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[Infect Med 18(8):388-395, 2001. © 2001 Cliggott Publishing Co., Division of SCP/Cliggott Communications, Inc.]
Sound management of Lyme disease (LD) rests with accurate identification of disease manifestations coupled with evidence-based approaches to therapy. Early disease usually responds very well to appropriate antibiotics. Patients with neurologic disease and arthritis may pose difficulties in management but ultimately have a good prognosis in most cases. A tetracycline (usually doxycycline) is the agent of choice for early LD not involving the CNS. Amoxicillin is recommended for children younger than 8 years. For CNS involvement, third-generation cephalosporins can be used. Lyme arthritis usually responds to a 4-week course of oral antibiotics, but following this with parenteral therapy may be considered if the arthritis does not resolve. Methods of prevention include personal protection methods, prophylactic antibiotics following a tick bite, and the LD vaccine.
Lyme disease (LD) is, by far, the most common vector-borne disease in the United States. It is among the top 10 notifiable diseases in both sexes and in all age groups. Most states have reported cases of LD (Figure), and it is a major public health problem in southern New England, the mid-Atlantic states, and parts of the upper Midwest. The actual number of cases may be much larger than reported.
Figure. Distribution of cases of Lyme disease by county, 1982-1998.
LD is caused by spirochetes belonging to the genus Borrelia. Several species can produce disease. In the United States, Borrelia burgdorferi sensu stricto is responsible for virtually all cases, while in Europe, LD is also caused by Borrelia garinii and Borrelia afzelli. There are clinical differences in the disease manifestations, particularly with respect to neurologic involvement, between infections caused by these species. Furthermore, within species, there is considerable genetic diversity, which has led to concerns about diagnostic testing and vaccine development. Like other spirochetes, these organisms can cause persistent infection with symptoms that may persist or recur over a long period. A prominent host inflammatory response accounts for many of the manifestations of LD.
The reservoir of B burgdorferi in nature is the white-footed mouse. The usual vector of LD is the deer tick, Ixodes scapularis, which acquires the spirochete by feeding on the mouse. Human disease results when there is prolonged (24 to 48 hours) attachment of the tick to the skin, during which time bacteria may pass into the dermis.
Following inoculation of B burgdorferi into skin, the characteristic skin lesion, erythema migrans (EM), appears in the majority of cases (early localized LD). EM is an annular erythematous lesion that typically enlarges over several days; it may resolve spontaneously or as a result of antibiotic treatment, and many patients then exhibit no further disease manifestations. If the spirochete gains access to the systemic circulation, infection may occur in a variety of tissues, resulting in joint, cardiac, ocular, and central and peripheral nervous system involvement. Even without treatment, early disseminated disease may resolve; however, it may also progress and result in significant morbidity (and occasional- ly death, from third-degree heart block). Persistent infection in the joints, eyes, or CNS can result in late clinical manifestations. Table 1 lists the main clinical manifestations according to the stage of disease.
Tick exposure in an area where LD is endemic is generally considered a prerequisite for the diagnosis of LD, although many patients do not recall a tick bite. Clinical recognition of EM is sufficient for diagnosis of early LD. When other compatible disease manifestations are observed but EM is lacking, diagnosis may be facilitated by laboratory tests. In most instances, the clinician will use serologic testing, typically an enzyme-linked immunosorbent assay (ELISA) for antibodies to B burgdorferi. The current recommendations call for the use of Western immunoblotting (a more specific assay) to confirm any positive or equivocal ELISA results; interpretive criteria for Western blots are published and usually accompany reports of laboratory results. The reliability of the urine antigen detection assay for LD is highly questionable. A discussion of the use of polymerase chain reaction technology for diagnosis of LD is beyond the scope of this article.
A variety of antibiotics show good in vitro activity against B burgdorferi. These include several third-generation cephalosporins and the macrolides (minimum inhibitory concentrations [MICs] are generally 0.1 µg/ mL or less and minimum bactericidal concentrations [MBCs] are generally 0.5 µg/mL or less).[5-7] Tetracyclines, particularly doxycycline, are very active (MIC90, 0.25 µg/mL) but have somewhat higher MBCs.[5,7] The MIC for amoxicillin is also low (0.03 µg/mL or less), but bactericidal activity (MBC, 0.8 to 2 µg/mL) is reduced; the MBCs for penicillin are even higher. The MBC for cefuroxime axetil is 1 µg/mL. Quinolones are less active than other antibiotics in vitro.
Many studies of antibiotic therapy for LD have been performed over the last 2 decades, in both the United States and Europe. Most of these trials have involved adult patients and have focused on specific clini- cal manifestations, such as EM and aseptic meningitis. Most of the current published recommendations derive from the available literature and from expert opinion. The most important considerations in antibiotic selection for a given situation are the clinical manifestations and organ system involvement. For example, more aggressive therapy with parenteral antibiotics is recommended for CNS involvement or third-degree heart block, while early localized disease usually responds well to a course of oral therapy. Recommendations for treatment of LD, based on the clinical situation, are summarized in Table 2.
For early disease not involving the CNS, a tetracycline is the agent of choice. Advantages of tetracyclines include their good in vitro activity against B burgdorferi and their long- established track record in clinical trials and in practice. Doxycycline is often considered the best drug in this class based on its excellent bioavailability, ease of dosing (twice daily), and better tolerability than other tetracyclines. Because it is lipophil- ic, doxycycline also has reasonably good CNS penetration (up to 26% of plasma levels). Two studies from Europe involving patients with early neuroborreliosis have shown the efficacy of doxycycline to be comparable to that of parenteral penicillin G or ceftriaxone; similar studies have not been performed in the United States. Doxycycline also compared favorably with parenteral ceftriaxone for early disseminated LD, not involving the CNS. A retrospective study suggested that tetracycline, given for a mean of 4 months, was successful in treating chronic infection. Situations in which CNS involvement is possible, such as in the patient with early disseminated disease, are better served by doxycycline therapy than by alternative oral antibiotics that do not attain adequate CNS levels (if CNS infection is established, parenteral therapy is recommended -- see below).
Another advantage of doxycycline is that it is considered the agent of choice for treating human granulocytic ehrlichiosis, which is transmitted by deer ticks and may occur simultaneously with early LD. Disadvantages of the tetracyclines include the potential hazards to the fetus and young child, photosensitivity reactions (significant, since early LD is usually treated in the warmer months), and esophageal burns. Although tetracyclines are usually avoided in the young child, up to 2 weeks of doxycycline therapy can be given safely without risking dental staining.
Of the oral b-lactam antibiotics, amoxicillin and cefuroxime axetil have been the most extensively studied in LD clinical trials. The combination of amoxicillin with probenecid demonstrated efficacy comparable to that of doxycycline in a trial of adult patients with early LD and in adults with Lyme arthritis. However, in the latter study, subsequent neurologic involvement appeared more frequently in patients who received amoxicillin. Based on its in vitro activity and on limited published studies, amoxicillin is considered the oral agent of choice for children younger than 8 years. One recent prospective study appears to support the efficacy of amoxicillin in treating early LD in that population. Probenecid can be used to raise serum levels of amoxicillin, but whether that is advantageous is unclear; in actual practice, this is generally omitted.
Cefuroxime axetil has been compared with doxycycline in adults with early LD and appears to have equal efficacy with fewer adverse reactions.[16,17] A pediatric trial showed the efficacy and safety of cefuroxime axetil to be comparable with those of amoxicillin. Cefuroxime axetil is more expensive than doxycycline or amoxicillin. Oral third-generation cephalosporins have been less well studied.
Erythromycin is active in vitro but has not been found to perform well in clinical practice. It is generally considered a second- or third-line agent. Clarithromycin has been evaluated in one noncomparative pilot study, which found efficacy similar to that reported for other agents in early LD. Azithromycin would appear to be an attractive agent, based on its ease of administration (once daily), long half-life, and intracellular penetration (B burgdorferi can survive intracellularly). In early LD, its efficacy has been shown in some studies to be comparable to that of amoxicillin/probenecid and doxycycline[20,21]; however, another trial demonstrated amoxicillin to be more effective than azithromycin in resolving acute manifestations and preventing additional symptoms. A potential drawback to the use of macrolides is their relatively poor penetration into the CNS. None of the macrolides are approved by the FDA for treating LD.
The parenteral agents that have been evaluated most extensively are pen-icillin G and the third-generation cephalosporins cefotaxime and ceftriaxone. The latter agents have better in vitro activity against B burgdorferi, attain higher serum concentrations, and have superior penetration into the CNS. Studies comparing the efficacy of these agents have generally favored the cephalosporins for early disseminated and late LD. For patients with CNS involvement, they are considered the agents of choice. The ease of once-daily dosing has made ceftriaxone a suitable agent for outpatient intravenous therapy. While it is relatively safe, the prolonged use of ceftriaxone in the treatment of LD (including patients with unsubstantiated diagnoses) has been reported to result in biliary complications. The literature generally does not support the use of ceftriaxone for courses longer than 4 weeks. If parenteral penicillin G is used, it must be dosed every 4 hours, which is a disadvantage. Doxycycline can also be used intravenously but offers relatively little advantage over the highly bioavailable oral form of the drug.
Standard recommendations over the years have called for oral antibiotic therapy for patients with isolated cranial neuritis. Peripheral facial nerve palsy (PFNP) is, by far, the most common and well studied of the LD-associated cranial neuropathies. In areas where LD is endemic, LD is probably the most common identifiable cause of PFNP (particularly if the palsy is bilateral). Recent studies have shown that many, if not most, cases of PFNP will be associated with concomitant CNS inflammation. Among both adult and pediatric patients with PFNP, cerebrospinal fluid (CSF) abnormalities, including the presence of lymphocytic pleocytosis, antibody to B burgdorferi, and borrelial DNA, are frequently observed.
From a treatment perspective, it is not absolutely clear whether all such patients require parenteral antibiotic therapy. In fact, a retrospective European study of patients who had had PFNP in the era before LD was recognized and treated with antibiotics found no pattern of neurologic or other sequelae attributable to LD, even though a number of these patients probably had LD-associated PFNP. However, the potential exists for significant CNS sequelae in some patients with PFNP, just as with Lyme meningitis. Experts are divided on the issue of whether all cases of LD-associated PFNP should have a CSF evaluation. Clearly, however, the clinician practicing in an area where LD is endemic should evaluate patients with PFNP carefully, including LD serology, and perform lumbar puncture if there are any symptoms or signs suggesting CNS involvement. Oral doxycycline can be used to treat such patients, but if CSF abnormalities are discovered, parenteral ceftriaxone would offer the best chance for eradication of CNS infection.
Early literature on LD suggested the need for parenteral antibiotics for arthritis. Experience and the results of clinical trials have shown that about 90% of cases of Lyme arthritis respond to a 4-week course of oral antibiotics. Some patients may continue to have joint swelling and other symptoms at the completion of treatment, but most of these resolve with time and can be treated symptomatically with NSAIDs. Those whose symptoms do not resolve may be given a second course of oral antibiotic or a course of intravenous antibiotic; few published data guide the decision to use parenteral therapy in this situation, so the approach must be individualized. However, if there is evidence of concomitant CNS involvement, parenteral therapy with ceftriaxone may offer a better cure rate. A small minority of patients have antibiotic treatment- resistant arthritis. Such patients usually have the HLA-DR4 haplotype. (This genetic marker is found in about 20% of the general population, and testing for it is rarely needed in clinical practice.)
An older study from Europe suggested that a 10-day course of oral antibiotics for early LD could result not only in a poor clinical response but also in the ability to cultivate B burgdorferi from affected tissues in some such patients. Treatment of Lyme meningitis for only 10 days has been associated with a high rate of residual symptoms.[31,32] On the other hand, many cases of LD undoubtedly resolve spontaneously. There is little question that antibiotic therapy can hasten clinical resolution and prevent the occurrence of late complications, but no studies have clearly defined the optimum duration of treatment. Further, surveys of physicians' practices suggest that there is no consensus among practitioners.[33,34] Most standard recommendations give a minimum duration of treatment, for any disease manifestation, of 2 weeks. Uncomplicated early disease is generally treated for 2 to 4 weeks with an oral antibiotic. Because arthritis can be slow to resolve, a 4-week course is usually recommended for Lyme arthritis. Lyme meningitis should be treated with a minimum of 2 weeks of intravenous ceftriaxone; treatment may be extended for 1 to 2 weeks depending on the response of the patient.
Chronic neurologic disease is not only challenging to diagnose but frequently is difficult to manage. Likewise, the appropriate management of patients who have persistent symptoms (for example, cognitive impairment, musculoskeletal pain) following treatment for LD has been controversial. Difficulties in accurate diagnosis of "chronic Lyme disease," as it is often called, have been associated with prolonged and often inappropriate therapy, sometimes with significant adverse drug reactions.[23,24]
Overtreatment is undoubtedly common. Some experts argue that more than 2 months of treatment is seldom needed, while others question whether chronic CNS disease actually exists as a separate diagnostic entity. Oral doxycycline, given for 1 to 11 months, was reported to be efficacious in one uncontrolled study of patients with chronic LD. A recent placebo-controlled study involving adult patients with persistent symptoms and a history of LD was unable to demonstrate any benefit from a 30-day course of intravenous ceftriaxone followed by a 60-day course of oral doxycycline.
One truism is found throughout the literature, as well as in clinical experience: timely and accurate diagnosis and appropriate treatment have a clear influence on response to therapy, need for additional antibiotics, and ultimate prognosis.
Transmission of B burgdorferi from mother to fetus has been described but appears to be extremely uncommon. Pregnant women should be treated in accordance with treatment recommendations for nonpregnant adults, with the exception that tetracyclines should be avoided because of their effect on fetal bones and teeth.
In addition to antibiotic therapy for the infection, some patients may benefit from supplementary therapies. NSAIDs are often used to treat constitutional symptoms as well as arthritis. Topical eye care is often required for patients who are unable to oppose their eyelids because of facial palsy. Increased intracranial pressure associated with acute CNS disease may respond to acetazol- amide. Synovectomy may be necessary in a small minority of patients with arthritis refractory to antibiotic therapy.
Costs of antibiotics and costs of treatment failures must both be factored into a cost-effectiveness analysis. Oral doxycycline given for 3 weeks was compared with intravenous ceftriaxone administered at home for 2 weeks in a model that evaluated multiple possible scenarios. Doxycycline proved to be considerably more cost-effective. Another study evaluated several testing/treatment strategies using doxycycline given orally for 30 days. In this study, for patients with only constitutional symptoms, the no test/no treatment approach was the most cost-effective. When an EM rash was present, empiric therapy without testing was the best strategy. For patients with constitutional symptoms and a history of tick bite and rash, the most cost-effective approach was serologic testing, with treatment provided only for those with positive results. Prolonged intravenous treatment of LD can be a very costly proposition, in addition to posing hazards of adverse drug reactions. The costs of prevention are discussed below.
Until recently, the emphasis on the prevention of LD has focused on efforts to reduce the likelihood of tick attachment. Avoidance of tick-infested areas is often recommended, but evidence suggests that many people acquire infection in their home environment. Maintenance of this environment, especially removal of leaf litter (larval deer ticks attach to leaves), can reduce the risk of acquiring LD at home. Personal protective measures are also widely recommended; these include wearing light-colored clothing, wearing long sleeves and long pants, tucking pants legs into socks, and application of DEET or other tick repellents to skin or clothing. Unfortunately, none of these measures has been demonstrated to reliably prevent LD in case-control studies. Tick checks to identify and remove Ixodes ticks make sense but may not be practiced routinely by at-risk individuals. If a deer tick is found, it should be grasped with forceps or tweezers close to the mouth parts and pulled directly outward. If the attachment is less than 24 hours, infection usually does not follow.
In a study of antibiotic prophylaxis in an area where LD is endemic (Connecticut), it was reported that the risk of acquiring LD from a given deer tick attachment was 1.2%. In this study, no efficacy of prophylaxis could be established. A meta-analysis of several studies comparing antibiotic prophylaxis with placebo also concluded that antibiotics were not significantly effective in preventing clinical LD. This paper and others note that in the groups that received antibiotics, significant adverse effects from the antibiotics occurred with a frequency similar to that of early LD in the groups that did not receive antibiotic prophylaxis.
A recent study done in an area of New York where LD is hyperendemic compared a single 200-mg oral dose of doxycycline with placebo in subjects 12 years and older who had documented I scapularis attachments. EM developed in 0.4% of doxycycline recipients, compared with 3.2% in the placebo group. No extracutaneous manifestations of LD occurred in any subject, and there were no asymptomatic seroconversions. Nausea and vomiting were common in doxycycline recipients. The relevance of the efficacy demonstrated in this study to areas with lower infection rates is unknown.
The cost-effectiveness of prophylaxis has been studied, with the authors suggesting that antibiotics would be clearly justified only if the risk of infection after a tick bite were 3.6% or more; this level of risk may apply in a few communities. In the New York study, a minimum of 40 deer tick attachments would have needed to be treated to prevent 1 case of EM, calling into question the cost-effectiveness of prophylaxis. Most authorities have recommended that for most instances of tick attachment, the patient should be advised to be vigi-lant about rashes and constitutional symptoms and to seek medical care if they occur, and that antibiotics should not be given prophylactically.
However, prophylaxis would be reasonable in certain situations. If the tick is engorged with blood, indicating more prolonged attachment and higher risk of disease, prophylaxis would be more likely to be beneficial. Other circumstances in which prophylactic antibiotics might be considered include multiple simultaneous tick attachments, presence of neurologic conditions or arthritis, and when there is a previous history of LD. If a course of antibiotic prophylaxis is deemed necessary, it should be given promptly; single-dose doxycycline would be reasonable for older children and adults, but safety and efficacy of a regimen for younger children and pregnant women has not been established.
Most efforts to develop an LD vaccine have focused on the outer surface protein A (ospA) of B burgdorferi. This protein is expressed by organisms residing in the tick vector but is largely replaced by the expression of ospC after the spirochete enters the human host. OspA vaccines are believed to work in this unique fashion: after immunization, the human responds with production of IgG antibody, which is ingested by the tick during its blood meal; antibody to ospA is lethal to the spirochete within the tick, so viable organisms nev-er reach the human. Recombinant ospA vaccines are produced in an Escherichia coli vector, purified and, in the case of the currently available vaccine, combined with an aluminum hydroxide adjuvant.
Two studies involving intramuscularly administered ospA vaccines, which were simultaneously reported, demonstrated impressive efficacy in preventing LD.[45,46] As a result of the pivotal trial of the ospA vaccine manufactured by SmithKline Beecham (now GlaxoSmithKline) (Philadelphia), that product (LYMErix) was licensed in late 1998 for use in adults aged 15 to 70 years. In that trial, 10,936 volunteers aged 15 to 70 years were randomized to receive either placebo or 30-µg doses of ospA at 0, 1, and 12 months. After the first 2 immunizations, cases of clinical LD occurred in 43 placebo recipients and in 22 vaccine recipients (vaccine ef- ficacy, 49%). After the third dose, vaccine efficacy rose to 76%; the response was age-dependent, with some diminution of efficacy in older persons. Also, after the third dose, asymptomatic seroconversion (indicating infection with B burgdorferi during the study period) occurred in 15 controls but in no vaccine recipients.
Antibody responses to ospA were also measured in a subset of volunteers. The vaccine was shown to be immunogenic, with a significant anamnestic response following the third dose. Further analysis of these data demonstrated that cases of LD in vaccine recipients occurred mainly in those whose geometric mean titer (GMT) was below 400 ELISA units/mL and that a GMT of 1400 ELISA units/mL or greater was associated with a high likelihood of protection in the next LD season.
No further field efficacy trials have been conducted with this vaccine, but several studies have been done based on this immunologic correlate of protection. The results of accelerated vaccination schedules at 0, 1, and 6 months and 0, 1, and 2 months demonstrate immunoge- nicity similar to that of the 0-, 1-, and 12-month regimen, in terms of both the GMT and the proportion of subjects attaining titers of 1400 ELISA units/mL or greater after the third dose. It is probable that the accelerated schedules will provide comparable protection, but as of this writing, only the original dosing has FDA approval.
OspA antibody titers also have been measured longitudinally in cohorts of subjects in an effort to define duration of immunity. Declining titers over time have suggested the need for periodic boosters, perhaps with the first booster immunization 2 years after the primary series, but there is no firm recommendation (or FDA approval) concerning booster doses.
The ospA vaccines have proved to be well tolerated. In all studies, injection site pain has been the most common adverse reaction (24% in the pivotal study). Hypersensitivity reactions are rare. No pattern of significant adverse events, including arthritis, has been associated with the vaccine in clinical trials, in postmarketing experience involving over a million doses, or in analysis of cases reported to the federal Vaccine Adverse Event Reporting System; this information is available on the FDA Web site (www.FDA.gov). The lack of association with arthritis is important, since ospA may play a pathogenic role in treatment-resistant Lyme arthritis seen in natural infection with B burgdorferi. There is no clinical or laboratory evidence that ospA alone can induce significant arthritis.
The cost of vaccinating against LD has been addressed. Results depend on the assumptions made. In areas where LD is highly endemic, vaccination would appear cost-effective, while in other areas, the cost would be harder to justify.
The CDC's Advisory Council on Immunization Practices has recommended that LD vaccine be considered for persons aged 15 to 70 years who reside, work, or recreate in areas of high or moderate risk of exposure to infected ticks. Both geographic location and a person's activities and behaviors relating to tick exposure are important determinants of risk of infection. Pediatric studies have been completed and show favorable safety and immunogenicity, but FDA approval for use in children younger than 15 years is still pending.
In patients who have been vaccinated, the ospA antibody can cause the ELISA result to be positive. The Western blot will also have a 31-kilodalton band corresponding to ospA antibody, but theoretically no other bands should appear in the absence of natural infection with B burgdorferi. Hence, the Western blot is the critical serologic test in immunized persons in whom LD is suspected. However, some Western blot tests have given unusual patterns of reactivity related only to vaccination. This phenomenon requires further study and may incur the need for alternative serologic methods.
|Disease stage||Timing after tick bite||Clinical manifestations|
|Early localized||3 - 30 d||Erythema migrans (EM) -- single; variable constitutional symptoms: myalgia, arthralgia, fever, headache, fatigue; regional lymphadenopathy|
|Early disseminated||1 - 12 wk||EM -- single or multiple; constitutional symptoms; neck pain; meningitis; cranial neuritis (eg, facial palsy); radiculoneuritis; carditis (variable heart block); eye involvement|
|Late disease||<= 2 mo||Arthritis; chronic CNS involvement|
|Clinical manifestation||Usual treatment||Alternative agents|
|Early localized disease||Doxycycline (PO)
|Macrolides (erythromycin, clarithromycin, azithromycin)|
|Early disseminated disease|
|No CNS involvement, no more than first-degree heart block||Doxycycline (PO)
|With CNS involvement, symptomatic carditis, PR interval > 0.3 s, or second- or third-degree heart block||Ceftriaxone (IV)||Penicillin G (IV)
Doxycycline (IV or PO)
Penicillin G (IV)
|CNS involvement||Ceftriaxone (IV)||Penicillin G (IV)
Doxycycline (IV or PO)
|*||See text for details and for duration of treatment. Agents of choice are given in italics.|
|Doxycycline: 100 mg bid (pediatric: 2 - 4 mg/kg/d divided bid)|
|Amoxicillin: 500 mg tid (pediatric: 50 mg/kg/d divided tid)|
|Cefuroxime axetil: 500 mg bid (pediatric: 20 - 30 mg/kg/d divided bid)|
|Erythromycin: 250 mg qid (pediatric: no data)|
|Clarithromycin: 500 mg bid (pediatric: no data)|
|Azithromycin: 500 mg on day 1 and 250 mg qd (pediatric: no data)|
|Ceftriaxone: 2 g qd (pediatric: 100 mg/kg/d)|
|Penicillin G: 20 million units/d divided q4 - 6h (pediatric: 200,000 - 400,000 units/kg/d divided q4 - 6h)|
|||For severe or refractory cases.|
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