or PostLyme Disease Syndrome

Followingan episode of Lymedisease that is treatedappropriately, some persons havea variety of subjectivecomplaints (such as myalgia,arthralgia, or fatigue). Someof these patients havebeen classified as having”chronic Lyme disease” or”postLyme disease syndrome,” whichare poorly defined entities.These patients appear tobe a heterogeneous group.Although European patients rarelyhave been reported tohave residual infection (orperhaps reinfection) with B. burgdorferi[98], this has yetto be substantiated eitherin a large seriesof appropriately treated Europeanpatients or in astudy of North Americanpatients. Residual subjective symptomsthat last weeks ormonths also may persistafter other medical diseases(both infectious and noninfectious).It has also beenrecognized that the prevalenceof fatigue and/or arthralgiasin the general populationis >10% [5256, 58,59, 99].

In areas ofendemicity, coinfection with B. microtior the Ehrlichia speciesthat causes HGE mayexplain persistent symptoms fora small number ofthese patients [17, 19].Randomized controlled studies oftreatment of patients whoremain unwell after standardcourses of antibiotic therapyfor Lyme disease arein progress. To date,there are no convincingpublished data showing thatrepeated or prolonged coursesof oral or ivantimicrobial therapy are effectivefor such patients. Theconsensus of the IDSAexpert-panel members is thatthere is insufficient evidenceto regard “chronic Lymedisease” as a separatediagnostic entity.

Acknowledgments

We thank Drs.Peter Gross, John Nowakowski,Karl Li, and JoséMunoz for helpful comments,as well as BettyBosler, Eleanor Bramesco, andLisa Giarratano for assistance.

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