Given the severity of the QoL impairments, the panel viewed the need for clinical intervention as high.
Additionally, the panel considered that antibiotic risk varies by agent and route of administration. Although all of the regimens in the NIH-sponsored retreatment trials incorporated iv. ceftriaxone, the use of iv. antibiotics is discretionary and should be based on an individualized risk–benefit assessment. The risks associated with iv. antibiotics have two main origins. The first is the medication itself and includes allergic reactions and other adverse events, such as cholecystitis from ceftriaxone. The second source of risk is the iv. access device.
The risks associated with iv. access are well known. A meta-analysis of the risks associated with iv. access, in general, found that risks varied by access type; peripheral iv. catheters caused 0.5 bloodstream infections per 1000 intravascular device days, while surgically implanted long-term central venous devices – cuffed and tunneled catheters – caused 1.6 infections per 1000 intravascular device days .
Combined, there were seven device-related adverse events among the four retreatment trials and approximately 8110 days of device use, yielding 0.86 device-related adverse events per 1000 intravascular device days, which is lower than the rate found in the meta-analysis. Although the risk associated with iv. antibiotics is significant, in situations where the QoL impairments are substantial, retreatment with iv. antibiotics may be wholly appropriate.
There is substantial evidence on the clinical safety of amoxicillin, cefuroxime axetil, doxycycline and azithromycin, which are commonly used to treat Lyme disease [105,106]. In a community-based trial, none of the subjects randomized to amoxicillin experienced a serious adverse event . Similarly, the trials by Klempner et al. confirmed the safety of oral doxycycline for longer-term use . Regardless of treatment agent and route of administration, it is expected that the concomitant use of probiotics would reduce the risk of C. difficile colitis and antibiotic-associated diarrhea [44,45].
Values: The panel placed a high value on reducing the morbidity associated with chronic Lyme disease and improving the patient’s QoL as well as on the need for individualized risk/benefit assessment and informed shared decision-making. The panel also placed a high value on the ability of the clinician to exercise clinical judgment. In the view of the panel, guidelines should not constrain the treating clinician from exercising clinical judgment in the absence of strong compelling evidence to the contrary.
Clinicians should discuss antibiotic retreatment with all patients who have persistent manifestations of Lyme disease. These discussions should provide patient-specific risk–benefit assessments for each treatment option and include information regarding C. difficile infections and the preventative effect of probiotics (although none of the subjects in the retreatment trials developed a C. difficile infection). (Strong recommendation, very low-quality evidence. Note: In GRADE, a strong recommendation may be made in the face of very low-quality evidence when the risk–benefit analysis favors a particular intervention such that most patients would make the same choice.)
Role of patient preferences: low
The benefits of educating patients about the potential benefits of retreatment and the risks associated with various treatment options, including not treating, clearly outweigh any attendant risks associated with education.
While continued observation alone is an option for patients with few manifestations, minimal QoL impairments and no evidence of disease progression, in the panel’s judgment, antibiotic retreatment will prove to be appropriate for the majority of patients who remain ill. Prior to instituting antibiotic retreatment, the original Lyme disease diagnosis should be reassessed and clinicians should evaluate the patient for other potential causes of persistent disease manifestations. The presence of other tick-borne illnesses should be investigated if that had not already been done. Additionally, clinicians and their patients should jointly define what constitutes an adequate therapeutic trial for this particular set of circumstances.
When antibiotic retreatment is undertaken, clinicians should initiate treatment with 4–6 weeks of the selected antibiotic; this time span is well within the treatment duration parameters of the retreatment trials. Variations in patient-specific details and the limitations of the evidence imply that the proposed duration is a starting point and clinicians may, in a variety of circumstances, need to select therapeutic regimens of longer duration.
Treatment options are extensive and choices must be individualized. Each of these options would benefit from further study followed by a GRADE assessment of the evidence and consideration of associated risks and benefits, but until this information is available, clinicians may act on the currently available evidence.
In choosing between regimens, clinicians should consider the patient’s responsiveness to previous treatment for Lyme disease, whether the illness is progressing and the rate of this progression; whether the patient has impaired immune system functioning or has received immunosuppressant corticosteroids [54,114] and whether other co-morbidities or conditions would impact antibiotic selection or efficacy. The possibility of co-infections should be investigated (see Recommendation 2e for discussion regarding co-infections complicating the diagnosis and treatment of Lyme disease).
Clinicians should also weigh the extent to which the illness interferes with the patient’s QoL, including their ability to fully participate in work, school, social and family-related activities and the strength of their initial response against the risks associated with the various therapeutic options. Antibiotic selection should also consider medication tolerability, cost, the need for lifestyle adjustments to accommodate the medication and patient preferences.
For patients with mild impairments who had a strong-to-moderate response to the initial antibiotic, repeat use of that agent is favored. Patients with moderate impairments or only a modest response to the initial antibiotic may benefit from switching to a different agent or combination of agents; the latter to include at least one agent that is able to effectively reach intracellular compartments [109,110]. Injectable penicillin G benzathine or iv. agents such as ceftriaxone are other options.
For patients with significant impairments and/or a minimal or absent therapeutic response, a combination of oral antibiotics or injectable penicillin G benzathine or iv. ceftriaxone alone, or in combination with other agents, is preferred. For patients who experienced disease progression despite earlier therapy, treatment with injectable penicillin G benzathine or an iv. agent, such as ceftriaxone, alone or in combination with other antibiotics, is advisable. Additionally, minimal or absent responses and disease progression require a re-evaluation of the original diagnosis. (Recommendation, very low-quality evidence)
Role of patient preferences
High: The heterogeneous nature of the patient population seen in clinical practice, particularly with regard to variations in disease severity, QoL impairments and aversion to treatment-related risk, is likely to affect the risk–benefit assessment. Although many patients will value the opportunity to improve their individual QoL through antibiotic treatment over the risk of adverse events, others may prefer to avoid the risks associated with treatment. Hence, treatment options, including their associated risks and benefits, should be discussed with the patient in the context of shared medical decision-making.
Clinicians should re-assess patients immediately following the completion of the initial course of retreatment to evaluate the effectiveness of retreatment and the need for therapeutic adjustments. Reassessment may need to be done much earlier and with greater scrutiny in patients with severe disease or when the therapeutic intervention carries substantial risk.
For patients who improve yet continue to have persistent manifestations and continuing QoL impairments following 4–6 weeks of antibiotic retreatment, decisions regarding the continuation, modification or discontinuation of treatment should be based on several factors. In addition to the factors listed in Recommendation 3b, the decision to continue treatment may depend on the length of time between the initial and subsequent retreatment, the strength of the patient’s response to retreatment, the severity of the patient’s current impairments, whether diagnostic tests, symptoms or treatment response suggest ongoing infection and whether the patient relapses when treatment is withdrawn.
In cases where the patient does not improve after 4–6 weeks of antibiotic retreatment, clinicians should reassess the clinical diagnosis as well as the anticipated benefit. They should also confirm that other potential causes of persistent manifestations have been adequately investigated prior to continuing antibiotic retreatment. Decisions regarding the continuation, modification or discontinuation of treatment should consider the factors noted above as well as the definition of an adequate therapeutic trial.
Whenever retreatment is continued, the timing of subsequent follow-up visits should be based on the level of the therapeutic response, the severity of ongoing disease, the duration of current therapy and the need to monitor for adverse events (see remarks section below). (Recommendation, very low-quality evidence).
Role of patient preferences
High: See Recommendation 3b.
The lack of pharmaceutical interest and its concomitant funding does not encourage the innovative research that is essential to improving care for patients with Lyme disease. When pharmaceutical interest is lacking, clinical practices often become the source of therapeutic innovation, preceding rather than following clinical trials.
The US FDA recognizes the important role that clinical innovation plays in patient care, stating: ‘Valid new uses for drugs already on the market are often first discovered through serendipitous observations and therapeutic innovations, subsequently confirmed by well-planned and executed clinical investigations ’. In providing clinicians with therapeutic flexibility, the agency makes room for clinicians to fashion patient-centered care, with treatment decisions being driven by the specific circumstances of an individual’s illness. The benefits related to therapeutic flexibility are quite evident in orphan diseases, where an estimated 90% of all prescribed medications represent off-label use and if not for that practice, clinicians would often have no effective therapies to employ . In this respect, patient care in Lyme disease is like that of other research-orphaned diseases, relying heavily on innovative clinicians to develop treatments that improve health and reduce morbidity.
Innovative therapies may employ unconventional dosages of standard medications, novel combinations of currently accepted practices, new applications of standard interventions or may use accepted therapy or approved drugs for non-approved indications . Unlike research, the primary purpose of innovative care is to benefit the individual patient . Clinicians employing innovative therapies need to verify that the innovation is intended to be in the patient’s best interest and recognize that informed consent requires that the patient understand that the recommended therapy is not standard treatment . In this context, the panel concluded that it is necessary for clinicians to provide patients with treatment options and engage in shared medical decision-making.
This determination is in keeping with the approach used by other physician-developed guidelines. The American Academy of Pediatrics guidelines recognize that in the face of low-quality evidence or where the risk–benefit equilibrium is balanced, ‘guideline developers generally should not constrain the clinician’s discretion ’. Guideline developers commonly consider not only RCTs, but also observational trials, animal model studies, expert opinion, clinical experience, patient values and judgments regarding the potential harms of an intervention as well as the potential harms of inaction . Moreover, when the condition in question poses great risk or QoL impairments, guideline panels may recommend an intervention even when the evidence base is uncertain, mixed or incompletely developed .
The panel endorses the view that informed choice is the ethical ideal in circumstances involving scientific uncertainty because it recognizes the patient’s right to self-determination . Patients with significant QoL or functional impairments may be willing to take on a far greater degree of risk than those who are relatively unaffected by ongoing disease manifestations. However, because the degree of relative risk aversion varies significantly among patients, it is important that patients be given sufficient information to make a meaningful choice regarding treatment options.
The demonstrated persistence of B. burgdorferi in specific individuals [42,47,48,133–135,145,146] and animal models [76,138,139,147] suggests a need for treatment regimens which address the mechanisms underlying bacterial persistence yet these mechanisms may not be fully identified and those that have been are not fully understood. Emerging evidence supports potential roles for these mechanisms: immune evasion via physical seclusion of Bb within immunologically protected tissue sites such as the CNS, joints and eyes [147–149], collagen-rich tissues , cells [151–154] and biofilms ; alterations in Osp profiles through antigenic variation [156–159], phasic variation  and alteration in Bb morphology (including cell-wall deficient forms, spherocytes and ‘cyst’ forms) [161–166]; immune modulation via alterations in complement [167–169], neutrophil and dendritic cell functioning [170,171], and changes in cytokine and chemokine levels [129,172,173] and innate antibiotic tolerance of some B. burgdorferi populations .
In the absence of a clear scientific understanding of persistent infection, different views regarding whether and how to address potential mechanisms have developed [175,176]. While some clinicians may elect to wait for more definitive answers, other clinicians, given the QoL impairments some patients bear, may elect to provide innovative care based on the information at hand. Antibiotic options for treating persistent manifestations include all agents known to be effective against B. burgdorferi [87,54,75,109,110,112]. While the use of agents proven to be effective in clinical research trials may be preferred, clinicians may choose antibiotics based on their clinical experiences and those of others [177–181]. While agents with favorable in vitro findings may also merit consideration, antibiotics that were ineffective in clinical trials are best avoided.
Treatment regimens may employ either a sole agent or combinations of antibiotics, depending on which mechanisms of persistence the clinician is attempting to thwart. The delivery method – oral, iv., IM – is dependent on the agents selected, disease severity and patient preferences. It is reasonable to start with dosages examined in clinical trials, but clinicians may decide to adjust dosages in individual patients with the goal of improving outcomes by achieving adequate drug levels in all infected tissues.
Oral antibiotics which demonstrated effectiveness in clinical trials include the cell wall agents amoxicillin [74,91], phenoxymethylpenicillin [46,48] and cefuroxime axetil [88,91,92]. Other cell wall agents may also be clinically useful; however, first-generation cephalosporins are known to be ineffective . Oral agents within the tetracycline and macrolide classes, which disrupt ribosomal function and are capable of entering cellular compartments, are also effective in Lyme disease. Individual agents include doxycycline [53,183–190], tetracycline , azithromycin [49,74,190,191] and clarithromycin [110,192]. However, erythromycin, which performed well in vitro, was ineffective in vivo [50,193] and the macrolide telithromycin has been linked to drug-induced liver injury . Several of the EM trials reviewed earlier in this document used higher antibiotic dosages than suggested by the panel in Recommendation 2b [47–49,74,88]. For example, Luft et al. and Weber et al. prescribed azithromycin 500 mg/day [74,191]. Strle et al. and Barsic et al. prescribed azithromycin 500 b.i.d. on day 1 followed by 500 mg daily [47,49]. Nadelman prescribed doxycycline 100 mg t.i.d. . In certain circumstances, clinicians may decide that higher doses are required.
Metronidazole and tinidazole effectively kill cell wall deficient forms of B. burgdorferi in vitro [195,196], but their effectiveness in vivo, in either oral or iv. form, has not been investigated in clinical trials.
Ceftriaxone, 2 g iv. per day is known to be effective [16,17,32,33,54,112] and iv. cefotaxime , another cephalosporin, has also been recommended. Intravenous penicillin is less effective and requires more frequent dosing ’. Additional iv. cell wall agents from the carbapenem and monobactam classes were effective in vitro, but have not been studied clinically .
IM benzathine penicillin is another useful cell wall agent and it avoids the risks associated with gaining iv. access. A case report noted its effectiveness in antibiotic resistant Lyme arthritis .
If the initial course of antibiotic retreatment does not produce a complete response, clinicians should consider various options. Patients who had an incomplete response with one agent may be responsive to another; thus, switching agents may prove successful. Alternatively, combination therapy may be appropriate in select patients. Examples include those with known or suspected co-infections and patients who had incomplete responses to single-agent therapy.
Aside from antibiotics, few therapeutic strategies have been employed to address non-infectious mechanisms of ongoing disease yet individual patients have benefitted from non-antibiotic therapies. For example, some patients with ‘antibiotic-resistant’ Lyme arthritis obtained a localized (joint-specific) benefit from synovectomy [197,198]. The rationale being that ongoing synovitis is a reflection of an auto-immune process . Additionally, an autoimmune-mediated polyneuropathy that was secondary to a proven B. burgdorferi infection of the CNS improved following IVIG therapy, whereas prior antibiotic interventions failed to halt the progression of the polyneuropathy . Other methods of immunomodulation may prove useful in the future, especially if it can be established that immune dysregulation is the specific mechanism underlying an individual’s persistent disease. However, unless an ongoing infection can be definitively ruled out, caution is required because immunomodulation could cause an occult infection to flare.
Reconciling divergent guidelines
The ILADS panel recommendations differ from those of the IDSA. Different guideline panels reviewing the same evidence can develop disparate recommendations that reflect the underlying values of the panel members, which may result in conflicting guidelines [200,201]. The IOM explains that conflicting guidelines most often result ‘when evidence is weak; developers differ in their approach to evidence reviews (systematic vs non-systematic), evidence synthesis or interpretation and/or developers have varying assumptions about intervention benefits and harms’ . Conflicting guidelines exist for over 25 conditions and there is no current system for reconciling conflicting guidelines . Supplementary Appendix I reconciles the differences between the ILADS and IDSA treatment recommendations by clinical situation.
Expert commentary & five-year view Section:
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Lyme disease is a complex illness and patients may experience both acute and persistent manifestations. The science regarding disease mechanisms is limited, uncertain and evolving. However, the profoundly negative impact that persistent manifestations exert on patients’ wellbeing as measured on validated QoL assessment tools is well documented. Therefore, critical treatment goals include: disease prevention, treating to cure where possible and otherwise improving patient QoL and preventing disease progression. Following the GRADE model, ILADS recommends that patient goals and values regarding treatment options be identified and strongly considered during a shared decision-making process. Because the GRADE process for formulating evidence-based treatment recommendations fosters transparency and recognizes that patient values may play a pivotal role, GRADE is particularly useful when addressing questions marked by significant scientific uncertainty.
Looking forward over the next 5 years, significant advances are expected in both technology and clinical research that may significantly impact the quality of patient care in Lyme disease. Since the discovery of Lyme disease in 1981, researchers have identified more than 15 new tick-borne pathogens. Progress in identifying new tick-borne pathogens and in understanding the clinical ramifications of simultaneous tick-borne diseases may help improve both the diagnosis and treatment of tick-borne diseases. Advances in genomics and proteonomics should permit researchers to identify differences in B. burgdorferi species and strains and explore their clinical implications. Significant advances in diagnostic testing may permit clinicians to distinguish the infected from the non-infected and cured and provide clinicians with a laboratory measure of therapeutic progress. Finally, advances in information technology as well as the methodology for conducting large-scale clinically relevant trials will provide evidence that addresses topics that clinicians and patients deem meaningful to improving patient QoL. These fundamental changes may change the clinical landscape and enable optimal care treatment regimens to be established.
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The state of the evidence in the diagnosis and treatment of Lyme disease is limited, conflicting and evolving. Accordingly, the recommendations in these guidelines reflect an evidence-based, patient-centered approach that many clinicians will find helpful; they are not intended to be viewed as a mandate or as a legal standard of care. Guidelines are not a substitute for clinical judgment. The International Lyme and Associated Diseases Society encourages clinicians to consider the specific details of an individual patient’s situation when determining an appropriate treatment plan.
Financial & competing interests disclosure
DJ Cameron is the President of the International Lyme and Associated Diseases Society. LB Johnson is Executive Director of LymeDisease.org. EL Maloney is a Provider of continuing medical education courses on tick-borne diseases. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing assistance from A Delong was utilized in the production of this manuscript.
Lyme disease is a complex illness and patients may experience both acute and persistent manifestations.
Persistent manifestations may produce profound quality-of-life impairments, yet the mechanisms that produce persistent manifestations are poorly understood.
The available evidence regarding the treatment of known tick bites, erythema migrans (EM) rashes and persistent disease is limited.
Grading of Recommendations Assessment, Development and Evaluation-based analyses found the evidence regarding these scenarios was of very low quality due to limitations in trial designs, imprecise findings, outcome inconsistencies and non-generalizability of trial findings.
It is impossible to state a meaningful success rate for the prevention of Lyme disease by a single 200 mg dose of doxycycline because the sole trial of that regimen utilized an inadequate observation period and unvalidated surrogate end point.
Success rates for treatment of an EM rash were unacceptably low, ranging from 52.2 to 84.4% for regimens that used 20 or fewer days of azithromycin, cefuroxime, doxycycline or amoxicillin/phenoxymethylpenicillin (rates were based on patient-centered outcome definitions and conservative longitudinal data methodology).
In a well-designed trial of antibiotic retreatment in patients with severe fatigue, 64% in the treatment arm obtained a clinically significant and sustained benefit from additional antibiotic therapy.
The optimal treatment regimen for the management of known tick bites, EM rashes and persistent disease has not yet been determined. Accordingly, it is too early to standardize restrictive protocols.
Given the number of clinical variables that must be managed and the heterogeneity within the patient population, clinical judgment is crucial to the provision of patient-centered care.
Based on the Grading of Recommendations Assessment, Development and Evaluation model, International Lyme and Associated Diseases Society recommends that patient goals and values regarding treatment options be identified and strongly considered during a shared decision-making process.
Research is needed to better define the disease process, to identify variables associated with poor outcomes and to establish highly effective therapeutic regimens for known tick bites, EM rashes and persistent disease.
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