Special Report
Cost Effectiveness of Oral as Compared with Intravenous Antibiotic Therapy for Patients with Early Lyme Disease or Lyme Arthritis
N Engl J Med 1997; 337:357-364July 31, 1997
- Article
Lyme disease, which is caused by the tick-transmitted spirochete Borrelia burgdorferi, 1 usually begins with an expanding skin lesion, erythema migrans, accompanied by malaise and fatigue, fever, headache, stiff neck, and myalgias or arthralgias.2,3 Weeks later, some patients have objective neurologic signs, such as meningitis, cranial neuritis, or radiculoneuritis,4 or cardiac abnormalities, particularly atrial–ventricular block.5 Months later, intermittent or chronic episodes of arthritis often develop in untreated patients.6 Months to years later, a small percentage of patients have subtle signs of encephalopathy (memory deficit, irritability, or somnolence), or polyneuropathy characterized by spinal radicular pain or distal paresthesias.7-10
The recommended treatment for early Lyme disease is oral therapy with either doxycycline (100 mg twice daily for 21 days) or amoxicillin (500 mg three times daily for 21 days).1,11-13 For Lyme arthritis, the recommended treatment is oral therapy with either doxycycline (100 mg twice daily for 30 days) or amoxicillin and probenecid (500 mg of each four times daily for 30 days).11,14 Intravenous ceftriaxone (2 g daily for 14 days) is recommended when neurologic manifestations are present early in the course of the disease,11,15 and chronic neuroborreliosis is usually treated with intravenous ceftriaxone (2 g daily for 30 days).15,16 Some physicians consider intravenous ceftriaxone the optimal therapy for any late manifestation of disease.
Actual practice varies widely. In an epidemiologic study of antibiotic-prescribing patterns in Maryland during 1990 and 1991, 88 percent of 169 patients with erythema migrans were treated with oral antibiotics, whereas approximately 12 percent were given intravenous ceftriaxone.17 Of 114 patients with arthritic, neurologic, or cardiac manifestations of Lyme disease, 32 percent were treated with intravenous ceftriaxone and 68 percent received doxycycline or another oral antibiotic agent.
A particular concern has been whether chronic neuroborreliosis may develop months or years after treatment with oral antibiotic regimens for either early Lyme disease or Lyme arthritis.14,18 In this report, we address the question of whether oral doxycycline or intravenous ceftriaxone is more cost effective in the treatment of early Lyme disease or Lyme arthritis. We consider the efficacy, side effects, and cost of each regimen.
Methods
Basic Model
We constructed a Markov state-transition simulation model, using a standard computer program (Decision Maker19,20) to analyze decision trees and perform sensitivity analyses. We considered two groups of patients: those with early Lyme disease and those with Lyme arthritis who had no clinical evidence of neurologic involvement. We compared oral therapy with 100 mg of doxycycline twice daily for three weeks (in patients with early Lyme disease) or four weeks (in those with Lyme arthritis) and at-home intravenous administration of 2 g of ceftriaxone once a day for two weeks (in patients with early Lyme disease) or four weeks (in those with Lyme arthritis).
Decision Tree
In the simulation, patients were initially evaluated in the ambulatory setting, and a decision was made to use one of the two treatments. Decision-tree figures have been deposited with the National Auxiliary Publications Service (NAPS). At the end of each month of the simulation, patients moved from one state of health to another (see the Appendix for a list of the 11 health states), depending on the probability of intervening events.
Potential complications of antibiotic therapy included anaphylaxis and other major or minor adverse reactions. Major complications could necessitate the early termination of antibiotic therapy, resulting in a decreased efficacy of treatment. Such complications included pseudomembranous colitis in patients receiving either regimen and biliary tract disease (which could lead to cholecystitis and subsequent cholecystectomy), intravenous-catheter–associated bloodstream infection, and hypersensitivity reactions in those receiving intravenous ceftriaxone.
Patients could receive intravenous ceftriaxone either as initial therapy or as treatment for late neurologic sequelae of Lyme disease (i.e., neuroborreliosis). Neuroborreliosis could also develop in patients receiving initial treatment for Lyme disease, and those receiving treatment for neuroborreliosis might have relapses. We assumed that patients with recrudescent disease continued to have subtle neurologic symptoms for the remainder of their lives.
Summary of the Data
Oral Doxycycline
In this analysis we focused on the most commonly prescribed and recommended antibiotic agents for the treatment of Lyme disease: oral doxycycline and intravenous ceftriaxone. There have been numerous trials of oral doxycycline or tetracycline in patients with early Lyme disease.12,13,21-23 However, most of these studies did not document the time from treatment to the development of recurrent disease (e.g., late neurologic sequelae) or the mean duration of follow-up, making it difficult to calculate rates of recurrence.12,13 In three studies, patients had late symptoms that were suggestive of neuroborreliosis, but the objective findings needed to make this diagnosis were not documented.12,13,22
To our knowledge, only one randomized trial to date has examined the use of doxycycline in patients with Lyme arthritis.14 A total of 40 patients with Lyme arthritis were randomly assigned to treatment with either doxycycline or amoxicillin and probenecid. Eighteen of 20 patients receiving 100 mg of doxycycline twice daily required no further treatment. One of these 18 patients (6 percent) had polyneuropathy, documented by electromyography at 18 months (unpublished data). During the subsequent 3.3 years, there were no additional cases of neuroborreliosis. These data were used in our decision model to calculate the risk of neuroborreliosis each month after antibiotic treatment. A figure showing the results of this analysis is available elsewhere (NAPS). Since the risk of late neurologic sequelae is likely to be lower in patients with early Lyme disease than in those with Lyme arthritis, we used these data to establish the upper limit of the risk of neuroborreliosis in doxycycline-treated patients with early Lyme disease.
Toxic effects of oral doxycycline include minor complications, such as gastrointestinal irritation and photosensitivity reactions in approximately 15 percent of patients,13,22 and major complications requiring the early cessation of therapy, including severe gastrointestinal symptoms in 1.6 percent of patients,22 anaphylactic reactions in 0.01 percent,24,25 and pseudomembranous enterocolitis.26 Pseudomembranous colitis is rare in patients receiving treatment with doxycycline, with only case reports in the medical literature.27,28 In our base-case analysis, we have assumed that pseudomembranous colitis accounts for only 1 in 10,000 major complications. Although mortality from antibiotic-associated enterocolitis is low, one study reported two deaths directly attributable to antibiotic-associated enterocolitis among 75 surgical patients.29
Intravenous Ceftriaxone
Several studies have examined ceftriaxone for the treatment of patients with either early22,30 or late15 manifestations of Lyme disease. In the single study comparing intravenous ceftriaxone with oral doxycycline, reported elsewhere in this issue of the Journal, Dattwyler and colleagues found that the clinical-cure rates for the two therapies were similar at nine months: 85 percent of patients receiving ceftriaxone and 88 percent of those receiving doxycycline had clinical cures.22 Nine months after treatment, there were no cases of neuroborreliosis in either treatment group.
Only one study, to our knowledge, has examined the use of ceftriaxone specifically in patients with Lyme arthritis.14 In a separate phase of this study comparing doxycycline with amoxicillin and probenecid, 16 patients who had not had responses to oral therapy were treated with ceftriaxone (2 g daily for two weeks). Only 1 of the 16 patients had subsequent neurologic complications, a subtle encephalopathy accompanied by cerebrospinal fluid abnormalities, which occurred approximately 18 months after treatment with ceftriaxone. Even though these results are not significantly different from those in patients receiving doxycycline, in our base-case analysis we have assumed that the risk of neuroborreliosis in patients receiving intravenous ceftriaxone for either early Lyme disease or Lyme arthritis is 50 percent of the risk in patients receiving oral doxycycline. Other groups have studied the use of ceftriaxone for the treatment of patients with late Lyme disease.15 However, these studies did not report the results separately for patients with Lyme arthritis and those with neuroborreliosis.
Ceftriaxone has also been studied as a treatment for acute or chronic neuroborreliosis. As Table 1Table 1
Efficacy of Intravenous Ceftriaxone Therapy for Patients with Neuroborreliosis. shows, four regimens have been examined, all with similar efficacies.7,15,31 The weighted average efficacy for the 75 patients was 80 percent. Only two of the studies reported on the late recurrence of neurologic symptoms in patients with initial cures.7,31 The weighted average annualized rate of neurologic recurrence was 63 percent. Since neither study had a mean follow-up period longer than eight months, we assumed that the risk of recurrent neurologic symptoms was limited to the first year after successful initial treatment of neuroborreliosis.As shown in Table 2Table 2
Probabilities of Complications and Adjustments for Quality of Life Used in the Analysis., adverse events associated with intravenous ceftriaxone include anaphylaxis32; major complications such as pseudomembranous colitis,30,33 biliary tract disease,34 catheter-associated infection, and hypersensitivity reactions15; and minor complications consisting primarily of gastrointestinal symptoms.15,32 We systematically used lower-bound estimates in the base case to favor the use of ceftriaxone in our analysis.Quality of Life
We adjusted life expectancy for the quality of life in both the short term (e.g., during hospitalization) and the long term (e.g., with neuroborreliosis), basing the quality-adjustment factors on the judgments of experienced physicians. For the quality of life in the long term, otherwise healthy patients were assigned a quality-adjustment factor of 1. As shown in Table 2, life with chronic neurologic symptoms characteristic of Lyme encephalopathy (e.g., subtle memory deficits, headache, or fatigue) or polyneuropathy (spinal radicular pain or distal paresthesias)1,35 was assigned a quality-adjustment factor of 0.95, meaning that a year of life with these symptoms was considered to be worth only 95 percent of a year of life without them. That is, people would be willing to give up 5 percent of their life expectancy to preserve the full quality of life. Factors affecting the quality of life in the short term were also assigned quality-adjustment factors. Patients receiving intravenous antibiotic therapy, for instance, had a quality-adjustment factor of 0.97 during the month in which they received this treatment, to account for the associated inconvenience and discomfort. We determined the effect of these quality-of-life factors in sensitivity analyses.
Costs
Costs rather than charges were used to represent the consumption of resources. Charges may reflect reimbursement policies and a profit motive for certain cost centers, making them a somewhat arbitrary representation of resource use. The costs of hospitalization for complications of antibiotic therapy (e.g., Clostridium difficile colitis or biliary tract disease) and for ambulatory visits and treatments (e.g., oral and intravenous antibiotic therapy) are shown in Table 3Table 3
Average Costs of Therapy..Results
Base-Case Analysis
Quality-adjusted life expectancy was similar for the two treatments. For a 30-year-old patient presenting with early Lyme disease, 3 weeks of treatment with doxycycline resulted in an average quality-adjusted life expectancy of 43.9 life-years, and 2 weeks of treatment with intravenous ceftriaxone resulted in 43.8 quality-adjusted life-years, a difference of roughly 14 days. Furthermore, the average lifetime cost of oral therapy with doxycycline ($544) was $3,216 less than that of intravenous ceftriaxone ($3,760).
For a 30-year-old patient presenting with Lyme arthritis, 1 month of treatment with doxycycline resulted in 43.9 quality-adjusted life-years, and 4 weeks of treatment with intravenous ceftriaxone resulted in 43.8 quality-adjusted life-years, a difference of roughly 22 days. The average lifetime cost of oral therapy with doxycycline ($546) was $6,144 less than that of intravenous ceftriaxone ($6,690). We also performed the analysis with costs and effectiveness (quality-adjusted life expectancy) discounted at a rate of 3 percent per year. Under these assumptions, oral and intravenous therapy resulted in 23.7 quality-adjusted life-years for patients with either early Lyme disease or Lyme arthritis. In addition, oral therapy was still less expensive both for patients with early Lyme disease and for those with Lyme arthritis, costing $3,150 and $6,060 less than intravenous antibiotic therapy, respectively.
Sensitivity Analyses
Under what circumstances might intravenous antibiotic therapy be more effective than oral therapy, and how would this improvement influence the cost effectiveness of intravenous treatment? We answered those questions by performing sensitivity analyses for all major parameters in the model. Unless stated otherwise, sensitivity analyses examined the treatment of patients with Lyme arthritis and were calculated with the use of a discount rate of 3 percent per year for both costs and effectiveness.
Efficacy of Intravenous Ceftriaxone
In the base-case analysis, we assumed that the risk of neuroborreliosis in patients receiving intravenous ceftriaxone was 0.5 that in patients receiving oral doxycycline (i.e., the relative risk was 0.5, and the cumulative absolute risk was 2.25 percent at three years). In sensitivity analyses, oral therapy remained the preferred strategy unless the relative risk of neuroborreliosis in patients receiving intravenous ceftriaxone was less than 0.05 that in patients receiving oral therapy. The marginal cost effectiveness of intravenous ceftriaxone therapy remained prohibitively high, even with a very low relative risk of neuroborreliosis (i.e., a very high efficacy). For instance, if the relative risk of late neurologic sequelae were 0.01 for intravenous ceftriaxone, the marginal cost effectiveness would be $960,000 per quality-adjusted life-year gained. In fact, if the use of intravenous ceftriaxone prevented all cases of neuroborreliosis, the treatment would still cost more than $685,000 more than oral doxycycline per quality-adjusted life-year gained.
We next analyzed changes in the efficacy of ceftriaxone, assuming that the probability of major or minor complications was zero and the quality of life during intravenous therapy was 1.0. Even with these highly favorable assumptions, the marginal cost effectiveness of ceftriaxone was high. As shown in Figure 1Figure 1
Marginal Cost Effectiveness of Intravenous Ceftriaxone, as Compared with Oral Doxycycline Therapy, in Relation to the Relative Risk of Neuroborreliosis after Intravenous Therapy as Compared with Oral Therapy., ceftriaxone would cost an additional $201,000 per quality-adjusted life-year even if the risk of chronic neuroborreliosis after treatment were zero (i.e., the efficacy were 1.0). When the risk of neuroborreliosis after ceftriaxone therapy is slightly more than 0.8 that in patients receiving oral therapy, oral therapy provides a longer quality-adjusted life expectancy and therefore is both less expensive and more effective than intravenous therapy. At a relative risk approaching 0.8, the marginal cost-effectiveness ratio for ceftriaxone approaches infinity.Complications of Intravenous Ceftriaxone
We determined the effect of a reduction in the risk of major and minor complications associated with intravenous ceftriaxone. In the base case, the probability of both major and minor complications was roughly 0.1. Ceftriaxone was preferable only if the probability of major complications was less than 0.02. Even when the probability of both major and minor complications was zero, intravenous ceftriaxone cost an additional $621,000 per quality-adjusted life-year gained. In the best-case analysis for ceftriaxone, in which the probability of major and minor complications was zero and the quality of life during therapy was 1.0, ceftriaxone still cost an additional $550,000 per quality-adjusted life-year gained.
Quality of Life with Intravenous Ceftriaxone
In the base case, we assumed that the quality of life was 0.97 during the four weeks of ceftriaxone therapy. Even if intravenous therapy did not reduce the quality of life, it would still result in a loss of approximately 1 /2 weeks of quality-adjusted life expectancy, as compared with oral therapy, because of complications associated with the treatment.
We determined the effect of variations in the quality of life during oral or intravenous therapy (Figure 2Figure 2
Three-Way Sensitivity Analysis of the Quality of Life with Intravenous Ceftriaxone, the Quality of Life with Oral Doxycycline, and the Relative Risk of Chronic Neuroborreliosis Associated with Intravenous Ceftriaxone as Compared with Oral Doxycycline.). We also examined the efficacy of ceftriaxone by calculating threshold lines for four different values for the relative risk of neuroborreliosis in patients receiving ceftriaxone instead of doxycycline. Even if the relative risk of late neurologic sequelae among patients receiving ceftriaxone were 0.1 that for patients receiving oral therapy, doxycycline would still be preferable at the base-case values for quality of life during treatment with either of these antibiotics.Quality of Life for Patients with Neuroborreliosis
As shown in Figure 3Figure 3
Two-Way Sensitivity Analysis of the Quality of Life Associated with Chronic Neuroborreliosis and the Risk of Neuroborreliosis after Therapy with Intravenous Ceftriaxone as Compared with the Risk after Oral Doxycycline Therapy., variations in the quality of life for patients with neuroborreliosis do not alter the choice of treatment. Although the quality-adjusted life expectancy with both doxycycline and ceftriaxone decreases as the quality of life associated with neuroborreliosis decreases, doxycycline remains preferable. However, with a lower relative risk of neuroborreliosis after intravenous therapy (i.e., a higher treatment efficacy), the quality of life does have an effect on the optimal treatment. For example, if intravenous ceftriaxone had an efficacy of 1.0, the quality-adjustment factor for neuroborreliosis would have to be less than 0.80 before the marginal cost effectiveness of this therapy was less than $50,000 per quality-adjusted life-year. If the quality-adjustment factor for neuroborreliosis were zero (i.e., the neurologic sequelae were fatal), intravenous ceftriaxone would cost only $8,740 per quality-adjusted life-year gained.We verified that the results of these analyses are not altered by demographic variables (e.g., age, sex, and ethnic group). For example, treatment with ceftriaxone offers no advantage over treatment with doxycycline for patients between the ages of 20 and 70 years. In addition, the difference in average lifetime costs between the two treatments varies by less than $100 across this age range.
Discussion
Although current regimens of oral antibiotic therapy are effective in treating patients with early Lyme disease or Lyme arthritis, concern about the risk of late neurologic sequelae still leads to the consideration of more aggressive treatment with intravenous antibiotic agents. Our analysis of treatment with intravenous ceftriaxone (2 g per day) as compared with oral doxycycline (100 mg twice daily) shows that oral therapy is as effective as intravenous therapy and is less costly for patients with either early Lyme disease or Lyme arthritis. In nondiscounted analyses, oral therapy as compared with intravenous therapy results in a gain of two to three quality-adjusted weeks of life expectancy at an average savings of $3,200 to $6,100 per patient. When the cost and effectiveness are discounted 3 percent per year, the two therapies have similar outcomes, with little change in the cost savings, since most of the costs occur early in the simulation (i.e., within the first year).
Few data are available on the efficacy of intravenous ceftriaxone in the prevention of neuroborreliosis. In our base-case analysis, we assumed that the cumulative risk of neuroborreliosis after ceftriaxone therapy was half that after oral doxycycline. Despite this assumption, oral therapy was preferable.
We next explored the effects of variations in our assumptions and in the values of parameters that might sway the analysis in favor of intravenous therapy. Although there are circumstances in which intravenous therapy with ceftriaxone has a favorable marginal cost-effectiveness ratio, these circumstances are quite unlikely. For instance, with the base-case assumptions for the efficacy of ceftriaxone, the quality of life during treatment with oral doxycycline would have to decline to less than 10 percent of that of an otherwise healthy person, with little change in the quality of life during treatment with intravenous ceftriaxone, before intravenous therapy would be preferable.
We also explored the effect of changes in the quality of life with neuroborreliosis. Most patients with late neurologic sequelae after Lyme arthritis have subtle symptoms. To the extent that intravenous ceftriaxone can prevent these late neurologic deficits, an increase in the severity of the symptoms, modeled by decreasing the quality of life associated with neuroborreliosis, improves the relative outcomes for patients receiving ceftriaxone. With the base-case assumptions for the efficacy of ceftriaxone, even if the quality of life with neuroborreliosis were zero (i.e., the neurologic deficits were fatal), oral doxycycline would still be preferable. If the efficacy of ceftriaxone were increased so that the risk of neuroborreliosis was only one quarter that associated with oral therapy, the quality of life with neuroborreliosis would have to be less than 85 percent of that of an otherwise healthy person before ceftriaxone would be preferable. Finally, even if intravenous ceftriaxone had an efficacy of 1.0 and no associated major or minor complications, intravenous therapy would still cost an additional $201,000 per quality-adjusted life-year, making it a very expensive use of resources.
It is important to emphasize that there are legitimate indications for intravenous antibiotic therapy in patients with Lyme disease. Such therapy is preferable for the treatment of patients who have objective neurologic abnormalities, with the possible exception of those with facial palsy alone.1,11 Thus, it is critical to identify patients who have meningitis or radiculopathy in association with early Lyme disease or encephalopathy or polyneuropathy in association with Lyme arthritis, because they should be treated with intravenous ceftriaxone. Moreover, patients seem to have a faster response to intravenous antibiotic therapy, and it may therefore be preferable for patients with severe arthritis and Baker's cysts that have ruptured or are in danger of rupturing, for those with arthritis that is refractory to oral therapy, and for those with life-threatening manifestations of disease such as complete heart block. For most patients with early Lyme disease or Lyme arthritis, however, intravenous therapy appears to be no more effective than oral therapy, is more likely to result in serious complications, and is substantially more expensive.
Supported by a grant (Cooperative Agreement No. CCU110291) from the Centers for Disease Control and Prevention.
NAPS See NAPS document no. 05416 for 2 pages of supplementary material. Order from NAPS c/o Microfiche Publications, P.O. Box 3513, Grand Central Station, New York, NY 10163-3513.
We are indebted to Felicia Montineri, M.S., R.Ph., for her gracious assistance in obtaining cost data for antibiotic home-infusion therapies.
Source Information
From the Divisions of Clinical Decision Making (M.H.E., S.G.P.) and Rheumatology (A.C.S., R.A.K.), Department of Medicine, New England Medical Center, Boston.
Address reprint requests to Dr. Eckman at the Division of Clinical Decision Making, Box 302, New England Medical Center, 750 Washington St., Boston, MA 02111.
Appendix
The 11 Markov states of health are (1) Lyme disease during oral therapy, (2) Lyme disease during a primary course of intravenous therapy, (3) chronic neurologic symptoms after treatment, (4) the absence of symptoms after oral therapy, (5) the absence of symptoms after a partial course of oral therapy (terminated because of a major side effect), (6) the absence of symptoms after intravenous therapy, (7) the absence of symptoms after a partial course of intravenous therapy (terminated because of a major side effect), (8) the absence of symptoms after a full course of intravenous therapy for late neurologic sequelae, (9) the absence of symptoms after a partial course of intravenous therapy for late neurologic sequelae, (10) chronic neurologic symptoms after unsuccessful treatment with intravenous antibiotics, and (11) death. Patients who are unable to complete a full course of antibiotic therapy are at increased risk for recurrent neurologic symptoms.
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Frank Dressler, Patricia I. Irigoyen, Norman T. Ilowite, Hans-Iko Huppertz. 2011. Lyme Arthritis. , 115-134.
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F. Dressler, H.-I. Huppertz. (2008) Lyme-Arthritis bei Kindern und Jugendlichen. Zeitschrift für Rheumatologie 67:2, 121-127
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D. Lipsker, B. Jaulhac. (2008) Manifestaciones cut??neas de las borreliosis. EMC - Dermatolog??a 42:1, 1-11
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Katarina Ogrinc, Mateja Logar, Stanka Lotrič-Furlan, Daša Cerar, Eva Ružić-Sabljić, Franc Strle. (2006) Doxycycline versus ceftriaxone for the treatment of patients with chronic Lyme borreliosis. Wiener klinische Wochenschrift 118:21-22, 696-701
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Gary P. Wormser, Raymond J. Dattwyler, Eugene D. Shapiro, John J. Halperin, Allen C. Steere, Mark S. Klempner, Peter J. Krause, Johan S. Bakken, Franc Strle, Gerold Stanek, Linda Bockenstedt, Durland Fish, J. Stephen Dumler, Robert B. Nadelman. (2006) The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clinical Infectious Diseases 43:9, 1089-1134
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Allen C. Steere, Sheryn M. Angelis. (2006) Therapy for Lyme arthritis: Strategies for the treatment of antibiotic-refractory arthritis. Arthritis & Rheumatism 54:10, 3079-3086
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