ILADS: BORRELIOOSIN HOITO-OHJEET!

Asiantuntijana Soile Juvonen TTT

Valvojat:Jatta1001, Borrelioosiyhdistys, Waltari, Bb

Vastaa Viestiin
soijuv
Viestit:3040
Liittynyt:Ke Tammi 21, 2009 14:16
Re: ILADS: BORRELIOOSIN HOITO-OHJEET!

Viesti Kirjoittaja soijuv » La Elo 02, 2014 17:28

Role of patient preferences

Low: The benefits of educating patients about potential disease manifestations clearly outweigh any attendant risks associated with education.
Remarks

Lyme disease often results from unrecognized tick bites [32,84], which do not provide an opportunity for administering antibiotic prophylaxis. When antibiotic prophylaxis is employed for known bites, it is imperative that treatment begin without delay. A recent murine study demonstrated that prophylaxis was most effective when given immediately after a bite and that effectiveness diminished with treatment delays [85]. Although no studies to date have specifically investigated the efficacy of antibiotic prophylaxis for bites from other Ixodes species, it is reasonable to provide prophylaxis for such bites pending future research.

The evidence supporting use of 20 days of antibiotics is limited to the previously mentioned murine trials [69,70]. In the first trial, investigators demonstrated that a long-acting form of doxycycline, with measurable levels for 19 days, was 100% effective for preventing Lyme disease [69]. In the dual-exposure model, the long-acting form of doxycycline was 100% effective for preventing B. burgdorferi and A. phagocytophilum infections [70]. No long-acting, injectable doxycycline preparation is available for use in humans [62], which is why the panel recommends using 100–200 mg of doxycycline twice daily for a minimum of 20 days. One advantage to this regimen is that it would also address situations where patients are exposed to both B. burgdorferi and A. phagocytophilum.

Analysis of the single-dose doxycycline trial highlights the problems inherent in formulating treatment recommendations on the basis of a single study and demonstrates that a randomized, placebo-controlled study design, in and of itself is not a guarantee that the study will produce high-quality evidence. The panel recognizes that recommendations based solely on animal models are also problematic. Therefore, the panel encourages the NIH to fund appropriately designed trials in order to investigate 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 [86], some clinicians may prefer to prescribe higher daily doses [52,86–89]. Regardless of the selected dose, clinicians should advise patients to take probiotics daily while on antibiotic therapy. Probiotics reduce the risk of C. difficile colitis and antibiotic-associated diarrhea [44,45].

‘Watchful waiting’ does not satisfy a strict definition of prophylaxis. Rather than acting to prevent disease, this option seeks the early identification and treatment of Lyme disease infections resulting from a known bite. The hallmark of early disease is the EM rash; and as previously noted, almost a third of reported surveillance cases of Lyme disease lack this finding [16,18,63]. Given the possible absence of an EM rash in a patient with a known bite, this option not only withholds primary preventative therapy, it potentially loses an opportunity to provide secondary prevention as well, should the early, non-EM manifestations of the infection be missed. However, patients wishing to avoid antibiotics may prefer this option, in which case clinicians should emphasize that patients must immediately report the occurrence of Lyme-related symptoms so that appropriate antibiotic therapy can be instituted.

In cases where doxycycline is contraindicated, clinicians may consider using other antibiotics known to be effective in Lyme disease, such as amoxicillin, cefuroxime or azithromycin, although there is no evidence to guide decisions with regard to the dose and duration of use for these agents. The excluded trials of antibiotic prophylaxis investigated the therapeutic efficacy of 10 days of amoxicillin, three-times daily [58]; penicillin, four-times daily [56,57] and tetracycline, four-times daily [57]. None of the trials was able to demonstrate efficacy, primarily due to the low incidence of disease in the placebo groups [56,57].

Some guidelines recommend that clinicians learn to estimate attachment times for recovered ticks based on their scutal index, but expertise is required to do this and it is unrealistic to assume that all clinicians can or will acquire such skills. In the single-dose doxycycline study, 9.9% of the bites from nymphal ticks that exhibited any degree of engorgement resulted in the development of an EM at the bite site [59]. Therefore, the panel determined that it was prudent to routinely offer prophylaxis under such circumstances and that withholding therapy from patients who failed to meet an arbitrary minimum tick attachment time was inappropriate. Similarly, the panel recognizes that clinicians frequently lack information regarding current infection rates for a given tick population (often because the research to establish local infectivity rates has not been done) and that tick infection rates in the same locale vary significantly on an annual basis [90]. Therefore, the panel concluded that meeting a specific tick infection rate should not be a prerequisite for antibiotic prophylaxis.
Q2. Should the treatment of an EM rash be restricted to 20 or fewer days of the first-line oral agents (azithromycin, cefuroxime, doxycycline and phenoxymethylpenicillin/amoxicillin)?
Evidence

The panel conducted a Medline search on 5 March 2013 for prospective randomized clinical trials investigating the effectiveness of 5–20 days of oral azithromycin, cefuroxime, doxycycline, phenoxymethylpenicillin or amoxicillin for the treatment of EM. The search used the following strategy: (erythema migrans OR erythema chronicum migrans OR lyme OR lyme borreliosis) AND (amoxicillin/therapeutic use OR azithromycin/therapeutic use OR penicillin/therapeutic use OR cefuroxime/therapeutic use OR doxycycline/therapeutic use) AND (Clinical trial OR comparative study OR meta-analysis). The search identified 76 papers; 51 reported trial outcomes.

A preliminary assessment found that 27 papers described studies that either investigated antibiotic treatment of non-EM presentations (23); were primarily interested in disseminated disease (3) or did not involve any of the antibiotics of interest (1). These were not considered further. An additional 15 trials were excluded because additional review demonstrated that they were either retrospective studies (2); incompletely randomized (1); used a symptom list during post-treatment assessments that did not include commonly reported symptoms of the disease (7) or had a non-completion rate of 20% or higher (5). Thus, nine trials met the requirements for this GRADE analysis and were evaluated in detail (Tables 4 & 5) [46–49,53,74,88,91,92].
Data table

Table 4. Quality of the evidence, in aggregate, that supports restricting the antibiotic treatment of erythema migrans to 20 or fewer days.
Data table

Table 5. Summary of findings regarding the effectiveness of treating an erythema migrans rash with 20 or fewer days of antibiotics based on a re-analysis of the original trial data to reflect patient-centered outcomes.
Rating the quality of the evidence
Bias

None of the trials compared all four antibiotic classes (azithromycin, cefuroxime, doxycycline and phenoxymethylpenicillin/amoxicillin). The nine trials had significant differences in design elements including: antibiotic agents investigated, duration of therapy, outcome definitions, length of observation period and longitudinal data methods; these differences potentially biased findings in favor of one or more agents and make it difficult to draw broad conclusions regarding the effectiveness of the various agents.

Observation periods ranged from 3 to 24 months. The optimum duration of post-treatment observation for EM has not been determined, in part, because while disease relapse is known to occur, the duration of the latent period is variable and can be prolonged [32,33,93]. For example, one trial reviewed here reported a relapse at 20 months [46] and Logigian et al. found that in their subjects (all of whom had neurologic manifestations of Lyme disease), the median time from EM to chronic CNS symptoms was 26 months, with a range of 1–168 months. Thus, trials with longer observation periods are more likely to capture disease relapse and subsequently report lower success rates. Therefore, variations in the length of the observation period may bias efficacy findings in favor of agents that were investigated in trials utilizing short observation periods.

Recognizing this, investigators in two of the EM trials cited the need for longer observation periods in their discussions [47,74]; one suggested that to accurately compare agents, observation periods would need to extend 2 years post-treatment [47]. Of the nine trials reviewed by the panel, only one [46] met this suggested standard and, given that relapse may occur even later, 2 years may not be sufficient.

The lack of standardized outcome definitions also introduces bias. The trials used broad definitions of treatment success that differed by trial [46–49,53,74,88,91,92]. All required the complete resolution of EM and an absence of new findings but, to varying degrees, each trial allowed subjects with improved yet persistent symptoms and subjects who had developed new symptoms consistent with Lyme disease during the observation period to be included within the success group. Thus, treatment success was not synonymous with the full restoration of the pre-Lyme disease health status and prevention of late manifestations of Lyme disease and, therefore, all of the trials were biased toward finding treatment to be effective.

The choice of longitudinal data methods may bias findings by either overstating or understating success rates [94] and the nine trials employed different methods for handling subjects who did not complete the study as designed [46–49,53,74,88,91,92]. Seven trials used complete-case methodology [46–48,53,74,88,91], one reported results in both complete-case and last observation carried forward [92] and one trial employed an intention-to-treat (ITT) approach [49].

Complete-case methodology is likely to overstate treatment success because subjects who leave the trial prematurely due to treatment ineffectiveness or intolerance are excluded from outcome calculations [94,95]. Thus, the trials that used this approach were biased towards finding higher treatment success rates. Last observation carried forward completes the data set for missing subjects by imputing the value from the most recent visit to all subsequently missed observation points, implying outcomes are static [94,95]. Because relapses occur in Lyme disease, this methodology may overstate treatment success; thus, the trials that used last observation carried forward were likely biased towards finding higher treatment success rates.

ITT models evaluate subjects by their assigned treatment, regardless of compliance [94,95]. These models also impute data for the missing and the chosen values reflect assumptions regarding the likelihood that certain potential outcomes actually occurred [95]. Potential assumptions range from worst-case to best-case scenarios. In general, ITT methodology is thought to better represent clinical realities, where patients may inadvertently or purposefully supplement treatment with other interventions that affect outcomes or elect to abandon ineffective treatment altogether [94,96]. The EM trial that employed ITT methodology assumed that missing subjects fulfilled the worst case scenario, that is, had failed [49], biasing the trial toward finding treatment less successful. However, adopting a conservative approach to efficacy determinations avoids the potential harms associated with overstating treatment success and understating treatment failures.
Precision

The number of trials that investigated a given antibiotic was limited and sample sizes in the individual trials were small. Trial numbers per agent ranged from 3 to 5 and median sample sizes per agent ranged from 28 to 63. Small sample sizes are susceptible to random chance and small study bias [97–99].

Only three of the nine trials reported CIs for treatment efficacy [74,88,92]; a fourth reported CIs for the risk of a drug eruption [53].
Consistency

Outcomes, as originally reported by the nine trials, were inconsistent. Two trials simultaneously evaluated the effectiveness of azithromycin, doxycycline and phenoxymethylpenicillin/amoxicillin plus probenecid [46,53]. Strle et al. reported that 28% of subjects, overall, had post-treatment signs/symptoms. By agent, 15% of azithromycin, 26% of doxycycline and 43% phenoxymethylpenicillin subjects had post-treatment manifestations [46]. In contrast, Massarotti et al. reported that azithromycin, doxycycline and amoxicillin plus probenecid were equally efficacious [53].

Seven trials compared two of the three agents, although the pairings differed [48,49,74,88,91,92,100]. Weber et al. found that azithromycin and phenoxymethylpenicillin were comparable, while Luft et al. found amoxicillin to be more efficacious for preventing late disease than azithromycin [48,74]. Azithromycin was more efficacious than doxycycline in the 1993 trial by Strle et al., but Barsic et al. found the two agents equivalent [47,49].

In a separate analysis, success rates for the individual agents were determined after uniform patient-centered outcome definitions and longitudinal data methods were applied to the original data (see Benefits section below and Table 5). These results were also inconsistent. Success, in relation to treatment duration, demonstrated inter- and intra-agent inconsistencies. For example, when the treatment duration was 11–19 days, cefuroxime (78.6%) outperformed phenoxymethylpenicillin/amoxicillin (52.2%) but for 20 days of treatment, success for phenoxymethylpenicillin/amoxicillin (84.4%) was greater than that of cefuroxime (61.5%). Success rates for individual agents were also inconsistent; both cefuroxime and phenoxymethylpenicillin/amoxicillin had higher success rates with shorter, rather than longer, treatment durations.
Directedness (generalizability)

Findings are applicable to patients with EM rashes, without evidence of CNS dissemination. It cannot be assumed that findings are applicable to patients with Lyme disease inclusive of CNS dissemination, other tick-borne diseases or immunocompromised states [101]. Nor can it be assumed that findings are applicable to non-EM early Lyme disease [102]. Given the clinical variations between the genospecies [103,104], results from European trials, where Borrelia afzelii is the dominant cause of EM rashes [102], may not be applicable to the US patients.
Evidence quality, in aggregate

The quality of the evidence addressing the effectiveness of 5–20 days of antibiotics for the treatment of EM is very low, implying that the true effectiveness of a 5–20 day course of antibiotics for the treatment of an EM rash is likely to be substantially different from the trials’ reported effectiveness rate.
Benefits

The limitations of the evidence from the original trials reduce the reliability of their findings. Given that no trial directly compared all classes of agents (azithromycin, cefuroxime, doxycycline and phenoxymethylpenicillin/amoxicillin) and direct comparisons between individual trials are hampered by differences in outcome definitions, length of the observation periods and longitudinal data methodologies, the ability to draw valid conclusions regarding the relative effectiveness of commonly prescribed antibiotic regimens is impaired.

To provide comparative information on patient-centered outcomes by agent – information of clinical import to clinicians and patients – the original trial data were reanalyzed. To minimize biases due to variations in trial design, standardized, patient-centered definitions of treatment success and failure and uniform statistical methodology, utilizing the conservative approach of Barsic et al. [49], were applied to the original trial data. To avoid overstating the effectiveness of the investigated antibiotics, the panel specifically chose to assume that those who failed to complete the trial were treatment failures.

Success was defined as the complete resolution of EM and all associated symptoms and findings, without evidence of disease relapse or the development of new manifestations consistent with Lyme disease during the observation period. The panel viewed this outcome definition as the outcome that would matter most to patients and thought it was consistent with the expectation that the appropriate treatment of an EM rash should restore the patient to their pre-morbid baseline.

Failure included any outcome short of that. Subjects described by the investigators as failures and those who were retreated (regardless of the post-retreatment outcome) were considered failures for the purpose of this outcome analysis. Subjects who had ongoing symptoms at the final end point, including those described as ‘partial responders’, were also considered failures. In some instances, this resulted in subjects being re-categorized as failures. Subjects who were ‘unevaluable’, wrongly enrolled, non-compliant, withdrawn prematurely due to adverse reactions to their assigned antibiotic or lost to follow-up were also considered failures for the purpose of this analysis.

Success rates across the nine trials differed significantly. The lowest, 52.2% (CI: 30.6, 73.3), was in the phenoxymethylpenicillin arm of the 1992 trial by Strle et al. and the highest, 93.3% (CI: 68.1, 99.8), was in the high-dose cefuroxime arm in the trial by Eppes and Childs (see Supplementary Appendix III). The two arms with the highest success rates had exceptionally small sample sizes; one arm had 13 subjects, the other had 15 [91]. The two arms with the lowest success rates also had small samples sizes, 23 subjects in one and 26 in the other [46,53].

Success rates were subsequently regrouped by agent and treatment duration and weighted average success rates for the various regimens were then calculated. The outcome results from arms which had non-completion rates equal to or exceeding 20% were excluded from the calculations. As shown in Table 5, success rates for a given treatment duration vary by antibiotic class. Twenty days of phenoxymethyl-penicillin/amoxicillin had the highest overall success rate of all of the regimens, 84.4%, while 11–19 days of these same agents had the lowest success rate, 61.5%.
Harms

Serious adverse events, defined as allergic reactions, C. difficile infections, any adverse event resulting in withdrawal from study or change in therapeutic agent and any adverse event labeled by the investigators as ‘serious’ occurred in 20 of 1068 subjects (1.9%) (Table 5). None of the adverse events was specifically categorized as allergic reactions. The majority of serious adverse events involved the skin (11), including non-specific skin rash (6) [74], drug eruptions (4) [53] and serious photosensitivity reaction (1) [46]. Gastrointestinal adverse events were also common, including poor medication palatability in pediatric subjects (2) [91], nausea and vomiting (1) [48] and diarrhea (5) [49,74,88]. A single subject was treated for C. difficile infection shortly after completing treatment [91]. No deaths were reported.

Although the panel did not consider a Jarisch–Herxheimer reaction an adverse event, four EM trials reported a Jarisch–Herxheimer reaction in 60 of 351 subjects (17.1%) (range 12.1–18.7%) [47,53,88,91].
Risk–benefit assessment

The harms associated with restricting treatment of an EM rash to 20 or fewer days of oral azithromycin, cefuroxime, doxycycline and phenoxymethylpenicillin/amoxicillin outweigh the benefits. In assessing the risk–benefit profile, the panel determined that the failure rates for antibiotic treatment of 20 or fewer days were unacceptably high and that for those who failed treatment, the magnitude of the potential harm created by delaying definitive treatment, which includes the increased risk of developing a chronic and more difficult to treat form of the disease, was too great.

Although it is generally assumed that antibiotic regimens of shorter duration will be associated with a lower rate of significant adverse events, adverse event rates for oral antibiotics are generally quite low regardless of the duration of use [105–107]. The panel concluded that while antibiotic treatment regimens of 20 or fewer days may result in slightly fewer significant adverse events compared with regimens of longer duration, that benefit does not offset the potential harms associated with the unacceptably high failure rates resulting from this treatment approach. Furthermore, as previously noted, the concomitant use of probiotics should reduce the risk of C. difficile colitis and antibiotic-associated diarrhea [44,45].
Values

The panel placed a high value on avoiding both: the unnecessary progression from a potentially curable infection to one that is chronic and the morbidity and costs associated with chronic disease. The panel also placed a high value on the ability of the clinician to exercise clinical judgment. In the view of the panel, guidelines should not constrain the treating clinician from exercising clinical judgment in the absence of strong and compelling evidence to the contrary.
Recommendation 2a

Treatment regimens of 20 or fewer days of phenoxymethyl-penicillin, amoxicillin, cefuroxime or doxycycline and 10 or fewer days of azithromycin are not recommended for patients with EM rashes because failure rates in the clinical trials were unacceptably high. Failure to fully eradicate the infection may result in the development of a chronic form of Lyme disease, exposing patients to its attendant morbidity and costs, which can be quite significant. (Recommendation, very low-quality evidence).
Role of patient preferences

Moderate: Although many patients will value avoiding the risk of treatment failure over a potentially modest increase in the risk of significant adverse events that may be associated with longer treatment durations, others may prefer to avoid the additional risks of longer treatment. Clinicians should inform patients that the combined failure rate for the individual agents investigated in the previously discussed EM trials were judged by this panel to be unacceptably high when antibiotic treatment was restricted to 20 or fewer days; the evidence supporting the use of longer treatment durations is limited and of low quality [41–43] and increases in antibiotic duration may increase the risk of antibiotic-associated adverse events, although the risks associated with oral antibiotics are low and some of this risk can be mitigated by the concomitant use of probiotics [44,45,108]. Treatment risks, benefits and options should be discussed with the patient in the context of shared medical decision-making.
Recommendation 2b

Clinicians should prescribe amoxicillin, cefuroxime or doxycycline as first-line agents for the treatment of EM. Azithromycin is also an acceptable agent, particularly in Europe, where trials demonstrated it either outperformed or was as effective as the other first-line agents [46–49]. Initial antibiotic therapy should employ 4–6 weeks of amoxicillin 1500–2000 mg daily in divided doses, cefuroxime 500 mg twice daily or doxycycline 100 mg twice daily or a minimum of 21 days of azithromycin 250–500 mg daily. Pediatric dosing for the individual agents is as follows: amoxicillin 50 mg/kg/day in three divided doses, with a maximal daily dose of 1500 mg; cefuroxime 20–30 mg/kg/day in two divided doses, with a maximal daily dose of 1000 mg and azithromycin 10 mg/kg on day 1 then 5–10 mg/kg daily, with a maximal daily dose of 500 mg. For children 8 years and older, doxycycline is an additional option. Doxycycline is dosed at 4 mg/kg/day in two divided doses, with a maximal daily dose of 200 mg. Higher daily doses of the individual agents may be appropriate in adolescents.

Selection of the antibiotic agent and dose for an individual patient should take several factors into account. In the absence of contraindications, doxycycline is preferred when concomitant Anaplasma or Ehrlichia infections are possibilities. Other considerations include the duration and severity of symptoms, medication tolerability, patient age, pregnancy status, co-morbidities, recent or current corticosteroid use [54,55], cost, the need for lifestyle adjustments to accommodate certain antibiotics and patient preferences. Variations in patient-specific details and the limitations of the evidence imply that clinicians may, in a variety of circumstances, need to select therapeutic regimens utilizing higher doses, longer durations or combinations of first-line agents. (Recommendation, very low-quality evidence)
Role of patient preferences

Moderate: See Recommendation 2a.
Recommendation 2c

Clinicians should provide ongoing assessments to detect evidence of disease persistence, progression or relapse or the presence of other tick-borne diseases. Lacking a test of cure, ongoing assessments are crucial for determining if treatment has been clinically effective (see remarks following Recommendation 2f). The first assessment should immediately follow the completion of therapy and subsequent evaluations should occur on an as-needed basis. (Recommendation, very low-quality evidence)
Role of patient preferences

Low: The benefits of monitoring the response to treatment clearly outweigh any attendant risks associated with monitoring.
Recommendation 2d

Clinicians should continue antibiotic therapy for patients who have not fully recovered by the completion of active therapy. Ongoing symptoms at the completion of active therapy were associated with an increased risk of long-term failure in some trials and therefore clinicians should not assume that time alone will resolve symptoms (see remarks following Recommendation 2f). There is a wide range of options and choices must be individualized, based on the strength of the patient’s initial response. Dosage ranges for oral agents are as noted in Recommendation 2b.

Strong-to-moderate responses favor extending the duration of therapy of the initial agent at the same dosage. Modest responses may prompt an increase in the dosage of the initial antibiotic or a switch to a different first-line agent. Tetracycline, with a total daily dose of 1000–1500 mg in three or four divided doses, is an additional option [50,109]. Due to its favorable pharmacokinetics, tetracycline may be more effective than doxycycline when initial therapy is non-curative [109].

Minimal or absent responses suggest a need for a combination of first-line agents, which includes at least one antibiotic that is able to effectively reach intracellular compartments [109,110]. Injectable penicillin G benzathine (Bicillin LA), totaling 1.2–3.6 million units weekly, or iv. agents such as ceftriaxone are other options. Intramuscular (IM) benzathine penicillin avoids the risks associated with gaining iv. access and it was effective in seemingly recalcitrant Lyme arthritis [111]. Ceftriaxone, 2 g iv. per day is known to be effective [16,17,32,33,54,112] and iv. cefotaxime [113], another cephalosporin, has also been recommended. iv. penicillin is less effective and requires more frequent dosing [114]. Additional iv. cell wall agents from the carbapenem and monobactam classes were effective in vitro, but have not been studied clinically [115].

Disease progression or recurrence suggests that the iv. agents or injectable penicillin G benzathine, as discussed above, may be required. For patients requiring antibiotic therapy beyond the initial treatment period, subsequent decisions regarding the modification or discontinuation of treatment should be based on the therapeutic response and treatment goals. Additionally, minimal or absent responses and disease progression require a re-evaluation of the original diagnosis (see remarks following Recommendation 2f). (Recommendation, very low-quality evidence).
Role of patient preferences

Moderate: While most patients will place a high value on the potential of regaining their pre-morbid health status and preventing chronic illness by continuing treatment, a substantial portion may also value avoiding unnecessary antibiotics. Hence, treatment risks, benefits and options should be discussed with the patient in the context of shared medical decision-making.
Recommendation 2e

Clinicians should retreat patients who were successfully treated initially, but subsequently relapse or have evidence of disease progression. Support for retreatment is drawn from the EM trials themselves. In seven of the nine trials reviewed in this analysis [46,48,53,74,88,91,92], subjects who had evidence of treatment failure during the observation period were offered retreatment. Regimens used either oral [46,48,53,74,88,91,92] or iv. antibiotics [48,53,74,88,92], with the choice of agent and route apparently reflecting the investigators’ clinical assessments and treatment preferences.

Therapeutic options include repeating the initial agent, changing to another oral agent or instituting injectable penicillin G benzathine or iv. ceftriaxone therapy. The previously listed dosage ranges for the individual agents would be appropriate. Choices must be individualized and based on several factors, including: the initial response to treatment; the time to relapse or progression; the current disease severity and the level of QoL impairments.

Prior to instituting additional antibiotic therapy, the original diagnosis should be reassessed and clinicians should evaluate patients for other potential causes that would result in the apparent relapse or progression of symptoms and/or findings (see remarks following Recommendation 2f).

The presence of other tick-borne diseases, in particular, should be investigated if that had not already been done. I. scapularis transmits several pathogens and the resulting infections may produce symptoms similar to those of Lyme disease. Thus, apparent relapse or disease progression following antibiotic therapy for Lyme disease may be indicative of a concurrent co-infection and not the failure to eradicate B. burgdorferi. The presence of other Ixodes-borne infections may increase the severity and duration of Lyme disease symptoms [116,117]. Treatment of dually infected patients has not been studied, therefore, the optimal antibiotic regimen for the Lyme disease component is unknown. The possibility of co-infections should not be casually dismissed. Two published surveys of Lyme disease patients found that many respondents were infected with more than one tick-borne pathogen [118,119]. A survey of 3090 patients diagnosed with Lyme disease found that laboratory confirmed cases of babesiosis and anaplasmosis were reported by 32.3 and 4.8% of respondents, respectively [119].

Following a long period of disease latency, minimal manifestations causing little deterioration in the patient’s QoL favor continued observation or repeating therapy with the initial agent; mild manifestations or QoL impairments may prompt a switch to a different first-line agent, tetracycline [50,109], or a combination of first-line agents (which includes at least one antibiotic that is able to effectively reach intracellular compartments) [109,110,120]. Intravenous or IM antibiotics such as injectable penicillin G benzathine or iv. ceftriaxone are other options.

Disease relapse or progression with mild manifestations or QoL impairments occurring within a few months of treatment suggests a need for longer regimens using either a combination of oral first-line agents, injectable penicillin G benzathine or iv. ceftriaxone. Regardless of the duration of disease latency, when disease manifestations or QoL impairments are significant or rapidly progressive, injectable penicillin G benzathine or iv. ceftriaxone may be required. Subsequent decisions regarding the modification or discontinuation of a patient’s treatment should be based on the individual’s therapeutic response and preferences (Recommendation, very low-quality evidence).
Role of patient preferences

High: While most patients will place a high value on the potential of regaining their pre-morbid health status and improving their QoL and preventing chronic disease through continued antibiotic treatment, a substantial portion will also value avoiding potentially unnecessary antibiotics. Hence, treatment risks, benefits and options should be discussed with the patient in the context of shared medical decision-making.
Recommendation 2f

Clinicians should educate patients regarding the potential manifestations of Lyme disease, carefully explaining that disease latency can be prolonged. Education should also include information on preventing future bites, the manifestations of the other tick-borne diseases that they may have contracted as well as the symptoms and signs of a C. difficile infection and the preventative effect of probiotics. Patients should be encouraged to immediately report the occurrence of any recurrent or newly developing manifestation of Lyme disease as well as those suggestive of other tick-borne diseases or a C. difficile infection. Clinicians should emphasize that the need to report manifestations of tick-borne diseases never expires. (Recommendation, very low-quality evidence)
Role of patient preferences

Low: The benefits of educating patients about potential disease manifestations clearly outweigh any attendant risks associated with education.
Remarks

This patient-centered analysis of the evidence from nine clinical trials of EM treatment demonstrates that treatment regimens which used 20 or fewer days of antibiotics were often ineffective. The findings of this analysis are consistent with those from a recently published observational study of EM. In the study by Aucott et al., the authors reported that 21 of 63 (33.3%) patients treated with three weeks of doxycycline met the study’s definition of post-treatment Lyme disease syndrome in that they experienced disease manifestations during the 3–6 month post-treatment interval [121]. Furthermore, reports of neurocognitive problems were 9% higher at the 6-month end point than at baseline.

Identifying patients at higher risk for treatment failure and offering them more extensive treatment may improve outcomes. Outcomes might also be improved by assessing the immediate post-treatment response and taking appropriate action. Several studies suggested that certain clinical presentations are associated with a higher risk of treatment failure. Results from two trials suggested that patients who remained symptomatic at the completion of therapy [74] or 1 month post-treatment [88] were at higher risk for long-term failure. These findings form the basis for Recommendation 2c. Other high-risk presentations included: increased severity of initial symptoms [50], paresthesia [88], dysesthesias [53], irritability [52], arthralgia [52], multiple EM [88] and the presence of co-infections [117]. In such circumstances, clinicians should consider lengthening the initial phenoxymethylpenicillin, amoxicillin, cefuroxime or doxycycline therapy to a minimum of 6 weeks or extending azithromycin treatment to a minimum of 4 weeks.

Relapse and/or disease progression may occur at any time and this analysis notes that longer observation periods increase the likelihood of detecting disease relapse, which would decrease the long-term efficacy noted in these trials. This conflicts with the oft stated position that success rates improve with time [71]. In a trial frequently cited in support of this position, success rates did increase over time when calculated on a complete case basis (the trial’s chosen methodology for handling longitudinal data) [122]. However, the ITT data supplied in Table 3 of that paper documented that the absolute numbers of successfully treated subjects declined significantly between the 12- and 30-month visits. In the 10-day doxycycline arm, complete success peaked at 12 months, with 44 of 61 (72.1%) returning to their pre-Lyme disease baseline while at 30 months, only 35 of 61 (57.4%) were categorized this way [122]. Readers should note that while Table 3 of the study is entitled ‘Clinical Response Based on an Intention-To-Treat Analysis of Patients for Whom Information Was Available*’, this was not an ITT analysis. Calculating response rates based on a portion of the group rather than on all who were randomized to a particular arm is contrary to ITT principles.

Additionally, given that prior B. burgdorferi infections do not provide durable immunoprotection [123], clinicians should consider the possibility that the patient was re-infected and seek information to confirm or dispel that this occurred [124]. In the absence of clear evidence of re-infection, clinicians and patients will need to consider the relative risks and benefits of assuming that relapsing symptoms such as EM lesions or flu-like symptoms in the summer are indicative of ongoing infection and not re-infection.

Disease manifestations may appear to relapse and/or progress for reasons unrelated to Lyme disease. In addition to the possible presence of co-infections, many other illnesses and conditions have clinical features which may overlap with those of Lyme disease; some examples are: infections due to Epstein–Barr virus or syphilis; autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and vasculitis; metabolic and endocrine disorders such as diabetes, hypo- or hyperthyroidism and adrenal dysfunction; degenerative neurologic diseases such as Parkinson’s disease and amyotrophic lateral sclerosis and neurologic conditions such as peripheral neuropathy and dysautonomia; musculoskeletal diseases including fibromyalgia and osteoarthritis, psychiatric disorders, especially depression and anxiety and other conditions such as chronic fatigue syndrome and sleep apnea. (Note: this list is not intended to be exhaustive and patient-specific circumstances will guide the physician in determining whether other potential etiologies of relapsing or progressive manifestations need to be investigated.)
Q3. Should patients with persistent manifestations of Lyme disease be retreated with antibiotics?
Evidence

The panel conducted a Medline search on 5 March 2013 for RCTs investigating the effectiveness of antibiotic retreatment in patients with persistent manifestations of Lyme disease following treatment considered by some to be standard and appropriate antibiotic therapy for their stage of illness. The search used this strategy: chronic Lyme disease OR Lyme encephalopathy OR persistent Lyme disease AND antibacterial Agents/administration & dosage and this filter: clinical trial.

Five RCTs conducted in the USA were identified. Four met the inclusion criteria for this analysis [16–18]. A fifth trial had a non-completion rate in excess of 20% [87] and was excluded from this analysis on that basis. A Swedish trial was also excluded due to excessive incomplete data [125].

The four trials had unique designs. In one trial, Klempner et al. exclusively enrolled seropositive subjects and treatment consisted of 30 days of iv. ceftriaxone followed by 60 days of oral doxycycline or an identical placebo regimen [18]. A second trial by that same group used an identical design except enrolled subjects were exclusively seronegative [18]. Krupp et al. enrolled seropositive subjects with severe fatigue; participants received either 30 days of iv. ceftriaxone or an identical placebo [17]. Fallon et al. enrolled seropositive subjects with Lyme encephalopathy; treatment consisted of either 10 weeks of iv. ceftriaxone or an identical placebo [16].
Bias

The designs of three of the four trials introduced the potential for type II errors [126,127], which biased the trials against antibiotic retreatment. Type II errors occur when there is a failure to reject a false null hypothesis. With regard to treatment trials, type II errors would wrongly label effective treatment as ineffective.

Type II errors may arise when the designated treatment effect for a trial is too large. The primary end point in the trials by Klempner et al. was improvement in QoL, as measured by gains in the 36-item short-form health survey (SF-36) mental and physical component summary scores [18]. A biostatistical review of those trials noted that the minimal clinically important difference (MCID) in SF-36 scores have not been established for Lyme disease and it demonstrated that the designated treatment effect sizes for categorizing subjects as ‘improved’ likely exceeded the MCIDs of the SF-36 scores by several-fold [126].

The enrollment criteria and subsequent data analysis of the trials by Klempner et al. also raise the possibility of a type II error [127]. Subjects were not required to meet a specific level of symptom severity, which allowed for the recruitment of subject groups with baseline heterogeneity on the primary end point. Due to outcome averaging, studies failing to account for such baseline heterogeneity in their sample population are more apt to report no treatment effect. Of the four trials, only the trials by Klempner et al. failed to address baseline heterogeneity issues and these were the only trials which failed to find a treatment effect on any end point. In contrast, the subjects in the study by Krupp et al. were homogeneous with regard to fatigue and the post hoc analysis of Fallon et al. addressed baseline heterogeneity on this end point as well, with both trials finding a positive treatment effect on fatigue [16,17].

Delayed processing speed was not an inclusion criterion for the trial by Krupp et al. and subjects had minimal baseline deficits on this end point. The designated treatment effect, which was based on earlier studies of Lyme patients [128], called for an increase in processing speed that was unrealistically high for this group of subjects in that meeting the designated treatment effect would have required the subjects’ processing speed to exceed healthy population norms [126]. Thus, the trial was biased on this end point [126].

All four trials enrolled subjects who had previously received extensive antibiotic treatment for Lyme disease yet remained ill. The presence of treatment refractory subjects biased the trials against finding treatment to be effective.

Krupp et al. also investigated an experimental biologic marker of current disease, namely, the presence of outer surface protein A (OspA) in the cerebrospinal fluid of Lyme patients. Although the trial was designed with clearance of OspA from the cerebrospinal fluid as a primary end point [17], only 16% of the subjects had OspA in their baseline cerebrospinal fluid [17], making it impossible to demonstrate a treatment effect in 84% of the subjects. Accordingly, this trial failed to validate the use of OspA as a surrogate marker and the trial was biased against finding treatment to be effective on this end point.

Results can be biased if unmasking occurs. Although they had no direct evidence that this occurred, Krupp et al. raised the concern that masking in their study may have been compromised as subjects in the ceftriaxone arm were more likely to correctly guess their treatment group than the placebo subjects. However, two reviews of the NIH-sponsored retreatment trials noted that the correct guesses could reflect that the subjects in the ceftriaxone arm were feeling better and, therefore, properly attributed this change to being on active therapy [126,127].
Precision

Sample sizes in the individual trials were small, ranging from 37 to 78 [16–18]. Small sample sizes are susceptible to random chance and small study bias [97–99].

The trial by Fallon et al. was underpowered. It enrolled 37 patients, yet its design required 45 subjects to achieve at least 80% power to detect an effect size of 1.1 with a two-sided test with α <0.05 [16]. The mental processing speed end point in the trial by Krupp et al. was designed with only 74% power [17].

Although the trials by Klempner et al. were sufficiently powered, the trials called for an unrealistically large treatment effect that likely exceeded the MCID for changes in the SF-36 scores of Lyme disease patients [126]. The selection of a smaller, and more appropriate, effect size would have required significantly larger sample sizes to achieve sufficient statistical power [126].
Consistency

Krupp et al. found retreatment provided a clinically meaningful reduction in severe fatigue and the post hoc analysis by Fallon et al. corroborated this finding [16,17]. In the treatment response rates in the trial by Krupp et al., 64% improved in the treatment arm versus 18.5% in the placebo arm (p < 0.001) was similar to the response rates of Fallon et al., where 66.7% of treated subjects improved versus 25% of the placebo group (p < 0.05) [16,17].

Cognitive benefits were evaluated by Krupp et al. and Fallon et al. [16,17]., but consistency cannot be judged because the trial by Krupp et al. was inadequately designed for this end point (see bias and precision sections above).

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 [18]. As discussed above, the trials by Klempner et al. were inadequately designed, calling for a treatment effect that likely exceeded the MCID [126]. As such, the absence of a treatment benefit in these trials is uninformative.
Directness (generalizability)

The directness (generalizability) of the evidence is limited because entrance criteria led to the enrollment of subjects who are not representative of the full clinical spectrum of patients with persistent symptoms. Trial subjects had been ill for prolonged periods of time and had received extensive antibiotic treatment prior to enrollment [16–18]. Subjects in the antibiotic arms of the trials by Klempner et al. and Fallon et al. had been ill, on average, for 4.7 and 9.0 years, respectively [16,18]. Thirty-three percent of the subjects in the trials by Klempner et al. had been treated with 30 days of iv. ceftriaxone and subjects in the trial by Krupp et al. had received, on average, 7.2 weeks of antibiotic therapy, with 47.3% having been previously treated with a minimum of 2 weeks of iv. ceftriaxone [17,18]. Prior antibiotic treatment in the subjects by Fallon et al. was significantly higher. The average duration of therapy was 9.5 months, which included 2.3 months of iv. ceftriaxone use [16].

The trials also excluded patients with characteristics commonly seen in clinical practice. All four trials excluded patients with co-infections or confounding illnesses/conditions [16–18]. Fallon excluded patients who were negative on current ELISA and western blot testing and Krupp et al. excluded those who lacked both a history of a physician-documented EM and serologic confirmation of late manifestations [16,17]. However, seronegative status would not necessarily deter clinicians from offering antibiotic therapy [87,75]. Once subjects were enrolled, trial designs restricted the investigators’ ability to prescribe non-antibiotic therapy to subjects, which is a common clinical practice. For example, the need for pain medication resulted in one subject being dropped from the trial by Fallon et al. [16]. Investigators’ primary responsibility is to the trial and not potential enrollees, while clinicians are chiefly concerned with providing care to ill patients and thus they may choose to employ broader treatment criteria. Highly selective research entry criteria and treatment restrictions, like those employed in the four retreatment trials, serve the purpose of ensuring internal validity, but may do so at the expense of external validity, undermining the generalizability of the results to the population of patients clinicians see in practice.
Evidence quality, in aggregate

The quality of the evidence regarding the effectiveness of antibiotic retreatment in patients with persistent symptoms following standard and appropriate antibiotic therapy for Lyme disease is very low (Table 6), implying that the true effectiveness of retreatment is likely to be substantially different from the effectiveness rates seen in the four NIH-sponsored retreatment trials.
Data table

Table 6. Quality of the evidence, in aggregate, that supports antibiotic retreatment in patients with persistent symptoms of Lyme disease.
Benefits

Retreatment with ceftriaxone was effective in two of the four trials (Table 7). Krupp et al. found that 28 days of ceftriaxone was more effective than placebo (64 vs 18.5%; p < 0.001) for producing a clinically significant reduction in severe fatigue, a primary outcome [17]. The effect size was moderate to large [127]. Fallon et al. found that subjects treated with 70 days of iv. ceftriaxone achieved a moderate improvement (effect size = 0.81) in generalized cognitive function at 2 weeks post-therapy compared with those in the placebo arm (effect size = 0.30) (p = 0.053), although the preferential effect of drug versus placebo was not sustained at 14 weeks post-therapy [16]. The mechanisms leading to the subsequent loss of the cognitive gains are unknown; however, this long-term outcome may indicate that the offered therapy was incomplete. A planned secondary analysis demonstrated an interaction effect between baseline impairments and treatment, such that the ceftriaxone effect increased with higher baseline severity; this was demonstrated for the measures of pain and physical dysfunction at week 12 and sustained to week 24 [16]. On post hoc analysis, Fallon et al. also demonstrated a positive treatment effect on severe fatigue. Of the subjects in the trial by Fallon et al., who met the fatigue entrance criteria of the trial by Krupp et al., those who received ceftriaxone experienced significant reductions in the level of their fatigue compared with those who received placebo (66.0 vs 25.0%; p < 0.05).
Data table

Table 7. Summary of findings regarding the effectiveness of antibiotic retreatment in patients with persistent manifestations of Lyme disease.
Harms

The NIH-sponsored retreatment trials described 15 serious adverse events among the 221 subjects (6.8%) [16–18]. Each event was associated with ceftriaxone itself or the need for venous access; 60 days of oral doxycycline therapy was not associated with any significant adverse event. Six individuals experienced allergic reactions [16–18], including one case of anaphylaxis [17]. Seven events were related to the iv. line [16–18], four cases involved line-related infections (all on placebo) [16,17], two cases involved thrombi [16] and one subject developed a pulmonary embolus [18]. Additionally, there was one case of cholecystitis [16] and one case of gastrointestinal bleeding with fever and anemia [18].
Risk–benefit assessment

The clinical population of patients with persistent manifestations of Lyme disease is heterogeneous; therefore, the risk–benefit assessment needs to be done on an individualized basis, taking into account the severity of an individual’s persistent disease, their responsiveness to treatment, their ability to tolerate side effects associated with additional and potentially long-term treatment as well as their willingness to accept the risk associated with antibiotic treatment or, conversely, the level of their desire to avoid treatment-associated risk.

The scientific evidence regarding potential etiologic mechanisms for the development of persistent manifestations of Lyme disease continues to evolve. Proposed mechanisms include immune dysregulation of various types, tissue injury, infection-induced secondary conditions, unrecognized or undertreated co-infections and persistent infection [129,130]. Of these, we think the weight of the evidence supports persistent infection, although other mechanisms may co-exist and the exact etiology for persistent manifestations may vary from patient to patient. Given this uncertainty, the panel concluded that the evidence at hand regarding persistent infection and the potential benefits of retreatment are adequate to support those who wish to treat but is not overwhelming enough to mandate treatment.

The panel also determined that there is no compelling evidence to support routinely withholding antibiotic retreatment from ill patients. While antibiotics are not always effective, the importance of providing patients with the opportunity to receive an adequate trial of antibiotic therapy is heightened by the lack of other effective treatment approaches. Palliative care may be helpful in addressing some symptoms in some cases, but it is important to bear in mind that palliative interventions also carry risks. Additionally, clinicians must not assume that palliative interventions would provide adequate treatment in the face of an underlying persistent infection. Therefore, in the panel’s judgment, antibiotic retreatment will prove to be appropriate for the majority of patients who remain ill and thus it is inappropriate to constrain clinicians from exercising their clinical judgment.

In making these determinations, the panel considered the strength of the evidence addressing the effectiveness of antibiotic retreatment, the burden of disease and the risks associated with various antibiotic options. The panel weighed each in light of the marked heterogeneity within this patient population.

Potential benefits include the restoration of health, improved QoL and prevention of further decline in health status. While complete restoration of health was not identified in any of the four retreatment trials, the moderate-to-large treatment effect on severe fatigue demonstrated in the trial by Krupp et al. and the sustained interaction effects between baseline severity and improvements in pain and physical functioning seen in the trial by Fallon et al. suggested to the panel that retreatment may improve the QoL of some patients.

Others have reached a similar conclusion. In a recent review of the four retreatment trials, Fallon et al. make the point that guidelines restricting the use of antibiotics in patients with persistent manifestation of Lyme disease are based on the erroneous dismissal of the treatment efficacy demonstrated in two of the trials [127]. The authors state that such guidelines ‘are not helpful to clinicians and patients’ [127].

In addition to the NIH-sponsored retreatment trials, retreatment was also shown to be beneficial in clinical trials of EM treatment and in a case series involving the treatment of late neurologic disease. Investigators in seven of the nine EM trials discussed above retreated subjects who failed initial therapy [47,48,53,74,88,91,92]. Decisions to retreat were often based on symptoms alone and investigators frequently reported on the success of retreatment. In three trials, biopsy specimens from the EM site were culture-positive for B. burgdorferi 1–3 months post-treatment [47,48,92]. In two of these, subjects were retreated with oral antibiotics and follow-up cultures 3 [47] or 4 months later [92] were negative. Thus, these trials simultaneously demonstrated persistent infection following standard therapy and the value of retreatment.

In a study by Logigian et al., one subject relapsed at 8 months post-treatment, was retreated, became well once again and remained so for the remainder of the study [33]. Several observational studies also demonstrated benefits from antibiotic retreatment [87,109,110,131].

The panel also considered the risk of withholding antibiotics from patients with a potentially treatable B. burgdorferi infection. Currently available laboratory tests are unable to confirm or deny persistent infection on a routine basis yet persisting infection has been demonstrated in patients with Lyme disease by PCR and culture [47,113,132–136]. A recently published xenodiagnostic study in humans demonstrated positive results in one of eight subjects with post-treatment manifestations of Lyme disease; a subsequent xenodiagnostic specimen obtained from the same subject 8 months later was also positive [137]. Animal studies have corroborated the human findings, documenting bacterial persistence by culture, PCR and histopathologic testing of post-treatment necropsy specimens and by xenodiagnosis [76,138,139]. Given these realities, withholding antibiotic retreatment risks allow an infection to continue unchecked.

The panel weighed the burden of chronic illness that Lyme disease imposes on patients. In the four retreatment trials analyzed here, the subjects’ QoL was consistently worse than that of control populations and reductions in employment or educational activities were common [16–18]. A community-based trial of antibiotic retreatment found the QoL of its subjects was the same or worse as that of individuals with depression, diabetes, heart disease, osteoarthritis and rheumatoid arthritis [87]. Surveys of Lyme disease patients further document the negative impact of persistent manifestations. One survey of openly recruited Lyme disease patients identified 2424 patients whose initial clinical diagnosis of Lyme disease was confirmed with positive serology and who had persistent manifestations of Lyme disease despite antibiotic treatment [140]. Of this cohort, 25% had received public support or disability benefits and the majority of respondents in this subset received these payments for 2 or more years. A second online survey identified 1087 respondants diagnosed with Lyme disease (based on the presence of an EM rash or positive two-tier testing that used the CDC interpretive criteria) who had ongoing manifestations of Lyme disease for 6 or more months [119]. Using a CDC metric of health-related QoL, the survey found that this group averaged 19.6 and 15.5 days/month of poor physical and mental health days, respectively. Not surprisingly, 71.6% rated their health as fair or poor. This rate is higher than that seen in other chronic diseases including congestive heart failure, fibromyalgia, post- stroke and post-myocardial infarction status, diabetes and multiple sclerosis and the survey findings corroborate those of the community-based retreatment trial mentioned above. By comparision, in a general population with an average age of 46, only 16% rated their health as fair or poor [119]. The respondants also reported significant economic impacts – 39.4% stopped working and an additional 28.3% reduced their work hours or role; 37.3% spent at least US$5000 in out-of-pocket Lyme-related expenses.

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