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PEDIATRICS Vol. 109 No. 6 June 2002, pp. 1173-1177

EXPERIENCE AND REASON

Comparative Study of Cefuroxime Axetil Versus Amoxicillin in Children With Early Lyme Disease


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Cefuroxime axetil has been shown to have efficacy comparable to doxycycline in adults with early Lyme disease (LD). Because of toxicity, doxycycline is usually avoided in children. For children who are unable to tolerate amoxicillin, there is currently no proven alternative oral therapy for LD. This randomized, unblinded study compared 2 dosage regimens of cefuroxime axetil (20 mg/kg/d and 30 mg/kg/d) with amoxicillin (50 mg/kg/d), each given for 20 days. Children were enrolled if they were 6 months to 12 years of age, had erythema migrans, and met other eligibility requirements. Serologic testing occurred at entry and after 6 months. Follow-up evaluations for safety, tolerability, and efficacy occurred at 10 and 20 days, 6 months, and 1 year. Forty-three children were randomized (13 in the amoxicillin group, 15 in each cefuroxime axetil group); 39 completed 12 months of follow-up. At the completion of treatment, there was total resolution of erythema migrans in 67% of the amoxicillin group, 92% of the low-dose cefuroxime group, and 87% of the high-dose cefuroxime group, and resolution of constitutional symptoms occurred in 100%, 69%, and 87%, respectively. All patients had a good outcome, with no long-term problems associated with LD. One patient, who was well at the first 2 follow-up visits, was treated with doxycycline because of new constitutional symptoms. Mild diarrhea occurred in a small number of participants in each group (1 patient was diagnosed and treated for Clostridium difficile-associated diarrhea, which occurred after completing the full course of study medication). No hypersensitivity reactions occurred. The number of patients in this trial was not sufficient to demonstrate a statistically significant difference between the 3 groups; however, both amoxicillin and cefuroxime axetil seem to be safe, efficacious treatments for children with early LD.

Key Words: Lyme disease • cefuroxime • antibiotic therapy

Abbreviations: LD, Lyme disease • EM, erythema migrans • MBC, minimum bactericidal concentration


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Early clinical manifestations of Lyme disease (LD) include erythema migrans (EM), single or multiple, and constitutional symptoms, including headache, myalgias, arthralgias, and fever. Early disseminated LD may also result in neurologic and cardiac involvement. The standard treatment for adults with early LD has been oral doxycycline.1,2 Because of potential toxicities with doxycycline, amoxicillin is generally recommended for children younger than 8 years who have early LD1–3 despite limited published data concerning this use of amoxicillin in children. Both of these agents have been shown to be effective in clinical trials which have mainly involved adults.4–6 Although children constitute a significant proportion of reported cases of LD, few treatment studies have included children. Currently, there is no approved alternative antibiotic for children allergic to amoxicillin.

Clinical trials in adults have shown that oral cefuroxime axetil is an effective alternative to doxycycline and has fewer side effects.7,8 The objective of this study was to evaluate the safety, efficacy, and tolerability of cefuroxime axetil oral suspension and of amoxicillin oral suspension in the treatment of early LD in children.

Amoxicillin and cefuroxime axetil are active in vitro against most strains of Borrelia burgdorferi with minimum bactericidal concentrations (MBC) of 0.8 to 2.0 µg/mL9,10 and 1.0 µg/mL, respectively.9 Both drugs have good bioavailability when administered orally, with reasonably similar peak levels and areas under the curve. The optimal dose for treatment of Lyme borreliosis should provide therapeutic concentrations (>MBC for the drug against B burgdorferi) without inducing significant toxicity. A dose of 50 mg/kg of amoxicillin is commonly recommended for children with LD. Previous pharmacokinetic studies in children11 suggest that 20 to 30 mg/kg/d of cefuroxime axetil would be a reasonable dosage range for this infection. The duration of treatment for early LD is typically 14 to 30 days.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Pediatric subjects were recruited from private pediatric offices in the Delaware Valley region (Delaware, Pennsylvania, and New Jersey). Inclusion criteria were 6 months old to12 years and physician-diagnosed EM. Patients were excluded if they were allergic to penicillins or cephalosporins, had significant past or current medical conditions, or had neurologic findings (other than isolated peripheral facial palsy). Before subject randomization, informed consent was obtained from a legal guardian and informed assent was obtained from all subjects ages 7 and above. Subjects were then randomized to receive 1 of 3 medication regimens for 20 days: amoxicillin 50 mg/kg/d (maximum dose: 1500 mg/d) divided every 8 hours, cefuroxime axetil 20 mg/kg/d (maximum dose: 750 mg/d) divided every 12 hours, or cefuroxime axetil 30 mg/kg/d (maximum dose: 1000 mg/d) divided every 12 hours. Serologic testing included enzyme-linked immunoassay, IgM Western blot, and IgG Western blot, and was performed at study entry and at 6 months. Serology was performed, as previously described,12,13 at a central facility within 3 days of specimen collection. Follow-up physical examinations occurred at 7 to 10 days, 3 weeks, and 6 months, with a final telephone follow-up at 12 months after study entry to assess any late-occurring complications. The following were evaluated: clinical presentation (including photograph of EM), resolution of EM, and other disease manifestations, occurrence of new disease manifestations, compliance, and adverse effects related to antibiotic therapy. Tolerability of antibiotic therapy was assessed by asking parents to respond to questions using a 4-point Likert scale.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Forty-three patients were randomized over 25 months during 1997–1999. Thirty-nine completed 12 months of follow-up. A priori power analysis was completed for the study.14 The analysis assumed: 1) data were on the nominal level of measurement; 2) {chi}2 analysis would be conducted between the 2 smallest posthoc comparisons; and 3) the analysis would be sensitive to differences at P <= .05. The power estimate for small expected differences was 0.083. In other words, there was only an 8.3% chance of finding small expected differences between groups if such differences exist. Therefore, statistical comparisons were not performed; instead, results are discussed clinically.

Clinical characteristics of participants at the time of enrollment are shown in Table 1. Among the 3 treatment groups, there were no apparent differences in age, sex, duration of illness before evaluation, presence of fever, multiple EM, facial palsy, or initial serologic results. The results of serology testing at 6 months and resolution of LD symptoms are reported in Table 2. Three patients in the low-dose cefuroxime group and 1 patient in the amoxicillin group were not fully evaluable as stated in the Table. There were no apparent differences in resolution of early LD among the groups. One child in the high-dose cefuroxime group, who had originally presented with high fever and solitary EM developed new constitutional symptoms after treatment. There had been no objective physical findings at the 10- and 20-day follow-up visits. He received a course of doxycycline for 30 days and all symptoms resolved. No other child required additional antibiotic therapy. There was no difference in serologic reactivity at 6 months among the 3 groups. All patients in all groups were well at the 6-month and 1-year follow-up evaluation. No long-term complications of LD were observed.


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  		TABLE 1. Clinical Characteristics of Patients Enrolling in the Study

 

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  		TABLE 2. Resolution of LD

 
Compliance with medication was good for all patients completing the study. Relatively few adverse reactions were reported; no serious adverse reactions occurred (Table 3). Two subjects in the low-dose cefuroxime group withdrew from the study within the first 3 days of treatment because of poor palatability; the parent of 1 of these reported vomiting after each dose. Mild diarrhea was reported in a minority of subjects in each treatment group. One parent reported at the 6-month visit that her child had been diagnosed and treated for C difficile-associated diarrhea by a nonstudy physician shortly after completing the 20 days of treatment with low-dose cefuroxime axetil. Jarisch-Herxheimer reactions were suspected by study physicians for 1 amoxicillin and 1 low-dose cefuroxime recipient, although neither had a skin eruption.


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  		TABLE 3. Adverse Reactions (Parental Report)

 
A parent survey of tolerability of the medications was conducted at each follow-up contact, using a 4-point Likert scale. Results of the survey indicated that both drugs were generally easy to administer and well tolerated. Parents of children receiving amoxicillin agreed or strongly agreed 98% of the time that it was easy to administer and well tolerated, compared with 79% and 88% of responses from parents of children receiving low-dose and high-dose cefuroxime axetil, respectively. Several patients who received cefuroxime axetil complained about the taste of the oral suspension. Some parents reported that palatability of cefuroxime axetil was improved if each dose was followed with white grape juice or a tablespoon of chocolate syrup.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
LD has become a major public health problem in endemic regions,1 which include southern New England, the mid-Atlantic states, and parts of the upper Midwest. After inoculation of B burgdorferi into skin, the characteristic skin lesion, EM, appears in the majority of cases (early localized LD). EM can resolve spontaneously, or as a result of antibiotic treatment, with no additional disease manifestations. If the spirochete gains access to the systemic circulation, infection may occur in a variety of tissues, resulting in joint, central and peripheral nervous system, cardiac, and ocular involvement. The goals of antibiotic therapy of early LD are to resolve the acute manifestations and to prevent late complications.

Many clinical trials of antibiotic therapy for LD have been performed over the last 2 decades in both the United States and Europe. Most of these trials have involved adult patients and have focused on specific clinical manifestations, such as EM or neurologic disease. Two pediatric observational databases, 1 retrospective15 and 1 prospective,16 have demonstrated that early recognition and treatment with an appropriate antibiotic prevents long-term complications. Our randomized comparative study is the first US trial to specifically evaluate antibiotic therapies in a pediatric population.

Of the oral ß-lactam antibiotics, amoxicillin and cefuroxime axetil have been the most extensively studied in LD clinical trials. The combination of amoxicillin and probenecid demonstrated efficacy comparable with doxycycline in a trial of adult patients with early LD4 and in adults with Lyme arthritis.6 However, in the latter study, subsequent neurologic involvement appeared more frequently in patients who received amoxicillin and probenecid. Based on its in vitro activity and on limited published studies, amoxicillin is considered the oral agent of choice for children under 8 years of age. The present prospective study supports the efficacy of amoxicillin in treating early LD in a childhood population.

Cefuroxime axetil has been compared with doxycycline in adults with early LD7,8 and seems to have equal efficacy with fewer adverse reactions. Nadelman et al7 compared cefuroxime axetil, 500 mg twice daily, with doxycycline, 100 mg 3 times daily, each used for 20 days, and found similar rates of improvement with low rates of subsequent complications of LD. In a similarly designed study, Luger et al8 reported fewer drug associated adverse events with cefuroxime axetil. Based on the results of these studies, the Food and Drug Administration approved cefuroxime axetil tablets for use in early LD in adults.

Our study compared the use of cefuroxime axetil oral suspension to amoxicillin oral suspension in early LD in children. Two doses of cefuroxime axetil were tried, corresponding to the 20 mg/kg/d dose for pharyngitis and the 30 mg/kg/d dose for otitis media and sinusitis. In terms of resolution of acute signs and symptoms and prevention of late complications, all 3 regimens worked very well. All children in each group were felt to be cured of LD, with no evidence of complications, after 1 year of follow-up. This period of follow-up should be sufficient to detect most late occurring manifestations of LD.

Serologic testing was used in this study, along with clinical presentations, to demonstrate comparability of the groups at study entry. In fact, there was a trend toward greater initial seroreactivity on the IgM Western blot in the cefuroxime groups. This might correlate with the higher numbers of disseminated EM, which in turn, suggests longer duration of infection before antibiotic treatment. Serologic testing was repeated at 6 months as a surrogate marker for successful treatment. Its use in this regard is not standard, and in clinical practice, follow-up antibody tests are sometimes misleading. However, the lack of a late IgG response, combined with the good clinical response, was reassuring for both cefuroxime- and amoxicillin-treated groups.

In this trial, both amoxicillin and cefuroxime axetil seemed safe. No allergic reactions occurred. Diarrhea during treatment was reported in a minority of children and was considered mild in all cases. Jarisch-Herxheimer reactions, which occur as a result of killing of spirochetes (and are not considered allergic reactions), were suspected in 1 amoxicillin and 1 low-dose cefuroxime axetil recipient. Tolerability of treatment was generally good for both drugs, although palatability was an issue for some cefuroxime-treated patients.

The number of patients in this trial was not sufficient to demonstrate a significant difference between the 3 groups or even statistically valid comparability. Many published trials concerning LD treatment have this limitation in common. However, our safety and efficacy results were good for each group and are in keeping with what has been reported from previous LD trials, in particular those involving the use of cefuroxime axetil in adults. The ideal dose of cefuroxime axetil cannot be discerned from this trial; however, both 20 and 30 mg/kg/d seemed efficacious, with no significant difference in adverse effect profile.

In July 2000, the Infectious Diseases Society of America published its guidelines for the treatment of LD.2 Amoxicillin and doxycycline were recommended as the oral drugs of choice. Because of its higher cost, cefuroxime axetil was recommended as the alternative oral agent, including an implied endorsement for pediatric use at a dose of 30 mg/kg/d. The Red Book from the American Academy of Pediatrics Committee on Infectious Diseases also suggests cefuroxime axetil as an alternative treatment.3 We believe this study provides evidence for the safety and efficacy of both cefuroxime axetil and amoxicillin for the treatment of early LD in children. For children allergic to amoxicillin, this evidence will be considered particularly important.

Stephen C. Eppes, MD*,{ddagger} and Judith A. Childs, PhD*

* Alfred I. DuPont Hospital for Children, Wilmington, DE 19899
{ddagger} Jefferson Medical College, Philadelphia, PA

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   ACKNOWLEDGMENTS
 
This study was funded, in part, by a grant from Glaxo-Wellcome, Research Triangle Park, North Carolina.

The following pediatricians and pediatric practices in the Delaware Valley region are gratefully acknowledged for enrolling patients in our study: Brandywine Pediatrics (Robert S. Walter, MD), Wilmington, Delaware; Broomall Pediatric Associates, West Goshen, Pennsylvania; Gloucester County Pediatrics, Deptford, New Jersey; Kids First (Henry Karcsh, DO), Kennett Square, Pennsylvania; Kids First (Cheryl F. Lowe, MD, Vicky L. Scheid, MD, and Kristen Shapren, MD), West Grove, Pennsylvania; Pediatric Associates, Newark, Delaware; Pediatric Associates of the Main Line, Wynnewood, Pennsylvania; Pike Creek Pediatric Associates, Wilmington, Delaware; South Jersey Family Care Center, Salem, New Jersey; and Debra R. Zussman, MD, and Pamela J. Stone, MD, Chadds Ford, Pennsylvania.


   FOOTNOTES
 
Received for publication Apr 16, 2001; Accepted Feb 21, 2002.

Reprint requests to (S.C.E.) Alfred I. duPont Hospital for Children, Division of Infectious Diseases, 1600 Rockland Rd, Wilmington, DE 19899. E-mail: seppes{at}nemours.org

This study was presented at the Infectious Diseases Society of America annual meeting, November 19, 1999, Philadelphia, PA.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Falagas ME, Gorbach SL. IDCP practice guidelines. Infect Dis Clin Pract.1996; 5 :217 –225
  2. Wormser GP, Nadelman RB, Dattwyler RJ, et al. Practice guidelines for the treatment of Lyme disease. Clin Infect Dis.2000; 31(suppl 1)S1 –S14
  3. American Academy of Pediatrics. Lyme disease. In: Abramson J, ed. 2000 Red Book. 25th ed. Elk Grove Village, IL: AmericanE Academy of Pediatrics; 2000:377
  4. Dattwyler RJ, Volkman DJ, Conaty SM, Platkin SP, Luft BJ. Amoxycillin plus probenecid versus doxycycline for treatment of erythema migrans borreliosis. Lancet.1990; 336 :1404 –06[Medline]
  5. Massorotti EM, Luger SW, Rahn DW, et al. Treatment of early Lyme disease. Am J Med.1992; 92 :396 –403[Medline]
  6. Steere AC, Levin RE, Mulloy PJ, et al. Treatment of Lyme arthritis. Arthritis Rheum.1994; 37 :878 –888[Medline]
  7. Nadelman RB, Luger SW, Frank E, et al. Comparison of cefuroxime axetil and doxycycline in treatment of patients with early Lyme disease. Ann Intern Med.1992; 117 :273 –280[Medline]
  8. Luger SW, Paparone P, Wormser GP, et al. Comparison of cefuroxime axetil and doxycycline in treatment of patients with early Lyme disease associated with erythema migrans. Antimicrob Agents Chemother.1995; 39 :661 –667[Abstract]
  9. Levin JM, Nelson JA, Segreti J, Harrison B, Benson CA, Strle F. In vitro susceptibility of Borrelia burgdorferi to 11 antimicrobial agents. Antimicrob Agents Chemother.1993; 37 :1444 –1446[Abstract]
  10. Johnson RC, Kodner CB, Jurkovich PJ, Collins JJ. Comparative in vitro and in vivo susceptibilities of the Lyme disease spirochete Borrelia burgdorferi to cefuroxime and other antimicrobial agents. Antimicrob Agents Chemother.1990; 34 :2133 –2136[Medline]
  11. Powell DA, James NC, Ossi MJ, Nahata MC, Donn KH. Pharmacokinetics of cefuroxime axetil suspension in infants and children. Antimicrob Agents Chemother.1991; 35 :2042 –2045[Medline]
  12. Fawcett PT, Rose CD, Gibney KM, Doughty RA. Frequency and specificity of antibodies which cross-react with Borrelia burgdorferi antigens. J Rheumatol.1992; 19 :582 –587[Medline]
  13. Fawcett PT, Rose CD, Gibney KM. Comparative evaluation of adsorption with E coli on ELISA tests for Lyme borreliosis. J Rheumato.l1995; 22 :684 –688[Medline]
  14. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, NJ: Lawrence Erlbaum Associates; 1988
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PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics



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This Article
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