Evidence assessments and guideline recommendations in lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease

Evidence assessments andguideline recommendationsin Lyme disease: the clinicalmanagement of known tickbites, erythema migransrashes and persistent disease Expert Rev. Anti Infect. Ther. Early online, 1–33 (2014) Evidence-based guidelines for the management of patients with Lyme disease were developed by the International Lyme and Associated Diseases Society (ILADS). The guidelines address three clinical questions – the usefulness of antibiotic prophylaxis for known tick bites, theeffectiveness of erythema migrans treatment and the role of antibiotic retreatment in patients Elizabeth L Malone with persistent manifestations of Lyme disease. Healthcare providers who evaluate and 1International Lyme and Associated manage patients with Lyme disease are the intended users of the new ILADS guidelines, Diseases Society, PO Box 341461, which replace those issued in 2004 (Exp Rev Anti-infect Ther 2004;2:S1–13). These clinical Bethesda MD, 20827-1461, USA2LymeDisease.org, PO Box 1352, Chico, practice guidelines are intended to assist clinicians by presenting evidence-based treatment For personal use only.
recommendations, which follow the Grading of Recommendations Assessment, Development 3Partnership for Healing and Health Ltd, and Evaluation system. ILADS guidelines are not intended to be the sole source of guidance PO Box 84, Wyoming, MN 55092, USA*Author for correspondence: in managing Lyme disease and they should not be viewed as a substitute for clinical Tel.: +1 914 666 4665 judgment nor used to establish treatment protocols.
KEYWORDS: antibiotic prophylaxis • antibiotics • erythema migrans • GRADE • Lyme disease • persistent disease• treatment Evidence-based medicine is the integration of with persistent manifestations of Lyme disease.
best research evidence with clinical expertise ILADS anticipates performing GRADE assess- and patient values ]. The International Lyme ments on additional topics related to the diag- and Associated Diseases Society (ILADS) has nosis and treatment of tick-borne diseases in adopted the Grading of Recommendations Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 The GRADE scheme classifies the quality (GRADE) system as its basis for evidence of the evidence as high, moderate, low or assessment and the development of recommen- very low. The quality of evidence from ran- dations to ensure a transparent and trustwor- domized controlled trials (RCTs) is initially thy guideline process –.
rated as high, but may be downgraded based These guidelines address three fundamental on five limitations: study bias, publication treatment questions: the usefulness of antibiotic bias, indirectness (generalizability), impreci- prophylaxis for known tick bites, the effective- sion and inconsistency. Evidence quality from ness of erythema migrans (EM) treatment and observational studies is generally low, but the role of antibiotic retreatment in patients may be upgraded based on a large effect or This is an open-access article distributed under the terms of the CC-BY-NC-ND 3.0 License which permitsusers to download and share the article for non-commercial purposes, so long as the article is reproduced inthe whole without changes, and provided the original source is credited.

2014 Informa UK Ltd Cameron, Johnson & Maloney tertiary prevention (by treating patients whose illness may be recommendations as strong or weak, these guidelines use the responsive to additional therapy, thereby reducing the morbid- terms ‘recommendation' or ‘strong recommendation' for or ity associated with the chronic forms of the disease).
against a medical intervention. The GRADE scheme itself is a ILADS is mindful of the role of patient preferences and val- continually evolving system. These guidelines attempt to ues in GRADE as well as the IOM's call for patient-centered incorporate the current state of GRADE.
care that is responsive to the needs, values and expressed prefer- Although Lyme disease is not rare, the treatment of Lyme ences of individual patients [. Patient-centered care focuses disease has not attracted pharmaceutical interest and the evi- on achieving treatment outcomes that patients value , dence base for treating Lyme disease is best described as sparse, including the restoration of health, prevention of health deteri- conflicting and emerging. For example, Hayes and Mead of the oration and the provision of treatments that have the potential CDC performed a systematic review of the evidence regarding to improve quality of life (QoL). To facilitate the development the treatment of late neurologic Lyme disease and their of treatment plans addressing the unique circumstances and val- GRADE-based evaluation rated the quality of the evidence as ues of individual patients, patient-centered care encourages very low . The ILADS guidelines working group reached a shared medical decision-making.
similar conclusion after assessing the research evidence pertain- Shared decision-making takes into account the best scientific ing to its three clinical questions, rating the evidence quality as evidence available, clinical expertise and the role of patient's very low. The low quality of evidence seen in Lyme disease is values and preferences in deciding among available treatment consistent with the evidence base for the field as a whole.
options [. Despite the terminology, decision-making is not Indeed, the majority of recommendations in infectious disease truly shared between clinician and patient; the responsibility medicine generally are based on low-quality evidence .
for choosing between options remains with the clinician.
When high-quality evidence is not available, guideline panels To effectively engage in shared decision-making, patients need are faced with making recommendations based on low- or very to understand the implications of their choices. Physicians low-quality evidence. Although evidence alone is never suffi- should not assume that patients share their values in making cient to determine guideline recommendations , when evi- risk/benefit determinations. Studies have demonstrated that dence is weak, the values of those on the panel, including patients and physicians may have very different assessments of differing specialty perspectives, may carry more weight ]. One preferences and risk tolerance . In addition, there is consider- of the goals of the GRADE scheme is to make the value judg- able variation among individual patients in their tolerance for ments underlying recommendations transparent.
risk and in what they regard as a valuable benefit. Patients may When the evidence base is of low or very low quality, guide- also tolerate more risk when they have severe presentations of dis- For personal use only.
line panels should be circumspect about making strong recom- ease or when there are no other treatment options available .
mendations to avoid encouraging uniform practices that are not In the GRADE system, recommendations take into account in the patient's best interest and to ensure that research regard- not only the quality of the evidence, but also the balance ing benefits and risks is not suppressed . Guidelines panels between benefits and harms and patient values and preferences .
should also make the role of their values and those of patients in In instances where a GRADE evaluation concludes that the evi- recommendations explicit and should promote informing and dence quality is low or very low or that there are trade-offs empowering patients to engage in shared decision-making ].
between risks and benefits that depend on the values of the indi- This panel has placed a high value on the ability of the clini- vidual, the GRADE system recommends that recommendations cian to exercise clinical judgment. In the view of the panel, should identify a range of therapeutic options and acknowledge guidelines should not constrain the treating clinician from that different choices may be appropriate for different patients.
exercising clinical judgment in the absence of strong and com- In assessing the balance between the risks and benefits of anti- pelling evidence to the contrary .
biotic treatments for Lyme disease, the panel weighed the bur- Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 In addition, this panel believes the goals of medical care in den of disease, the magnitude and relative importance of Lyme disease are to prevent the illness whenever possible and patient-centered outcomes as well as treatment-associated risks to cure the illness when it occurs. When this is not possible, and the risks attendant on not treating. The panel acknowledged the panel believes the emphasis for treatment should be on that the health-related and economic consequences of chronic reducing patient morbidity. Therefore, the panel placed a high disease are enormous for individuals, families, communities, value on reducing patient risks for developing the chronic form healthcare systems and the nation, impacting the wellbeing of of the disease and on reducing the serious morbidity associated individuals, family functioning and economic productivity –.
with these disease forms. Thus, the panel's values align with Therefore, the panel recommends that patients be informed of the Institute of Medicine (IOM) goal of reducing the impact the risks and benefits of treating and not treating, including the of chronic illness at the individual and national levels by, risks of continuing to suffer significant morbidity or permitting among other things, treating the treatable . To this end, the a serious systemic infection to progress.
panel valued primary prevention (by effectively treating a tick The panel assessed risks and benefits of treatment on a gen- bite), secondary prevention (by treating an EM rash sufficiently eralized basis. In addition, the panel recognizes that there is a so as to restore health and prevent disease progression) and need for clinicians, in the context of shared medical decision- Expert Rev. Anti Infect. Ther.
ILADS Lyme disease guidelines making, to engage in a risk–benefit assessment that reflects the manifestations is uncertain, their impact is clear. Two retro- individual values of the particular patient.
spective cohorts , two case series , a meta-analysis , Guidelines for the diagnosis and treatment of Lyme disease two prospective European studies and four NIH-sponsored are conflicting [Supplementary material clinical trials describe significant long-term consequences can be found online at of Lyme disease. Findings include: highlighted the conflicting Lyme guidelines of ILADS and the • Thirty-four percent of a population-based, retrospective Infectious Diseases Society of America (IDSA) and noted that cohort were ill an average of 6.2 years after antibiotic treat- the National Guidelines Clearinghouse has identified at least 25 different conditions in which conflicting guidelines exist • Sixty-two percent of a retrospective evaluation of 215 Lyme According to the IOM, conflicting guidelines most often arise disease patients from Westchester County, NY, remained ill when evidence is weak, organizations use different assessment an average of 3.2 years after antibiotic treatment ; schemes or when guideline developers place different values on • A meta-analysis of 504 patients treated for Lyme disease found the benefits and harms of interventions this group had more fatigue, musculoskeletal pain and neuro- The adoption of GRADE by ILADS is, in part, an effort to cognitive difficulties than 530 controls [. Additionally, it use the same assessment scheme as the IDSA, although it demonstrated that persistent Lyme disease symptoms were a should be noted that the IDSA's Lyme disease guidelines listed distinct set of symptoms, which differed from those of fibro- on the National Guidelines Clearinghouse were originally pub- myalgia, chronic fatigue syndrome and depression ]; lished in 2006 and do not reflect the organization's adoption • Among 23 European pediatric patients with objective findings of GRADE for guideline revisions after 2008. Additionally, the of Lyme neuroborreliosis sequelae, daily activities or school use of GRADE is one element of ILADS' compliance with the performance were negatively impacted in 10 (43%) ; eight standards identified by the IOM as being integral to cre- • A European study of adults treated for neuroborreliosis ating trustworthy treatment guidelines found that at 30 months post-treatment, 16% were cogni- The guidelines were developed in phases. A working group tively impaired ; identified three questions to address, conducted a literature • On entrance, patients enrolling in the four NIH-sponsored search and subsequent assessment of the evidence quality and clinical trials on antibiotic retreatment had experienced poor evaluated the role of patient preferences and values for each ques- long-term outcomes from their prior therapy. Participants in tion. A preliminary draft of the guidelines was sent to the full the two trials by Klempner et al. had persistent symptoms, guidelines panel and, subsequently, outside reviewers for review which were sufficiently severe as to interfere with daily func- For personal use only.
and comment, with the document being further refined. The panel and working group members were required to disclose • Using a combined total of 22 standardized measures of QoL, potential financial conflicts of interest. The full panel, which fatigue, pain and cognition –, the investigators of the consisted of the board of directors of ILADS, determined that four NIH-sponsored retreatment trials documented that the fee for service payments are inherent in the provision of health- patients' QoL was consistently worse than that of control care and did not disqualify experienced clinicians from serving populations and equivalent to that of patients with on the guideline panel nor did serving on the boards of non- congestive heart failure ; pain levels were similar to those profit organizations related to Lyme disease. Financial relation- of post-surgical patients and fatigue was on par with that seen ships exceeding US$10,000 per year that were not intrinsic to in multiple sclerosis . compares the QoL scores of medical practice were viewed as potential conflicts; no panel or the NIH Lyme disease participants at the time of their study working group members held such financial conflicts of interest.
enrollment to those of patients with other chronic diseases,including diabetes, heart disease, depression, osteoarthritis, Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 rheumatoid arthritis, lupus, fibromyalgia and epilepsy .
The burden of Lyme disease for individuals and society remainshigh. Despite the availability of numerous preventative meas- Executive summary of treatment recommendations ures , the incidence of acute Lyme disease is significant.
With the goal of fostering evidence-based, patient-centered care The CDC currently estimates that the annual number of new for patients with Lyme disease, the panel performed a deliber- cases of Lyme disease in the USA exceeds 300,000 [; how ate GRADE assessment of the pertinent trial evidence regarding these individual patients fare is an important consideration and three fundamental treatment questions and reviewed the risks ILADS is primarily interested in preventing and reducing the and benefits of antibiotic therapies used in the treatment of morbidity associated with chronic disease. Although some pro- Lyme disease. The panel also considered the ramifications of spective studies found long-term outcomes were good, many withholding antibiotic treatments or using non-curative regi- had significant limitations . There is substantial evidence mens and acknowledged that either may result in a significant of varying quality demonstrating that the severity , disease burden. Following the completion of these activities, duration [and cost of persistent manifestations the panel drew several conclusions regarding the treatment of of Lyme disease can be profound. While the etiology of these Lyme disease.
Cameron, Johnson & Maloney Table 1. Long-term consequences (or impairments) of Lyme disease.
Impairments in other illnesses – (mean) QoL PCS – range 1–100 (the lower the score, the worse the QoL)† Klempner et al., seropositive Diabetes (42), heart disease (39), depression (45), osteoarthritis Klempner et al., seropositive (39) and rheumatoid arthritis Cameron recurrent Fallon et al.
QoL MCS – range 1–100 (the lower the score, the worse the QoL)‡ Klempner et al., seropositive Diabetes (48), heart disease (49), depression (37), osteoarthritis Klempner et al., seropositive (49) and rheumatoid arthritis Cameron recurrent Fallon et al.
Fatigue – FSS – range 0–7, severe fatigue (>4.0)§ Krupp et al., post-treatment ALS (4.35), multiple sclerosis Fallon et al.
FIQ – range 0–100 (the higher the score, the greater the impairment){ Klempner et al., seropositive Fibromyalgia (58–78) Klempner et al., seropositive Pain – MPQ range 0–78 and VAS range 0–10 (the higher the scores, the greater the pain) # Fallon et al.
Widespread pain after breast cancer surgery (7.0) For personal use only.
Fallon et al.
Fibromyalgia (6.48) Neurocognitive dysfunction index†† Fallon et al.
†The PCS on the SF-36 measure of QoL is a measure of physical health, role physical, bodily pain and general health .
‡The MCS on the SF-36 measure of QoL is a measure of mental health, emotional role functioning, social functioning and vitality [.
§The FSS assesses the impact of fatigue on everyday functioning [.
{The FIQ is a measure of ‘functional disability, ability to have a job, pain intensity, sleep function, stiffness, anxiety, depression and the overall sense of wellbeing'adopted by Burckhardt et al. for fibromyalgia ] and subsequently used in Lyme disease [.
#The MPQ estimates the sensory and affective elements of pain, both qualitatively and quantitatively .
††An index based on motor, psychomotor, attention, total memory, Buschke, Benton, working memory, fluency, IQ by Barona, IQ by NAART-R, immediate memory anddelayed memory; higher values indicate better cognitive functioning. Additional outcomes described in the NIH-sponsored retreatment trials include cognitive, role func-tioning and pain on MOS abnormalities , psychopathology and a OspA measure of spinal fluid .
ALS: Amyotrophic lateral sclerosis; FIQ: Fibromyalgia impact questionnaire; FSS: Fatigue severity scale; MCS: Mental component score; MPQ: McGill Pain Questionnaire;MOS: Medical outcome scale; PCS: Physical component score; SD: Standard deviation; VAS: Visual analog scale; QoL: Quality of life.
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 Based on these conclusions, the panel formulated treatment preventable infection to one that is chronic and associated with recommendations reflecting ILADS values and patient preferen- significant morbidity and costs. The panel placed a high value ces. Recommendations for the individual clinical questions are on not causing the abrogation of the immune response. The summarized here. A detailed discussion of each question, panel also placed a high value on the ability of the clinician to including the complete GRADE analysis, the risk–benefit eval- exercise clinical judgment. In the view of the panel, guidelines uation, ILADS statement of values and the subsequent individ- should not constrain the treating clinician from exercising clini- ual treatment recommendations, in full, follows this summary.
cal judgment in the absence of strong and compelling evidenceto the contrary.
Q1. Does a single 200 mg dose of doxycycline following atick bite provide effective prophylaxis for Lyme disease? Recommendation 1a Organizational values Clinicians should not use a single 200 mg dose of doxycycline The panel placed a high value on preventing disease, thereby for Lyme disease prophylaxis (Recommendation, very low- avoiding both the unnecessary progression from a potentially quality evidence).
Expert Rev. Anti Infect. Ther.
ILADS Lyme disease guidelines Role of patient preferences fewer days of azithromycin are not recommended for patients Low: The relative trade-offs between risks and benefits are clear with EM rashes because failure rates in the clinical trials were enough that most patients will place a high value on avoiding a unacceptably high. Failure to fully eradicate the infection may seronegative state and its attendant delays in diagnosis and result in the development of a chronic form of Lyme disease, exposing patients to its attendant morbidity and costs, whichcan be quite significant. (Recommendation, very low-quality Recommendation 1b Clinicians should promptly offer antibiotic prophylaxis forknown Ixodes tick bites in which there is evidence of tick feed- Role of patient preferences ing, regardless of the degree of tick engorgement or the infec- Moderate: Although many patients will value avoiding the risk tion rate in the local tick population. The preferred regimen is of treatment failure over a potentially modest increase in the 100–200 mg of doxycycline, twice daily for 20 days. Other risk of significant adverse events that may be associated with treatment options may be appropriate on an individualized longer treatment durations, others may prefer to avoid the basis (Recommendation, very low-quality evidence).
additional risks of longer treatment. Clinicians should inform Role of patient preferences patients that: the combined failure rate for the individual Moderate: Most patients will place a high value on preventing agents investigated in the previously discussed EM trials were chronic illness. However, some patients will value avoiding judged by this panel to be unacceptably high when antibiotic unnecessary antibiotics and prefer to not treat a tick bite pro- treatment was restricted to 20 or fewer days (provide the phylactically. Hence, treatment risks, benefits and options appropriate value for each); the evidence supporting the use of should be discussed with the patient in the context of shared longer treatment durations is limited and of low quality and increases in antibiotic duration may increase the risk ofantibiotic-associated adverse events, although the risks associ- Recommendation 1c ated with oral antibiotics are low and some of this risk can be During the initial visit, clinicians should educate patients regard- mitigated by the concomitant use of probiotics . Treat- ing the prevention of future tick bites, the potential manifesta- ment risks, benefits and options should be discussed with the tions of both early and late Lyme disease and the manifestations patient in the context of shared medical decision-making.
of the other tick-borne diseases that may have been contracted asa result of the recent bite. Patients receiving antibiotic prophy- Recommendation 2b laxis should also be given information describing the symptoms Clinicians should prescribe amoxicillin, cefuroxime or doxycy- For personal use only.
and signs of a Clostridium difficile infection and the preventative cline as first-line agents for the treatment of EM. Azithromycin effect of probiotics. Patients should be encouraged to immedi- is also an acceptable agent, particularly in Europe, where trials ately report the occurrence of any and all tick-borne disease man- demonstrated it either outperformed or was as effective as the ifestations and manifestations suggestive of a C. difficile infection other first-line agents . Initial antibiotic therapy should (Recommendation, very low-quality evidence).
employ 4–6 weeks of amoxicillin 1500–2000 mg daily individed doses, cefuroxime 500 mg twice daily or doxycycline Role of patient preferences 100 mg twice daily or a minimum of 21 days of azithromycin Low: The benefits of educating patients about potential disease 250–500 mg daily. Pediatric dosing for the individual agents is manifestations clearly outweigh any attendant risks associated as follows: amoxicillin 50 mg/kg/day in three divided doses, with education.
with a maximal daily dose of 1500 mg; cefuroxime 20–30 mg/ Q2. Should the treatment of an EM rash be restricted to kg/day in two divided doses, with a maximal daily dose of 20 or fewer days of oral azithromycin, cefuroxime, 1000 mg and azithromycin 10 mg/kg on day 1 then 5–10 mg/ Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 kg daily, with a maximal daily dose of 500 mg. For children Organizational values 8 years and older, doxycycline is an additional option. Doxycy- The panel placed a high value on avoiding both the unneces- cline is dosed at 4 mg/kg/day in two divided doses, with a sary progression from a potentially curable infection to one maximal daily dose of 200 mg. Higher daily doses of the indi- that is chronic and the morbidity and costs associated with vidual agents may be appropriate in adolescents.
chronic disease. The panel also placed a high value on the abil- Selection of the antibiotic agent and dose for an individual ity of the clinician to exercise clinical judgment. In the view of patient should take several factors into account. In the absence the panel, guidelines should not constrain the treating clinician of contraindications, doxycycline is preferred when concomitant from exercising clinical judgment in the absence of strong and Anaplasma or Ehrlichia infections are possibilities. Other con- compelling evidence to the contrary.
siderations include the duration and severity –ofsymptoms, medication tolerability, patient age, pregnancy sta- Recommendation 2a tus, co-morbidities, recent or current corticosteroid use Treatment regimens of 20 or fewer days of phenoxymethyl- cost, the need for lifestyle adjustments to accommodate certain penicillin, amoxicillin, cefuroxime or doxycycline and 10 or antibiotics and patient preferences. Variations in patient-specific Cameron, Johnson & Maloney details and the limitations of the evidence imply that clinicians preventing chronic illness by continuing treatment, a substantial may, in a variety of circumstances, need to select therapeutic portion may also value avoiding unnecessary antibiotics. Hence, regimens utilizing higher doses, longer durations or combina- treatment risks, benefits and options should be discussed with tions of first-line agents (Recommendation, very low-quality the patient in the context of shared medical decision-making.
Recommendation 2e Role of patient preferences Clinicians should retreat patients who were successfully treated Moderate: See recommendation 2a.
initially but subsequently relapse or have evidence of diseaseprogression. Therapeutic options include repeating the initial Recommendation 2c agent, changing to another oral agent or instituting injectable Clinicians should provide ongoing assessments to detect evi- penicillin G benzathine or iv. ceftriaxone therapy. Choices dence of disease persistence, progression or relapse or the pres- must be individualized and based on several factors, including: ence of other tick-borne diseases. Lacking a test of cure, the initial response to treatment; the time to relapse or progres- ongoing assessments are crucial for determining if treatment has been clinically effective. The first assessment should imme- QoL impairments.
diately follow the completion of therapy and subsequent evalu- Prior to instituting additional antibiotic therapy, the original ations should occur on an as-needed basis (Recommendation, diagnosis should be reassessed and clinicians should evaluate very low-quality evidence).
patients for other potential causes that would result in theapparent relapse or progression of symptoms and/or findings Role of patient preferences (see remarks following Recommendation 2f). The presence of Low: The benefits of monitoring the response to treatment other tick-borne diseases, in particular, should be investigated if that had not already been done.
Following a long period of disease latency, minimal manifes- tations causing little deterioration in the patient's QoL favor Recommendation 2d continued observation or repeating therapy with the initial Clinicians should continue antibiotic therapy for patients who agent; mild manifestations or QoL impairments may prompt a have not fully recovered by the completion of active therapy.
switch to a different first-line agent, tetracycline or the use of a Ongoing symptoms at the completion of active therapy were combination of first-line agents. Disease relapse or progression associated with an increased risk of long-term failure in some with mild manifestations or QoL impairments occurring within For personal use only.
trials and therefore clinicians should not assume that time alone a few months of treatment suggests a need for longer regimens will resolve symptoms. There is a wide range of options and using either tetracycline, a combination of oral first-line agents, choices must be individualized, based on the strength of the injectable penicillin G benzathine or iv. ceftriaxone. Regardless patient's initial response.
of the duration of disease latency, when disease manifestations Strong-to-moderate responses favor extending the duration or QoL impairments are significant or rapidly progressive, of therapy of the initial agent; modest responses may prompt injectable penicillin G benzathine or iv. ceftriaxone may be an increase in the dose of the original antibiotic or a switch to required. Subsequent decisions regarding the modification or a different first-line agent or tetracycline. Minimal or absent discontinuation of a patient's treatment should be based on responses suggest a need for a combination of first-line agents, individual therapeutic response and preferences (Recommenda- which includes at least one that is able to effectively reach tion, very low-quality evidence).
intracellular compartments; injectable penicillin G benzathine(Bicillin LA) or intravenous (iv.) ceftriaxone are other options.
Role of patient preferences Disease progression or recurrence suggests that the iv. antibiot- Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 High: While most patients will place a high value on the ics or injectable penicillin G benzathine, as discussed previ- potential of regaining their pre-morbid health status and ously, may be required. For patients requiring antibiotic improving their QoL and preventing chronic disease through therapy beyond the initial treatment period, subsequent deci- continued antibiotic treatment, a substantial portion will also sions regarding the modification or discontinuation of treat- value avoiding potentially unnecessary antibiotics. Hence, treat- ment should be based on the therapeutic response and ment risks, benefits and options should be discussed with the treatment goals. Additionally, minimal or absent responses and patient in the context of shared medical decision-making.
disease progression require a re-evaluation of the original diag-nosis (see remarks following Recommendation 2f). (Recom- Recommendation 2f mendation, very low-quality evidence).
Clinicians should educate patients regarding the potential man-ifestations of Lyme disease, carefully explaining that disease Role of patient preferences latency can be prolonged. Education should also include infor- Moderate: While most patients will place a high value on the mation on preventing future bites, the manifestations of the potential of regaining their pre-morbid health status and other tick-borne diseases that they may have contracted as well Expert Rev. Anti Infect. Ther.
ILADS Lyme disease guidelines as the symptoms and signs of a C. difficile infection and the presence of other tick-borne illnesses should be investigated if preventative effect of probiotics. Patients should be encouraged that had not already been done. Additionally, clinicians and to immediately report the occurrence of any recurrent or newly their patients should jointly define what constitutes an adequate developing manifestation of Lyme disease as well as those sug- therapeutic trial for this particular set of circumstances.
gestive of other tick-borne diseases or a C. difficile infection.
When antibiotic retreatment is undertaken, clinicians should Clinicians should emphasize that the need to report manifesta- initiate treatment with 4–6 weeks of the selected antibiotic; this tions of tick-borne diseases never expires (Recommendation, time span is well within the treatment duration parameters of the very low-quality evidence).
retreatment trials. Variations in patient-specific details and thelimitations of the evidence imply that the proposed duration is a Role of patient preferences starting point and clinicians may, in a variety of circumstances, Low: The benefits of educating patients about potential disease need to select therapeutic regimens of longer duration.
manifestations clearly outweigh any attendant risks associated Treatment options are extensive and choices must be indi- with education.
vidualized. Each of these options would benefit from furtherstudy followed by a GRADE assessment of the evidence and Q3. Should patients with persistent manifestations of consideration of associated risks and benefits, but until this Lyme disease be retreated with antibiotics? information is available, clinicians may act on the currently Organizational values available evidence.
The panel placed a high value on reducing the morbidity asso- In choosing between regimens, clinicians should consider the ciated with chronic Lyme disease and improving the patient's patient's responsiveness to previous treatment for Lyme disease, QoL as well as on the need for individualized risk/benefit whether the illness is progressing and the rate of this progres- assessment and informed shared decision-making. The panel sion; whether untreated co-infections are present; whether the also placed a high value on the ability of the clinician to exer- patient has impaired immune system functioning or has cise clinical judgment. In the view of the panel, guidelines received immunosuppressant corticosteroids and whether other should not constrain the treating clinician from exercising clini- co-morbidities or conditions would impact antibiotic selection cal judgment in the absence of strong compelling evidence to or efficacy. Clinicians should also weigh the extent to which the contrary.
the illness interferes with the patient's QoL, including theirability to fully participate in work, school, social and family- Recommendation 3a related activities and the strength of their initial response Clinicians should discuss antibiotic retreatment with all patients against the risks associated with the various therapeutic options.
For personal use only.
who have persistent manifestations of Lyme disease. These discus- Antibiotic selection should also consider medication tolerability, sions should provide patient-specific risk–benefit assessments for cost, the need for lifestyle adjustments to accommodate the each treatment option and include information regarding C. diffi- medication and patient preferences.
cile infection and the preventative effect of probiotics (although For patients with mild impairments who had a strong-to- none of the subjects in the retreatment trials developed C. difficile moderate response to the initial antibiotic, repeat use of that infection). (Strong recommendation, very low-quality evidence.
agent is favored. Patients with moderate impairments or only a Note: In GRADE, a strong recommendation may be made in the modest response to the initial antibiotic may benefit from face of very low-quality evidence when the risk–benefit analysis switching to a different agent or combination of agents. For favors a particular intervention such that most patients would patients with significant impairments and/or a minimal or make the same choice).
absent therapeutic response, a combination of oral antibiotics,injectable penicillin G benzathine or iv. ceftriaxone (with the Role of patient preferences latter two used alone or in combination with other agents) is Low: The benefits of educating patients about the potential Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 preferred. For patients who experienced disease progression benefits of retreatment and the risks associated with various despite earlier therapy, treatment with injectable penicillin G treatment options, including not treating, clearly outweigh any benzathine or iv. ceftriaxone, alone or in combination with attendant risks associated with education.
other antibiotics, is advisable. Additionally, minimal or absentresponses and disease progression require a re-evaluation of the Recommendation 3b original diagnosis (Recommendation, very low-quality evidence).
While continued observation alone is an option for patientswith few manifestations, minimal QoL impairments and no Role of patient preferences evidence of disease progression, in the panel's judgment, antibi- High: The heterogeneous nature of the patient population seen otic retreatment will prove to be appropriate for the majority in clinical practice, particularly with regard to variations in dis- of patients who remain ill. Prior to instituting antibiotic ease severity, QoL impairments and aversion to treatment- retreatment, the original Lyme disease diagnosis should be reas- related risk is likely to affect the risk–benefit assessment.
sessed and clinicians should evaluate the patient for other Although many patients will value the opportunity to improve potential causes of persistent disease manifestations. The their individual QoL through antibiotic treatment over the risk Cameron, Johnson & Maloney of adverse events, others may prefer to avoid the risks associ- prophylaxis following an I. scapularis bite that were conducted ated with treatment. Hence, treatment options, including their in the USA and two meta-analyses involving some or all of associated risks and benefits, should be discussed with the those trials were identified and reviewed . Three trials patient in the context of shared medical decision-making.
were excluded because they investigated the efficacy of various10-day antibiotic regimens rather than the efficacy of a single Recommendation 3c 200 mg dose of doxycycline . Given that the two meta- Clinicians should re-assess patients immediately following the analyses drew substantially from these trials, both were completion of the initial course of retreatment to evaluate the excluded. The fourth trial evaluated the effectiveness of a single effectiveness of retreatment and the need for therapeutic adjust- 200 mg dose of doxycycline following a tick bite for the pre- ments. Reassessment may need to be done much earlier and vention of an EM rash at the bite site [.
with greater scrutiny in patients with severe disease or whenthe therapeutic intervention carries substantial risk.
For patients who improve yet continue to have persistent The single-dose doxycycline trial was designed using prevention manifestations and continuing QoL impairments following 4–6 of an EM rash at the bite site as a surrogate for the prevention weeks of antibiotic retreatment, decisions regarding the contin- of Lyme disease . This surrogate has not been validated.
uation, modification or discontinuation of treatment should be Although 15 years of CDC surveillance data documented that based on several factors. In addition to those listed in Recom- 31% of reported surveillance cases lacked an EM rash , the mendation 3b, the decision to continue treatment may depend single-dose doxycycline trial was not designed to detect cases of on the length of time between the initial and subsequent Lyme disease in which the rash was absent. Instead, the trial retreatment, the strength of the patient's response to retreat- design regarded all subjects lacking an EM as disease negative, ment, the severity of the patient's current impairments, whether thus biasing the trial in favor of finding treatment effective.
diagnostic tests, symptoms or treatment response suggest ongo- It should be noted that the single-dose doxycycline trial ing infection and whether the patient relapses when treatment identified three subjects with clinical and laboratory evidence is withdrawn.
(seroconversion) of early Lyme disease who lacked an EM at In cases where the patient does not improve after 4–6 weeks the bite site, thus demonstrating that the prevention of an EM of antibiotic retreatment, clinicians should reassess the clinical rash at the bite site is not an appropriate surrogate for preven- diagnosis as well as the anticipated benefit. They should also tion of Lyme disease .
confirm that other potential causes of persistent manifestations Later manifestations of Lyme disease may take months or have been adequately investigated prior to continuing antibiotic years to develop . The trial's 6-week observation period For personal use only.
retreatment. Decisions regarding the continuation, modification was therefore insufficient to detect treatment failure and thus or discontinuation of treatment should consider the factors biased the trial toward finding treatment to be effective ].
noted above as well as the definition of an adequate Investigators neglected to state that failed treatment resulted therapeutic trial.
in seronegative disease as exhibited by one subject in the Whenever retreatment is continued, the timing of subse- study [. This unfavorable outcome was not included in the quent follow-up visits should be based on the level of the ther- risk–benefit assessment, biasing the study in favor of treatment.
apeutic response, the severity of ongoing disease, the durationof current therapy and the need to monitor for adverse events.
(Recommendation, very low-quality evidence).
The single-dose doxycycline trial was incapable of measuringthe effectiveness of a single 200 mg dose of doxycycline for Role of patient preferences Lyme disease prevention because outcome measurements were High: See Recommendation 3b.
limited to documenting the occurrence of an EM rash at the Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 bite site as opposed to all disease manifestations . However, The complete discussion of the individual clinical the trial did demonstrate that treatment with doxycycline resulted in fewer EM rashes than placebo, 1 of 235 (0.4%) and Q1. Does a single 200 mg dose of doxycycline following a 8 of 247 (3.2%), respectively (p < 0.04) ]. Yet the data here tick bite provide effective prophylaxis for Lyme disease? are sparse, coming from a single study with few events, and, thus, imprecise.
The panel conducted a Medline search on 5 March 2013 for The corresponding relative treatment effectiveness was RCTs and meta-analyses, which investigated using a single dose reported to be 87%, with a 95% CI of 25–98% . The wide of doxycycline for antibiotic prophylaxis of Ixodes scapularis CI indicates that the finding was imprecise. This value, how- bites. The search used this strategy: Ixodes scapularis bites OR ever, appears to be incorrect. Although the authors reported using the Fisher exact test to calculate the odds ratio, by our migrans/prevention OR Lyme disease/prevention and these fil- calculations, the correct CI is 0.003–0.968, corresponding to a ters: comparative study, clinical trial, meta-analysis, humans.
95% CI on the scaled risk difference from 3.2 to 99.7%. This The search identified 99 papers. Four trials of antibiotic wider 95% CI suggests the study findings are consistent with a Expert Rev. Anti Infect. Ther.
ILADS Lyme disease guidelines Table 2. Quality of the evidence, in aggregate, supporting single-dose doxycycline for Lyme diseaseprophylaxis.
Inappropriate surrogate Not applicable to patients bitten by species other than Ixodes scapularis Insufficient duration of Not applicable to patients exposed to multiple tick-borne diseases Insufficient reporting of Efficacy not applicable to other antibiotics negative treatment- Effectiveness findings applicable to associated outcomes prevention of EM only and not other, non-EM presentations EM: Erythema migrans.
much smaller minimum treatment effect, with the lower limit reason for the apparently lower efficacy of single-dose oral of the CI reflecting the possibility of only a 3.2% reduction in doxycycline in mice is unclear. It is worth noting that the 95% the risk of EM in the antibiotic arm compared with placebo.
CI in the study by Nadelman et al. was quite large, 3.2–99.7% Thus, the trial was not well powered to precisely measure the (see precision discussion above), suggesting that true treatment treatment effect despite being adequately powered to detect effectiveness was approximately 50% , a value comparable to that of the murine study .
Although the dropout rate was low (11%), the assumption that none of the participants who dropped out developed an EM is unsupported and biased the estimated incidence in each The directness of the trial is limited to patients bitten by arm downward. Furthermore, had a single EM in the antibiotic I. scapularis ticks treated with a single-dose doxycycline. The arm been missed due to patient dropout, then the statistical effectiveness of single-dose regimens using other antibiotics and significance of the primary outcome would have been lost the effectiveness of single-dose doxycycline in other Ixodes (p = 0.11). It is unsettling when changing one participant's species have not been evaluated. Further, animal models suggest outcome can dramatically affect a study's conclusion.
single-dose oral doxycycline prophylaxis is less effective whenmultiple pathogens are simultaneously transmitted to a host For personal use only.
; therefore, the findings are not applicable to patients No other clinical trials have evaluated the effectiveness of a sin- exposed to B. burgdorferi and A. phagocytophilum and the appli- gle 200 mg dose of doxycycline for the prevention of an EM cability to patients exposed to B. burgdorferi and other rash at the bite site; therefore, the consistency of this finding in co-infecting pathogens cannot be assumed.
humans cannot be judged.
However, the effectiveness of doxycycline prophylaxis has been Evidence quality, in aggregate studied in a murine model [and the findings were inconsis- Overall, the quality of the evidence supporting the use of a sin- tent with that of the single-dose doxycycline trial [. In contrast gle 200 mg dose doxycycline following a tick bite is very to the human trial, which used a surrogate marker, the murine low implying that the true effectiveness of a single study used tissue cultures and post-treatment necropsy findings 200 mg dose of doxycycline is likely to be substantially differ- to provide direct evidence of treatment effectiveness. In the ent from the trial's reported effectiveness rate ].
murine model, single-dose oral doxycycline was 43% effective for Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 preventing Lyme disease [. A second murine study using ticks dually infected with Borrelia burgdorferi and Anaplasma phagocy- The single 200 mg dose doxycycline trial design employed an tophilum demonstrated that single-dose oral doxycycline was unvalidated and inappropriate surrogate and the duration of 20 and 30% effective for preventing B. burgdorferi and A. phago- the observation period was inadequate. The reported 87% cytophilum infections, respectively .
efficacy of single-dose doxycycline therapy was with regard to While it has been suggested that the lower efficacy of doxy- the observed reduction in the incidence of an EM rash at the cycline in the murine studies was related to differences between bite site in the doxycycline subjects compared with the pla- mice and humans with regard to the duration of time that cebo subjects ], but the reliability of this finding is doxycycline levels exceeded the minimal inhibitory concentra- diminished by its imprecision and its clinical significance is tion for B. burgdorferi following a single oral dose of doxycy- questionable (see quality of evidence discussion above).
cline (T > minimal inhibitory concentration) [, subsequent Therefore, the trial's significant design deficiencies prohibit pharmacodynamic modeling found that other pharmacody- conclusions regarding the efficacy and, thus, the benefits of namic parameters correlated better with efficacy [. However, single-dose doxycycline therapy for the prevention of these findings were based on flawed assumptions. Thus, the Lyme disease.
Cameron, Johnson & Maloney Table 3. Summary of findings regarding the effectiveness of single-dose doxycycline for prevention oferythema migrans rashes.
Incidence placebo Incidence single-dose doxy Treatment efficacy 87%; 95% CI: 3.2–99.7% Safety of single-dose doxycycline.
N = 235; Adverse events: 1 patient who failed therapy was persistently seronegative; no other serious adverse events.
EM: Erythema migrans.
exercise clinical judgment. In the view of the panel, guidelines Treatment failure may result in seronegative Lyme disease.
should not constrain the treating clinician from exercising clini- Although the single-dose doxycycline trial was not designed to cal judgment in the absence of strong and compelling evidence determine whether this regimen could result in seronegative to the contrary.
Lyme disease, the subject in the doxycycline arm who failedtreatment remained negative on follow-up serologic testing, Recommendation 1a suggesting that this occurred . Clinical trials, case reports Clinicians should not use a single 200 mg dose of doxycycline and studies in non-human primates have also documented for Lyme disease prophylaxis. (Recommendation, very low- instances of seronegative disease . While the mecha- quality evidence) nisms allowing for seronegative disease have yet to be fullyinvestigated, antibiotic treatment has been shown to abrogate Role of patient preferences the immune response in Coccidioides spp. , primary syphi- Low: The relative trade-offs between risks and benefits are clear lis , rheumatic fever as well as Lyme disease . It is enough that most patients will place a high value on avoiding a postulated that antibiotic therapy reduces the antigenemia seronegative state and its attendant delays in diagnosis and needed for the immune system to establish an immunologic response [. Inducing a seronegative disease state may lead todiagnostic and treatment delays, which are associated with Recommendation 1b poorer outcomes, and the development of a chronic form of Clinicians should promptly offer antibiotic prophylaxis for the illness [.
known Ixodes tick bites, in which there is evidence of tick feeding,regardless of the degree of tick engorgement or the infection rate For personal use only.
in the local tick population. The preferred regimen is 100– The potential harms of the single-dose oral doxycycline pro- 200 mg of doxycycline, twice daily for 20 days. Other treatment phylactic regimen and the magnitude of those harms signifi- options may be appropriate on an individualized basis (see cantly outweigh its benefits. In assessing the risk–benefit remarks below). (Recommendation, very low-quality evidence).
profile, the panel considered the unknown efficacy of singledose prophylaxis in preventing the development of Lyme dis- Role of patient preferences ease and the magnitude of the potential harm created by induc- Moderate: Most patients will place a high value on preventing ing a seronegative state, including its concomitant diagnostic chronic illness. However, some patients will value avoiding and treatment delays and the resultant increased risk of devel- unnecessary antibiotics and prefer to not treat a tick bite pro- oping a chronic form of the disease, which is more difficult to phylactically. Hence, treatment risks, benefits and options treat successfully. The panel also considered findings from a should be discussed with the patient in the context of shared murine model, which demonstrated that the effectiveness of Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 single-dose doxycycline is further reduced in dual infectionsinvolving B. burgdorferi and A. phagocytophilum, an important Recommendation 1c consideration in many regions of the USA. Additionally, the During the initial visit, clinicians should educate patients panel noted that the effects of this regimen on the clinical pre- regarding the prevention of future tick bites, the potential sentation, detection and prevention of other common Ixodes- manifestations of both early and late Lyme disease and the borne co-infections are unknown.
manifestations of the other tick-borne diseases that may havebeen contracted as a result of the recent bite. Patients receiv- ing antibiotic prophylaxis should also be given information The panel placed a high value on preventing disease, thereby describing the symptoms and signs of a C. difficile infection avoiding both the unnecessary progression from a potentially and the preventative effect of probiotics. Patients should be preventable infection to one that is chronic and associated with encouraged to immediately report the occurrence of any and significant morbidity and costs. The panel placed a high value all tick-borne disease manifestations and manifestations sug- on not causing the abrogation of the immune response. The gestive of a C. difficile infection (Recommendation, very low- panel also placed a high value on the ability of the clinician to quality evidence).
Expert Rev. Anti Infect. Ther.
ILADS Lyme disease guidelines Role of patient preferences to provide secondary prevention as well, should the early, non- Low: The benefits of educating patients about potential disease EM manifestations of the infection be missed. However, manifestations clearly outweigh any attendant risks associated patients wishing to avoid antibiotics may prefer this option, in with education.
which case clinicians should emphasize that patients mustimmediately report the occurrence of Lyme-related symptoms so that appropriate antibiotic therapy can be instituted.
Lyme disease often results from unrecognized tick bites , In cases where doxycycline is contraindicated, clinicians may which do not provide an opportunity for administering antibi- consider using other antibiotics known to be effective in Lyme otic prophylaxis. When antibiotic prophylaxis is employed for disease, such as amoxicillin, cefuroxime or azithromycin, known bites, it is imperative that treatment begin without although there is no evidence to guide decisions with regard to delay. A recent murine study demonstrated that prophylaxis the dose and duration of use for these agents. The excluded tri- was most effective when given immediately after a bite and als of antibiotic prophylaxis investigated the therapeutic efficacy that effectiveness diminished with treatment delays .
of 10 days of amoxicillin, three-times daily ]; penicillin, four- Although no studies to date have specifically investigated the times daily and tetracycline, four-times daily . None of efficacy of antibiotic prophylaxis for bites from other Ixodes the trials was able to demonstrate efficacy, primarily due to the species, it is reasonable to provide prophylaxis for such bites low incidence of disease in the placebo groups .
pending future research.
Some guidelines recommend that clinicians learn to estimate The evidence supporting use of 20 days of antibiotics is lim- attachment times for recovered ticks based on their scutal ited to the previously mentioned murine trials . In the first index, but expertise is required to do this and it is unrealistic trial, investigators demonstrated that a long-acting form of to assume that all clinicians can or will acquire such skills. In doxycycline, with measurable levels for 19 days, was 100% the single-dose doxycycline study, 9.9% of the bites from effective for preventing Lyme disease . In the dual-exposure nymphal ticks that exhibited any degree of engorgement model, the long-acting form of doxycycline was 100% effective resulted in the development of an EM at the bite site .
for preventing B. burgdorferi and A. phagocytophilum infec- Therefore, the panel determined that it was prudent to rou- tions . No long-acting, injectable doxycycline preparation is tinely offer prophylaxis under such circumstances and that available for use in humans , which is why the panel recom- withholding therapy from patients who failed to meet an arbi- mends using 100–200 mg of doxycycline twice daily for a min- trary minimum tick attachment time was inappropriate. Simi- imum of 20 days. One advantage to this regimen is that it larly, the panel recognizes that clinicians frequently lack would also address situations where patients are exposed to information regarding current infection rates for a given tick For personal use only.
both B. burgdorferi and A. phagocytophilum.
population (often because the research to establish local infec- Analysis of the single-dose doxycycline trial highlights the tivity rates has not been done) and that tick infection rates in problems inherent in formulating treatment recommendations the same locale vary significantly on an annual basis ]. There- on the basis of a single study and demonstrates that a random- fore, the panel concluded that meeting a specific tick infection ized, placebo-controlled study design, in and of itself is not a rate should not be a prerequisite for antibiotic prophylaxis.
guarantee that the study will produce high-quality evidence. Thepanel recognizes that recommendations based solely on animal Q2. Should the treatment of an EM rash be restricted to models are also problematic. Therefore, the panel encourages the 20 or fewer days of the first-line oral agents NIH to fund appropriately designed trials in order to investigate (azithromycin, cefuroxime, doxycycline and the optimum duration of treatment for a known Ixodes bite.
Given that doxycycline dosages of 100 mg twice daily may not provide adequate levels in all tissues or in all patients , The panel conducted a Medline search on 5 March 2013 for Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 some clinicians may prefer to prescribe higher daily doses prospective randomized clinical trials investigating the effective- [. Regardless of the selected dose, clinicians should ness of 5–20 days of oral azithromycin, cefuroxime, doxycy- advise patients to take probiotics daily while on antibiotic ther- cline, phenoxymethylpenicillin or amoxicillin for the treatment apy. Probiotics reduce the risk of C. difficile colitis and of EM. The search used the following strategy: (erythema antibiotic-associated diarrhea .
migrans OR erythema chronicum migrans OR lyme OR lyme ‘Watchful waiting' does not satisfy a strict definition of pro- borreliosis) AND (amoxicillin/therapeutic use OR azithromy- phylaxis. Rather than acting to prevent disease, this option cin/therapeutic use OR penicillin/therapeutic use OR cefurox- seeks the early identification and treatment of Lyme disease ime/therapeutic use OR doxycycline/therapeutic use) AND infections resulting from a known bite. The hallmark of early (Clinical trial OR comparative study OR meta-analysis). The disease is the EM rash; and as previously noted, almost a third search identified 76 papers; 51 reported trial outcomes.
of reported surveillance cases of Lyme disease lack this find- A preliminary assessment found that 27 papers described ing . Given the possible absence of an EM rash in a studies that either investigated antibiotic treatment of non-EM patient with a known bite, this option not only withholds pri- presentations (23); were primarily interested in disseminated mary preventative therapy, it potentially loses an opportunity disease (3) or did not involve any of the antibiotics of interest Cameron, Johnson & Maloney Table 4. Quality of the evidence, in aggregate, that supports restricting the antibiotic treatment of ery-thema migrans to 20 or fewer days.
No single trial design Limited number of No trial investigated all Not applicable to 4 classes of antibiotics.
non-EM early Lyme; Small sample sizes As originally reported: Trials differed by - Efficacies of individual agents, duration of agents were inconsistent therapy, length of - Relative efficacies investigating the same European trials may observation in most agents were inconsistent not be applicable to When uniform design definitions of success elements applied and Lack of a standard outcomes assessed by outcome definition treatment duration: - Inconsistent intra-agent longitudinal data - Inconsistent relative outcomes in inter-agentcomparisons †Several comparative studies described differing durations of therapy.
EM: Erythema migrans; ITT: Intention to treat.
(1). These were not considered further. An additional 15 trials more likely to capture disease relapse and subsequently report were excluded because additional review demonstrated that lower success rates. Therefore, variations in the length of the they were either retrospective studies (2); incompletely random- observation period may bias efficacy findings in favor of agents ized (1); used a symptom list during post-treatment assessments that were investigated in trials utilizing short observation For personal use only.
that did not include commonly reported symptoms of the dis- ease (7) or had a non-completion rate of 20% or higher (5).
Recognizing this, investigators in two of the EM trials cited Thus, nine trials met the requirements for this GRADE analy- the need for longer observation periods in their discus- sis and were evaluated in detail –.
sions ; one suggested that to accurately compare agents,observation periods would need to extend 2 years post- Rating the quality of the evidence treatment . Of the nine trials reviewed by the panel, only one [met this suggested standard and, given that relapse may None of the trials compared all four antibiotic classes (azithro- occur even later, 2 years may not be sufficient.
mycin, cefuroxime, doxycycline and phenoxymethylpenicillin/ The lack of standardized outcome definitions also introduces amoxicillin). The nine trials had significant differences in bias. The trials used broad definitions of treatment success that design elements including: antibiotic agents investigated, dura- differed by trial . All required the complete res- tion of therapy, outcome definitions, length of observation olution of EM and an absence of new findings but, to varying Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 period and longitudinal data methods; these differences poten- degrees, each trial allowed subjects with improved yet persistent tially biased findings in favor of one or more agents and make symptoms and subjects who had developed new symptoms con- it difficult to draw broad conclusions regarding the effectiveness sistent with Lyme disease during the observation period to be of the various agents.
included within the success group. Thus, treatment success was Observation periods ranged from 3 to 24 months. The opti- not synonymous with the full restoration of the pre-Lyme dis- mum duration of post-treatment observation for EM has not ease health status and prevention of late manifestations of been determined, in part, because while disease relapse is Lyme disease and, therefore, all of the trials were biased toward known to occur, the duration of the latent period is variable finding treatment to be effective.
and can be prolonged [. For example, one trial reviewed The choice of longitudinal data methods may bias findings here reported a relapse at 20 months [and Logigian et al.
by either overstating or understating success rates and the found that in their subjects (all of whom had neurologic mani- nine trials employed different methods for handling subjects festations of Lyme disease), the median time from EM to who did not complete the study as designed .
chronic CNS symptoms was 26 months, with a range of Seven trials used complete-case methodology , 1–168 months. Thus, trials with longer observation periods are one reported results in both complete-case and last observation Expert Rev. Anti Infect. Ther.
ILADS Lyme disease guidelines Table 5. Summary of findings regarding the effectiveness of treating an erythema migrans rash with 20 orfewer days of antibiotics based on a re-analysis of the original trial data to reflect patient-centeredoutcomes.
Number of trials, success rate by agent† Return to baseline Return to baseline Return to baseline Serious adverse events, defined as allergic reactions, Clostridium difficile infections, anyadverse event resulting in withdrawal from study or change in therapeutic agent, andany adverse event labeled by the investigators as ‘serious' occurred in 21 of1068 subjects (2.0%) . None of the adverse events was specificallycategorized as allergic reactions. The majority of serious adverse events involved the skin(13), including non-specific skin rash (6) [, drug eruptions (6) [and seriousphotosensitivity reaction (1) . Gastrointestinal adverse events were also common,including poor medication palatability in pediatric subjects (2) , nausea and vomiting(1) and diarrhea (5) [. A single subject was treated for C. difficile infectionshortly after completing treatment [. No deaths were reported.
†CIs for the individual trials are available in Supplementary Appendix III.
Azith: Azithromycin; Cefur: Cefuroxime; Doxy: Doxycycline; PMP/Amox: Phenoxymethylpenicillin/amoxicillin.
carried forward and one trial employed an intention-to-treat conservative approach to efficacy determinations avoids the For personal use only.
(ITT) approach .
potential harms associated with overstating treatment success Complete-case methodology is likely to overstate treatment and understating treatment failures.
success because subjects who leave the trial prematurely due totreatment ineffectiveness or intolerance are excluded from out- come calculations . Thus, the trials that used this approach The number of trials that investigated a given antibiotic was were biased towards finding higher treatment success rates. Last limited and sample sizes in the individual trials were small.
observation carried forward completes the data set for missing Trial numbers per agent ranged from 3 to 5 and median sam- subjects by imputing the value from the most recent visit to all ple sizes per agent ranged from 28 to 63. Small sample sizes subsequently missed observation points, implying outcomes are are susceptible to random chance and small study bias .
static . Because relapses occur in Lyme disease, this meth- Only three of the nine trials reported CIs for treatment effi- odology may overstate treatment success; thus, the trials that cacy [; a fourth reported CIs for the risk of a drug used last observation carried forward were likely biased towards finding higher treatment success rates.
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 ITT models evaluate subjects by their assigned treatment, regardless of compliance [. These models also impute data Outcomes, as originally reported by the nine trials, were incon- for the missing and the chosen values reflect assumptions sistent. Two trials simultaneously evaluated the effectiveness of regarding the likelihood that certain potential outcomes actually occurred . Potential assumptions range from worst-case to amoxicillin plus probenecid [. Strle et al. reported that best-case scenarios. In general, ITT methodology is thought to 28% of subjects, overall, had post-treatment signs/symptoms.
better represent clinical realities, where patients may inadver- By agent, 15% of azithromycin, 26% of doxycycline and tently or purposefully supplement treatment with other inter- 43% phenoxymethylpenicillin subjects had post-treatment man- ventions that affect outcomes or elect to abandon ineffective ifestations . In contrast, Massarotti et al. reported that azi- treatment altogether [. The EM trial that employed ITT thromycin, doxycycline and amoxicillin plus probenecid were methodology assumed that missing subjects fulfilled the worst equally efficacious [.
case scenario, that is, had failed , biasing the trial toward Seven trials compared two of the three agents, although the finding treatment less successful. However, adopting a pairings differed . Weber et al. found that Cameron, Johnson & Maloney azithromycin and phenoxymethylpenicillin were comparable, original trial data. To avoid overstating the effectiveness of while Luft et al. found amoxicillin to be more efficacious for pre- the investigated antibiotics, the panel specifically chose to venting late disease than azithromycin . Azithromycin was assume that those who failed to complete the trial were more efficacious than doxycycline in the 1993 trial by Strle et al., treatment failures.
but Barsic et al. found the two agents equivalent .
Success was defined as the complete resolution of EM and In a separate analysis, success rates for the individual agents all associated symptoms and findings, without evidence of were determined after uniform patient-centered outcome defini- disease relapse or the development of new manifestations tions and longitudinal data methods were applied to the origi- consistent with Lyme disease during the observation period.
nal data (see Benefits section below and ). These results The panel viewed this outcome definition as the outcome were also inconsistent. Success, in relation to treatment dura- that would matter most to patients and thought it was con- tion, demonstrated inter- and intra-agent inconsistencies. For sistent with the expectation that the appropriate treatment of example, when the treatment duration was 11–19 days, cefur- an EM rash should restore the patient to their pre-morbid amoxicillin (52.2%) but for 20 days of treatment, success for Failure included any outcome short of that. Subjects phenoxymethylpenicillin/amoxicillin (84.4%) was greater than described by the investigators as failures and those who were that of cefuroxime (61.5%). Success rates for individual agents retreated (regardless of the post-retreatment outcome) were were also inconsistent; both cefuroxime and phenoxymethylpe- considered failures for the purpose of this outcome analysis.
nicillin/amoxicillin had higher success rates with shorter, rather Subjects who had ongoing symptoms at the final end point, than longer, treatment durations.
including those described as ‘partial responders', were alsoconsidered failures. In some instances, this resulted in subjects being re-categorized as failures. Subjects who were ‘unevaluable', Findings are applicable to patients with EM rashes, without wrongly enrolled, non-compliant, withdrawn prematurely due evidence of CNS dissemination. It cannot be assumed that to adverse reactions to their assigned antibiotic or lost to findings are applicable to patients with Lyme disease inclusive follow-up were also considered failures for the purpose of of CNS dissemination, other tick-borne diseases or immuno- this analysis.
compromised states ]. Nor can it be assumed that findings Success rates across the nine trials differed significantly. The are applicable to non-EM early Lyme disease . Given the lowest, 52.2% (CI: 30.6, 73.3), was in the phenoxymethylpeni- clinical variations between the genospecies ], results from cillin arm of the 1992 trial by Strle et al. and the highest, European trials, where Borrelia afzelii is the dominant cause of 93.3% (CI: 68.1, 99.8), was in the high-dose cefuroxime arm For personal use only.
EM rashes , may not be applicable to the US patients.
in the trial by Eppes and Childs (see ).
The two arms with the highest success rates had exceptionally Evidence quality, in aggregate small sample sizes; one arm had 13 subjects, the other had The quality of the evidence addressing the effectiveness of 15 . The two arms with the lowest success rates also had 5–20 days of antibiotics for the treatment of EM is very low, small samples sizes, 23 subjects in one and 26 in the implying that the true effectiveness of a 5–20 day course of antibiotics for the treatment of an EM rash is likely to be sub- Success rates were subsequently regrouped by agent and stantially different from the trials' reported effectiveness rate.
treatment duration and weighted average success rates for thevarious regimens were then calculated. The outcome results from arms which had non-completion rates equal to or exceed- The limitations of the evidence from the original trials reduce ing 20% were excluded from the calculations. As shown the reliability of their findings. Given that no trial directly in , success rates for a given treatment duration vary by Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 compared all classes of agents (azithromycin, cefuroxime, doxy- antibiotic class. Twenty days of phenoxymethyl-penicillin/ cycline and phenoxymethylpenicillin/amoxicillin) and direct amoxicillin had the highest overall success rate of all of the reg- comparisons between individual trials are hampered by differ- imens, 84.4%, while 11–19 days of these same agents had the ences in outcome definitions, length of the observation periods lowest success rate, 61.5%.
and longitudinal data methodologies, the ability to draw validconclusions regarding the relative effectiveness of commonly prescribed antibiotic regimens is impaired.
Serious adverse events, defined as allergic reactions, C. difficile To provide comparative information on patient-centered infections, any adverse event resulting in withdrawal from study outcomes by agent – information of clinical import to clini- or change in therapeutic agent and any adverse event labeled cians and patients – the original trial data were reanalyzed.
by the investigators as ‘serious' occurred in 20 of 1068 subjects To minimize biases due to variations in trial design, stan- (1.9%) . None of the adverse events was specifically dardized, patient-centered definitions of treatment success categorized as allergic reactions. The majority of serious and failure and uniform statistical methodology, utilizing the adverse events involved the skin (11), including non-specific conservative approach of Barsic et al. , were applied to the skin rash (6) , drug eruptions (4) ] and serious Expert Rev. Anti Infect. Ther.
ILADS Lyme disease guidelines photosensitivity reaction (1) . Gastrointestinal adverse Role of patient preferences events were also common, including poor medication palat- Moderate: Although many patients will value avoiding the risk ability in pediatric subjects (2) , nausea and vomiting of treatment failure over a potentially modest increase in the (1) [and diarrhea (5) . A single subject was treated risk of significant adverse events that may be associated with for C. difficile infection shortly after completing treatment .
longer treatment durations, others may prefer to avoid the No deaths were reported.
additional risks of longer treatment. Clinicians should inform Although the panel did not consider a Jarisch–Herxheimer patients that the combined failure rate for the individual agents reaction an adverse event, four EM trials reported a Jarisch– investigated in the previously discussed EM trials were judged Herxheimer reaction in 60 of 351 subjects (17.1%) (range by this panel to be unacceptably high when antibiotic treat- 12.1–18.7%) .
ment was restricted to 20 or fewer days; the evidence support-ing the use of longer treatment durations is limited and of low quality –and increases in antibiotic duration may increase The harms associated with restricting treatment of an EM rash the risk of antibiotic-associated adverse events, although the to 20 or fewer days of oral azithromycin, cefuroxime, doxycy- risks associated with oral antibiotics are low and some of this cline and phenoxymethylpenicillin/amoxicillin outweigh the risk can be mitigated by the concomitant use of probiot- benefits. In assessing the risk–benefit profile, the panel deter- ics . Treatment risks, benefits and options should be mined that the failure rates for antibiotic treatment of 20 or discussed with the patient in the context of shared medical fewer days were unacceptably high and that for those who failed treatment, the magnitude of the potential harm createdby delaying definitive treatment, which includes the increased Recommendation 2b risk of developing a chronic and more difficult to treat form of Clinicians should prescribe amoxicillin, cefuroxime or doxycy- the disease, was too great.
cline as first-line agents for the treatment of EM. Azithromycin Although it is generally assumed that antibiotic regimens of is also an acceptable agent, particularly in Europe, where trials shorter duration will be associated with a lower rate of demonstrated it either outperformed or was as effective as the significant adverse events, adverse event rates for oral antibiotics other first-line agents . Initial antibiotic therapy should are generally quite low regardless of the duration of employ 4–6 weeks of amoxicillin 1500–2000 mg daily in use –. The panel concluded that while antibiotic treat- divided doses, cefuroxime 500 mg twice daily or doxycycline ment regimens of 20 or fewer days may result in slightly fewer 100 mg twice daily or a minimum of 21 days of azithromycin significant adverse events compared with regimens of longer 250–500 mg daily. Pediatric dosing for the individual agents is For personal use only.
duration, that benefit does not offset the potential harms asso- as follows: amoxicillin 50 mg/kg/day in three divided doses, ciated with the unacceptably high failure rates resulting from with a maximal daily dose of 1500 mg; cefuroxime 20–30 mg/ this treatment approach. Furthermore, as previously noted, the kg/day in two divided doses, with a maximal daily dose of concomitant use of probiotics should reduce the risk of C. dif- 1000 mg and azithromycin 10 mg/kg on day 1 then 5–10 mg/ ficile colitis and antibiotic-associated diarrhea [.
kg daily, with a maximal daily dose of 500 mg. For children8 years and older, doxycycline is an additional option. Doxycy- cline is dosed at 4 mg/kg/day in two divided doses, with a The panel placed a high value on avoiding both: the unneces- maximal daily dose of 200 mg. Higher daily doses of the indi- sary progression from a potentially curable infection to one vidual agents may be appropriate in adolescents.
that is chronic and the morbidity and costs associated with Selection of the antibiotic agent and dose for an individual chronic disease. The panel also placed a high value on the abil- patient should take several factors into account. In the absence ity of the clinician to exercise clinical judgment. In the view of of contraindications, doxycycline is preferred when concomitant Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 the panel, guidelines should not constrain the treating clinician Anaplasma or Ehrlichia infections are possibilities. Other con- from exercising clinical judgment in the absence of strong and siderations include the duration and severity of symptoms, compelling evidence to the contrary.
medication tolerability, patient age, pregnancy status, co-mor-bidities, recent or current corticosteroid use , cost, the Recommendation 2a need for lifestyle adjustments to accommodate certain antibiot- Treatment regimens of 20 or fewer days of phenoxymethyl- ics and patient preferences. Variations in patient-specific details penicillin, amoxicillin, cefuroxime or doxycycline and 10 or and the limitations of the evidence imply that clinicians may, fewer days of azithromycin are not recommended for patients in a variety of circumstances, need to select therapeutic with EM rashes because failure rates in the clinical trials were regimens utilizing higher doses, longer durations or combina- unacceptably high. Failure to fully eradicate the infection may tions of first-line agents. (Recommendation, very low-quality result in the development of a chronic form of Lyme disease, exposing patients to its attendant morbidity and costs, whichcan be quite significant. (Recommendation, very low-quality Role of patient preferences Moderate: See Recommendation 2a.
Cameron, Johnson & Maloney Recommendation 2c Recommendation 2f). (Recommendation, very low-quality Clinicians should provide ongoing assessments to detect evi- dence of disease persistence, progression or relapse or the pres-ence of other tick-borne diseases. Lacking a test of cure, ongoing Role of patient preferences assessments are crucial for determining if treatment has been Moderate: While most patients will place a high value on the clinically effective (see remarks following Recommendation 2f).
potential of regaining their pre-morbid health status and pre- The first assessment should immediately follow the completion venting chronic illness by continuing treatment, a substantial of therapy and subsequent evaluations should occur on an as- portion may also value avoiding unnecessary antibiotics. Hence, needed basis. (Recommendation, very low-quality evidence) treatment risks, benefits and options should be discussed withthe patient in the context of shared medical decision-making.
Role of patient preferencesLow: The benefits of monitoring the response to treatment Recommendation 2e clearly outweigh any attendant risks associated with monitoring.
Clinicians should retreat patients who were successfully treatedinitially, but subsequently relapse or have evidence of disease pro- Recommendation 2d gression. Support for retreatment is drawn from the EM trials Clinicians should continue antibiotic therapy for patients who themselves. In seven of the nine trials reviewed in this analy- have not fully recovered by the completion of active therapy.
sis [, subjects who had evidence of treatment failure Ongoing symptoms at the completion of active therapy were during the observation period were offered retreatment. Regimens associated with an increased risk of long-term failure in some used either oral [] or iv. antibiotics [], with trials and therefore clinicians should not assume that time alone the choice of agent and route apparently reflecting the inves- will resolve symptoms (see remarks following Recommendation tigators' clinical assessments and treatment preferences.
2f). There is a wide range of options and choices must be indi- Therapeutic options include repeating the initial agent, vidualized, based on the strength of the patient's initial changing to another oral agent or instituting injectable penicil- response. Dosage ranges for oral agents are as noted in lin G benzathine or iv. ceftriaxone therapy. The previously Recommendation 2b.
listed dosage ranges for the individual agents would be appro- Strong-to-moderate responses favor extending the duration priate. Choices must be individualized and based on several fac- of therapy of the initial agent at the same dosage. Modest tors, including: the initial response to treatment; the time to responses may prompt an increase in the dosage of the initial relapse or progression; the current disease severity and the level antibiotic or a switch to a different first-line agent. Tetracy- of QoL impairments.
For personal use only.
cline, with a total daily dose of 1000–1500 mg in three or four Prior to instituting additional antibiotic therapy, the original divided doses, is an additional option . Due to its favor- diagnosis should be reassessed and clinicians should evaluate able pharmacokinetics, tetracycline may be more effective than patients for other potential causes that would result in the doxycycline when initial therapy is non-curative .
apparent relapse or progression of symptoms and/or findings Minimal or absent responses suggest a need for a combina- (see remarks following Recommendation 2f).
tion of first-line agents, which includes at least one antibiotic The presence of other tick-borne diseases, in particular, that is able to effectively reach intracellular compart- should be investigated if that had not already been done. I.
ments [. Injectable penicillin G benzathine (Bicillin LA), scapularis transmits several pathogens and the resulting infec- totaling 1.2–3.6 million units weekly, or iv. agents such as cef- tions may produce symptoms similar to those of Lyme disease.
triaxone are other options. Intramuscular (IM) benzathine peni- Thus, apparent relapse or disease progression following antibi- cillin avoids the risks associated with gaining iv. access and it otic therapy for Lyme disease may be indicative of a concurrent was effective in seemingly recalcitrant Lyme arthritis ]. Cef- co-infection and not the failure to eradicate B. burgdorferi. The Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 triaxone, 2 g iv. per day is known to be effective [ presence of other Ixodes-borne infections may increase the and iv. cefotaxime , another cephalosporin, has also been severity and duration of Lyme disease symptoms . Treat- recommended. iv. penicillin is less effective and requires more ment of dually infected patients has not been studied, there- frequent dosing [. Additional iv. cell wall agents from the fore, the optimal antibiotic regimen for the Lyme disease carbapenem and monobactam classes were effective in vitro, component is unknown. The possibility of co-infections should but have not been studied clinically ].
not be casually dismissed. Two published surveys of Lyme dis- Disease progression or recurrence suggests that the iv. agents ease patients found that many respondents were infected with or injectable penicillin G benzathine, as discussed above, may more than one tick-borne pathogen [. A survey of be required. For patients requiring antibiotic therapy beyond 3090 patients diagnosed with Lyme disease found that labora- the initial treatment period, subsequent decisions regarding the tory confirmed cases of babesiosis and anaplasmosis were modification or discontinuation of treatment should be based reported by 32.3 and 4.8% of respondents, respectively ].
on the therapeutic response and treatment goals. Additionally, Following a long period of disease latency, minimal manifes- minimal or absent responses and disease progression require a tations causing little deterioration in the patient's QoL favor re-evaluation of the original diagnosis (see remarks following continued observation or repeating therapy with the initial Expert Rev. Anti Infect. Ther.
ILADS Lyme disease guidelines agent; mild manifestations or QoL impairments may prompt a 63 (33.3%) patients treated with three weeks of doxycycline switch to a different first-line agent, tetracycline , or a met the study's definition of post-treatment Lyme disease syn- combination of first-line agents (which includes at least one drome in that they experienced disease manifestations during antibiotic that is able to effectively reach intracellular compart- the 3–6 month post-treatment interval . Furthermore, ments) []. Intravenous or IM antibiotics such as reports of neurocognitive problems were 9% higher at the injectable penicillin G benzathine or iv. ceftriaxone are other 6-month end point than at baseline.
Identifying patients at higher risk for treatment failure and Disease relapse or progression with mild manifestations or offering them more extensive treatment may improve outcomes.
QoL impairments occurring within a few months of treatment Outcomes might also be improved by assessing the immediate suggests a need for longer regimens using either a combination post-treatment response and taking appropriate action. Several of oral first-line agents, injectable penicillin G benzathine or iv.
studies suggested that certain clinical presentations are associated ceftriaxone. Regardless of the duration of disease latency, when with a higher risk of treatment failure. Results from two trials disease manifestations or QoL impairments are significant or suggested that patients who remained symptomatic at the com- rapidly progressive, injectable penicillin G benzathine or iv. cef- pletion of therapy ] or 1 month post-treatment were at triaxone may be required. Subsequent decisions regarding the higher risk for long-term failure. These findings form the basis modification or discontinuation of a patient's treatment should be based on the individual's therapeutic response and preferen- included: increased severity of initial symptoms , paresthe- ces (Recommendation, very low-quality evidence).
sia ], dysesthesias , irritability , arthralgia , multipleEM and the presence of co-infections ]. In such circum- Role of patient preferences stances, clinicians should consider lengthening the initial phe- High: While most patients will place a high value on the noxymethylpenicillin, amoxicillin, cefuroxime or doxycycline potential of regaining their pre-morbid health status and therapy to a minimum of 6 weeks or extending azithromycin improving their QoL and preventing chronic disease through treatment to a minimum of 4 weeks.
continued antibiotic treatment, a substantial portion will also Relapse and/or disease progression may occur at any time value avoiding potentially unnecessary antibiotics. Hence, treat- and this analysis notes that longer observation periods increase ment risks, benefits and options should be discussed with the the likelihood of detecting disease relapse, which would patient in the context of shared medical decision-making.
decrease the long-term efficacy noted in these trials. This con-flicts with the oft stated position that success rates improve Recommendation 2f with time . In a trial frequently cited in support of this posi- For personal use only.
Clinicians should educate patients regarding the potential man- tion, success rates did increase over time when calculated on a ifestations of Lyme disease, carefully explaining that disease complete case basis (the trial's chosen methodology for han- latency can be prolonged. Education should also include infor- dling longitudinal data) . However, the ITT data supplied mation on preventing future bites, the manifestations of the in of that paper documented that the absolute numbers other tick-borne diseases that they may have contracted as well of successfully treated subjects declined significantly between as the symptoms and signs of a C. difficile infection and the the 12- and 30-month visits. In the 10-day doxycycline arm, preventative effect of probiotics. Patients should be encouraged complete success peaked at 12 months, with 44 of 61 (72.1%) to immediately report the occurrence of any recurrent or newly returning to their pre-Lyme disease baseline while at 30 months, developing manifestation of Lyme disease as well as those sug- only 35 of 61 (57.4%) were categorized this way . Readers gestive of other tick-borne diseases or a C. difficile infection.
should note that while of the study is entitled ‘Clinical Clinicians should emphasize that the need to report manifesta- Response Based on an Intention-To-Treat Analysis of Patients tions of tick-borne diseases never expires. (Recommendation, for Whom Information Was Available*', this was not an ITT Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 very low-quality evidence) analysis. Calculating response rates based on a portion of thegroup rather than on all who were randomized to a particular Role of patient preferences arm is contrary to ITT principles.
Low: The benefits of educating patients about potential disease Additionally, given that prior B. burgdorferi infections do manifestations clearly outweigh any attendant risks associated not provide durable immunoprotection , clinicians should with education.
consider the possibility that the patient was re-infected andseek information to confirm or dispel that this occurred [.
In the absence of clear evidence of re-infection, clinicians and This patient-centered analysis of the evidence from nine clinical patients will need to consider the relative risks and benefits of trials of EM treatment demonstrates that treatment regimens assuming that relapsing symptoms such as EM lesions or flu- which used 20 or fewer days of antibiotics were often ineffec- like symptoms in the summer are indicative of ongoing infec- tive. The findings of this analysis are consistent with those tion and not re-infection.
from a recently published observational study of EM. In the Disease manifestations may appear to relapse and/or progress study by Aucott et al., the authors reported that 21 of for reasons unrelated to Lyme disease. In addition to the Cameron, Johnson & Maloney possible presence of co-infections, many other illnesses and by gains in the 36-item short-form health survey (SF-36) men- conditions have clinical features which may overlap with those tal and physical component summary scores . A biostatistical of Lyme disease; some examples are: infections due to Epstein– review of those trials noted that the minimal clinically impor- Barr virus or syphilis; autoimmune diseases such as rheumatoid tant difference (MCID) in SF-36 scores have not been estab- arthritis, multiple sclerosis and vasculitis; metabolic and endo- lished for Lyme disease and it demonstrated that the designated crine disorders such as diabetes, hypo- or hyperthyroidism and treatment effect sizes for categorizing subjects as ‘improved' adrenal dysfunction; degenerative neurologic diseases such as likely exceeded the MCIDs of the SF-36 scores by several-fold Parkinson's disease and amyotrophic lateral sclerosis and neuro- logic conditions such as peripheral neuropathy and dysautono- The enrollment criteria and subsequent data analysis of the mia; musculoskeletal diseases including fibromyalgia and trials by Klempner et al. also raise the possibility of a type II osteoarthritis, psychiatric disorders, especially depression and error . Subjects were not required to meet a specific level of anxiety and other conditions such as chronic fatigue syndrome symptom severity, which allowed for the recruitment of subject and sleep apnea. (Note: this list is not intended to be exhaustive groups with baseline heterogeneity on the primary end point.
and patient-specific circumstances will guide the physician in Due to outcome averaging, studies failing to account for such determining whether other potential etiologies of relapsing or baseline heterogeneity in their sample population are more apt progressive manifestations need to be investigated.) to report no treatment effect. Of the four trials, only the trialsby Klempner et al. failed to address baseline heterogeneity Q3. Should patients with persistent manifestations of issues and these were the only trials which failed to find a treat- Lyme disease be retreated with antibiotics? ment effect on any end point. In contrast, the subjects in the study by Krupp et al. were homogeneous with regard to fatigue The panel conducted a Medline search on 5 March 2013 for and the post hoc analysis of Fallon et al. addressed baseline het- RCTs investigating the effectiveness of antibiotic retreatment in erogeneity on this end point as well, with both trials finding a patients with persistent manifestations of Lyme disease follow- positive treatment effect on fatigue .
ing treatment considered by some to be standard and appropri- Delayed processing speed was not an inclusion criterion for ate antibiotic therapy for their stage of illness. The search used the trial by Krupp et al. and subjects had minimal baseline def- this strategy: chronic Lyme disease OR Lyme encephalopathy icits on this end point. The designated treatment effect, which OR persistent Lyme disease AND antibacterial Agents/ was based on earlier studies of Lyme patients , called for an administration & dosage and this filter: clinical trial.
increase in processing speed that was unrealistically high for Five RCTs conducted in the USA were identified. Four met this group of subjects in that meeting the designated treatment For personal use only.
the inclusion criteria for this analysis . A fifth trial had a effect would have required the subjects' processing speed to non-completion rate in excess of 20% [and was excluded exceed healthy population norms . Thus, the trial was from this analysis on that basis. A Swedish trial was also biased on this end point [.
excluded due to excessive incomplete data [.
All four trials enrolled subjects who had previously received four trials had unique designs. In extensive antibiotic treatment for Lyme disease yet remained ill.
Klempner et al. exclusively enrolled seropositive subjects and The presence of treatment refractory subjects biased the trials treatment consisted of 30 days of iv. ceftriaxone followed by against finding treatment to be effective.
60 days of oral doxycycline or an identical placebo regimen [.
Krupp et al. also investigated an experimental biologic A second trial by that same group used an identical design marker of current disease, namely, the presence of outer surface except enrolled subjects were exclusively seronegative .
protein A (OspA) in the cerebrospinal fluid of Lyme patients.
Krupp et al. enrolled seropositive subjects with severe fatigue; Although the trial was designed with clearance of OspA from participants received either 30 days of iv. ceftriaxone or an the cerebrospinal fluid as a primary end point , only 16% of Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 identical placebo . Fallon et al. enrolled seropositive subjects the subjects had OspA in their baseline cerebrospinal fluid , with Lyme encephalopathy; treatment consisted of either making it impossible to demonstrate a treatment effect in 84% 10 weeks of iv. ceftriaxone or an identical placebo [.
of the subjects. Accordingly, this trial failed to validate the useof OspA as a surrogate marker and the trial was biased against finding treatment to be effective on this end point.
The designs of three of the four trials introduced the potential Results can be biased if unmasking occurs. Although they for type II errors , which biased the trials against antibi- had no direct evidence that this occurred, Krupp et al. raised otic retreatment. Type II errors occur when there is a failure to the concern that masking in their study may have been com- reject a false null hypothesis. With regard to treatment trials, promised as subjects in the ceftriaxone arm were more likely to type II errors would wrongly label effective treatment correctly guess their treatment group than the placebo subjects.
as ineffective.
However, two reviews of the NIH-sponsored retreatment trials Type II errors may arise when the designated treatment noted that the correct guesses could reflect that the subjects in effect for a trial is too large. The primary end point in the tri- the ceftriaxone arm were feeling better and, therefore, properly als by Klempner et al. was improvement in QoL, as measured attributed this change to being on active therapy [.
Expert Rev. Anti Infect. Ther.
ILADS Lyme disease guidelines The trials also excluded patients with characteristics com- Sample sizes in the individual trials were small, ranging from monly seen in clinical practice. All four trials excluded patients 37 to 78 . Small sample sizes are susceptible to random with co-infections or confounding illnesses/conditions –.
chance and small study bias .
Fallon excluded patients who were negative on current ELISA The trial by Fallon et al. was underpowered. It enrolled and western blot testing and Krupp et al. excluded those who 37 patients, yet its design required 45 subjects to achieve at lacked both a history of a physician-documented EM and sero- least 80% power to detect an effect size of 1.1 with a two-sided logic confirmation of late manifestations [. However, sero- test with a <0.05 [. The mental processing speed end point negative status would not necessarily deter clinicians from in the trial by Krupp et al. was designed with only 74% offering antibiotic therapy [. Once subjects were enrolled, trial designs restricted the investigators' ability to prescribe Although the trials by Klempner et al. were sufficiently pow- non-antibiotic therapy to subjects, which is a common clinical ered, the trials called for an unrealistically large treatment effect practice. For example, the need for pain medication resulted in that likely exceeded the MCID for changes in the SF-36 scores one subject being dropped from the trial by Fallon et al.
of Lyme disease patients ]. The selection of a smaller, and Investigators' primary responsibility is to the trial and not more appropriate, effect size would have required significantly potential enrollees, while clinicians are chiefly concerned with larger sample sizes to achieve sufficient statistical power [.
providing care to ill patients and thus they may choose toemploy broader treatment criteria. Highly selective research entry criteria and treatment restrictions, like those employed in Krupp et al. found retreatment provided a clinically meaningful the four retreatment trials, serve the purpose of ensuring inter- reduction in severe fatigue and the post hoc analysis by nal validity, but may do so at the expense of external validity, Fallon et al. corroborated this finding . In the treatment undermining the generalizability of the results to the popula- response rates in the trial by Krupp et al., 64% improved in the tion of patients clinicians see in practice.
treatment arm versus 18.5% in the placebo arm (p < 0.001) wassimilar to the response rates of Fallon et al., where 66.7% of Evidence quality, in aggregate treated subjects improved versus 25% of the placebo group The quality of the evidence regarding the effectiveness of antibi- (p < 0.05) .
otic retreatment in patients with persistent symptoms following Cognitive benefits were evaluated by Krupp et al. and standard and appropriate antibiotic therapy for Lyme disease is Fallon et al. , but consistency cannot be judged because very low , implying that the true effectiveness of retreat- the trial by Krupp et al. was inadequately designed for this end ment is likely to be substantially different from the effectiveness For personal use only.
point (see bias and precision sections above).
rates seen in the four NIH-sponsored retreatment trials.
The trials by Klempner et al., in contrast to those of Krupp et al. and Fallon et al., reported finding no benefit from antibiotic retreatment . As discussed above, the trials by Retreatment with ceftriaxone was effective in two of the four Klempner et al. were inadequately designed, calling for a treat- trials . Krupp et al. found that 28 days of ceftriaxone ment effect that likely exceeded the MCID [. As such, the was more effective than placebo (64 vs 18.5%; p < 0.001) for absence of a treatment benefit in these trials is uninformative.
producing a clinically significant reduction in severe fatigue, aprimary outcome [. The effect size was moderate to large [.
Fallon et al. found that subjects treated with 70 days of iv. cef- The directness (generalizability) of the evidence is limited triaxone achieved a moderate improvement (effect size = 0.81) because entrance criteria led to the enrollment of subjects who in generalized cognitive function at 2 weeks post-therapy com- are not representative of the full clinical spectrum of patients pared with those in the placebo arm (effect size = 0.30) Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 with persistent symptoms. Trial subjects had been ill for pro- (p = 0.053), although the preferential effect of drug versus longed periods of time and had received extensive antibiotic placebo was not sustained at 14 weeks post-therapy ]. The treatment prior to enrollment . Subjects in the antibiotic mechanisms leading to the subsequent loss of the cognitive arms of the trials by Klempner et al. and Fallon et al. had gains are unknown; however, this long-term outcome may indi- been ill, on average, for 4.7 and 9.0 years, respectively [.
cate that the offered therapy was incomplete. A planned sec- Thirty-three percent of the subjects in the trials by ondary analysis demonstrated an interaction effect between Klempner et al. had been treated with 30 days of iv. ceftriaxone baseline impairments and treatment, such that the ceftriaxone and subjects in the trial by Krupp et al. had received, on aver- effect increased with higher baseline severity; this was demon- age, 7.2 weeks of antibiotic therapy, with 47.3% having been strated for the measures of pain and physical dysfunction at previously treated with a minimum of 2 weeks of iv. ceftriax- week 12 and sustained to week 24 . On post hoc analysis, one . Prior antibiotic treatment in the subjects by Fallon et al. also demonstrated a positive treatment effect on Fallon et al. was significantly higher. The average duration of severe fatigue. Of the subjects in the trial by Fallon et al., who therapy was 9.5 months, which included 2.3 months of iv. cef- met the fatigue entrance criteria of the trial by Krupp et al., triaxone use .
Cameron, Johnson & Maloney Table 6. Quality of the evidence, in aggregate, that supports antibiotic retreatment in patients withpersistent symptoms of Lyme disease.
Small sample sizes Consistent finding of Subjects had prolonged treatment effects treatment effectiveness on fatigue in the trials by Subjects had a history of extensive antibiotic Fallon et al.
Inconsistent findings on Excluded subjects with co- treatment effectiveness Lack of pertinent between the trials by medication use commonly Krupp et al., Fallon et al.
seen in practice – Restricted use of non- Klempner et al.
antibiotic medications, limiting practice refractory subjects reductions in the level of their fatigue compared with those of retreatment are adequate to support those who wish to treat who received placebo (66.0 vs 25.0%; p < 0.05).
but is not overwhelming enough to mandate treatment.
The panel also determined that there is no compelling evi- dence to support routinely withholding antibiotic retreatment The NIH-sponsored retreatment trials described 15 serious from ill patients. While antibiotics are not always effective, the adverse events among the 221 subjects (6.8%) . Each event importance of providing patients with the opportunity to was associated with ceftriaxone itself or the need for venous receive an adequate trial of antibiotic therapy is heightened by access; 60 days of oral doxycycline therapy was not associated the lack of other effective treatment approaches. Palliative care with any significant adverse event. Six individuals experienced may be helpful in addressing some symptoms in some cases, allergic reactions , including one case of anaphylaxis .
but it is important to bear in mind that palliative interventions Seven events were related to the iv. line , four cases involved also carry risks. Additionally, clinicians must not assume that For personal use only.
line-related infections (all on placebo) , two cases involved palliative interventions would provide adequate treatment in thrombi [and one subject developed a pulmonary embolus .
the face of an underlying persistent infection. Therefore, in the Additionally, there was one case of cholecystitis and one case panel's judgment, antibiotic retreatment will prove to be appro- of gastrointestinal bleeding with fever and anemia [.
priate for the majority of patients who remain ill and thus it isinappropriate to constrain clinicians from exercising their clinical judgment.
The clinical population of patients with persistent manifesta- In making these determinations, the panel considered the tions of Lyme disease is heterogeneous; therefore, the risk– strength of the evidence addressing the effectiveness of antibi- benefit assessment needs to be done on an individualized basis, otic retreatment, the burden of disease and the risks associated taking into account the severity of an individual's persistent dis- with various antibiotic options. The panel weighed each ease, their responsiveness to treatment, their ability to tolerate in light of the marked heterogeneity within this patient side effects associated with additional and potentially long-term treatment as well as their willingness to accept the risk associ- Potential benefits include the restoration of health, improved Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 ated with antibiotic treatment or, conversely, the level of their QoL and prevention of further decline in health status. While desire to avoid treatment-associated risk.
complete restoration of health was not identified in any of the The scientific evidence regarding potential etiologic mecha- four retreatment trials, the moderate-to-large treatment effect nisms for the development of persistent manifestations of Lyme on severe fatigue demonstrated in the trial by Krupp et al. and disease continues to evolve. Proposed mechanisms include the sustained interaction effects between baseline severity and immune dysregulation of various types, tissue injury, infection- improvements in pain and physical functioning seen in the trial induced secondary conditions, unrecognized or undertreated by Fallon et al. suggested to the panel that retreatment may co-infections and persistent infection []. Of these, we improve the QoL of some patients.
think the weight of the evidence supports persistent infection, Others have reached a similar conclusion. In a recent review although other mechanisms may co-exist and the exact etiology of the four retreatment trials, Fallon et al. make the point that for persistent manifestations may vary from patient to patient.
guidelines restricting the use of antibiotics in patients with per- Given this uncertainty, the panel concluded that the evidence sistent manifestation of Lyme disease are based on the errone- at hand regarding persistent infection and the potential benefits ous dismissal of the treatment efficacy demonstrated in two of Expert Rev. Anti Infect. Ther.
ILADS Lyme disease guidelines Table 7. Summary of findings regarding the effectiveness of antibiotic retreatment in patients withpersistent manifestations of Lyme disease.
Impairment: fatigue Krupp et al.
Fallon et al.
Post hoc success in the subset of subjects who had a baselineFSS-11 score of 4.0 or higher Fallon et al.
Secondary analysis – Patients with more joints in pain at baseline had a Fallon et al.
preferential improvement withceftriaxone on measures of pain(p = 0.07) at week 24 Impairment: neurocognitive dysfunction Fallon et al.
Secondary analysis – Patients with more joints in pain at baseline had apreferential improvement withceftriaxone on cognitive indexmeasures at week 24 (p = 0.04) Krupp et al.
The authors noted that baseline cognitive deficits ‘were relatively mildwhich may have contributed to thelack of a treatment effect oncognition'.
**Impairment: QoL physical functioning For personal use only.
Due to design deficiencies, the lack of a demonstrable treatment effect isuninformative Due to design deficiencies, the lack of a demonstrable treatment effect isuninformative Fallon et al.
Secondary analysis – sustained improvement in physical functioningto week 24 could also be seen whenbaseline severity of impairment was notincluded as a covariate (p = 0.09) atweek 24 Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 Impairment: QoL mental health Due to design deficiencies, the lack of a demonstrable treatment effect isuninformative †Outcome for measures described in Table 1.
‡The FSS assesses the impact of fatigue on everyday functioning [210].
§The MPQ estimates the sensory and affective elements of pain, both qualitatively and quantitatively.
#Neurocognitive dysfunction index ‡‡The PCS on the SF-36 measure of QoL is a measure of physical health, role physical, bodily pain and general health [209].
§§The MCS on the SF-36 measure of QoL is a measure of mental health, role emotional, social function and vitality [209].
FSS: Fatigue severity scale; GI: Gastrointestinal; MCS: Mental component of health; MPQ: McGill Pain Questionnaire; PCS: Physical component of health; VAS: Visualanalog scale; QoL: Quality of life.
Cameron, Johnson & Maloney Table 7. Summary of findings regarding the effectiveness of antibiotic retreatment in patients withpersistent manifestations of Lyme disease (cont.).
Impairment: QoL mental health (cont.) Due to design deficiencies, the lack of a demonstrable treatment effect isuninformative Fallon et al.
Fifteen serious adverse reactions among the 221 subjects (6.8%) –. Six subjects Krupp et al.
experienced allergic reactions , including one case of anaphylaxis ; four and Fallon et al.
developed line-related infections (all on placebo) , two developed thrombi [and there was one case of each of the following: pulmonary embolus ,cholecystitis , GI bleed with fever and anemia †Outcome for measures described in ‡The FSS assesses the impact of fatigue on everyday functioning [.
§The MPQ estimates the sensory and affective elements of pain, both qualitatively and quantitatively.
#Neurocognitive dysfunction index ‡‡The PCS on the SF-36 measure of QoL is a measure of physical health, role physical, bodily pain and general health .
§§The MCS on the SF-36 measure of QoL is a measure of mental health, role emotional, social function and vitality .
FSS: Fatigue severity scale; GI: Gastrointestinal; MCS: Mental component of health; MPQ: McGill Pain Questionnaire; PCS: Physical component of health; VAS: Visualanalog scale; QoL: Quality of life.
the trials [. The authors state that such guidelines ‘are not the same subject 8 months later was also positive ]. Animal helpful to clinicians and patients' ].
studies have corroborated the human findings, documenting In addition to the NIH-sponsored retreatment trials, retreat- bacterial persistence by culture, PCR and histopathologic test- ment was also shown to be beneficial in clinical trials of EM ing of post-treatment necropsy specimens and by xenodiagno- For personal use only.
treatment and in a case series involving the treatment of late sis . Given these realities, withholding antibiotic neurologic disease. Investigators in seven of the nine EM trials retreatment risks allow an infection to continue unchecked.
discussed above retreated subjects who failed initial ther- The panel weighed the burden of chronic illness that Lyme apy . Decisions to retreat were often based on disease imposes on patients. In the four retreatment trials ana- symptoms alone and investigators frequently reported on the lyzed here, the subjects' QoL was consistently worse than that of success of retreatment. In three trials, biopsy specimens from control populations and reductions in employment or educa- the EM site were culture-positive for B. burgdorferi 1–3 months tional activities were common . A community-based trial post-treatment . In two of these, subjects were retreated of antibiotic retreatment found the QoL of its subjects was the with oral antibiotics and follow-up cultures 3 or 4 months same or worse as that of individuals with depression, diabetes, later were negative. Thus, these trials simultaneously dem- heart disease, osteoarthritis and rheumatoid arthritis . Surveys onstrated persistent infection following standard therapy and of Lyme disease patients further document the negative impact the value of retreatment.
of persistent manifestations. One survey of openly recruited Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 In a study by Logigian et al., one subject relapsed at Lyme disease patients identified 2424 patients whose initial clin- 8 months post-treatment, was retreated, became well once again ical diagnosis of Lyme disease was confirmed with positive serol- and remained so for the remainder of the study . Several ogy and who had persistent manifestations of Lyme disease observational studies also demonstrated benefits from antibiotic despite antibiotic treatment ]. Of this cohort, 25% had retreatment .
received public support or disability benefits and the majority of The panel also considered the risk of withholding antibiotics respondents in this subset received these payments for 2 or more from patients with a potentially treatable B. burgdorferi infec- years. A second online survey identified 1087 respondants diag- tion. Currently available laboratory tests are unable to confirm nosed with Lyme disease (based on the presence of an EM rash or deny persistent infection on a routine basis yet persisting or positive two-tier testing that used the CDC interpretive crite- infection has been demonstrated in patients with Lyme disease ria) who had ongoing manifestations of Lyme disease for 6 or by PCR and culture [–. A recently published xenodi- more months ]. Using a CDC metric of health-related QoL, agnostic study in humans demonstrated positive results in one the survey found that this group averaged 19.6 and 15.5 days/ of eight subjects with post-treatment manifestations of Lyme month of poor physical and mental health days, respectively.
disease; a subsequent xenodiagnostic specimen obtained from Not surprisingly, 71.6% rated their health as fair or poor. This Expert Rev. Anti Infect. Ther.
ILADS Lyme disease guidelines rate is higher than that seen in other chronic diseases including Recommendation 3a congestive heart failure, fibromyalgia, post- stroke and post- Clinicians should discuss antibiotic retreatment with all patients myocardial infarction status, diabetes and multiple sclerosis and who have persistent manifestations of Lyme disease. These dis- the survey findings corroborate those of the community-based cussions should provide patient-specific risk–benefit assessments retreatment trial mentioned above. By comparision, in a general for each treatment option and include information regarding population with an average age of 46, only 16% rated their C. difficile infections and the preventative effect of probiotics health as fair or poor [. The respondants also reported signifi- (although none of the subjects in the retreatment trials devel- cant economic impacts – 39.4% stopped working and an addi- oped a C. difficile infection). (Strong recommendation, very tional 28.3% reduced their work hours or role; 37.3% spent at low-quality evidence. Note: In GRADE, a strong recommenda- least US$5000 in out-of-pocket Lyme-related expenses.
tion may be made in the face of very low-quality evidence Given the severity of the QoL impairments, the panel when the risk–benefit analysis favors a particular intervention viewed the need for clinical intervention as high.
such that most patients would make the same choice.) Additionally, the panel considered that antibiotic risk varies by agent and route of administration. Although all of the regi- Role of patient preferences: low mens in the NIH-sponsored retreatment trials incorporated iv.
The benefits of educating patients about the potential benefits ceftriaxone, the use of iv. antibiotics is discretionary and should of retreatment and the risks associated with various treatment be based on an individualized risk–benefit assessment. The risks options, including not treating, clearly outweigh any attendant associated with iv. antibiotics have two main origins. The first risks associated with education.
is the medication itself and includes allergic reactions and otheradverse events, such as cholecystitis from ceftriaxone. The sec- Recommendation 3b ond source of risk is the iv. access device.
While continued observation alone is an option for patients The risks associated with iv. access are well known. A meta- with few manifestations, minimal QoL impairments and no analysis of the risks associated with iv. access, in general, found evidence of disease progression, in the panel's judgment, antibi- that risks varied by access type; peripheral iv. catheters caused otic retreatment will prove to be appropriate for the majority 0.5 bloodstream infections per 1000 intravascular device days, of patients who remain ill. Prior to instituting antibiotic while surgically implanted long-term central venous devices – retreatment, the original Lyme disease diagnosis should be reas- cuffed and tunneled catheters – caused 1.6 infections per sessed and clinicians should evaluate the patient for other 1000 intravascular device days .
potential causes of persistent disease manifestations. The pres- Combined, there were seven device-related adverse events ence of other tick-borne illnesses should be investigated if that For personal use only.
among the four retreatment trials and approximately 8110 days had not already been done. Additionally, clinicians and their of device use, yielding 0.86 device-related adverse events per patients should jointly define what constitutes an adequate 1000 intravascular device days, which is lower than the rate therapeutic trial for this particular set of circumstances.
found in the meta-analysis. Although the risk associated with When antibiotic retreatment is undertaken, clinicians should iv. antibiotics is significant, in situations where the QoL initiate treatment with 4–6 weeks of the selected antibiotic; this impairments are substantial, retreatment with iv. antibiotics time span is well within the treatment duration parameters of may be wholly appropriate.
the retreatment trials. Variations in patient-specific details and There is substantial evidence on the clinical safety of amoxi- the limitations of the evidence imply that the proposed duration cillin, cefuroxime axetil, doxycycline and azithromycin, which is a starting point and clinicians may, in a variety of circumstan- are commonly used to treat Lyme disease []. In a ces, need to select therapeutic regimens of longer duration.
community-based trial, none of the subjects randomized to Treatment options are extensive and choices must be indi- amoxicillin experienced a serious adverse event . Similarly, vidualized. Each of these options would benefit from further Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 the trials by Klempner et al. confirmed the safety of oral doxy- study followed by a GRADE assessment of the evidence and cycline for longer-term use [. Regardless of treatment agent consideration of associated risks and benefits, but until this and route of administration, it is expected that the concomitant information is available, clinicians may act on the currently use of probiotics would reduce the risk of C. difficile colitis and available evidence.
antibiotic-associated diarrhea .
In choosing between regimens, clinicians should consider the Values: The panel placed a high value on reducing the mor- patient's responsiveness to previous treatment for Lyme disease, bidity associated with chronic Lyme disease and improving the whether the illness is progressing and the rate of this progres- patient's QoL as well as on the need for individualized risk/ sion; whether the patient has impaired immune system func- benefit assessment and informed shared decision-making. The tioning or has received immunosuppressant corticosteroids panel also placed a high value on the ability of the clinician to and whether other co-morbidities or conditions would exercise clinical judgment. In the view of the panel, guidelines impact antibiotic selection or efficacy. The possibility of should not constrain the treating clinician from exercising clini- co-infections should be investigated (see Recommendation 2e cal judgment in the absence of strong compelling evidence to for discussion regarding co-infections complicating the diagno- the contrary.
sis and treatment of Lyme disease).
Cameron, Johnson & Maloney Clinicians should also weigh the extent to which the illness treatment may depend on the length of time between the ini- interferes with the patient's QoL, including their ability to fully tial and subsequent retreatment, the strength of the patient's participate in work, school, social and family-related activities response to retreatment, the severity of the patient's current and the strength of their initial response against the risks associ- impairments, whether diagnostic tests, symptoms or treatment ated with the various therapeutic options. Antibiotic selection response suggest ongoing infection and whether the patient should also consider medication tolerability, cost, the need for relapses when treatment is withdrawn.
lifestyle adjustments to accommodate the medication and In cases where the patient does not improve after 4–6 weeks of antibiotic retreatment, clinicians should reassess the clinical For patients with mild impairments who had a strong-to- diagnosis as well as the anticipated benefit. They should also moderate response to the initial antibiotic, repeat use of that confirm that other potential causes of persistent manifestations agent is favored. Patients with moderate impairments or only have been adequately investigated prior to continuing antibiotic a modest response to the initial antibiotic may benefit from retreatment. Decisions regarding the continuation, modification switching to a different agent or combination of agents; the or discontinuation of treatment should consider the factors latter to include at least one agent that is able to effectively noted above as well as the definition of an adequate therapeutic reach intracellular compartments . Injectable penicillin G benzathine or iv. agents such as ceftriaxone are other Whenever retreatment is continued, the timing of subse- quent follow-up visits should be based on the level of the ther- For patients with significant impairments and/or a minimal apeutic response, the severity of ongoing disease, the duration or absent therapeutic response, a combination of oral antibiot- of current therapy and the need to monitor for adverse events ics or injectable penicillin G benzathine or iv. ceftriaxone alone, (see remarks section below). (Recommendation, very low- or in combination with other agents, is preferred. For patients quality evidence).
who experienced disease progression despite earlier therapy,treatment with injectable penicillin G benzathine or an iv.
Role of patient preferences agent, such as ceftriaxone, alone or in combination with High: See Recommendation 3b.
other antibiotics, is advisable. Additionally, minimal orabsent responses and disease progression require a re-evaluation of the original diagnosis. (Recommendation, very low-quality The lack of pharmaceutical interest and its concomitant fund- ing does not encourage the innovative research that is essentialto improving care for patients with Lyme disease. When phar- For personal use only.
Role of patient preferences maceutical interest is lacking, clinical practices often become High: The heterogeneous nature of the patient population the source of therapeutic innovation, preceding rather than fol- seen in clinical practice, particularly with regard to variations lowing clinical trials.
in disease severity, QoL impairments and aversion to The US FDA recognizes the important role that clinical treatment-related risk, is likely to affect the risk–benefit innovation plays in patient care, stating: ‘Valid new uses for assessment. Although many patients will value the opportu- drugs already on the market are often first discovered through nity to improve their individual QoL through antibiotic serendipitous observations and therapeutic innovations, subse- treatment over the risk of adverse events, others may prefer quently confirmed by well-planned and executed clinical to avoid the risks associated with treatment. Hence, treatment investigations ['. In providing clinicians with therapeutic options, including their associated risks and benefits, should flexibility, the agency makes room for clinicians to fashion be discussed with the patient in the context of shared medical patient-centered care, with treatment decisions being driven by the specific circumstances of an individual's illness. The bene- Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 fits related to therapeutic flexibility are quite evident in orphan Recommendation 3c diseases, where an estimated 90% of all prescribed medications Clinicians should re-assess patients immediately following the represent off-label use and if not for that practice, clinicians completion of the initial course of retreatment to evaluate the would often have no effective therapies to employ . In this effectiveness of retreatment and the need for therapeutic adjust- respect, patient care in Lyme disease is like that of other ments. Reassessment may need to be done much earlier and research-orphaned diseases, relying heavily on innovative clini- with greater scrutiny in patients with severe disease or when cians to develop treatments that improve health and reduce the therapeutic intervention carries substantial risk.
For patients who improve yet continue to have persistent Innovative therapies may employ unconventional dosages of manifestations and continuing QoL impairments following standard medications, novel combinations of currently accepted 4–6 weeks of antibiotic retreatment, decisions regarding the practices, new applications of standard interventions or may continuation, modification or discontinuation of treatment use accepted therapy or approved drugs for non-approved indi- should be based on several factors. In addition to the factors cations . Unlike research, the primary purpose of innovative listed in Recommendation 3b, the decision to continue care is to benefit the individual patient [. Clinicians Expert Rev. Anti Infect. Ther.
ILADS Lyme disease guidelines employing innovative therapies need to verify that the innova- manifestations include all agents known to be effective tion is intended to be in the patient's best interest and recog- against B. burgdorferi . While the use of nize that informed consent requires that the patient understand agents proven to be effective in clinical research trials may be that the recommended therapy is not standard treatment [.
preferred, clinicians may choose antibiotics based on their In this context, the panel concluded that it is necessary for clinical experiences and those of others –. While agents clinicians to provide patients with treatment options and with favorable in vitro findings may also merit consideration, engage in shared medical decision-making.
antibiotics that were ineffective in clinical trials are This determination is in keeping with the approach used by best avoided.
other physician-developed guidelines. The American Academy Treatment regimens may employ either a sole agent or com- of Pediatrics guidelines recognize that in the face of low-quality binations of antibiotics, depending on which mechanisms of evidence or where the risk–benefit equilibrium is balanced, persistence the clinician is attempting to thwart. The delivery ‘guideline developers generally should not constrain the clin- method – oral, iv., IM – is dependent on the agents selected,ician's discretion '. Guideline developers commonly consider disease severity and patient preferences. It is reasonable to start not only RCTs, but also observational trials, animal model with dosages examined in clinical trials, but clinicians may studies, expert opinion, clinical experience, patient values and decide to adjust dosages in individual patients with the goal of judgments regarding the potential harms of an intervention as improving outcomes by achieving adequate drug levels in all well as the potential harms of inaction . Moreover, when infected tissues.
the condition in question poses great risk or QoL impairments, Oral antibiotics which demonstrated effectiveness in clinical guideline panels may recommend an intervention even trials include the cell wall agents amoxicillin , phenoxyme- when the evidence base is uncertain, mixed or incompletely thylpenicillin [and cefuroxime axetil . Other cell wall agents may also be clinically useful; however, first- The panel endorses the view that informed choice is the eth- generation cephalosporins are known to be ineffective [.
ical ideal in circumstances involving scientific uncertainty Oral agents within the tetracycline and macrolide classes, which because it recognizes the patient's right to self-determination disrupt ribosomal function and are capable of entering cellular [. Patients with significant QoL or functional impairments compartments, are also effective in Lyme disease. Individual may be willing to take on a far greater degree of risk than those agents include doxycycline , tetracycline , azithro- who are relatively unaffected by ongoing disease manifestations.
mycin and clarithromycin . However, eryth- However, because the degree of relative risk aversion varies sig- romycin, which performed well in vitro, was ineffective in vivo nificantly among patients, it is important that patients be given and the macrolide telithromycin has been linked to For personal use only.
sufficient information to make a meaningful choice regarding drug-induced liver injury ]. Several of the EM trials reviewed treatment options.
earlier in this document used higher antibiotic dosages than The demonstrated persistence of B. burgdorferi in specific suggested by the panel in Recommendation 2b –. For individuals [–] and animal models [ example, Luft et al. and Weber et al. prescribed azithromycin suggests a need for treatment regimens which address the 500 mg/day . Strle et al. and Barsic et al. prescribed azi- mechanisms underlying bacterial persistence yet these mecha- thromycin 500 b.i.d. on day 1 followed by 500 mg daily [.
nisms may not be fully identified and those that have been are Nadelman prescribed doxycycline 100 mg t.i.d. ]. In certain not fully understood. Emerging evidence supports potential circumstances, clinicians may decide that higher doses are roles for these mechanisms: immune evasion via physical seclu- sion of Bb within immunologically protected tissue sites such Metronidazole and tinidazole effectively kill cell wall defi- as the CNS, joints and eyes [, collagen-rich tissues [, cient forms of B. burgdorferi in vitro , but their effective- cells –and biofilms [; alterations in Osp profiles ness in vivo, in either oral or iv. form, has not been Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 through antigenic variation , phasic variation ] and investigated in clinical trials.
alteration in Bb morphology (including cell-wall deficient Ceftriaxone, 2 g iv. per day is known to be effec- forms, spherocytes and ‘cyst' forms) –]; immune modula- tive ] and iv. cefotaxime [, another cephalospo- tion via alterations in complement ], neutrophil and den- rin, has also been recommended. Intravenous penicillin is less dritic cell functioning [, and changes in cytokine and effective and requires more frequent dosing ['. Additional iv.
chemokine levels and innate antibiotic tolerance of cell wall agents from the carbapenem and monobactam classes some B. burgdorferi populations .
were effective in vitro, but have not been studied clinically ].
In the absence of a clear scientific understanding of persis- IM benzathine penicillin is another useful cell wall agent and tent infection, different views regarding whether and how to it avoids the risks associated with gaining iv. access. A case address potential mechanisms have developed . While report noted its effectiveness in antibiotic resistant Lyme some clinicians may elect to wait for more definitive answers, other clinicians, given the QoL impairments some patients If the initial course of antibiotic retreatment does not pro- bear, may elect to provide innovative care based on the infor- duce a complete response, clinicians should consider various mation at hand. Antibiotic options for treating persistent options. Patients who had an incomplete response with one Cameron, Johnson & Maloney agent may be responsive to another; thus, switching agents may and values regarding treatment options be identified and prove successful. Alternatively, combination therapy may be strongly considered during a shared decision-making process.
appropriate in select patients. Examples include those with Because the GRADE process for formulating evidence-based known or suspected co-infections and patients who had incom- treatment recommendations fosters transparency and recog- plete responses to single-agent therapy.
nizes that patient values may play a pivotal role, GRADE is Aside from antibiotics, few therapeutic strategies have been particularly useful when addressing questions marked by sig- employed to address non-infectious mechanisms of ongoing nificant scientific uncertainty.
disease yet individual patients have benefitted from non- Looking forward over the next 5 years, significant advances are expected in both technology and clinical research that ‘antibiotic-resistant' Lyme arthritis obtained a localized (joint- may significantly impact the quality of patient care in Lymespecific) benefit from synovectomy [. The rationale being disease. Since the discovery of Lyme disease in 1981, that ongoing synovitis is a reflection of an auto-immune pro- researchers have identified more than 15 new tick-borne cess . Additionally, an autoimmune-mediated polyneurop- pathogens. Progress in identifying new tick-borne pathogens athy that was secondary to a proven B. burgdorferi infection of and in understanding the clinical ramifications of simulta- the CNS improved following IVIG therapy, whereas prior anti- neous tick-borne diseases may help improve both the diagno- biotic interventions failed to halt the progression of the poly- sis and treatment of tick-borne diseases. Advances in neuropathy . Other methods of immunomodulation may genomics and proteonomics should permit researchers to prove useful in the future, especially if it can be established identify differences in B. burgdorferi species and strains and that immune dysregulation is the specific mechanism underly- explore their clinical implications. Significant advances in ing an individual's persistent disease. However, unless an ongo- diagnostic testing may permit clinicians to distinguish the ing infection can be definitively ruled out, caution is required infected from the non-infected and cured and provide clini- because immunomodulation could cause an occult infection cians with a laboratory measure of therapeutic progress.
Finally, advances in information technology as well as themethodology for conducting large-scale clinically relevant tri- Reconciling divergent guidelines als will provide evidence that addresses topics that clinicians The ILADS panel recommendations differ from those of the and patients deem meaningful to improving patient QoL.
IDSA. Different guideline panels reviewing the same evidence These fundamental changes may change the clinical land- can develop disparate recommendations that reflect the under- scape and enable optimal care treatment regimens to be lying values of the panel members, which may result in con- For personal use only.
flicting guidelines . The IOM explains that conflictingguidelines most often result ‘when evidence is weak; developers differ in their approach to evidence reviews (systematic vs non- The state of the evidence in the diagnosis and treatment of Lyme disease systematic), evidence synthesis or interpretation and/or develop- is limited, conflicting and evolving. Accordingly, the recommendations ers have varying assumptions about intervention benefits and in these guidelines reflect an evidence-based, patient-centered approach harms' . Conflicting guidelines exist for over 25 conditions that many clinicians will find helpful; they are not intended to be and there is no current system for reconciling conflicting guide- viewed as a mandate or as a legal standard of care. Guidelines are not lines . reconciles the differences between a substitute for clinical judgment. The International Lyme and Associ- the ILADS and IDSA treatment recommendations by clinical ated Diseases Society encourages clinicians to consider the specific details of an individual patient' s situation when determining an appropriatetreatment plan.
Expert commentary & five-year view Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by 216.65.77.156 on 08/05/14 Lyme disease is a complex illness and patients may experience Financial & competing interests disclosure both acute and persistent manifestations. The science regard- DJ Cameron is the President of the International Lyme and Associated ing disease mechanisms is limited, uncertain and evolving.
Diseases Society. LB Johnson is Executive Director of LymeDisease.org.
However, the profoundly negative impact that persistent EL Maloney is a Provider of continuing medical education courses on manifestations exert on patients' wellbeing as measured on tick-borne diseases. The authors have no other relevant affiliations or validated QoL assessment tools is well documented. There- financial involvement with any organization or entity with a financial fore, critical treatment goals include: disease prevention, interest in or financial conflict with the subject matter or materials treating to cure where possible and otherwise improving discussed in the manuscript apart from those disclosed. Writing assis- patient QoL and preventing disease progression. Following tance from A Delong was utilized in the production of this the GRADE model, ILADS recommends that patient goals Expert Rev. Anti Infect. Ther.
ILADS Lyme disease guidelines • 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 • 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 def- initions 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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Caring for People with Dementia and A Step-by-Step Evidence-Based Approach Visit igec.uiowa.edu for more information and references This approach begins with evaluation and treatment of common causes of behaviors, then uses nondrug approaches to management. Antipsychotics are reserved for severe cases due to potential side

mpmo.gc.ca

PROJECT AGREEMENT FOR THE QUEBEC LITHIUM SPODUMENE MINE IN PREAMBLE WHEREAS the Government of Canada is committed to improving the efficiency of the federal environmental assessment (EA) and regulatory review processes for major resource projects to enable a more effective assessment and mitigation of potential environmental effects, while protecting the health and safety of Canadians and promoting innovation and competitiveness within the Canadian resource industry sectors; AND WHEREAS the Government of Canada is committed to undertaking a process of early, effective and meaningful consultation with Aboriginal groups, including Treaty First Nations, Non-Treaty First Nations, Métis and Inuit people, concerning contemplated federal Crown (Crown) conduct with respect to, among other things, major resource projects that may adversely affect established or potential Aboriginal and treaty rights under Section 35 of the Constitution Act, 1982; AND WHEREAS the Government of Canada has created the Major Projects Management Office (MPMO) for the purpose of overseeing and tracking the federal review, which includes the EA, regulatory reviews and Aboriginal consultation activities for major resource projects; AND WHEREAS Quebec Lithium Inc. (the Proponent) has submitted a project description in support of its proposed 3,800 tonnes per day open-pit spodumene mine located about 60 km north of Val-d'Or, 38 km south-east of Amos and 15 km south-west of Barraute, Quebec; AND WHEREAS the Canadian Environmental Assessment Agency (CEA Agency) has commenced a comprehensive study pursuant to the former Canadian Environmental Assessment Act (CEAA)1; AND WHEREAS the CEA Agency and Fisheries and Oceans Canada (DFO) have regulatory and statutory duties in relation to the proposed project; AND WHEREAS nothing in this Project Agreement (the Agreement) fetters the powers, statutory authorities and functions of federal departments/agencies and their respective Ministers; NOW THEREFORE the signatories (the Parties) to this Agreement commit to work together to facilitate an effective, accountable, transparent, timely and predictable federal review in relation to the proposed project and to contribute to fulfilling the Crown's duty to consult with Aboriginal groups.