Lyme borreliosis treatment

Dermatologic Therapy, Vol. 21, 2008, 101–109 Copyright Blackwell Publishing, Inc., 2008 Printed in the United States · All rights reserved Lyme borreliosis treatment
DANIELA VAñOUSOVÁ & JANA HERCOGOVÁDepartment of Dermatovenereology, 2nd Medical School, Charles University, University Hospital Bulovka, Prague, Czech Republic ABSTRACT: Lyme borreliosis is the most common human tick-borne illness in the Northern
Hemisphere. The causative agent is the spirochete Borrelia burgdorferi species complex, and the
hard-shell ticks of the genus Ixodes is responsible for pathogen transmission from animals to
humans. The incidence of the disease is increasing year by year and although lyme disease is not
fatal, it can affect the skin, heart, nervous, and musculoskeletal system with an impairment of quality
of life. The appropriate diagnosis of lyme disease should be promptly treated by antibiotics to prevent
late stage of the disease. The choice of antibiotics depends on many factors such as the stage of the
disease, the drug efficacy, adverse effects, type of delivery, duration of treatment, and cost. Treatment
failure occurs as a result of many reasons, re-infection is possible. The recommended treatment
schedule in the Czech Republic is presented.
KEYWORDS: acrodermatitis chronica atrophicans, Borrelia burgdorferi, borrelial lymphocytoma,
erythema migrans, treatment
Lyme borreliosis is the most common human family Spirochetaceae. It is named after the tick-borne illness in the Northern Hemisphere (1).
researcher Willy Burgdorfer, who first isolated the It has been known as an infectious disease since bacterium from a tick gut in 1982 (3). It is a spiral- 1975, although clinical signs have been described shaped, two membrane bacteria, that has two since the beginning of the 20th century (2). Although flagellae, linear chromosome, and 21 plasmids lyme disease is not fatal, it can cause skin, mus- that are extrachromosomal strands of DNA and culoskeletal, neurologic, and cardiovascular allow Borrelia to adapt very rapidly to changes in manifestation that may be difficult to treat. The causative agent is the spirochete Borrelia burgdorferi B. burgdorferi can be divided into several species.
species complex (3). Wild animals are the reservoir Genospecies Borrelia burgdorferi sensu stricto, for Borrelia and the hard-shelled ticks of the genus Borrelia Afzelii, and Borrelia garrinii referred to Ixodes are responsible for transmission of pathogen as B. burgdorferi sensu lato are pathogenic and to humans. The incidence of lyme borreliosis responsible for the clinical manifestation of lyme increases year by year. There were nearly twice as disease (5). B. burgdorferi sensu stricto is associ- many reported cases of lyme borreliosis in 2006 ated with arthritis and is the only pathogen of compared to 1997 in the Czech Republic. The incid- lyme disease in North America; B. garinii is ence is 42 cases per 100,000 inhabitants, and the associated with neurologic symptoms (6 – 8), and number of cases per year in 2006 was higher in com- B. afzelii with chronic skin manifestation, parison to the number of cases of erysipelas (4).
acrodermatitis chronica atrophicans (ACA) (9).
B. burgdorferi is a thin, extracellular bacterium All of them occur in Europe, but B. garinii and with a unique mode of motility belonging to the B. afzelii are more prevalent (10) and the latertwo species occur in Asia. All can cause the path- The study is supported by the grant of IGA MZ CR ognomic symptom of lyme borreliosis, erythema Address correspondence and reprint requests to: Daniela Ticks are the vectors of B. burgdorferi, Ixodes Vanousová, MD, Department of Dermatovenereology, 2nd Medical School, Charles University, University Hospital ricinus in Europe, Ixodes persulcatus in Euroasia Bulovka, Budínova 2, 180 81 Prague, Czech Republic, or and Ixodes scapularis in North America (9). Ixodes email: [email protected].
is infected by Borrelia when it feeds on infected VaNousová & Hercogová animals. All forms of Ixodes ticks feed on humans:larval, nymph, and adult form, but those in thenymph form are most commonly found. The res-ervoir of Borreliae is wild animals, rodents, and birds.
B. burgdorferi is transmitted as the tick is feed-ing, and the mechanism of spirochetal transmis-sion is through saliva. Ixodes ticks are slow feedersand require several days to become fully engorged.
That is the reason why early removal of ticks within24 hours reduces the possibility of infection. Only30–40% of patients are aware of a proceeding tickbite because of the small size of the nymph (1–2 mm).
Ticks can transmit also other microbiologic agents,i.e., Anaplasma phagocytophilum causing humangranulocytic anaplasmosis, Babesia divergens, and FIG. 2. Erythema migrans under the knee (right, upper part).
Babesia microti causing babesiosis.
Clinical symptoms
Lyme disease is a progressive disease that occursin three stages: early localized stage, early dissem-inated stage, and late disseminated stage. Clinicalpicture of lyme disease differs in North Americaand in Europe and it is the result of geneticdifferences between species of B. burgdorferi (1,11).
In 14 (the range can be from 1 to 180 days) daysafter tick bite, an expanding erythematous patchappears at the site of tick bite. Erythema migrans(FIGS. 1 and 2) is more than 5 cm in diameter andslowly expands. The character of the lesion canbe homogenous, annular, or target like. Erythema FIG. 3. Lymphocytoma borreliensis on the ear lobe (right,
koßer part).
migrans is the pathognomic sign of lyme borreliosis.
Untreated EM can persist for weeks and months.
On the other hand, it can disappear spontaneously of flu-like symptoms as headache, arthralgias, during some weeks. The infection can also pro- fatigue. This stage is the early localized stage.
ceed asymptomatically. Some patients complain borreliensis) is a rare cutaneous manifestation oflyme borreliosis that is diagnosed in up to 3% ofpatients with lyme borreliosis in Europe (FIG. 3).
It appears after 3 weeks (2 days to 6 months)near a tick bite (12). It presents as a red to bluishpapule or nodule with a diameter of up to a fewcentimeters typically localized usually on the earlobe in children, on the nipple–areola mammaein adults (12) or on other localization such as thescrotum. This lesion can appear in any stage oflyme borreliosis. It is very common amongchildren and rare in adults. Borrelial lymphocy-toma can be the only manifestation of the diseaseor it can be accompanied by other lyme diseasesymptoms most frequently by EM, but concomitantACA can be also observed (12). The duration of FIG. 1. Lymphocytoma borreliensis on the left mamilla
untreated BL takes several months to more than (left, upper part).
After weeks, Borreliae hematogenously spread, macula. The presence of EM is pathognomic.
causing general signs and symptoms with involvement Laboratory tests help assess infection in patients of other organs. Multiple EM, neurologic signs, with atypical skin lesions or when erythema carditis, and arthritis are typical for the second disappears. Enzyme-linked immunosorbent assay disseminated stage of lyme borreliosis. Multiple (ELISA) or indirect fluorescent antibody assay EM are secondary lesions. They are smaller (IFA) detecting IgM and IgG antibodies to B. and tend to be more uniform than solitary EM.
burgdorferi are the first step test recommended.
Neurologic involvement includes Bell’s palsy Interpretation of serologic results should be made neuritis affecting the peripheral seventh nerve, with caution as the presence of antiborrelial meningitis, meningoradiculitis. Arthritis is seen as antibodies indicates that the infection by the an intermittent, inflammatory mono- or oligo- spirochete has occurred, but does not indicate the arthritis mostly of large joints. Cardiac involvement presence of active infection. On the other hand, a manifests as an atrioventricular conduction defect.
negative result of serologic test does not exclude The late stage of lyme disease can manifest an infection. In EM, the present authors expect usually weeks or months and even years after increased levels of IgM antibodies in the first 4 contact with the spirochetal infection. This third weeks after onset of disease, followed by increased stage is characterized by arthritis and synovitis of levels of IgG antibodies. In ACA, the high level of large joints such as the knee, chronic neurologic IgG antibodies is expected. Sera from patients manifestation with peripheral neuropathy, and with treponemal infections (syphilis) cross-react CNS disorders as dementia or transverse myelitis.
significantly with Borrelia infection, and the sera Some changes can be irreversible. Cutaneous of some patients with lyme disease give a false- manifestations spread months to years in untreated positive Fluorescent treponemal antibody absorp- lyme disease. Acrodermatitis chronica atrophi- tion test (FTA-ABS) test result. Autoimmune diseases cans (FIG. 4) localized on the limbs is the typical and herpetic infections can give false-positive cutaneous manifestation of late stage in European results too. The use of immunoblots has increased patients (cases in America are very rare). It occurs the specificity of serologic testing for lyme disease as bluish red skin changes over the distal part of and is useful for verification of positive ELISA or the upper and lower extremities. Swelling occurs IFA results. Polymerase chain reaction detects the at the beginning, and skin atrophy in progress.
presence of B. burgdorferi-specific segments of Fibrotic nodules can develop above the joints and DNA in patient specimens – blood, cerebrospinal are typical. Other cutaneous disorders such as mor- fluid (CSF), urine, synovial fluid, and skin. The phea, lichen sclerosus et atrophicus, and granu- polymerase chain reaction method must be carefully loma annulare seem to have a spirochetal origin.
controlled to avoid false-positive results, becausethis method is highly sensitive. The best resultsare obtained from the skin, but they do not distinguish Diagnosis of lyme disease
between dead and viable spirochetal organism.
Borrelia organisms are microaerophilic and can Clinical diagnosis of an early stage of lyme borreliosis be cultured in vitro in BSK (Barbour, Stoenner, is based on the presence of expanding erythematous and Kelly) medium from skin, blood, CSF andsynovial fluid. It has long generation time 7–20 hours. It takes several weeks to obtain thecultivation result and therefore, Borrelia isolationdoes not belong to routine tests.
To assess the correct diagnosis of cutaneous manifestations, the histopathologic examinationof skin biopsy is needed. It applies especially inBL and ACA suspected lesions.
The diagnosis of EM is usually based on clinical picture when the lesion is typical and there is ahistory of attached tick. In case of nontypicalEM, serologic tests can help as well as the furtherclinical development of erythematous lesion. Thediagnosis of BL and ACA is based on increasedlevel of IgG antiborrelial antibodies and histo- FIG. 4. Acrodermatitis chronica atrophicans (left, koßer part).
pathologic examination of the skin specimen.
VaNousová & Hercogová Treatment
therapy. It is administered intravenously, andexcretion occurs in the kidney. Benzylpenicillin Lyme disease is treated by antibiotics. The aim of penetrates well into the skin, kidney, and mucous antibiotic treatment is to cure the presenting membrane, but badly into muscles, bones, nerve disease manifestation, to prevent the spreading of tissue, and brain. The penetration to CSF is low, bacteria, and thus to prevent later stage of the but it is increased in meningitis. Benzylpenicillin disease. B. burgdorferi sensu lato strains are does not penetrate into cells. The allergic reactions susceptible in vitro against doxycycline, amoxicillin, and risk of phlebitis when administered to peripheral azithromycin, cefuroxime axetil, benzylpenicillin venous are the most frequent side effects.
(14–17), and phenoxymethylpenicillin (18). Those Azithromycin is a macrolide antibiotic with antibiotics are widely used in the treatment of bacteriostatic activity. It shows good extracellular and intracellular distribution. The concentration Doxycycline is a broad-spectrum semisynthetic in tissues is much higher than in plasma. The antibiotic of the tetracycline family. It exhibits good penetration to CSF is low. Azithromycin is intra- and extracellular penetration with bacterio- absorbed in small intestine and excreted by the static activity on many bacteria. It has also an kidney. Because of long biological half time and antiinflammatory activity. Doxycycline is rapidly high accumulation in tissue, azithromycin is absorbed by the digestive tract and excreted by excreted by urine even on the fourth day after the kidney. It has a long biological half time and the administration. Hepatic impairment and penetrates well into the tissue. The penetration to hypersensitivity are the main contraindications.
CSF is low. The more frequent side effects are The increase in neurotoxicity and nephrotoxicity digestive problems with vomiting and diarrhea as may occur when administered with cyclosporine.
a result of the irritation of the mucous membrane.
The advantage is once-daily dosing and a possible The other side effect is phototoxicity that is dose dependent. The patient should not sun bathe Cefotaxime is a broad-spectrum third-generation during the treatment. Various cutaneous side cephalosporin. It is administrated intravenously effects were described too. Doxycycline is con- and has bactericide activity. Its analog is ceftriaxone.
traindicated also in pregnancy and during lacta- They differ in pharmacokinetics. Ceftriaxone has tion because of the possibility of causing dental a long biological half time that is advantageous stains and bone growth inhibition of the fetus.
for long generation time of B. burgdorferi and its Doxycycline should not be given to children under ability for regeneration of B. burgdorferi. It has a 9 years of age because of decreased growth rate good penetration to tissues, CSF, and synovial and tooth discoloration. It is not recommended to fluids as well. The prolonged prothrombin time in combine doxycycline treatment with a course of patients with the risk of bleeding is one of the retinoids. It is not necessary to reduce the dose side effects. Once-daily dosing is the advantage.
in renal failure. The advantage of doxycycline Ceftriaxone is highly recommended for neurologic, therapy is its therapeutic effect on a possible cardial, and articular manifestations during the co-infecting ehrlichial and rickettsial species.
second and third stages of lyme disease.
Doxycycline is the most effective in the early stage Cefuroxime axetil is a second-generation ceph- of the disease and in prevention of the chronic alosporin related to penicillin. Hypoprothrombinemia and alcohol intolerance are the main side effects.
Amoxicillin is a broad-spectrum penicillin Cefuroxime can be used in pregnancy. For cost antibiotic with bactericide activity. It reaches high plasmatic and tissue concentration after oral Various antibiotic treatment regiments are used administration. Its advantage is that it may be used in clinical practice. There are many studies evaluating in pregnancy, it is also suitable for children under the different durations of different antibiotics or 9 years of age and for patients allergic to doxycycline.
their combination for treatment of patients with The disadvantage of amoxicillin from the point of lyme disease (17,19–22). The stage of the disease, treating lyme borreliosis is that it does not treat presence of associated neurologic symptoms and co-infecting disorders such as ehrlichiosis and other factors such as duration of symptoms, aller- babesiosis. Penetration of amoxicillin into perivas- gies, age, and pregnancy status should be considered cular space is probably sufficient. It is recommended at the beginning of the treatment. It is advisable to adjust dose in patients with renal impairment.
to consult specialists in patients with cardiac, Benzylpenicillin is a penicillin G with bactericide neurologic, or rheumatologic manifestations. The activity, good tolerance, and low resistance during selection of antibiotics might take in consideration the drug efficacy, adverse effects, administration, typical EM is recommended to start immediately duration of treatment, taste (when administered (Table 1). The drug of choice is doxycycline. If to children), cost, and influence on bacterial resis- doxycycline cannot be used, i.e., because of allergy tance. Antibiotic treatment should be accompa- or during summer time, amoxicillin is the alternative.
nied with probiotics to minimize adverse effects Azithromycin is recommended as a second-line (23). In about 15% of patients, Jarish-Hexheimer choice for patients who are allergic to tetracycline reaction appears within the first 24 hours of and penicillin. But there are reported more treatment antibiotic treatment. Jarish-Hexheimer reaction failures of azithromycin compared to amoxicillin includes fever, shivering, weakness, cephalea, and (25). For solitary EM, oral antibiotic treatment for myalgia. Worsening of lyme borreliosis symptoms 14 –21 days provides the effective therapy. The is probably caused by reactive components released present authors prescribe longer course of antibiotic from dying spirochetes. In case of worsening or treatment to patients with longer history of EM, persisting symptoms during the treatment of lyme with extracutaneous clinical symptoms or when borreliosis, the possible co-infection has to be EM does not disappear in 14 days. Some patients considered. Anaplasma phagocytophilum caus- with EM may have hematogenous dissemination ing human granulocytic ehrlichiosis can be a with the absence of symptoms (26). Patients with coinfecting pathogen. A. phagocytophilum is an the involvement of central nervous system should intracellular bacteria that causes an acute non- be treated with intravenous antibiotics.
specific febrile illness characterized by highfever, malaise, severe headache, myalgias, and/orarthralgias in patients with exposure to tick within Treatment of BL
the last 3 weeks. Laboratory tests show leukopenia,trombocytopenia in blood count, elevation of serum A 14–21-day course of oral antibiotics (doxycycline, hepatic transaminase, higher erytrocyte sedimenta- amoxicillin, cefuroxime axetil) is recommended for tion rate and elevated C-reactive protein. The disease BL without accompanying symptoms (Table 1).
can have mild or even asymptomatic course.
According to the European Union Concerted A. phagocytophilum infection can be proved by Action on Lyme Borreliosis, the treatment can be serologic tests, PCR, and by light microscopy (the extended to 21–30 days because of the longer presence of morulae in granulocytes in peripheral pretreatment duration of BL. Azithromycin is not blood smear). The drug of choice for treatment recommended for the treatment of BL (27). The is doxycyline and rifampicin. Doxycycline should lymphocytoma regresses more slowly after anti- be considered the drug of choice for patients from biotic treatment than EM, the median is 3–4 weeks endemic areas wherein exposure to both pathogens (12). The speed of regression depends on the duration of BL before institution of therapy (12,28).
Treatment of EM
Treatment of multiple EM
The aim of the treatment is to prevent later Parenteral therapy should be used in case of manifestation of lyme disease. The treatment symptoms of disseminated lyme borreliosis.
is therefore indicated also to patients with spontane- Ceftriaxone or penicillin G given intravenously for ous disappearance of EM, although in this case 2–3 weeks should be administered in multiple EM, positive serologic tests are needed. The treatment of neurologic involvement, and carditis (Tables 2 and 3).
Table 1. Treatment of EM and borrelial lymphocytoma
aIn case of penicillin and doxycycline allergy.
bTreatment of borrelial lymphocytoma can be prolonged up to 28 days.
VaNousová & Hercogová Table 2. Treatment of neuroborreliosis, multiple EM
aIn case of penicillin and cefalosporin allergy.
Table 3. Treatment of Lyme carditis
Table 5. Treatment of ACA
Doxycycline, amoxicillin, and ceftriaxone are Treatment of post-lyme disease
recommended for arthritis (Table 4). The clinical syndrome
outcome is to be evaluated 6–12 months afterantibiotic therapy (22).
It is not well understood why some patients developsymptoms that include fatigue, neurocognitivedysfunction such a depression, mood and attention Treatment of ACA
disturbances or pain after receiving standardantibiotic course for the treatment of lyme disease.
Antibiotic treatment of ACA improves inflammatory Very often, prolonged courses of oral and parenteral changes and leads to regression of fibrotic nodules.
antibiotics are ordered, believing that persistent Atrophic changes of skin belong to irreversible infection with B. burgdorferi is responsible. The changes that do not improve even after successful study of patients with post-treatment chronic treatment with eradication of Borreliae. Therapeutic lyme disease with those symptoms showed no effect of doxycycline and/or amoxicillin as first-line evidence of persisting Borrelia infection, and addi- antibiotics (used in the treatment for 3 – 4 weeks) tional antibiotic therapy was not more beneficial and ceftriaxone and/or penicillin G used in case than administering placebo (29). On the other hand, of neurologic symptoms (for 2–4 weeks), are some other studies show that patients can benefit recommended to evaluate several months up to from longer re-treatment (30). The term “post-lyme 6 months after finishing the therapy (Table 5).
disease syndrome” reflects the postinfectious origin Sometimes it is necessary to repeat the course of of this condition. The etiopathogenesis of those antibiotic treatment because of no efficacy during chronic symptoms is not understood, and the the first course or because of the presence of effective therapy does not exist. Symptomatic Table 4. Treatment of lyme arthritis
Children
with all antibiotic regiments used in the treatmentof lyme borreliosis (21,25). The reason can be an Cutaneous manifestations of lyme borreliosis in inappropriate antibiotic, according to the stage of children include mainly EM and BL, as ACA is the disease, and inappropriate duration of treatment, very rare during childhood (31). Clinical studies of persistence of Borreliae in the tissue (36), persis- the antibiotic treatment of children under 15 years tence of atypical forms of spirochetes – cysts, of age who had solitary EM showed comparable irreversible tissue damage caused by borrelial efficacy and comparable appearance of minor infection, immunopathologic changes following and major manifestations of lyme borreliosis, eradication of agent, misdiagnosis, or even re- regardless of antibiotic used. Amoxicillin, infection (37). Re-infection is characterized as EM azytromycin, phenoxymethyl penicillin is recom- that appears at the different localization than mended. Cefuroximaxetil has more side effects (19) original EM lesion. In contrary, relapse (recurrence) (FIG. 3). Children with multiple EM can suffer is characterized as EM lesion localized at the from meningitis without obvious clinical sign same site as the original one. The present authors and symptoms of CNS involvement in up to 25% of expect the appearance of the relapsing erythema cases. It is recommended to treat such children within a few weeks with persisting increased levels intravenously with ceftriaxone (32,33) (FIG. 4).
of antiborrelial antibodies. After the antibiotic Children are treated in the same principles as treatment, recurrent episodes of lyme disease adults, but the present authors do not use doxycy- seem to be caused by re-infection rather than by cline in children under 8 years of age, the doses relapses (38). One study shows that treatment should be reduced by weight, and the maximal failure is associated with treatment delay (39).
dose for children is the recommended dose for The follow-up of patients after treatment is necessary to disclose both, the relapse and latecomplications. The present authors recommendto follow up the patients for 2 years after the Pregnancy and lactation
treatment. The follow-up includes evaluation ofclinical status and providing serologic tests Erythema migrans is the most frequent cutaneous ELISA and immunoblots every 3 months during manifestation of LB that the present authors see the first year and every 6 months during the in pregnant and lactating women. The Infectious Diseases Society of America recommends to treatthese patients as nonpregnant patients with theexception that doxycycline should be avoided Prophylaxis treatment
(34). Some other authors recommend treatmentof pregnant patients with intravenously administered Patients with the history of attached ticks that antibiotics (ceftriaxon, benzylpennicillin) for 14 were removed are encouraged to observe the site days during all three trimesters of pregnancy where the tick was attached. A routine use of anti- (35). The present authors use a 14-day-course of microbial prophylaxis and serologic testing is not benzylpenicillin (5 MU every 6 hours) given intra- recommended. The Infectious Disease Society of venously followed by amoxicillin (1 g three times America recommends administering a single dose daily) given orally for another 14 days for those of doxycycline for adult and children above 9 pregnant women who experienced a tick bite or years of age only when all the following circum- suffer from EM during the first trimester. Pregnant stances exist: (a) the attached tick had been reliably women with the manifestation of EM and/or a identified as an adult or nymph I. scapularis that tick bite in the second and third trimester are had been attached for more then 36 hours on the basis of the degree of engorgement of the tick In sum, skin manifestations of lyme disease with blood, (b) the prophylaxis can be started respond promptly to appropriate antibiotic therapy.
within 72 hours after the tick removal, (c) local Early manifestations, such as EM, respond more rate to infection of these ticks with B. burgdorferi quickly than BL and later manifestations, ACA.
is more than 20%, and (d) doxycycline treatment Both, IgM and IgG antiborrelial antibodies start to is not contraindicated (33). This is assessed for decrease during the time after the antibiotic America. In Europe, this approach is not entirely treatment, but they may persist for months to effective, as prophylaxis failure after administering years without any sign of disease activity (13).
200 mg of doxycycline after tick bite has been Failures in antibiotic treatment have been reported described (40). It is reasonable to consider a 10-day VaNousová & Hercogová course of amoxicillin for pregnant women with 12. Maraspin V, Cimperman J, Lotriç-Furlan S, et al. Solitary borrelial lymphocytoma in adult patients. Wien Klin The prevention of lyme borreliosis includes Wochenschr 2002: 114/13–14: 515 – 523.
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Source: http://lifelyme.org/lyme%20treatment.pdf