The International
Lyme and Associated
Evidence-based guidelines for the management of Lyme disease
The ILADS Working Group ILADS, P.O. Box 341461 Bethesda, MD 20827-1461, USA antibiotics, Babesia, Bartonella, Borrelia burgdorferi, Ehrlichia, guidelines, Lyme disease, tickborne diseases Future Drugs Ltd. All rights reserved. ISSN 1478-7210 The International Lyme and Associated Diseases Society
The ILADS Working Group
Daniel Cameron, MD, MPH Internal Medicine and Epidemiology, Mt. Kisco, New York Rheumatology, Basking Ridge, New Jersey Immunology, Palo Alto, California Family and Integrative Medicine, Colmar, Pennsylvania Sabra Bellovin, MD Family Practice, Portsmouth, Virginia Family Practice, Rhinebeck, New York Family PracticeRhinebeck, New York Joseph Burrascano, MD Internal MedicineEast Hampton, New York Constance Dickey, RN Registered NurseHampden, Maine Richard Horowitz, MD Internal MedicineHyde Park, New York Steven Phillips, MD Internal MedicineRidgefield, Connecticut Laurence Meer-Scherrer, MD Internal MedicineFlamatt, Switzerland Bernard Raxlen, MD Virginia Sherr, MD Emergency MedicineDanville, Pennsylvania President, Lyme Disease Association, Inc.
Jackson, New Jersey Raphael Stricker, MD Hematology and ImmunotherapySan Francisco, California Summary & disclaimer
These guidelines represent an evidence-based review of Lyme and associated tickborne diseases by the International Lyme andAssociated Diseases Society (ILADS). Although the guidelines present evidence-based approaches to the diagnosis and treatmentof Lyme and associated tickborne diseases, they were not intended to be a standard of medical care. Physicians must use their ownjudgment based on a thorough review of all available clinical information and the Lyme disease literature to decide on the bestcourse of treatment for an individual patient.
ILADS would like to thank the Turn the Corner Foundation, New York, NY, for financial support of formulation of the guide-lines; Medallion Media, Novato, CA, for editorial support of development of the guidelines; and the Lyme Disease Association,Inc., Jackson, NJ, for financial support of publication of the guidelines.
Expert Rev. Anti-infect. Ther. 2(1), (2004) ILADS guidelines for Lyme disease
Table of contents
I Introduction to guidelines
1. International Lyme and Associated Diseases Society
2. Chronic Lyme disease: a growing epidemic
3. The need for new guidelines
4. A problem of definitions
5. Competency and training
6. Role of primary care
7. Highlights of guidelines
II New presentations
8. Symptomatic presentation
9. Symptoms of Lyme disease
10. Increasing evidence of persistent infection
11. Disappointing results of symptomatic treatment
12. Severity of chronic Lyme disease
III Diagnostic concerns
13. Atypical early presentations
14. Chronic Lyme disease presentations
15. The limitations of physical findings
16. Sensitivity limitations of testing
17. Seronegative Lyme disease
18. Importance of differential diagnosis
19. Clinical judgment
20. Testing for coinfection
IV Treatment considerations
21. Prompt use of an antibiotic
22. Choosing an antibiotic
23. Oral antibiotic options
24. Intravenous option
25. Intramuscular option
26. Combination antibiotic treatment
27. Sequential treatment
28. Dosage
29. Duration of therapy
30. Empiric treatment
31. Persistent Lyme disease
32. Recurrent Lyme disease
33. Refractory Lyme disease
34. Treatment failure
35. Symptomatic treatment
36. Fibromyalgia
37. Decision to stop antibiotics
38. Alternative antibiotics
39. Therapy for coinfection
V Research needs
40. Ongoing development of guidelines
41. Validation of guidelines
42. Comparative studies
VI Periodic review of guidelines
43. Grading system for evidence-based guidelines
44. Table 1: Comparison of key IDSA and ILADS guidelines
45. Criteria for evidence-based guidelines
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Section I: Introduction to guidelines
The IDSA's symptomatic approaches to Lyme disease are This report, completed in November 2003, is intended to limited and exclude many individuals with persisting clinical serve as a resource for physicians, public health officials and and laboratory evidence of active B. burgdorferi infection. In organizations involved in the evaluation and treatment of addition, physicians treating individuals with Lyme and other Lyme disease.
tick-borne infections recognize the need for new guidelines tobetter serve the patient population [6].
1. International Lyme and Associated Diseases Society (ILADS)
Previous guidelines for management of Lyme disease have ILADS is an interdisciplinary organization of health science been published in the New England Journal of Medicine in professionals established in 1999 to accomplish the following 1990 by Rahn [7]; in Conn's Current Therapy in 1997 by Bur- rascano and in 1998 by Steere [8,9]; in Burrascano's Guidelines • Analyze the medical literature, position statements and on the ILADS website (www.ilads.org); and in the Journal of practice parameters related to Lyme and associated diseases Infectious Diseases by Wormser and colleagues in 2000 [6]. TheILADS Guidelines expand on these protocols using the evi- • Improve the management of these diseases through evaluation dence-based approach and Cochrane methodology employed of established and innovative therapies by the IDSA [6,10].
• Educate a broad range of healthcare providers and serve as Our goal is to present practitioners with practical and defen- an effective advocate for clinicians seeking cost-effective sible guidelines for treating all individuals with Lyme disease state-of-the-art treatment regimens including those with persistent, recurrent and relapsing ILADS identified the need for new and expanded guide- symptoms of B. burgdorferi infection.
lines for the diagnosis and treatment of Lyme and associated The ILADS Guidelines focus on which patients to evaluate, diseases. In 2001, a working party was formed to evaluate what tests to order, what antibiotics to use and what steps to take current practices and to encourage new standards of care.
to ensure that concerns over antibiotic use are addressed.
This report, completed in November 2003, is intended to The ILADS Working Group that formulated these guidelines serve as a resource for physicians, public health officials and included primary care clinicians, researchers, community health- organizations involved in the evaluation and treatment of care providers and patient advocates. In developing these treatment Lyme disease.
guidelines, the group considered factors such as incidence of Lymedisease; severity of disease in terms of morbidity; comorbidities and 2. Chronic Lyme disease: a growing epidemic
determinants of when Lyme disease is most likely to become The Centers for Disease Control and Prevention (CDC) chronic; feasibility, efficacy and cost of antibiotic treatment; impact consider Lyme disease the fastest growing vector-borne dis- of antibiotic therapy on quality of life, including adverse drug ease in the USA. By conservative estimate, the number of events; and the potential for drug resistance to develop.
new Lyme disease infections per year may be ten times Because of the complexity and variability of Lyme disease higher than the 17,730 cases reported to the CDC during symptoms, the guidelines are flexible. Treatment depends on the severity of each case, the patient's response to therapy and The prevalence of chronic Lyme disease ranges from 34% in the physician's own clinical judgment.
a population-based, retrospective cohort study [3] to 62% in aspecialty clinic located in an area endemic for Lyme disease [4].
4. A problem of definitions
Clinic patients presented with arthralgia, arthritis, cardiac and Lyme disease was initially investigated by CDC epidemiologists neurologic symptoms [4].
focusing on erythema migrans, heart block, meningitis and arthri- A widening array of chronic presentations is associated with tis. The ELISA test and later, the western blot, were introduced for the Lyme spirochete, Borrelia burgdorferi. There are great chal- seroepidemiologic studies. Chronic, persistent, recurrent and lenges in determining optimal cost-effective means for appropri- refractory Lyme disease were not included in these studies; ate diagnosis, clinical management and public health control of consequently cases of chronic Lyme disease still go unrecognized.
Lyme disease throughout the world. Additional problems include For the purpose of the ILADS guidelines, ‘chronic Lyme dis- the identification and management of tickborne coinfections ease' is inclusive of persistent symptomatologies including including Ehrlichia, Babesia and Bartonella species [5].
fatigue, cognitive dysfunction, headaches, sleep disturbanceand other neurologic features, such as demyelinating disease, 3. The need for new guidelines
peripheral neuropathy and sometimes motor neuron disease; Guidelines of the Infectious Disease Society of America neuropsychiatric presentations; cardiac presentations including (IDSA) fall short of meeting the needs for diagnosis and electrical conduction delays and dilated cardiomyopathy; and treatment of individuals with chronic Lyme disease [6]. The musculoskeletal problems. Symptoms may continue despite 30 latest IDSA Guidelines (2000) fail to take into account the days of treatment (persistent Lyme disease). The patient may compelling, peer-reviewed, published evidence confirming relapse in the absence of another tickbite or erythema migrans persistent, recurrent and refractory Lyme disease and, in rash (recurrent Lyme disease), or be poorly responsive to antibiotic fact, deny its existence [6].
treatment (refractory Lyme disease).
Expert Rev. Anti-infect. Ther. 2(1), (2004) ILADS guidelines for Lyme disease
By these definitions, almost two-thirds of 215 Lyme disease 8. Symptomatic presentation
patients in a recent retrospective cohort from an endemic Variable symptomatic presentations have been increasingly doc- region had chronic Lyme disease [4]. Case definitions for Lyme umented in Lyme disease, with the best example being enceph- disease have evolved and will continue to develop as a better alopathy [12]. Encephalopathic presentations were described in understanding of chronic Lyme disease emerges to shape a an initial cohort of 27 patients as a symptom complex includ- common lexicon.
ing memory loss (81%), fatigue (74%), headache (48%),depression (37%), sleep disturbance (30%) and irritability 5. Competency and training
(26%), often without objective markers [12]. Only two of the 27 The appropriateness of treatment hinges on the clinician's expe- patients presented with objective findings on lumbar puncture: rience in treating Lyme disease. Competence requires diagnos- one had pleocytosis (seven cells) and a second had an antibody tic and treatment skills heretofore not offered in medical school index of greater than one [12].
or postresidency training.
Neuropsychiatric presentations in acute and chronic Lyme Clinicians more practiced in treating Lyme disease achieve disease have been increasingly recognized and can include better outcomes and encounter fewer complications because of depression, anxiety and rage [13]. These are presumably related an enhanced ability to interpret clinical data, the prompt pre- to persistent infection and are potentially reversible with anti- scription of antibiotics and the use of measures to reduce biotics. Neuropsychiatric symptoms may reflect additional adverse events, e.g., employing acidophilus to replace normal psychosocial processes including the stress of coping with a intestinal flora that is depleted by antibiotics.
chronic illness.
Asch and colleagues found that more than half of 215 6. The increasing role of primary care
patients in a Lyme-endemic region had symptomatic presenta- The primary care physician has an important role as the first tions of chronic Lyme disease [4]. The patients presented with and at times, the principal medical contact for the person with chronic fatigue, headaches and joint pain (but not headaches Lyme disease.
alone) in this retrospective cohort study.
Primary care physicians focus on the resolution of symptoms, monitoring for side effects, maintenance or improvement of 9. Symptoms of Lyme disease
functional status and prevention of recurrent symptoms.
These guidelines incorporate the evidence used by primary • Low grade fevers, ‘hot flashes' or chills care physicians for the care of patients with Lyme disease.
• Night sweats• Sore throat 7. Highlights of guidelines
• Since there is currently no definitive test for Lyme disease,
• Swollen glands laboratory results should not be used to exclude an individual • Migrating arthralgias, stiffness and, less commonly, frank • Lyme disease is a clinical diagnosis and tests should be used to support rather than supersede the physician's judgment • The early use of antibiotics can prevent persistent, recurrent • Chest pain and palpitations and refractory Lyme disease • Abdominal pain, nausea • The duration of therapy should be guided by clinical response, rather than by an arbitrary (i.e., 30 day) treatment • Sleep disturbance • Poor concentration and memory loss • The practice of stopping antibiotics to allow for delayed • Irritability and mood swings recovery is not recommended for persistent Lyme disease. In these cases, it is reasonable to continue treatment for several months after clinical and laboratory abnormalities • Blurred vision and eye pain have begun to resolve and symptoms have disappeared Section II: New presentatons
• Testicular/pelvic pain Lyme disease was first described in 1977 as ‘Lyme arthritis' among patients initially thought to have arthritis or juvenile rheumatoid arthritis [11]. It was later renamed ‘Lyme disease' • Cranial nerve disturbance (facial numbness, pain, tingling, following recognition of a combination of cardiac, neurologic palsy or optic neuritis) and rheumatologic presentations, including heart block, men- ingitis and Bell's palsy. For more than 10 years, variable symp-tomatic conditions have been recognized including encepha- • ‘Lightheadedness' lopathy and neuropsychiatric presentations.
The International Lyme and Associated Diseases Society
10. Increasing evidence of persistent infection
Lyme disease was worse than that of patients with Type 2 dia- Persistent, recurrent and refractory presentations from ongoing betes or a recent heart attack, and equivalent to that of patients infection are the most feared of the long-term complications of with congestive heart failure or osteoarthritis. Moreover, the Lyme disease.
average Lyme disease duration of 4.7 years in subjects enrolling Laboratory culture of B. burgdorferi has documented per- in the study emphasized the chronic nature of the condition.
sistent infection in chronic Lyme disease patients, but the Finally, the failure of 1 month of i.v. ceftriaxone followed by yields are quite low by current methods [14]. In fact, there is 2 months of oral doxycycline delineated the potential for a poor no reliable, commercially available culture assay that can outcome in chronic Lyme disease [25].
confirm the eradication of the organism. Using experimentaltechniques, however, B. burgdorferi has been detected in vir- Section III: Diagnostic concerns
tually every organ in the body, and the spirochete has a The most important method for preventing chronic Lyme disease strong predilection for the central nervous system. Oral is recognition of the early manifestations of the disease.
antibiotic levels in the central nervous system are low, andthis fact may necessitate the addition of drugs with good 13. Atypical early presentations
penetration across the blood–brain barrier [15], such as Early Lyme disease classically presents with a single erythema intravenous ceftriaxone or cefotaxime.
migrans (EM or ‘bullseye') rash. The EM rash may be absent Most studies demonstrate a beneficial effect of antibiotics in in over 50% of Lyme disease cases, however [25]. Patients the management of chronic Lyme disease, but the extent of should be made aware of the significance of a range of rashes optimal treatment is still uncertain [4,12,13,16–22]. Recent clinical beyond the classic EM, including multiple, flat, raised or blis- trials questioning the benefits of antibiotics have been criti- tering rashes. Central clearing was absent in over half of a cized for enrolling patients with refractory Lyme disease who series of EM rashes [26]. Rashes can also mimic other common were sick for a mean of 4.7 years despite an average of three presentations including a spider bite, ringworm, or cellulitis.
courses of antibiotics, and for relying only on one treatment One series of eleven EM rashes was misdiagnosed and treated protocol (1 month of i.v. ceftriaxone followed by 2 months of as cellulitis, with all eleven patients showing clinical evidence low-dose oral doxycycline) [23]. In view of these methodologi- of Lyme disease progression [27].
cal problems, persistent infection remains a continued concern Physicians should be aware that fewer than 50% of all Lyme for physicians.
disease patients recall a tickbite [28]. Early Lyme disease should alsobe considered in an evaluation of ‘off-season' onset when flu-like 11. Disappointing results of symptomatic treatment
symptoms, fever and chills occur in the summer and fall. Early A theoretical immune mechanism has been proposed to recognition of atypical early Lyme disease presentation is most explain persistent symptoms in chronic Lyme disease, but no likely to occur when the patient has been educated on this topic.
clinical or laboratory test can confirm this theory. Theimmune mechanism theory is based on physiological events 14. New chronic Lyme disease presentations
(often in the form of cascades) that are not reversed by simply A detailed history may be helpful for suggesting a diagnosis of killing the infecting organism.
chronic Lyme disease. Headache, stiff neck, sleep disturbance The presentation of chronic Lyme disease can be identical and problems with memory and concentration are findings fre- to that of other multisystem disorders, including systemic quently associated with neurologic Lyme disease. Other clues to lupus erythematosus, rheumatoid arthritis and fibromyalgia.
Lyme disease have been identified, although these have not In the seminal article describing fibromyalgia in a Lyme dis- been consistently present in each patient: numbness and tin- ease population, antibiotic treatment failure and relapse of gling, muscle twitching, photosensitivity, hyperacusis, tinnitus, symptoms were considered to be proof of the absence of lightheadedness and depression.
B. burgdorferi infection, and persistent symptoms were Most patients diagnosed with chronic Lyme disease have an assumed to be due to postinfectious sequelae [24]. However, indolent onset and variable course. Neurologic and rheumatologic the failure of short-course (2–4 week) antibiotic treatment in symptoms are characteristic, and increased severity of symptoms 14 (94%) of 15 fibromyalgia patients is consistent with a per- on wakening is common. Neuropsychiatric symptoms alone are sistent, inadequately treated infection with B. burgdorferi [24].
more often seen in chronic than acute Lyme disease. Although The increasing successes of repeated and prolonged antibiotic many studies have found that such clinical features are often not treatment in chronic Lyme disease are more consistent with a unique to Lyme disease, the striking association of musculoskeletal persistent infection mechanism.
and neuropsychiatric symptoms, the variability of these symptomsand their recurrent nature may support a diagnosis of the disease.
12. Severity of chronic Lyme disease
For patients with chronic Lyme disease, the quality of life has
15. The limitations of physical findings
been evaluated in a clinical trial sponsored by the National A comprehensive physical examination should be performed, Institutes of Health (NIH) using a standardized questionnaire with special attention to neurologic, rheumatologic and cardiac [23]. The quality of life of the 107 individuals with chronic symptoms associated with Lyme disease.
Expert Rev. Anti-infect. Ther. 2(1), (2004) ILADS guidelines for Lyme disease
Physical findings are nonspecific and often normal, but arthritis, Although many individuals do not have confirmatory sero- meningitis and Bell's palsy may sometimes be noted. Available data logic tests, surveillance studies show that these patients may suggest that objective evidence alone is inadequate to make treat- have a similar risk of developing persistent, recurrent and ment decisions, because a significant number of chronic Lyme dis- refractory Lyme disease compared with the seropositive popula- ease cases may occur in symptomatic patients without objective tion. A prospective observational study of 1094 patients [21] and features on examination or confirmatory laboratory testing.
the Klempner clinical trials [23] found no difference in meas- Factors other than physical findings, such as a history of ured outcomes (e.g., success of retreatment) among seropositive potential exposure, known tickbites, rashes or symptoms con- or seronegative Lyme disease patients.
sistent with the typical multisystem presentation of Lymedisease, must also be considered in determining whether an 18. Continued importance of differential diagnosis
individual patient is a candidate for antibiotic therapy.
The differential diagnosis of Lyme disease requires consider-ation of both infectious and noninfectious etiologies.
16. Sensitivity limitations of testing
Among noninfectious causes are thyroid disease, degenera- Treatment decisions should not be based routinely or exclusively tive arthritis, metabolic disorders (vitamin B12 deficiency, dia- on laboratory findings [2,25]. The two-tier diagnostic criteria, betes), heavy metal toxicity, vasculitis and primary psychiatric requiring both a positive ELISA and western blot, lacks sensitivity and leaves a significant number of individuals with Lyme disease Infectious causes can mimic certain aspects of the typical undiagnosed and untreated [29,30]. These diagnostic criteria were multisystem illness seen in chronic Lyme disease. These include intended to improve the specificity of tests to aid in identifying viral syndromes such as parvovirus B19 or West Nile virus well-defined Lyme disease cases for research studies [31]. Though infection, and bacterial mimics such as relapsing fever, syphilis, arbitrarily chosen, these criteria have been used as rigid diagnostic leptospirosis and mycoplasma.
benchmarks that have prevented individuals with Lyme disease The clinical features of chronic Lyme disease can be indistin- from obtaining treatment. Diagnosis of Lyme disease by two-tier guishable from fibromyalgia and chronic fatigue syndrome.
confirmation fails to detect up to 90% of cases and does not These illnesses must be closely scrutinized for the possibility of distinguish between acute, chronic, or resolved infection [21].
etiological B. burgdorferi infection.
The CDC considers a western blot positive if at least 5 of 10 IgG bands or 2 of 3 IgM bands are positive [31]. However, other 19. Clinical judgment
definitions for western blot confirmation have been proposed Clinical judgment remains necessary in the diagnosis of late to improve the test sensitivity [30,32–36]. In fact, several studies Lyme disease. A problem in some studies that relied on objec- showed that sensitivity and specificity for both the IgM and tive evidence was that treatment occurred too late, leaving the IgG western blot range from 92 to 96% when only two specific patient at risk for persistent and refractory Lyme disease.
bands are positive [34–36].
As noted, time-honored beliefs in objective findings and two- Lumbar puncture has also been disappointing as a diagnostic tier serologic testing have not withstood close scrutiny test to rule out concomitant central nervous system infection. In [21,30,34,37]. Lyme disease should be suspected in patients with Lyme disease, evaluation of cerebrospinal fluid is unreliable for a newly acquired or chronic symptoms (headaches, memory and diagnosis of encephalopathy and neuropathy because of poor concentration problems and joint pain). Management of sensitivity (see Section II.8). For example, pleocytosis was present patients diagnosed on the basis of clinical judgment needs to be in only one of 27 patients (sensitivity 3%) and with only seven tested further in prospective trials, and diagnostic reproducibility cells [12]. The antibody index was positive (>1) in only one of 27 must be verified.
patients (sensitivity 3%) [12]. An index is the ratio between LymeELISA antibodies in the spinal fluid and Lyme ELISA antibodies 20. Testing for coinfection
in the serum. The proposed index of 1.3 would be expected to Polymicrobial infection is a new concern for individuals with have even worse sensitivity.
Lyme disease, and coinfection is increasingly reported in criti- Several additional tests for Lyme disease have been evaluated.
cally ill individuals [25,38]. Although B. burgdorferi remains the These include antigen capture, urine antigen and polymerase most common pathogen in tickborne illnesses, coinfections chain reaction. Each has advantages and disadvantages in terms including Ehrlichia and Babesia strains are increasingly noted of convenience, cost, assay standardization, availability and reli- in patients with Lyme disease, particularly in those with ability. These tests remain an option to identify people at high chronic illness. Bartonella is another organism that is carried risk for persistent, recurrent and refractory Lyme disease but by the same ticks that are infected with B. burgdorferi, and have not been standardized.
evidence suggests that it is a potential coinfecting agent inLyme disease [25].
17. Seronegative Lyme disease
Recent animal and human studies suggest that Lyme disease A patient who has tested seronegative may have a clinical pres- may be more severe and resistant to therapy in coinfected entation consistent with Lyme disease, especially if there is no patients [25,38]. Thus, concurrent testing and treatment for evidence to indicate another illness.
coinfection is mandatory in Lyme disease patients.
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Section IV: Treatment considerations
24. Intravenous antibiotic options
Since Lyme disease can become persistent, recurrent and It is common practice to consider intravenous antibiotics refractory even in the face of antibiotic therapy, evaluation upon failure of oral medications in patients with persistent, and treatment must be prompt and aggressive.
recurrent or refractory Lyme disease, and as the first line oftherapy for certain conditions, (i.e., encephalitis, meningitis, 21. Prompt use of antibiotics
optic neuritis, joint effusions and heart block).
Although no well designed studies have been carried out, the Ideally, the intravenous antibiotic should be selected on the available data support the prompt use of antibiotics to prevent basis of in vitro sensitivity testing or clinical experience [101].
chronic Lyme disease. Antibiotic therapy may need to be initi- Intravenous antibiotics are also justified by concern for penetra- ated upon suspicion of the diagnosis, even without definitive tion into the central nervous system [15].
proof. Neither the optimal antibiotic dose nor the duration of Until recently, ceftriaxone, cefotaxime and penicillin were therapy has been standardized, but limited data suggest a bene- the only intravenous antibiotics routinely studied for use in fit from increased dosages and longer treatment, comparable to Lyme disease. Intravenous imipenem, azithromycin and doxy- the data on tuberculosis and leprosy which are caused by simi- cycline have an adequate antispirochetal spectrum of activity larly slow-growing pathogens [25].
and may represent suitable alternative therapies. However, thelatter two drugs are often considered for intravenous use only 22. Choosing an antibiotic
if they are not tolerated orally.
In acute Lyme disease, the choice of antibiotics should be tai- There is a paucity of data on alternative intravenous antibiotics, lored to the individual and take into account the severity of the and their success is less predictable in chronic Lyme disease.
disease as well as the patient's age, ability to tolerate side effects,clinical features, allergy profile, comorbidities, prior exposure, 25. Intramuscular antibiotic options
epidemiologic setting and cost.
Intramuscular benzathine penicillin (1.2 to 2.4 million units Conversely, persistent and refractory Lyme disease treatment per week) is sometimes effective in patients who do not is more likely to include intravenous and/or intramuscular anti- respond to oral and intravenous antibiotics. If intramuscular biotics. The choices depend in part on the patient's response to benzathine penicillin is used, long-term therapy may be nec- antibiotic therapy and on the success of antibiotics in treating essary due to the low serum concentration of this form of other Lyme disease patients (see below).
penicillin [46]. Luft and colleagues report, "It was demon- Therapy usually starts with oral antibiotics, and some experts strated that while B. burgdorferi may be sensitive to relatively recommend high dosages. The choice of antibiotic therapy is small concentrations of penicillin and ceftriaxone, the organ- guided by weighing the greater activity of intravenous antibiotics ism is killed slowly. This implies that, as in syphilis, pro- in the central nervous system against the lower cost and easy longed blood levels of these drugs may be necessary in order administration of oral antibiotics for B. burgdorferi.
to ensure cure" [46].
One-third of a chronic Lyme disease population responded 23. Oral antibiotic options
to intramuscular benzathine penicillin (1.2 to 2.4 million For many Lyme disease patients, there is no clear advantage of units per week) [16–18]. Benzathine penicillin has mainly been parenteral therapy. Along with cost considerations and pressure used in patients who have had multiple relapses while receiv- to treat patients with Lyme disease with the least intervention, ing oral or intravenous antibiotic therapy or who are intoler- there is growing interest in the use of oral therapy.
ant of oral or intravenous antibiotics.
First-line drug therapies for Lyme disease may include (in alphabetical order): oral amoxicillin, azithromycin [39–41], 26. Combination antibiotic treatment
cefuroxime [42], clarithromycin [43], doxycycline and tetracy- Combination therapy with two or more antibiotics is now cline. These antibiotics have similar favorable results in com- increasingly used for refractory Lyme disease [11,41,45,46–49] parative trials of early Lyme disease. In one study, azithromy- and has also been given as initial therapy for some chronic cin performed slightly less well when compared to amoxicillin and doxycycline. However, the efficacy of azithromycin was This approach is already used for another tickborne illness, underestimated because the antibiotic was only given for babesiosis [50]. Oral amoxicillin, cefuroxime or (more 10 days [39].
recently) cefdinir combined with a macrolide (azithromycin One study has suggested that oral doxycycline (100 mg twice or clarithromycin) are examples of combination regimens that daily for 30 days) is as effective as intravenous ceftriaxone (2 g have proven successful in clinical practice, although control- daily for 30 days) in early disseminated Lyme disease [40]. Two led clinical trials are lacking in persistent, recurrent and European studies have demonstrated similar efficacy of oral refractory Lyme disease.
doxycycline and parenteral penicillin and ceftriaxone in early Combination therapy in patients with Lyme disease raises the Lyme disease [44,45].
risk of adverse events. This risk must be weighed against the There are no studies comparing oral with intravenous antibiotics improved response to combination therapy in Lyme disease for persistent, recurrent and refractory Lyme disease.
patients failing single agents [47–49].
Expert Rev. Anti-infect. Ther. 2(1), (2004) ILADS guidelines for Lyme disease
27. Sequential treatment
30. Empiric treatment
Clinicians increasingly use the sequence of an intravenous anti- The importance of establishing the diagnosis of Lyme disease is biotic followed by an oral or intramuscular antibiotic heightened in light of increasing concern about antibiotic over- [19,37,101,47,48]. In two recent case series that employed combina- use. After an appropriate history, physical examination and lab- tion therapy and sequential therapy, most patients were success- oratory testing are completed, empiric antimicrobial therapy fully treated [19,47]. A logical and attractive sequence would be should be initiated on the basis of clinical clues, the severity of to use intravenous therapy first (e.g., intravenous ceftriaxone), the patient's acute illness, underlying disease and the likelihood at least until disease progression is arrested and then follow with of B. burgdorferi infection. The ILADS working group recom- oral therapy for persistent and recurrent Lyme disease.
mends that empiric treatment be considered routine forpatients with a likely diagnosis of Lyme disease.
28. Dosage
Increasingly, clinicians recommend that certain drugs used for
31. Persistent Lyme disease
Lyme disease be given at higher daily doses: for example, Persistent Lyme disease is more resistant to treatment and more 3000–6000 mg of amoxicillin, 300–400 mg doxycycline and likely to produce a relapse. Although persistent Lyme disease may 500–600 mg of azithromycin. Some clinicians prescribe antibi- resolve without additional therapy, many experts believe that this otics using blood levels to guide higher doses. Close monitoring condition should be treated with repeated and prolonged antibiot- of complete blood counts and chemistries are also required with ics. Physicians should extend the duration of antibiotics to prevent this approach.
or delay recurrent and refractory Lyme disease.
With higher doses, there may be an increase in adverse events in general and gastrointestinal problems in particular. Acido- 32. Recurrent Lyme disease
philus has reportedly reduced the incidence of C. difficile colitis Despite previous antibiotic treatment, Lyme disease has a pro- and non-C. difficile antibiotic-related diarrhea.
pensity for relapse and requires careful follow-up for years. The Serious adverse effects of antibiotics, however, were less com- data suggest that failure to eradicate the organism may be the mon than previous estimates. In a recent clinical trial of chronic reason for a recurrence of symptoms [12]. Early and aggressive Lyme disease, the overall serious adverse event rate was 3% after treatment with antibiotics is indicated for recurrent Lyme dis- three months of antibiotics, including 1 month of intravenous ease. The ultimate impact from retreating each episode of antibiotics [23]. Clinicians who have experience with higher- recurrent Lyme disease is currently unclear.
dose antibiotic therapy must balance the benefit of higher druglevels achieved with this therapy against the modest risk of 33. Refractory Lyme disease
gastrointestinal and other side effects.
Refractory Lyme disease is a devastating condition that usually Research is needed to determine the added benefits of higher affects patients with persistent symptomatology and long-term doses of antibiotics in chronic Lyme disease.
disability. Prompt and aggressive institution of antibiotic ther-apy may be essential to prevent refractory disease. Increasing 29. Duration of therapy
evidence shows that antibiotics have a beneficial effect on the Because of the disappointing long-term outcome with shorter course of refractory Lyme disease even in cases where the courses of antibiotics, the practice of stopping antibiotics to patient is intolerant of antibiotics or when a previous regimen allow for a delayed recovery is no longer recommended for has failed. Several months of therapy are often required to pro- patients with persistent, recurrent and refractory Lyme disease.
duce clear evidence of improvement. During this time, sympto- Reports show failure rates of 30–62% within 3 years of short- matic treatment may be combined with antibiotic treatment.
course treatment using antibiotics thought to be effective forLyme disease [3,4,12]. Conversely for neurologic complications of 34. Treatment failure
Lyme disease, doubling the length of intravenous ceftriaxone When patients fail to respond or their conditions deteriorate after treatment from 2 to 4 weeks improved the success rate from 66 initiation of empiric therapy, a number of possibilities should be to 80% [12,51].
considered other than Jarisch-Herxheimer reaction. These include The management of chronic Lyme disease must be individual- adverse events that limit treatment, allergic history to medication, ized, since patients will vary according to severity of presentation inappropriate or inadequate dosing regimen, compliance prob- and response to previous treatment.
lems, incorrect medication, immune sequelae and sequestering of Concurrent risk factors (i.e., coinfections, previous treat- the organism (e.g., in the central nervous system). An alternative ment failures, frequent relapses, neurologic involvement, or diagnosis or coinfection should also be considered.
previous use of corticosteroids) or evidence of unusuallysevere Lyme disease should lead to the initiation of prolonged 35. Symptomatic treatment
and/or intravenous antibiotic treatment. Physicians should Although there may be a potential role for symptomatic treat- always assess the patient's response to treatment before decid- ment in chronic Lyme disease, this approach has little support ing on appropriate duration of therapy (i.e., weeks due to the strong possibility of persistent infection. Owing to the versus months).
potential hazard of immunosuppression and the poor outcome in The International Lyme and Associated Diseases Society
one study, steroid therapy is not recommended [52]. Surgical The ideal approach would be to continue therapy for Lyme dis- synovectomy is associated with significant morbidity and does ease until the Lyme spirochete is eradicated. Unfortunately there is not address neurologic presentations; it should be reserved for currently no test available to determine this point [25]. Therefore, knee pain failing antibiotic treatment [53]. Intra-articular ster- the clinician must rely on the factors outlined above to decide on oid injection may be useful as a temporizing procedure in the length of antibiotic therapy for chronic Lyme disease.
patients with persistent knee pain but this runs the risk ofmasking persistent infection.
38. Alternative antibiotics
Symptomatic therapy (particularly anti-inflammatory medi- There is compelling evidence that Lyme disease can result in cations, tricyclic antidepressants, selective serotonin re-uptake serious and potentially refractory illness. Use of alternative anti- inhibitors and hydroxychloroquine) may be useful in concert biotics to treat early Lyme disease with erythema migrans is with antibiotics and in individuals failing antibiotics.
generally not indicated unless coinfection is suspected.
Hyperbaric oxygen therapy (HBOT) is under study but is The ILADS Working Group believes that the risk of alterna- not recommended for routine therapeutic use [25,54]. Other tive antibiotics is acceptable in selected Lyme disease patients pre- treatments, including cholestyramine (CSM), antifungal senting with chronic Lyme disease. Alternative antibiotics therapy and antiviral agents require further study.
include less commonly used oral antibiotics (cefixime, cefdinir, Since patients are becoming more interested in alternative ther- metronidazole) and intravenous antibiotics (imipenem, azithro- apies (e.g., traditional Chinese medicine, anti-oxidants, hyper- mycin). The role of alternative antibiotics in low-risk patients is thermia, bee venom, naturopathy and homeopathy), physicians less certain and there is less consensus within the Working Group should be prepared to address questions regarding these topics.
as to whether the potential benefits outweigh the risks.
39. Therapy for coinfection
The outcome of treating fibromyalgia secondary to Lyme dis- Therapy for polymicrobial infection in Lyme disease is a rap- ease with nonantibiotic regimens has been poor. The most idly changing area of clinical practice [25]. Uncomplicated encouraging clinical trial showed success in only one of 15 Lyme disease may be managed without addressing coinfection patients and only modest improvement in 6 of 15 individuals by means of standard oral or parenteral antibiotic therapy.
with fibromyalgia despite 2 years of treatment [24].
Some but not all experts recommend therapy for subclinical Antibiotic therapy has been much more effective than sup- or chronic coinfection with Ehrlichia, Babesia or Bartonella on portive therapy in symptomatic patients with fibromyalgia the basis of their belief that responses are more prompt with secondary to Lyme disease.
this approach.
Fibromyalgia treatment alone without antibiotics raises the The dose, duration and type of treatment for coinfections risk of conversion to refractory chronic Lyme disease and/or have not been defined. Published reports of coinfection are lim- exacerbation of an undiagnosed persistent infection and is not ited to a small number of patients treated in open-label, non- recommended. Increasingly, clinicians do not feel comfortable randomized studies. Doxycycline has been indicated for Ehrli- treating fibromyalgia in Lyme disease without antibiotics.
chia. A recently published randomized trial determined thattreatment of severe Babesia microti with the combination of 37. Decision to stop antibiotics
atovaquone and azithromycin was as effective as the use of Several studies of patients with Lyme disease have recommended standard oral therapy with clindamycin and quinine [55].
that antibiotics be discontinued after 30 days of treatment. Com- The decision to use alternative antibiotics should be based plicating the decision to stop antibiotics is the fact that some on the individual case, including a careful assessment of the patients present with disease recurrence after the resolution of patient's risk factors and personal preferences. Patients man- their initial Lyme disease symptoms. This is consistent with aged in this way must be carefully selected and considered incomplete antibiotic therapy. Although the optimal time to dis- reliable for follow-up. Further controlled studies are needed continue antibiotics is unknown, it appears to be dependent on to address the optimal antimicrobial agents for coinfections the extent of symptomatology, the patient's previous response to and the optimal duration of therapy.
antibiotics and the overall response to therapy (see below).
Additional research is needed to determine which antibiotics Rather than an arbitrary 30-day treatment course, the work best for Bartonella, but fluoroquinolones, azithromycin, patient's clinical response should guide duration of therapy.
doxycycline and rifampin have good in vitro activity.
Patients must therefore be carefully evaluated for persistentinfection before a decision is made to withhold therapy.
Section V: Research needs
The decision to discontinue antibiotics should be made in The ILADS Working Group encourages centers that treat large consultation with the patient and should take into account numbers of Lyme disease patients symptomatically using IDSA such factors as the frequency and duration of persistent infec- treatment guidelines to perform a formal evaluation of their tion, frequency of recurrence, probability of refractory Lyme own programs. This will allow researchers to compare the disease, gains with antibiotics, the importance to the patient of results of treatment guidelines that use more antibiotics with discontinuing antibiotics and potential for careful follow-up.
those that do not.
Expert Rev. Anti-infect. Ther. 2(1), (2004) ILADS guidelines for Lyme disease
40. Ongoing development of treatment guidelines
43. Grading system for evidence-based guidelines
The IDSA guidelines recommending one-time short-term anti- The ILADS system for grading recommendations is similar biotic therapy have not been successful. Physician demands for to that used by the expert panel of the IDSA. However, the better outcomes have led to the development of the ILADS ILADS panel includes primary care clinicians, researchers guidelines, and the continued evolution of an evidence-based and international leaders in the treatment of Lyme disease.
approach is critical for the treatment of persistent, recurrent Thus, the ILADS group is more inclusive and clinically ori- and refractory Lyme disease.
ented than the IDSA panel, and the ILADS guidelines reflectthis diversity.
41. Validation of guidelines
Most studies of Lyme disease were retrospective, unblinded and
uncontrolled. Furthermore, the antibiotic dose and duration of
44. Table 1. Comparison of key IDSA and ILADS
therapy were not standardized.
The first double-blind clinical trial found that weekly benza- thine penicillin for 3 weeks was more effective than placebo for Lyme arthritis [56]. At the other end of the spectrum, a recentlycompleted randomized clinical trial failed to demonstrate any efficacy of 90 days of antibiotic therapy in previously treated patients with neurologic Lyme disease [23].
Two additional randomized trials are examining the practice Prolonged antibiotics of retreating chronic Lyme disease patients with antibiotics, and Benzathine penicillin these results should be available shortly [57,58]. The retreatment Intra-articular steroid approach is being validated using a single-center, prospectivesurveillance database.
Arthroscopic Synovectomy 42. Comparative studies
The IDSA and ILADS Guidelines differ substantially, revealing
Seronegative Lyme disease the wide variation in diagnosis and treatment (TABLE 1) [59,60].
Combination treatment This variation suggests that physicians do not use a uniformstrategy to diagnose and treat Lyme disease. Physicians often Empiric treatment treat for Lyme disease longer than 4 weeks and also retreat[8,19,47,48,57–62]. These decisions are made despite warnings 45. Criteria for evidence-based guidelines
against overdiagnosis and overtreatment [63–65].
The ILADS recommendations are based on two criteria [10]: Community-based clinicians and academic centers often • The strength of the evidence (denoted by categories A–E) have different criteria for diagnosis and divergent goals of care • The quality of the data (denoted by Roman numerals I–III) [8]. The guidelines and standards of practice used for diagnosisof Lyme disease in academic research settings may not be Recommendations rated ‘A' are considered good evidence to applicable or appropriate for community-based settings.
support the recommendation. Those rated ‘B' have moderate Moreover, the clinical manifestations of Lyme disease are evidence to support the recommendation. Those rated ‘C' are often subtle or atypical in the community.
considered optional. Measures designated ‘D' generally should Because important data concerning the treatment of chronic not be offered; those designated ‘E' are contraindicated.
Lyme disease was not considered by the IDSA expert panel, A rating of I indicates that at least one randomized controlled ILADS introduced an evidence-based review to determine which trial supports the recommendation; II, evidence from at least recommendations warranted revision. This evidence-based one well-designed clinical trial without randomization supports review gave rise to the current guidelines.
the recommendation; and III, ‘expert opinion'.
Section VI: Periodic review of guidelines
New data on treatment of Lyme disease is emerging, and Our data sources are English-language articles published from randomized controlled trials that address various unresolved 1975 to 2003. The selection panel synthesized the recom- issues in Lyme disease are ongoing. The ILADS Working mendations from published and expert opinion. Human Group has therefore developed a mechanism for routinely studies of Lyme disease were identified from MEDLINE and periodically reviewing this information and for updat- (1975 to 2003) and from references in pertinent articles and ing the guidelines on a regular basis. The most recent infor- reviews. Also included are abstracts and material presented at mation will be available from the ILADS website at professional meetings and the collective experience of the ILADS Working Group treating tens of thousands of Lymedisease patients. The International Lyme and Associated Diseases Society
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Source: http://www.ilads.org/lyme/ILADS_Guidelines.pdf

Meta: characterization of medical treatments at different abstraction levels

Politecnico di Torino Porto Institutional Repository [Article] MeTA: Characterization of medical treatments at different abstractionlevels Original Citation:Dario Antonelli; Elena Baralis; Giulia Bruno; Luca Cagliero; Tania Cerquitelli; Silvia Chiusano;Paolo Garza; Naeem A. Mahoto (2015). MeTA: Characterization of medical treatments at differentabstraction levels. In: vol. 6 n. 4, pp. 1-25. - ISSN 2157-6904

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th Biannual Meeting of the Hellenic (Greek) Society for Basic & Clinical Pharmacology Professor Arthur Christopoulos, B.Pharm., Ph.D., Drug Discovery, Monash University, Australia Today's science, tomorrow's medicines Athens 23-24 RegistrationYoung Investigators ForumChairs: Dr. E. Papadimitriou

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