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## Complete Summary

#### GUIDELINE TITLE

Infectious Diseases Society of America practice guidelines for clinical
assessment, treatment and prevention of Lyme disease, human granulocytic
anaplasmosis, and babesiosis.

#### BIBLIOGRAPHIC SOURCE(S)

Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner
MS, Krause PJ, Bakken JS, Strle F, Stanek G, Bockenstedt L, Fish D,
Dumler JS, Nadelman RB. The clinical assessment, treatment, and
prevention of lyme disease, human granulocytic anaplasmosis, and
babesiosis: clinical practice guidelines by the Infectious Diseases
Society of America. Clin Infect Dis 2006 Nov 1;43(9):1089-134.
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17029130)

#### GUIDELINE STATUS

This is the current release of the guideline.

This guideline updates a previous version: Wormser GP, Nadelman RB,
Dattwyler RJ, Dennis DT, Shapiro ED, Steere AC, Rush TJ, Rahn DW, Coyle
PK, Persing DH, Fish D, Luft BJ. Practice guidelines for the treatment
of Lyme disease. Clin Infect Dis 2000 Jul;31(Suppl 1):1-14.

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse**: This guideline
references a drug(s) for which important revised regulatory and/or
warning information has been released.

-   [September 11, 2007, Rocephin (ceftriaxone
    sodium)](http://www.fda.gov/medwatch/safety/2007/safety07.htm#Rocephin):
    Roche informed healthcare professionals about revisions made to the
    prescribing information for Rocephin to clarify the potential risk
    associated with concomitant use of Rocephin with calcium or
    calcium-containing solutions or products.

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 CONTRAINDICATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

-   Lyme disease

-   Human granulocytic anaplasmosis (HGA) (formerly known as human
    granulocytic ehrlichiosis)

-   Babesiosis

#### GUIDELINE CATEGORY

Evaluation\
Management\
Prevention\
Treatment

#### CLINICAL SPECIALTY

Cardiology\
Dermatology\
Family Practice\
Infectious Diseases\
Internal Medicine\
Neurology\
Obstetrics and Gynecology\
Ophthalmology\
Otolaryngology\
Pediatrics\
Rheumatology

#### INTENDED USERS

Allied Health Personnel\
Physicians

#### GUIDELINE OBJECTIVE(S)

-   To provide clinicians and other health care practitioners with
    recommendations for the management of patients in the United States
    with suspected or established Lyme disease, human granulocytic
    anaplasmosis (HGA, formerly known as human granulocytic
    ehrlichiosis), or babesiosis

-   To provide recommendations for prevention of these infections, all
    of which may be transmitted by certain species of *Ixodes* ticks

#### TARGET POPULATION

Patients with suspected or established Lyme disease, human granulocytic
anaplasmosis, or babesiosis

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Prevention**

1.  Avoidance of tick-infested areas

2.  Use of protective clothing

3.  Inspection of entire body to locate and remove ticks

4.  Tick and insect repellents

5.  Single-dose doxycycline prophylaxis after tick bite in special cases

**Evaluation**

1.  Recognition of clinical manifestations and complications of early
    and late Lyme disease, human granulocytic anaplasmosis, and
    babesiosis

2.  Diagnostic tests for Lyme disease

3.  Lumbar puncture and examination of cerebrospinal fluid in patients
    with suspected central nervous involvement of Lyme disease

4.  Examination of synovial fluid when arthritis or joint swelling is
    present

5.  Recognition of symptoms of post-Lyme disease syndrome

6.  Diagnostic tests for human granulocytic anaplasmosis and babesial
    infection, including blood smear evaluation, polymerase chain
    reaction (PCR), and serology

**Treatment/Management**

*Lyme Disease*

1.  Oral antibiotics including doxycycline, amoxicillin, and cefuroxime
    axetil (macrolides, including azithromycin, erythromycin, or
    clarithromycin only in patients who cannot take doxycycline,
    amoxicillin, or cefuroxime axetil)

2.  Parenteral antibiotics including ceftriaxone, cefotaxime, and
    penicillin G for Lyme Disease with neurologic involvement, severe
    heart involvement, and selected cases of Lyme arthritis

3.  Hospitalization, monitoring, and temporary pacemaker for Lyme
    carditis

4.  Symptomatic therapy for antibiotic-refractory Lyme arthritis,
    including nonsteroidal anti-inflammatory drugs (NSAIDs),
    intra-articular injections of corticosteroids, and disease-modifying
    anti-rheumatic drugs such as hydroxychloroquine

5.  Consultation with cardiologist or rheumatologist, as necessary

*Human Granulocytic Anaplasmosis*

1.  Doxycycline

2.  Rifampin

*Babesiosis*

1.  Combination of atovaquone plus azithromycin

2.  Combination of clindamycin plus quinine

3.  Partial or complete red blood cell exchange transfusion as indicated

#### MAJOR OUTCOMES CONSIDERED

-   Incidence and persistence of *Borrelia burgdorferi* infection

-   Incidence of Lyme disease, human granulocytic anaplasmosis, and
    babesiosis

-   Morbidity of disease

-   Efficacy of antibiotic chemoprophylaxis and treatment regimens

-   Resolution of symptoms

-   Adverse effects of antimicrobial therapy

-   Quality of life

-   Cost effectiveness of antimicrobial therapy

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

The guideline panel performed an extensive review of all of the
randomised controlled trials and open-label trials published in
peer-reviewed English language journals.

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

*Categories for Quality of Evidence on which Recommendations are Made*

I.  Evidence from at least one properly randomized, controlled trial

II. Evidence from at least one well-designed clinical trial without
    randomization, from cohort or case-controlled analytic studies
    (preferably from more than one center), from multiple time-series
    studies, or from dramatic results of uncontrolled experiments

III. Evidence from opinions of respected authorities on the basis of
     clinical experience, descriptive studies, or reports of expert
     committees

#### METHODS USED TO ANALYZE THE EVIDENCE

Review of Published Meta-Analyses\
Systematic Review

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

Not stated

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Not stated

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

**Strength of Recommendation**

A.  Strongly in favor

B.  Moderately in favor

C.  Optional

D.  Moderately against

E.  Strongly against

#### COST ANALYSIS

**Tick Bites and Prophylaxis**

One cost-effectiveness analysis concluded that a 2-week course of
doxycycline is indicated when the probability of infection with
*Borrelia burgdorferi* after a tick bite is [\>]{.underline}3.6% and
should be considered when the theoretical probability ranges from 1% to
3.5%. Some experts disagree with key assumptions in the model (many of
which tended to favor the use of antimicrobial prophylaxis) and consider
the duration of treatment to be excessive.  However, the findings do
argue against routine prophylaxis of all *Ixodes scapularis* tick bites,
since the frequency of Lyme disease was less than 3.6% among placebo
recipients in each of the four reported chemoprophylaxis trials.

**Late Lyme Disease**

In a cost-effectiveness analysis, intravenous (IV) therapy was found to
be no more cost-effective than oral therapy for patients with Lyme
arthritis; IV therapy was more likely to result in serious complications
and was substantially more expensive. Therefore, the authors concluded
that oral antibiotics are to be preferred in the initial treatment of
Lyme arthritis in the absence of concomitant neurological involvement.

#### METHOD OF GUIDELINE VALIDATION

Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

Not stated

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

Each recommendation includes a ranking for the strength and the quality
of evidence supporting it. Definitions of the levels of evidence (I-III)
and grades of recommendation (A-E) are repeated at the end of the Major
Recommendations field.

*Note: See Tables 3 and 4 of the original guideline document for
recommended antimicrobial regimens for the treatment of Lyme disease in
adults and children.*

**[Tick Bites and Prophylaxis of Lyme Disease]{.underline}**

The best currently available method for preventing infection with
*Borrelia burgdorferi* and other *Ixodes* species-transmitted pathogens
is to avoid exposure to vector ticks. If exposure to *I. scapularis* or
*I. pacificus* ticks is unavoidable, measures recommended to reduce the
risk of infection include the use of both protective clothing and tick
repellents, checking the entire body for ticks daily, and prompt removal
of attached ticks before transmission of these microorganisms can occur
**(B-III)**.

For prevention of Lyme disease after a recognized tick bite, routine use
of antimicrobial prophylaxis or serologic testing is not recommended
**(E-III)**. A single dose of doxycycline may be offered to adult
patients (200 mg dose) and to children [\>]{.underline}8 years of age (4
mg/kg up to a maximum dose of 200 mg) **(B-I)** when *all* of the
following circumstances exist: a) the attached tick can be reliably
identified as an adult or nymphal *I. scapularis* tick that is estimated
to have been attached for [\>]{.underline} 36 hours based on the degree
of engorgement of the tick with blood or on certainty about the time of
exposure to the tick; b) prophylaxis can be started within 72 hours of
the time that the tick was removed; c) ecologic information indicates
that the local rate of infection of these ticks with *B. burgdorferi* is
[\>]{.underline}20%; *and* d) doxycycline is not contraindicated. The
time limit of 72 hours is suggested because of the absence of data on
the efficacy of chemoprophylaxis for tick bites following tick removal
after longer time intervals. Infection of [\>]{.underline}20% of ticks
with *B. burgdorferi* generally occurs in parts of New England, in parts
of the Middle Atlantic States, and in parts of Minnesota and Wisconsin,
but not in most other locations in the United States. Whether use of
antibiotic prophylaxis after a tick bite will reduce the incidence of
human granulocytic anaplasmosis (HGA) or babesiosis is unknown.

Doxycycline is relatively contraindicated in pregnant women and children
\<8 years old. The panel does not believe that amoxicillin should be
substituted for doxycycline in persons for whom doxycycline prophylaxis
is contraindicated because of the absence of data on an effective
short-course regimen for prophylaxis, the likely need for a multi-day
regimen (and its associated adverse effects), the excellent efficacy of
antibiotic treatment of Lyme disease if infection were to develop, and
the extremely low risk that a person with a recognized bite will develop
a serious complication of Lyme disease **(D-III)**.

Prophylaxis after *I. pacificus* bites is generally not necessary
because infection rates with *B. burgdorferi* in these ticks are low in
almost the entire region in which the tick is endemic. However, if a
higher infection rate were documented in specific local areas
([\>]{.underline}20%), prophylaxis with single-dose doxycycline would be
justified if the other criteria mentioned above are met.

In order to prescribe antibiotic prophylaxis selectively to prevent Lyme
disease, health care practitioners in endemic areas should learn to
identify *I. scapularis* ticks, including its stages (see Figure 1 in
the original guideline document), and to differentiate ticks which are
at least partially engorged with blood (see Figures 2 A and B in the
original guideline document) **(A-III)**. Testing of ticks for
tick-borne infectious agents is not recommended, except in research
studies **(D-II)**.

Health care practitioners, particularly those in endemic areas, should
become familiar with the clinical manifestations and recommended
practices for diagnosing and treating Lyme disease, HGA, and babesiosis
**(A-III)**. Persons who have removed attached ticks from themselves
(including those who have received antibiotic prophylaxis) should be
monitored closely for signs and symptoms of tick-borne diseases for up
to 30 days and in particular for the development of an expanding skin
lesion at the site of the tick bite (erythema migrans) that may suggest
Lyme disease. Persons who develop a skin lesion or viral infection-like
illness within a month after removing an attached tick should promptly
seek medical attention to assess the possibility of having acquired a
tick-borne infection. HGA and babesiosis should be included in the
differential diagnosis of patients who develop fever after an *Ixodes*
tick bite in an area endemic for these infections **(A-II)**. A history
of having received the previously licensed recombinant outer surface
protein A (OspA) Lyme disease vaccine preparation should not alter the
above recommendations. The same can be said for having had a prior
episode of early Lyme disease.

**[Early Lyme Disease]{.underline}**

**Erythema Migrans**

Doxycycline (100 mg twice daily), amoxicillin (500 mg three times
daily), or cefuroxime axetil (500 mg twice daily) for 14 days (range 10
to 21 days for doxycycline and 14 to 21 days for amoxicillin or
cefuroxime axetil) is recommended for treatment of adult patients with
early localized or early disseminated Lyme disease associated with
erythema migrans, in the absence of specific neurologic manifestations
(see below) or advanced atrioventricular heart block **(A-I)**. Each of
these antimicrobial agents has been shown to be highly effective in the
treatment of erythema migrans and associated symptoms in prospective
studies. Doxycycline has the advantage of being effective for treatment
of HGA (but not for babesiosis), which may occur simultaneously with
early Lyme disease. Doxycycline is relatively contraindicated during
pregnancy or lactation, and in children \<8 years of age. Antibiotics
recommended for children are amoxicillin (50 mg/kg per day in three
divided doses \[maximum of 500 mg per dose\]), cefuroxime axetil (30
mg/kg per day in two divided doses \[maximum of 500 mg per dose\]), or
doxycycline if [\>]{.underline}8 years of age (4 mg/kg per day in two
divided doses \[maximum of 100 mg per dose\]) **(A-II)**.

Macrolide antibiotics are not recommended as first-line therapy for
early Lyme disease because those macrolides that have been compared with
other antimicrobials in clinical trials have been found to be less
effective **(E-I)**. When used, they should be reserved for patients who
are intolerant of, or should not take, amoxicillin, doxycycline, and
cefuroxime axetil. For adults with these limitations, recommended dosage
regimens of macrolide antibiotics are azithromycin 500 mg orally daily
for 7 to 10 days, clarithromycin 500 mg orally twice daily for 14 to 21
days (if not pregnant), or erythromycin 500 mg orally four times per day
for 14 to 21 days. The recommended dosages of these agents for children
are azithromycin 10 mg/kg daily (maximum of 500 mg per day);
clarithromycin 7.5 mg/kg twice daily (maximum of 500 mg per dose);
erythromycin 12.5 mg/kg four times daily (maximum of 500 mg per dose).
Patients treated with macrolides should be closely followed to ensure
resolution of the clinical manifestations.

First generation cephalosporins such as cephalexin are ineffective for
treatment of Lyme disease and should not be used **(E-II)**. When
erythema migrans cannot be reliably distinguished from
community-acquired bacterial cellulitis, a reasonable approach is to
treat with either cefuroxime axetil or amoxicillin-clavulanic acid
(dosage of amoxicillin-clavulanic acid for adults: 500 mg three times
daily; dosage for children: 50 mg/kg per day in three divided doses
\[maximum of 500 mg per dose\]), since these antimicrobials are
generally effective against both types of infection **(A-III)**.

Ceftriaxone, while effective, is not superior to oral agents and is more
likely than the recommended orally administered antimicrobials to cause
serious adverse effects. Therefore, ceftriaxone is not recommended for
treatment of patients with early Lyme disease in the absence of
neurologic involvement or advanced atrioventricular heart block
**(E-I)**.

**Lyme Meningitis and Other Manifestations of Early Neurologic Lyme
Disease**

The use of ceftriaxone (2 g once daily intravenously \[IV\] for 14 days
\[range 10 to 28 days\]) in early Lyme disease is recommended for adult
patients with acute neurologic disease manifested by meningitis or
radiculopathy **(B-I)**. Parenteral therapy with cefotaxime (2 g IV
every 8 h) or penicillin G (18 to 24 million units daily for patients
with normal renal function, divided into doses given every 4 h), may be
a satisfactory alternative **(B-I)**. For patients who are intolerant of
beta-lactam antibiotics, increasing evidence indicates that doxycycline
200-400 mg per day in two divided doses orally for 10 to 28 days may be
adequate **(B-I)**. Doxycycline is well absorbed orally and thus IV
administration should only rarely be needed.

For children, ceftriaxone (50 to 75 mg/kg/day in a single daily IV dose
(maximum, 2 g) **(B-I)** is recommended. An alternative is cefotaxime
(150 to 200 mg/kg/day) divided into 3 or 4 IV doses per day (maximum, 6
g/day) **(B-II)** or penicillin G (200,000 to 400,000 units/kg/day;
maximum, 18 to 24 million units/day) divided into doses given IV every 4
h for those with normal renal function **(B-I)**. Children
[\>]{.underline} 8 years of age have also been successfully treated with
oral doxycycline at a dose of 4 mg/kg/day in two divided doses (maximum
100 mg per dose) **(B-II)**.

Although antibiotic treatment may not hasten the resolution of seventh
cranial nerve palsy associated with *B. burgdorferi* infection,
antibiotics should be given to prevent further sequelae **(A-II)**.
Cranial nerve palsies in patients with Lyme disease are often associated
with a lymphocytic cerebrospinal fluid (CSF) pleocytosis, with or
without symptoms of meningitis. Panel members differed in their approach
to the neurologic evaluation of patients with Lyme disease-associated
seventh cranial nerve palsy. Some perform a CSF examination on all such
patients. Others do not because of the good clinical response with
orally administered antibiotics (even in the presence of a CSF
pleocytosis) and the absence of evidence of recurrent central nervous
system (CNS) disease in these patients. There was agreement that lumbar
puncture is indicated for those in whom there is strong clinical
suspicion of CNS involvement (e.g., severe or prolonged headache or
nuchal rigidity). Patients with normal CSF examinations and those in
whom CSF examination is deemed unnecessary because of lack of clinical
signs of meningitis, may be treated with a 14 day course (range 14 to 21
days) of the same antibiotics used for patients with erythema migrans
(see above) **(B-III)**. Those with both clinical and laboratory
evidence of CNS involvement should be treated with regimens effective
for Lyme meningitis as described above **(B-III)**.

**Lyme Carditis**

Patients with atrioventricular (AV) heart block and/or myopericarditis
associated with early Lyme disease may be treated with either oral or
parenteral antibiotic therapy for 14 days (range 14 to 21 days).
Hospitalization and continuous monitoring are advisable for symptomatic
patients, such as those with syncope, dyspnea, or chest pain. It is also
recommended for patients with second or third degree AV block, as well
as for those with first degree heart block when the PR interval is
prolonged to [\<]{.underline}300 msec, because the degree of block may
fluctuate and worsen very rapidly in such patients.

A parenteral antibiotic such as ceftriaxone is recommended as initial
treatment of hospitalized patients (see recommendations for treatment of
Lyme meningitis above) **(B-III)**. For patients with advanced heart
block a temporary pacemaker may be required; expert consultation with a
cardiologist is recommended. The pacemaker may be discontinued when the
advanced heart block has resolved. An oral antibiotic regimen should be
used for completion of therapy and for out-patients, as is used for
patients with erythema migrans without carditis (see above) **(B-III)**.

**Borrelial Lymphocytoma**

Available data indicate that borrelial lymphocytoma may be treated with
the same treatment regimens used to treat patients with erythema migrans
(see above) **(B-II)**.

**Pregnancy**

Pregnant and lactating patients may be treated in a fashion identical to
non-pregnant patients with the same disease manifestation, except that
doxycycline should be avoided **(B-III)**.

**[Late Lyme Disease]{.underline}**

**Lyme Arthritis**

Lyme arthritis can usually be treated successfully with antimicrobial
agents administered orally. Doxycycline (100 mg twice daily) **(B-I)**,
amoxicillin (500 mg three times daily) **(B-I)** or cefuroxime axetil
(500 mg twice daily) **(B-III)** for 28 days, is recommended for adult
patients without clinical evidence of neurologic disease. For children,
amoxicillin (50 mg/kg/day in three divided doses \[maximum of 500 mg per
dose\]) **(B-I)**, cefuroxime axetil (30 mg/kg/day in two divided doses
\[maximum of 500 mg per dose\]) **(B-III)**, or doxycycline if
[\>]{.underline}8 years of age (4 mg/kg/day in two divided doses
\[maximum of 100 mg per dose\]) **(B-I)** is recommended. Oral therapy
is easier to administer than IV antibiotics, is associated with fewer
serious complications and is considerably less expensive. However, it is
important to recognize that a small number of patients treated with oral
agents have subsequently manifested overt neuroborreliosis, which may
require IV therapy with a beta-lactam antibiotic (see below) for
successful resolution. Further controlled trials are needed to compare
the safety and efficacy of oral with IV therapy for Lyme arthritis.

Neurologic evaluation that may include lumbar puncture should be
performed for patients in whom there is a clinical suspicion of
neurologic involvement. Adult patients with arthritis and objective
evidence of neurologic disease should receive parenteral therapy with
ceftriaxone **(A-II)** for 2 to 4 weeks. Cefotaxime or penicillin G
administered parenterally is an acceptable alternative **(B-II)**. For
children, IV ceftriaxone or IV cefotaxime is recommended **(B-III)**;
penicillin G administered IV is an alternative **(B-III)**. See above
recommendations for treatment of patients with Lyme meningitis for
suggested doses of each of these antimicrobials.

For patients who have persistent or recurrent joint swelling after a
recommended course of oral antibiotic therapy, the panel members
recommend retreatment with another 4-week course of oral antibiotics or
with a 2 to 4 week course of ceftriaxone IV **(B-III)** (for dosages of
oral agents see the recommendations for treatment of erythema migrans
above and for dosages of parenteral agents see the above recommendations
for treatment of Lyme meningitis). A second 4-week course of oral
antibiotic therapy is favored by panel members for the patient whose
arthritis has substantively improved but has not yet completely
resolved, reserving IV antibiotic therapy for those patients whose
arthritis failed to improve at all or worsened. Clinicians should
consider waiting several months before initiating re-treatment with
antimicrobial agents because of the anticipated slow resolution of
inflammation after treatment. If patients have no resolution of
arthritis despite IV therapy and if polymerase chain reaction (PCR)
results on a sample of synovial fluid (and synovial tissue if available)
are negative, symptomatic treatment is recommended **(B-III)**.
Symptomatic therapy might consist of non-steroidal anti-inflammatory
agents, intra-articular injections of corticosteroids, or disease
modifying anti-rheumatic drugs (DMARDs) such as hydroxychloroquine;
expert consultation with a rheumatologist is recommended. If persistent
synovitis is associated with significant pain or limitation of function,
arthroscopic synovectomy may reduce the duration of joint inflammation
**(B-II)**.

**Late Neurologic Lyme Disease**

Adult patients with late neurologic disease affecting the central or
peripheral nervous system should be treated with IV ceftriaxone for 2 to
4 weeks **(B-II)**. Cefotaxime or penicillin G administered IV is an
alternative **(B-II)**. Response to treatment is usually slow and may be
incomplete. Retreatment is not recommended unless relapse is shown by
reliable objective measures. Ceftriaxone is also recommended for
children with late neurologic Lyme disease **(B-II)**. Cefotaxime or
penicillin G administered IV is an alternative **(B-III)**. See above
recommendations on the treatment of Lyme meningitis for suggested doses
of each of these antimicrobials.

**Acrodermatitis Chronica Atrophicans**

Available data indicate that acrodermatitis chronica atrophicans may be
treated with a 21-day course of the same antibiotics (doxycycline
**\[B-II\]**; amoxicillin **\[B-II\]**; cefuroxime axetil **\[B-III\]**)
used to treat patients with erythema migrans (see above). A controlled
study is warranted to compare oral with parenteral antibiotic therapy
for the treatment of acrodermatitis chronica atrophicans.

**Coinfection**

Coinfection with *Babesia microti* or *Anaplasma phagocytophilum* or
both may occur in patients with early Lyme disease (usually in patients
with erythema migrans) in geographic areas that are endemic for these
pathogens. Coinfection should be considered in patients who present with
more severe initial symptoms than are commonly observed with Lyme
disease alone, especially in those who have high-grade fever for more
than 48 hours despite antibiotic therapy appropriate for Lyme disease or
who have unexplained leukopenia, thrombocytopenia, or anemia
**(A-III)**. Coinfection might also be considered in the situation in
which there has been resolution of the erythema migrans skin lesion but
either no improvement or worsening of viral infection-like symptoms
**(B-III)**.

**Post-Lyme Disease Syndromes**

There is no well-accepted definition of post-Lyme disease syndrome. This
has contributed to confusion and controversy, and to lack of firm data
on its incidence, prevalence, and pathogenesis. In an attempt to provide
a framework for future research on this subject and to reduce diagnostic
ambiguity in study populations, a definition for post-Lyme disease
syndrome is proposed in the original guideline document (Table 6).
Whatever definition is eventually adopted, having once had objective
evidence of *B. burgdorferi* infection must be a conditio sine qua non.
Furthermore, when laboratory testing is done to support the original
diagnosis of Lyme disease, it is essential that it be performed by
well-qualified and reputable laboratories which use recommended and
appropriately validated testing methods and interpretive criteria.
Unvalidated test methods (such as urine antigen tests or blood
microscopy for borrelia) should not be used.

There is no convincing biologic evidence for the existence of
symptomatic chronic *B. burgdorferi* infection among patients after
recommended treatment regimens for Lyme disease. Antibiotic therapy has
not proven to be useful and is not recommended for patients with chronic
([\>]{.underline}6 months) subjective symptoms after recommended
treatment regimens for Lyme disease **(E-I)**.

**Therapeutic Modalities Not Recommended**

Due to lack of biologic plausibility, lack of efficacy, absence of
supporting data, or the potential for harm to the patient, the following
are *not* recommended for treatment of patients with any manifestation
of Lyme disease: first generation cephalosporins, fluoroquinolones,
carbapenems, vancomycin, metronidazole, tinidazole, amantadine,
ketolides, isoniazid, trimethoprim-sulfamethoxazole, fluconazole,
benzathine penicillin G, combinations of antimicrobials, pulsed-dosing
(i.e., dosing on some days but not others), long-term antibiotic
therapy, anti-bartonella therapies, hyperbaric oxygen, ozone, fever
therapy, intravenous immunoglobulin, cholestyramine, intravenous
hydrogen peroxide, specific nutritional supplements, and others (see
full text and Table 5 in the original guideline document) **(E-III)**.

**Human Granulocytic Anaplasmosis**

All symptomatic patients suspected to have HGA should be treated with
antimicrobial therapy because of the risk of complications **(A-III)**.
Suspicion for HGA is based on the acute onset of unexplained fever,
chills and headache, often in association with thrombocytopenia,
leukopenia, and/or increased liver enzymes in patients with exposure to
*I. scapularis* or *I. pacificus* ticks within the prior 3 weeks.
Confirmation of the diagnosis is based on laboratory testing (see full
text of the original guideline document), but antibiotic therapy should
*not* be delayed in a patient with a suggestive clinical presentation
pending the results. Identification of the characteristic
intra-granulocytic inclusions on blood smear is the most rapid
diagnostic method, but such inclusions are often scant in number or
sometimes absent; in addition, other types of inclusions unrelated to
HGA or overlying platelets can be misinterpreted by inexperienced
observers. Testing for antibody to *A. phagocytophilum* is the most
sensitive diagnostic method but only if a convalescent serum sample is
assayed.

Doxycycline is recommended as the treatment of choice for patients who
are suspected to have symptomatic HGA **(A-II)**. The dosage regimen for
adults is 100 mg given twice daily by mouth (or IV for those patients
unable to take an oral medication) for 10 days. This treatment regimen
should be adequate therapy for patients with HGA alone and for patients
who have coinfection with *B. burgdorferi*. Persistence of fever for
more than 48 hours after initiation of doxycycline suggests that the
diagnosis of HGA is incorrect or more remotely that the patient may be
coinfected with *Ba. microti*.

Although a 10 day treatment course of doxycycline may be offered to all
children as well **(C-III)**, the panel preferred a modified approach in
which severity of illness, age of the child, and the presence or absence
of coinfection with *B. burgdorferi* were each considered in order to
minimize an already low risk of drug toxicity. The suggested dosage of
doxycycline for children with HGA is 4 mg/kg/day in two divided doses
(maximum 100 mg per dose) given orally (or IV for children unable to
take an oral medication). Children at least 8 years of age may be
treated with a 10-day course of doxycycline. For severely ill children
younger than 8 years of age without concomitant Lyme disease, the panel
recommended an abbreviated treatment course of 4 to 5 days, i.e., for
approximately 3 days after resolution of fever **(B-III)**. Children
treated with an abbreviated course of therapy should be closely observed
to ensure resolution of clinical and laboratory abnormalities. If the
child has concomitant Lyme disease, then amoxicillin (50 mg/kg/day in
three divided doses \[maximum of 500 mg per dose\]) or cefuroxime axetil
(30 mg/kg/day in two divided doses \[maximum of 500 mg per dose\])
should be initiated at the conclusion of the course of doxycycline to
complete a 14 day total course of antibiotic therapy **(B-III)**.

Patients with mild illness due to HGA who are not optimally suited for
doxycycline treatment due to a history of drug allergy, pregnancy, or
age less than 8 years, may be treated with rifampin for 7 to 10 days
using a dosage regimen of 300 mg twice daily by mouth for adults and 10
mg/kg twice daily for children (maximum of 300 mg per dose) **(B-III)**.
Rifampin-treated patients should be closely observed to ensure
resolution of clinical and laboratory abnormalities. Since rifampin is
not effective therapy for Lyme disease, patients coinfected with *B.
burgdorferi* should also be treated with amoxicillin or cefuroxime
axetil as used for the treatment of erythema migrans (see above)
**(A-I)**. No other antimicrobial can be recommended for the treatment
of HGA **(E-III)**.

Treatment is not recommended for asymptomatic individuals who are
seropositive for antibodies to *A. phagocytophilum* **(E-III)**.

**Babesiosis**

All patients with active babesiosis should be treated with antimicrobial
therapy because of the risk of complications **(A-III)**. Diagnostic
criteria for active babesial infection should include the presence of
viral infection-like symptoms *and* identification of babesial parasites
in blood by smear evaluation or by PCR amplification of babesial DNA.
Symptomatic patients whose serum contains antibody to babesia but whose
blood lacks identifiable babesial parasites on smear or babesial DNA by
PCR should not receive treatment **(E-III)**. Treatment is also not
recommended for asymptomatic individuals regardless of the results of
serology, blood smears, or PCR **(E-III)**. Asymptomatic patients with
positive babesial smears and/or PCR should have these studies repeated
and a course of treatment considered if parasitemia persists for more
than 3 months **(B-III)**.

The combination of either atovaquone plus azithromycin or clindamycin
plus quinine for 7 to 10 days is the initial therapy that should be
considered for patients with babesiosis **(A-I)**. Clindamycin and
quinine should be given for those with severe babesiosis **(A-III)**. In
such patients clindamycin should be administered IV rather than orally
and exchange transfusion should be considered. Longer duration of
antimicrobial therapy may be necessary in highly and persistently
symptomatic patients until parasitemia is cleared, but no controlled
studies exist that define the risk/benefit ratio of more prolonged
therapy.

The dosage regimen of atovaquone plus azithromycin for adults is
atovaquone 750 mg orally every 12 hours and azithromycin 500 to 1,000 mg
on day 1 and 250 mg once a day thereafter by the oral route. For
immunocompromised patients with babesiosis, higher doses of azithromycin
(600 to 1,000 mg per day) may be used. The doses for children are
atovaquone 20 mg/kg every 12 hours (up to a maximum of 750 mg per dose)
and azithromycin 10 mg/kg/day once per day on day 1 (up to a maximum of
500 mg per dose) and 5 mg/kg/day once per day (up to a maximum of 250 mg
per dose) thereafter by the oral route.

The dosage regimen of clindamycin plus quinine for adults is clindamycin
300 to 600 mg every 6 hours IV, or 600 mg every 8 hours orally, and
quinine 650 mg every 6 to 8 hours orally. Doses for children are
clindamycin 7 to 10 mg/kg given IV or orally every 6 to 8 hours (up to a
maximum of 600 mg per dose) and quinine 8 mg/kg given orally every 8
hours (up to a maximum of 650 mg per dose).

Partial or complete red blood cell exchange transfusion is indicated for
those with severe babesiosis as indicated by high grade parasitemia
([\>]{.underline}10%), significant hemolysis, or renal, hepatic, or
pulmonary compromise **(A-III)**. No data are available to determine
whether partial exchange transfusion is preferable to whole blood
exchange; expert consultation with an infectious diseases expert and a
hematologist is recommended.

Patients with moderate to severe babesiosis should be monitored closely
during therapy to ensure clinical improvement and improvement of
parasitemia and other laboratory abnormalities **(A-III)**. In patients
with mild to moderate babesiosis, clinical improvement should occur
within 48 hours after antiprotozoal therapy is begun and symptoms should
completely resolve within three months of initiation of therapy. In
severely ill patients, the hematocrit and percentage of parasitized
erythrocytes should be monitored daily or every other day until the
patient has improved and the parasitemia has decreased to less than 5%.
Some patients may have persistence of low grade parasitemia for months
after specific antimicrobial therapy.

Physicians should consider the possibility of coinfection with *B.
burgdorferi* or *A. phagocytophilum* or both in patients with especially
severe or persistent symptoms despite appropriate anti-babesial therapy
**(A-III)**. Patients found to have coinfection should be treated with
additional antimicrobial therapy as described above. An underlying
immune deficiency (including asplenia or prior splenectomy, malignancy,
or human immunodeficiency virus \[HIV\] infection) also should be
considered in patients with severe or prolonged episodes of babesiosis.

Retreatment of patients with antibabesial therapy as outlined above
should be considered if babesial parasites or amplifiable babesial DNA
is detected in blood three or more months after initial therapy
regardless of symptom status **(A-III)**. However, such assays need not
be done routinely for immunocompetent patients who are asymptomatic.

**[Definitions of Strength of Recommendation and Quality of Evidence
Ratings]{.underline}**:

**Quality of Evidence**

I.  Evidence from at least one properly randomized, controlled trial

II. Evidence from at least one well-designed clinical trial without
    randomization, from cohort or case-control analytic studies
    (preferably from more than one center), from multiple time-series
    studies, or from dramatic results of uncontrolled experiments

III. Evidence from opinions of respected authorities on the basis of
     clinical experience, descriptive studies, or reports of expert
     committees

**Strength of Recommendation**

A.  Strongly in favor

B.  Moderately in favor

C.  Optional

D.  Moderately against

E.  Strongly against

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is identified and graded for each
recommendation (see \"Major Recommendations\").

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

-   Prevention of transmission of *Borrelia burgdorferi, Anaplasma
    phagocytophilum, and Babesia microti*

-   Appropriate assessment and treatment of Lyme disease, human
    granulocytic anaplasmosis, and babesiosis and prevention of late
    complications

#### POTENTIAL HARMS

-   Adverse effects of antimicrobial therapy

-   Drug-induced rashes occur with both amoxicillin and cefuroxime
    axetil. Doxycycline may cause photosensitivity, which may be
    problematic since early Lyme disease occurs most commonly during the
    summer months. Individuals treated with doxycycline are advised to
    avoid exposure to the sun while on therapy. Doxycycline should be
    taken with 8 oz of fluid to reduce the risk of esophageal irritation
    and with food to reduce gastrointestinal intolerance.

-   Oral therapy is easier to administer than intravenous antibiotics,
    is associated with fewer serious complications, and is considerably
    less expensive. Its disadvantage is that some patients treated with
    oral agents have subsequently manifested overt neuroborreliosis,
    which may require intravenous therapy for successful treatment.

### CONTRAINDICATIONS

#### CONTRAINDICATIONS

Doxycycline is relatively contraindicated during pregnancy or lactation,
and in children \< 8 years of age.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

It is important to realize that guidelines cannot always account for
individual variation among patients. They are not intended to supplant
physician judgment with respect to particular patients or special
clinical situations. IDSA considers adherence to these guidelines to be
voluntary, with the ultimate determination regarding their application
to be made by the physician in the light of each patient\'s individual
circumstances.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

#### IMPLEMENTATION TOOLS

Personal Digital Assistant (PDA) Downloads

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better\
Staying Healthy

#### IOM DOMAIN

Effectiveness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner
MS, Krause PJ, Bakken JS, Strle F, Stanek G, Bockenstedt L, Fish D,
Dumler JS, Nadelman RB. The clinical assessment, treatment, and
prevention of lyme disease, human granulocytic anaplasmosis, and
babesiosis: clinical practice guidelines by the Infectious Diseases
Society of America. Clin Infect Dis 2006 Nov 1;43(9):1089-134.
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17029130)

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2000 Jul (revised 2006 Jun)

#### GUIDELINE DEVELOPER(S)

Infectious Diseases Society of America - Medical Specialty Society

#### SOURCE(S) OF FUNDING

Infectious Diseases Society of America (IDSA)

#### GUIDELINE COMMITTEE

Infectious Diseases Society of America (IDSA) Standards and Practice
Guidelines Committee

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Authors*: Gary P. Wormser, MD, Division of Infectious Diseases,
Department of Medicine, New York Medical College; Raymond J. Dattwyler,
MD, Division of Allergy, Immunology and Rheumatology, Department of
Medicine, New York Medical College; Eugene D. Shapiro, MD, Departments
of Pediatrics and of Epidemiology and Public Health, Yale University
School of Medicine; John J. Halperin, MD, Atlantic Neuroscience
Institute, New York University School of Medicine; Allen C. Steere, MD,
Division of Rheumatology, Allergy and Immunology, Massachusetts General
Hospital, Harvard Medical School; Mark S. Klempner, MD, Boston
University School of Medicine and Boston Medical Center; Peter J.
Krause, MD, Department of Pediatrics, University of Connecticut School
of Medicine and Connecticut Children\'s Medical Center; Johan S. Bakken,
MD, PhD, Section of Infectious Diseases, St Luke\'s Hospital; Franc
Strle, MD, PhD, Department of Infectious Diseases, University Medical
Center, Ljubljana, Ljubljana; Gerold Stanek, MD, Medical University of
Vienna; Linda Bockenstedt, MD, Section of Rheumatology, Department of
Medicine, Yale University School of Medicine; Durland Fish, PhD,
Department of Epidemiology and Public Health, Yale University School of
Medicine; J. Stephen Dumler, MD, Division of Medical Microbiology,
Department of Pathology, The Johns Hopkins Medical Institutions; Robert
B. Nadelman, MD, Division of Infectious Diseases, Department of
Medicine, New York Medical College

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

G.P.W. has received consulting fees from Baxter and research support
from Immunetics, and he is a founder of Diaspex, a company that does not
offer products or services.

R.J.D. has served as a speaker for Pfizer and is part owner of
Biopeptides, a biotech company that develops vaccines and laboratory
diagnostics, including products for *Borrelia burgdorferi*.

J.J.H. has served as an expert witness on behalf of Lymerix
(GlaxoSmithKline).

A.C.S. has received consulting fees from Baxter.

P.J.K. has a patent pending with a university on a babesiosis diagnostic
procedure that is not yet on the market.

All other authors: No conflicts.

#### GUIDELINE STATUS

This is the current release of the guideline.

This guideline updates a previous version: Wormser GP, Nadelman RB,
Dattwyler RJ, Dennis DT, Shapiro ED, Steere AC, Rush TJ, Rahn DW, Coyle
PK, Persing DH, Fish D, Luft BJ. Practice guidelines for the treatment
of Lyme disease. Clin Infect Dis 2000 Jul;31(Suppl 1):1-14.

#### GUIDELINE AVAILABILITY

Electronic copies: Available from the [Infectious Diseases Society
(IDSA) Web
site](http://www.journals.uchicago.edu/cgi-bin/resolve?CID40897).

Print copies: Available from Gary P. Wormser, MD, Room 245, Munger
Pavilion, New York Medical College, Valhalla, NY 10595

#### AVAILABILITY OF COMPANION DOCUMENTS

The following is available:

-   Kish MA. Guide to development of practice guidelines. Clin Infect
    Dis 2001 Mar 15;32(6):851-4.

Electronic copies: Available from the [Clinical Infectious Diseases
Journal Web
site](http://www.journals.uchicago.edu/doi/full/10.1086/319366).

Print copies: Available from Infectious Diseases Society of America,
1300 Wilson Boulevard, Suite 300, Arlington, VA 22209.

A PDA version of the original guideline document is available from
[www.idsaguidelinesforhandhelds.org](http://www.idsaguidelinesforhandhelds.org/).

#### PATIENT RESOURCES

None available

#### NGC STATUS

This summary was completed by ECRI on May 1, 2001. The information was
verified by the guideline developer as of June 29, 2001. This summary
was updated on May 3, 2005 following the withdrawal of Bextra
(valdecoxib) from the market and the release of heightened warnings for
Celebrex (celecoxib) and other nonselective nonsteroidal
anti-inflammatory drugs (NSAIDs). This summary was updated by ECRI on
June 16, 2005, following the U.S. Food and Drug Administration advisory
on COX-2 selective and non-selective non-steroidal anti-inflammatory
drugs (NSAIDs). This NGC summary was updated on July 25, 2006. The
updated information was verified by the guideline developer on September
7, 2006. This summary was updated by ECRI Institute on October 3, 2007
following the U.S. Food and Drug Administration (FDA) advisory on
Rocephin (ceftriaxone sodium).

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is subject to
the guideline developer\'s copyright restrictions.

### DISCLAIMER

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Date Modified: 11/3/2008