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Clin Evid. 2004; 2004: 0910.
Published online 2004 August 1.
PMCID: PMC2907555

Lyme disease

Abstract

Introduction

Lyme disease is caused by infection with Borrelia burgdorferi transmitted by ticks in temperate areas, typically causing an expanding circular rash around the infectious tick attachment site. Early disseminated infection can cause neuropathies, meningitis, arthralgia and cardiac disease, although spontaneous resolution usually occurs over time. Untreated or inadequately treated Lyme disease can cause late disseminated infection, with arthritis, polyneuropathy and encephalopathy.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: what are the effects of measures to prevent Lyme disease? What are the effects of antibiotic treatment for Lyme disease arthritis? What are the effects of antibiotic treatments for late neurological Lyme disease? We searched: Medline, Embase, The Cochrane Library and other important databases up to September 2003 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 11 systematic reviews, RCTs or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: prophylactic antibiotic treatment of tick bite, treatment of Lyme disease arthritis with antibiotics, and treatment of late neurological Lyme disease with antibiotics.

Key Points

Lyme disease is caused by infection with Borrelia burgdorferi transmitted by ticks in temperate areas, typically causing an expanding circular rash around the infectious tick attachment site.

  • Early disseminated infection can cause neuropathies, meningitis, arthralgia and cardiac disease, although spontaneous resolution usually occurs over time.
  • Untreated or inadequately treated Lyme disease can cause late disseminated infection, with arthritis, polyneuropathy and encephalopathy.

Prophylactic antibiotics such as single dose doxycycline reduce the risk of developing early Lyme disease in people exposed to tick bites but increase the risk of adverse effects.

  • Limiting prophylactic treatment to people with engorged nymphal ticks may be the best strategy to maximise benefit and minimise harm from adverse effects.

In people with Lyme arthritis, penicillin increases resolution of symptoms compared with placebo.

  • Cefotaxime and ceftriaxone may improve symptoms compared with penicillin, but few good quality studies have been found.
  • Doxycycline may be as effective as amoxicillin plus probenecid at improving symptoms of Lyme arthritis.

In people with late neurological Lyme disease, cefotaxime may be more effective than penicillin at improving symptoms, but we don't know whether ceftriaxone is also beneficial.

  • Ceftriaxone may be no more effective than placebo at improving cognitive functioning in people with late neurological Lyme disease who had received prior treatment.
  • Ceftriaxone plus doxycycline has not been shown to improve health related quality of life in people with late neurological Lyme disease who have previously received treatment.

About this condition

Definition

Lyme disease is an inflammatory illness resulting from infection with spirochetes of the Borrelia burgdorferi genospecies transmitted to humans by ticks. Some infected people have no symptoms. The characteristic manifestation of early Lyme disease is erythema migrans: a circular rash at the site of the infectious tick attachment that expands over a period of days to weeks in 80-90% of people with Lyme disease. Early disseminated infection may cause secondary erythema migrans, disease of the nervous system (facial palsy or other cranial neuropathies, meningitis, and radiculoneuritis), musculoskeletal disease (arthralgia), and, rarely, cardiac disease (myocarditis or transient atrioventricular block). Untreated or inadequately treated Lyme disease can cause late disseminated manifestations weeks to months after infection. These late manifestations include arthritis, polyneuropathy, and encephalopathy. Diagnosis of Lyme disease is based primarily on clinical findings and a high likelihood of exposure to infected ticks. Serological testing is helpful in people with endemic exposure who have clinical findings consistent with later stage disseminated Lyme disease.

Incidence/ Prevalence

Lyme disease occurs in temperate regions of North America, Europe, and Asia. It is the most commonly reported vector borne disease in the USA, with over 23 000 cases reported a year. Most cases occur in the north-eastern and north-central states, with a reported annual incidence in endemic states as high as 133/100 000 people. In highly endemic communities, the incidence of Lyme disease may exceed 1000/100 000 people a year. In some countries of Europe, the incidence of Lyme disease has been estimated to be over 100/100 000 people a year. Foci of Lyme disease have been described in northern forested regions of Russia, in China, and in Japan. Transmission cycles of B burgdorferi have not been described in tropical areas or in the southern hemisphere.

Aetiology/ Risk factors

Lyme disease is caused by infection with any of the B burgdorferi sensu lato genospecies. Virtually all cases of Lyme disease in North America are the result of infection with B burgdorferi. In Europe, Lyme disease may be caused by B burgdorferi, B garinii, or B afzelii. The infectious spirochetes are transmitted to humans through the bite of certain Ixodes ticks. Humans who have frequent or prolonged exposure to the habitats of infected Ixodes ticks are at highest risk of acquiring Lyme disease. Individual risk depends on the likelihood of being bitten by infected tick vectors, which varies with the density of vector ticks in the environment, the prevalence of infection in ticks, and the extent of a person's contact with infected ticks. The risk of Lyme disease is often concentrated in focal areas. In the USA, risk is highest in certain counties within north-eastern and north-central states during the months of April to July. People become infected when they engage in activities in wooded or bushy areas that are favourable habitats for ticks, and deer and rodent hosts. A vaccine based on recombinant outer surface protein Osp-A was licensed for use in the USA but later removed from the market.

Prognosis

Lyme disease is rarely fatal. Untreated Lyme arthritis resolves at a rate of 10-20% a year; over 90% of facial palsies due to Lyme disease resolve spontaneously, and most cases of Lyme carditis resolve without sequelae. However, untreated Lyme disease can result in arthritis (50% of untreated people), meningitis or neuropathies (15% of untreated people), carditis (5-10% of untreated people with erythema migrans), and, rarely, encephalopathy.

Aims of intervention

To prevent Lyme disease; to ameliorate or eliminate the symptoms of established Lyme disease; to reduce sequelae, with minimal adverse effects.

Outcomes

For prophylaxis: incidence of Lyme disease, adverse events. For treatment: incidence, prevalence, or severity of symptoms and signs of short term manifestations; long term sequelae of infection; quality of life.

Methods

Clinical Evidence search and appraisal September 2003. Additional searches of authors' files. We search for comparisons of all antibiotics versus placebo and versus each other and have reported RCTs of sufficient quality that we found. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table
GRADE evaluation of interventions for Lyme disease

Glossary

Jarisch-Herxheimer reaction
An inflammatory reaction in tissues induced by antibiotic treatment of spirochetal diseases, and believed to be caused by an immunological reaction to the release of spirochetal antigens.
Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Neuroborreliosis
Central or peripheral neuropathy resulting from infection with Borrelia sp spirochetes.
Very low-quality evidence
Any estimate of effect is very uncertain.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

References

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2. O'Connel S, Granstorm M, Gray JS, et al. Epidemiology of European Lyme borreliosis. Zentralbl Bakteriol 1998;287:229–240. [PubMed]
3. Dennis DT. Epidemiology, ecology, and prevention of Lyme disease. In: Rahn DW, Evans J, eds. Lyme disease Philadelphia: American College of Physicians, 1998:7–34.
4. Rahn DW, Evans J, eds. Lyme disease Philadelphia: American College of Physicians, 1998.
5. Warshafsky S, Nowakowski J, Nadelman RB, et al. Efficacy of antibiotic prophylaxis for prevention of Lyme disease. J Gen Intern Med 1996;11:329–333. Search date 1995; primary sources Medline and hand searches of reference lists for English language papers. [PubMed]
6. Nadelman RB, Nowakowski J, Fish D, et al. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med 2001;345:79–84. [PubMed]
7. Costello CM, Steere AC, Pinkerton RE, et al. A prospective study of tick bites in an endemic area for Lyme disease. J Infect Dis 1989;159:136–139. [PubMed]
8. Shapiro ED, Gerber MA, Holabird NB, et al. A controlled trial of antimicrobial prophylaxis for Lyme disease after deer-tick bites. N Engl J Med 1992;327:1769–1773. [PubMed]
9. Agre F, Schwartz R. The value of early treatment of deer tick bites for the prevention of Lyme disease. Am J Dis Children 1993;147:945–947. [PubMed]
10. Steere AC, Green J, Schoen RT, et al. Successful parenteral penicillin therapy of established Lyme arthritis. N Engl J Med 1985;312:869–874. [PubMed]
11. Steere AC, Levin RE, Molloy PJ, et al. Treatment of Lyme arthritis. Arthritis Rheum 1994;37:878–888. [PubMed]
12. Dattwyler RJ, Halperin JJ, Volkman DJ, et al. Treatment of late Lyme borreliosis — randomized comparison of ceftriaxone and penicillin. Lancet 1998;1:1191–1194. [PubMed]
13. Oksi J, Nikoskelainen J, Vijanen MK. Comparison of oral cefixime and intravenous ceftriaxone followed by oral amoxicillin in disseminated Lyme borreliosis. Eur J Clin Microbiol Infect Dis 1998;17:715–719. [PubMed]
14. Hassler D, Zoller M, Haude H-D, et al. Cefotaxime versus penicillin in the late stage of Lyme disease — prospective, randomized therapeutic study. Infection 1990;18:16–20. [PubMed]
15. Klempner MS, Hu LT, Evans J, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 2001;345:85–92. [PubMed]
16. Kaplan RF, Trevino RP, Johnson GM, et al. Cognitive function in post-treatment Lyme disease: do additional antibiotics help? Neurology 2003;60:1916–1922. [PubMed]
17. Pfister H-W, Preac-Mursic V, Wilske B, et al. Randomized comparison of ceftriaxone and cefotaxime in Lyme neuroborreliosis. J Infect Dis 1991;163:311–318. [PubMed]
18. Ettestad PJ, Campbell GL, Welbel SF, et al. Biliary complications in the treatment of unsubstantiated Lyme disease. J Infect Dis 1995;171:356–361. [PubMed]
19. Krupp LB, Hyman LG, Grimson R, et al. Study and Treatment Of Post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology 2003;60:1923–1930. [PubMed]
2004; 2004: 0910.
Published online 2004 August 1.

Antibiotics versus placebo (prophylaxis)

Summary

INCIDENCE RATES Compared with placebo: A single dose of doxycycline is more effective at reducing the proportion of people with erythema migrans, or with any evidence of Lyme disease at the site of the tick bite in the preceding 72 hours. Doxycycline may also be more effective at reducing erythema migrans at the site of the tick bite after removal of partially engorged nymphal ticks. However, we do not know whether prophylaxis with penicillin, amoxicillin, and tetracycline is beneficial at reducing the incidence of erythema migrans in people with recognised tick bites in the preceding 72 hours ( moderate-quality evidence ).

Benefits

We found one systematic review and one subsequent RCT comparing prophylactic antibiotics versus placebo for the treatment of tick bite (see table 1 ). The review (search date 1995, 3 RCTs, 639 adults and children with recognised I scapularis tick bites in the preceding 72 hours; see comment below) found that prophylactic treatment with antibiotics (penicillin, amoxicillin [amoxycillin], and tetracycline) reduced the risk of developing clinical Lyme disease (erythema migrans) compared with placebo, but the difference was not significant (0/308 [0%] with antibiotics v 4/292 [1.4%] with placebo; ARR 1.4%, 95% CI 0% to 3%; P = 0.12). The subsequent large RCT (482 people ≥ 12 years old who had removed an attached I scapularis tick in the preceding 72 hours; see comment below) compared doxycycline (200 mg as a single dose) versus placebo with 6 weeks' follow up. It found that doxycycline significantly reduced the proportion of people with erythema migrans at the site of the tick bite and the proportion of people with any evidence of Lyme disease compared with placebo (erythema migrans: 1/235 [0.4%] with doxycycline v 8/247 [3.2%] with placebo; ARR 2.8%, 95% CI 0.4% to 5.2%; NNT 36, 95% CI 20 to 250; any evidence of Lyme disease defined as erythema migrans at the site of the tick bite, or at other sites, or a viral-like illness with laboratory evidence of Lyme disease: 3/235 [1.3%] with doxycycline v 11/247 [4.5%] with placebo; ARR 3.2%, 95% CI 0.2% to 6.2%; NNT 31, 95% CI 16 to 500). None of the 431 people who had serum samples tested at study entry and 3 and 6 weeks later had asymptomatic seroconversion for antibody to B burgdorferi. Erythema migrans at the site of the tick bite only occurred if the removed tick was in the nymph stage, was partially engorged, and was estimated to be attached for more than 72 hours. A subgroup analysis found that in people who removed partially engorged nymphal ticks, doxycycline significantly reduced erythema migrans at the site of the tick bite compared with placebo (1/78 [1.3%] with doxycycline v 8/81 [9.9%] with placebo; ARR 8.6%, 95% CI 1.4% to 15.8%; NNT 12, 95% CI 7 to 71).

Table 1
Prophylactic treatment of tick bite with antibiotics; results of placebo controlled RCTs (see text).

Harms

Two RCTs in the review found that penicillin and amoxycillin increased rash compared with placebo but the incidence was low (see table 1 ). The third RCT in the review found no adverse effects among persons who had been treated with antibiotics. The subsequent RCT (309 people who recorded data on adverse events) found that doxycycline significantly increased nausea and vomiting compared with placebo. However, it found no significant difference between treatments for abdominal discomfort, diarrhoea, and dizziness (nausea and vomiting: 33/156 [21.0%] with doxycycline v 6/153 [3.9%] with placebo; ARI 17.2%, 95% CI 9.8% to 24.6%; NNH 6, 95% CI 4 to 10; abdominal discomfort: 11/156 [7.1%] with doxycycline v 6/153 [3.9%] with placebo; P = 0.34; diarrhoea: 6/156 [3.8%] with doxycycline v 6/153 [3.9%] with placebo; P = 0.79; dizziness: 4/156 [2.6%] with doxycycline v 1/153 [0.7%] with placebo; P = 0.37).

Comment

The three RCTs included in the systematic review and the subsequent RCT were all conducted in Lyme disease endemic areas in North America. There is a possibility that people treated with antibiotics for tick bite may not develop erythema migrans but could progress to late stages of Lyme disease. However, none of the people who were treated with antibiotics in the RCTs had asymptomatic infection with B burgdorferi, or developed late manifestations of Lyme disease during follow up (ranging from 6 weeks to 3 years). The most recent and largest RCT found that for a baseline risk of 1% for contracting Lyme disease in the control group, the number needed to treat for a single dose of doxycycline 200 mg to prevent Lyme disease was 31. The same RCT found that the number needed to harm for nausea or vomiting from this treatment was six; therefore, about five people would develop nausea or vomiting for every person in whom Lyme disease was prevented. People in the RCT with adult ticks, non-engorged ticks, or both did not develop Lyme disease, although Lyme disease can occur after the bite of an engorged adult tick. If treatment was limited to people with engorged nymphal ticks (NNT 12), then two people would develop nausea and less than one person would develop vomiting for every person in whom Lyme disease was prevented.

Substantive changes

No new evidence

2004; 2004: 0910.
Published online 2004 August 1.

Antibiotics versus placebo (treatment of Lyme disease arthritis)

Summary

SYMPTOM SEVERITY Compared with placebo: Penicillin is more effective at increasing the proportion of people having complete resolution of Lyme disease arthritis ( moderate-quality evidence ). ADVERSE REACTIONS Some people have developed symptoms of neuroborreliosis and inflammatory tissue reactions (Jarisch-Herxheimer reaction) after oral antibiotic treatment of Lyme arthritis.

Benefits

We found no systematic review.

Penicillin versus placebo:

We found one RCT in people with Lyme disease arthritis. The RCT (40 people with Lyme disease arthritis) compared intramuscular benzathine penicillin versus saline placebo. It found that penicillin significantly increased the proportion of people having complete resolution of the arthritis compared with placebo (AR 7/20 [35%] with penicillin v 0/20 [0%] with placebo; P < 0.02).

Other antibiotics versus placebo:

We found no RCTs.

Harms

Some people have developed symptoms of neuroborreliosis after oral antibiotic treatment of arthritis. Other harms include those expected from antibiotics.

Comment

None.

Substantive changes

2004; 2004: 0910.
Published online 2004 August 1.

Doxycyline versus amoxicillin (treatment of Lyme disease arthritis)

Summary

SYMPTOM SEVERITY Compared with amoxicillin plus probenecid: Doxycycline, and amoxicillin plus probenecid are equally effective at improving symptoms of Lyme arthritis at 3 months ( moderate-quality evidence ). ADVERSE REACTIONS Some people have developed symptoms of neuroborreliosis and inflammatory tissue reactions (Jarisch-Herxheimer reaction) after oral antibiotic treatment of Lyme arthritis.

Benefits

Doxycycline versus amoxicillin plus probenecid:

We found one RCT in people with Lyme disease arthritis. The RCT (48 people with Lyme arthritis) compared oral doxycycline (100 mg twice daily for 30 days) versus oral amoxicillin (500 mg) plus probenecid (4 times daily for 30 days). After 3 months, an intention to treat analysis found no significant difference between treatments in rates of arthritis (AR 18/25 [72%] with doxycycline v 16/23 [70%] with amoxicillin plus probenecid; RR 1.04, 95% CI 0.72 to 1.49). In the doxycycline group, one person had recurrence of arthritis and another developed polyneuropathy after treatment. In the amoxicillin plus probenecid group, one person had recurrent arthritis, two developed polyneuropathy, and two developed encephalopathy.

Harms

Doxycycline versus amoxicillin plus probenecid:

Some people have developed symptoms of neuroborreliosis after oral antibiotic treatment of arthritis. Jarisch-Herxheimer reactions have been described in people treated for late Lyme disease. Other harms include those expected from antibiotics. In RCTs including people with Lyme arthritis, rash and gastrointestinal effects were reported with amoxicillin and probenecid.

Comment

The proportion of people who respond in comparative RCTs is difficult to interpret because, without a placebo comparison, it is unclear how many people would have improved without treatment.

Substantive changes

2004; 2004: 0910.
Published online 2004 August 1.

Ceftriaxone versus penicillin (treatment of Lyme disease arthritis)

Summary

SYMPTOM SEVERITY Compared with penicillin: Ceftriaxone may be more effective at increasing the proportion of people with improved symptoms of arthritis at 3 months ( very low-quality evidence ). ADVERSE REACTIONS Some people have developed symptoms of neuroborreliosis and inflammatory tissue reactions (Jarisch-Herxheimer reaction) after oral antibiotic treatment of Lyme arthritis.

Benefits

We found two RCTs in people with a variety of forms of late Lyme disease (including Lyme arthritis). The first RCT (23 people with late Lyme disease, 70% with arthritis) compared ceftriaxone (2 g iv every 12 hours for 14 days) versus penicillin (4 MU iv every 4 hours for 10 days). It found that ceftriaxone increased clinical improvement at 3 months but the difference was not significant (AR of improvement 12/13 [92%] with ceftriaxone v 5/10 [50%] with penicillin; RR 1.85, 95% CI 0.97 to 3.50). It found that, in a subgroup of people with arthritis, ceftriaxone increased the proportion of people with improved arthritis (AR 9/9 [100%] with ceftriaxone v 2/7 [29%] with penicillin; NNT 2, 95% CI 1 to 4). The second RCT (62 people with disseminated Lyme disease, 13 people with Lyme arthritis) did not report separate results for the subgroup with arthritis. It compared intravenous ceftriaxone followed by oral amoxicillin plus probenecid versus oral cefixime plus probenecid.

Harms

Some people have developed symptoms of neuroborreliosis after oral antibiotic treatment of arthritis. Jarisch-Herxheimer reactions have been described in people treated for late Lyme disease. One RCT reported symptoms suggestive of a mild Jarisch-Herxheimer reaction in 12/44 (27%) of people treated with ceftriaxone and 1/10 (10%) of people with penicillin. One RCT reported in an unspecified number of people with possible “Herxheimer-like” reactions, including fever, transient rash, and worsening of symptoms or cardiac arrhythmia, among people treated with cefixime and probenecid, and with ceftriaxone followed by amoxicillin. It found no significant difference in the risk of developing a prolonged form of such reactions with ceftriaxone plus amoxicillin compared with cefixime plus probenecid (18/30 [60%] with ceftriaxone plus amoxicillin treatment v 12/30 [40%] with cefixime plus probenecid; RR 1.50, 95% CI 0.88 to 2.54). Other harms include those expected from the antibiotics. In RCTs including people with Lyme arthritis, the following adverse effects were reported: diarrhoea and skin rash with ceftriaxone; and nausea, diarrhoea, and rash with ceftriaxone followed by amoxicillin.

Comment

Results of the RCTs that presented results for subgroups of people with Lyme arthritis should be interpreted with caution as people with arthritis were not randomly assigned to treatment groups. The RCTs were small, and the type, dose, and regimen of antibiotics used varied between trials. The enrolment criteria also varied between trials. Only one RCT had a placebo control. The proportion of people who respond in comparative RCTs is difficult to interpret because, without a placebo comparison, it is unclear how many people would have improved without treatment.

Substantive changes

2004; 2004: 0910.
Published online 2004 August 1.

Cefotaxime versus penicillin (treatment of Lyme disease arthritis)

Summary

SYMPTOM SEVERITY Compared with penicillin: Cefotaxime may be more effective at increasing the rates of full recovery at 2 years in people with late Lyme disease arthritis ( very low-quality evidence ). ADVERSE EFFECTS Some people have developed symptoms of neuroborreliosis and inflammatory tissue reactions (Jarisch-Herxheimer reaction) after oral antibiotic treatment of Lyme arthritis.

Benefits

We found one RCT comparing penicillin versus cefotaxime in people with a variety of forms of late Lyme disease (including Lyme arthritis). The RCT (135 people with late Lyme disease, 73 with arthritis) compared cefotaxime (6 g/day for 8–10 days) versus penicillin G (20 MU/day for 8–19 days). It found that cefotaxime significantly increased rates of full recovery 2 years after treatment compared with penicillin (AR 44/69 [64%] with cefotaxime v 25/66 [38%] with penicillin; RR 1.68, 95% CI 1.18 to 2.41; NNT 3, 95% CI 2 to 11). In the subgroup of people with arthritis, ceftriaxone significantly increased rates of full recovery compared with penicillin (17/39 [44%] with cefotaxime v 4/34 [12%] with penicillin; RR 3.7, 95% CI 1.4 to 9.9; NNT 4, 95% CI 2 to 10).

Harms

Some people have developed symptoms of neuroborreliosis after oral antibiotic treatment of arthritis. Jarisch-Herxheimer reactions have been described in people treated for late Lyme disease. One RCT reported symptoms suggestive of a mild Jarisch-Herxheimer reaction in 12/44 (27%) of people treated with ceftriaxone and 1/10 (10%) of people with penicillin, and one RCT reported “Herxheimer-like” reactions in 20.0% of people treated with penicillin and 40.5% of people treated with cefotaxime. One RCT reported in an unspecified number of people with possible “Herxheimer-like” reactions, including fever, transient rash, and worsening of symptoms or cardiac arrhythmia, among people treated with cefixime and probenecid, and with ceftriaxone followed by amoxicillin. It found no significant difference in the risk of developing a prolonged form of such reactions with ceftriaxone plus amoxicillin compared with cefixime plus probenecid (18/30 [60%] with ceftriaxone plus amoxicillin treatment v 12/30 [40%] with cefixime plus probenecid; RR 1.50, 95% CI 0.88 to 2.54). Other harms include those expected from the antibiotics. In RCTs including people with Lyme arthritis, the following adverse effects were reported: diarrhoea and skin rash with ceftriaxone; shock and colitis with penicillin; anaphylaxis and colitis with cefotaxime; rash and gastrointestinal effects with amoxicillin and probenecid; diarrhoea and rash with cefixime; and nausea, diarrhoea, and rash with ceftriaxone followed by amoxicillin.

Comment

Results of the RCTs that presented results for subgroups of people with Lyme arthritis should be interpreted with caution as people with arthritis were not randomly assigned to treatment groups. The RCTs were small, and the type, dose, and regimen of antibiotics used varied between trials. The enrolment criteria also varied between trials. Only one RCT had a placebo control. The proportion of people who respond in comparative RCTs is difficult to interpret because, without a placebo comparison, it is unclear how many people would have improved without treatment.

Substantive changes

2004; 2004: 0910.
Published online 2004 August 1.

Ceftriaxone plus doxycycline (treatment of late neurological Lyme disease)

Summary

SYMPTOM SEVERITY Compared with placebo: Cefatriaxone plus doxcycyline may be no more effective at 180 days at improving mood, pain, cognitive functioning or neuropsychological tests in people with persistent neurological symptoms who have been previously treated for Lyme disease ( very low-quality evidence ).

Benefits

Ceftriaxone plus doxycycline versus placebo:

We found one RCT comparing antibiotics with placebo in people previously treated for Lyme disease. The RCT (129 people, 78 people seropositive for B burgdorferi, 51 people who were seronegative) compared antibiotics (iv ceftriaxone 2 g/day for 30 days followed by oral doxycycline 100 mg twice daily for 60 days) versus placebo. All participants had persistent symptoms including arthralgia, myalgia, neurocognitive changes, altered sensation, malaise, headache, and sleep disturbance. At 180 days, a planned interim analysis found no significant difference between antibiotics and placebo in improvement in mood, pain, cognitive functioning, or neuropsychological tests. The analysis found that the chance of finding a significant difference in health related quality of life (measured by the SF-36 scale) after completion of the full study was less than 5%. The study was, therefore, terminated.

Harms

See harms under treatments for Lyme disease arthritis.

Ceftriaxone plus doxycycline versus placebo:

The RCT in people with previously treated Lyme disease found no significant difference in the overall rate of adverse events between antibiotic and placebo.

Subgroup analyses in people with late neurological Lyme disease:

In the other clinical trials of people with late neurological Lyme disease reported above, the following adverse effects were reported: shock and colitis with penicillin, and anaphylaxis and colitis with cefotaxime; rash with cefotaxime, and fever, diarrhoea, and elevated liver enzymes with ceftriaxone. One case control study found an association between biliary disease and ceftriaxone treatment of suspected late Lyme disease.

Comment

The RCTs of previously untreated people either recruited people with late Lyme disease, some of whom had neurological manifestations, or people with Lyme neuroborreliosis, some of whom had late disease. Results presented for these subsets of study participants may be subject to undetected biases, because people with late neurological disease were not randomly assigned to treatment groups. None of these RCTs had a placebo treated control group. The antibiotics used in RCTs, as well as doses and schedules, varied between trials. The enrolment criteria also varied between trials.

Substantive changes

2004; 2004: 0910.
Published online 2004 August 1.

Cefotaxime versus penicillin (treatment of late neurological Lyme disease)

Summary

SYMPTOM SEVERITY Compared with penicillin: Cefotaxime may be more effective at increasing complete recovery rates and at improving symptoms of neuropathy in people with late Lyme disease ( very low-quality evidence ).

Benefits

We found one RCT in people with late neurological Lyme disease The RCT (135 people with late Lyme disease, 93 with neuropathy) compared cefotaxime (6 g/day for 8–10 days) versus penicillin G (20 MU/day for 8–19 days). Two years after treatment, cefotaxime significantly increased complete recovery compared with penicillin (44/69 [64%] with cefotaxime v 25/66 [38%] with penicillin; RR 1.68, 95% CI 1.18 to 2.41). Similar results were reported for the subgroup with neuropathy (35/49 [71%] with cefotaxime v 20/44 [46%] with penicillin; RR 1.57, 95% CI 1.09 to 2.27).

Harms

See harms under treatments for Lyme disease arthritis.

People with late neurological Lyme disease:

The first RCT in people with previously treated Lyme disease found no significant difference in the overall rate of adverse events between antibiotic and placebo. The second RCT in people with previously treated Lyme disease also found no significant difference between ceftriaxone and placebo in overall minor adverse event rates. However, it found that ceftriaxone increased diarrhoea compared with placebo (diarrhoea: 43% with ceftriaxone v 25% with placebo; P value not reported). One person receiving ceftriaxone was admitted to hospital for anaphylaxis.

Subgroup analyses in people with late neurological Lyme disease:

In the other clinical trials of people with late neurological Lyme disease reported above, the following adverse effects were reported: shock and colitis with penicillin, and anaphylaxis and colitis with cefotaxime; rash with cefotaxime, and fever, diarrhoea, and elevated liver enzymes with ceftriaxone. One case control study found an association between biliary disease and ceftriaxone treatment of suspected late Lyme disease.

Comment

The RCTs of previously untreated people either recruited people with late Lyme disease, some of whom had neurological manifestations, or people with Lyme neuroborreliosis, some of whom had late disease. Results presented for these subsets of study participants may be subject to undetected biases, because people with late neurological disease were not randomly assigned to treatment groups. None of these RCTs had a placebo treated control group. The antibiotics used in RCTs, as well as doses and schedules, varied between trials. The enrolment criteria also varied between trials.

Substantive changes

2004; 2004: 0910.
Published online 2004 August 1.

Ceftriaxone versus placebo (in previously treated people with late neurological Lyme disease)

Summary

SYMPTOM SEVERITY Compared with placebo: We don't know whether ceftriaxone is more effective at improving cognitive functioning at 6 months in people with late neurological disease who have been previously treated with antibiotics ( very low-quality evidence ).

Benefits

We found one RCT (55 people seropositive for B burgdorferi) comparing intravenous ceftriaxone (2 g/day for 28 days) versus placebo. All participants had persistent fatigue 6 months after previous treatment with at least 3 weeks of antibiotics. It found that ceftriaxone significantly improved fatigue at 6 months compared with placebo. However, it found no significant difference in cognitive function (fatigue improved, defined as a decrease ≥ 0.7 units on modified Fatigue Severity Scale: 18/28 [64.0%] with ceftriaxone v 5/27 [18.5%] with placebo; RR 3.50; 95% CI 1.50 to 8.03; improved cognitive function defined as ≥ 25% improvement in Alpha–arithmetic Test score: 2/26 [8%] with ceftriaxone v 2/22 [9%] with placebo; P = 0.99). However, there was evidence of inadequate blinding, which may have influenced participants' perceptions of fatigue (71% of people receiving ceftriaxone correctly guessed their treatment).

Harms

See harms under treatments for Lyme disease arthritis.

People with late neurological Lyme disease:

The RCT in people with previously treated Lyme disease found no significant difference between ceftriaxone and placebo in overall minor adverse event rates. However, it found that ceftriaxone increased diarrhoea compared with placebo (diarrhoea: 43% with ceftriaxone v 25% with placebo; P value not reported). One person receiving ceftriaxone was admitted to hospital for anaphylaxis.

Subgroup analyses in people with late neurological Lyme disease:

In the other clinical trials of people with late neurological Lyme disease reported above, the following adverse effects were reported: shock and colitis with penicillin, and anaphylaxis and colitis with cefotaxime; rash with cefotaxime, and fever, diarrhoea, and elevated liver enzymes with ceftriaxone. One case control study found an association between biliary disease and ceftriaxone treatment of suspected late Lyme disease.

Comment

The RCTs of previously untreated people either recruited people with late Lyme disease, some of whom had neurological manifestations, or people with Lyme neuroborreliosis, some of whom had late disease. Results presented for these subsets of study participants may be subject to undetected biases, because people with late neurological disease were not randomly assigned to treatment groups. None of these RCTs had a placebo treated control group. The antibiotics used in RCTs, as well as doses and schedules, varied between trials. The enrolment criteria also varied between trials.

Substantive changes

2004; 2004: 0910.
Published online 2004 August 1.

Ceftriaxone versus cefotaxime (in previously treated people with late neurological Lyme disease)

Summary

SYMPTOM SEVERITY Compared with cefotaxime: We don't know whether ceftriaxone is more effective than cefotaxime at increasing the proportion of people who are asymptomatic at 8 months ( very low-quality evidence ).

Benefits

We found one RCT (33 people with Lyme neuroborreliosis of varying duration) comparing ceftriaxone (2 g iv/day for 10 days) versus cefotaxime (2 g iv every 8 hours for 10 days). Some of the people treated with ceftriaxone were asymptomatic before treatment, and so were excluded from analysis (3/17 [18%]). Of the remaining people, most (17/30 [57%]) had disease duration of over 30 days at study entry, and some (8/30 [27%]) had a duration over 60 days. The RCT found no significant difference between ceftriaxone and cefotaxime in the proportion of people who were asymptomatic after 8 months (8/14 [57%] with ceftriaxone v 9/16 [56%] with cefotaxime; RR 1.02, 95% CI 0.54 to 1.90).

Harms

See harms under treatments for Lyme disease arthritis.

Subgroup analyses in people with late neurological Lyme disease:

In the other clinical trials of people with late neurological Lyme disease reported above, the following adverse effects were reported: shock and colitis with penicillin, and anaphylaxis and colitis with cefotaxime; rash with cefotaxime, and fever, diarrhoea, and elevated liver enzymes with ceftriaxone. One case control study found an association between biliary disease and ceftriaxone treatment of suspected late Lyme disease.

Comment

The RCTs of previously untreated people either recruited people with late Lyme disease, some of whom had neurological manifestations, or people with Lyme neuroborreliosis, some of whom had late disease. Results presented for these subsets of study participants may be subject to undetected biases, because people with late neurological disease were not randomly assigned to treatment groups. None of these RCTs had a placebo treated control group. The antibiotics used in RCTs, as well as doses and schedules, varied between trials. The enrolment criteria also varied between trials.

Substantive changes


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