Treatment of neuroborreliosis in childhood NEUROBORRELIOSIS IN CHILDHOOD: TREATMENT WITH PENICILLIN SODIUM AND CEFTRIAXONE M. M. Millner, G. H. Thalhammer ABSTRACT Beta-lactam antibiotics like ceftriaxone and penicillin G sodium have been shown to be active against Borrelia burgdorferi in vitro. Results of quantitative determinations of both antibiotic substances in cerebrospinal fluid of children are limited. 75 children (median age 96 months, range 10 to 176 months) with probable or definite neuroborreliosis were treated with ceftriaxone (1 x 50-90 mg/kg/day) or penicillin G sodium (4 x 80,000-120,000 I.U./kg/day) intravenously for 14 days. On day ten of therapy levels of penicillin G sodium (1, 1.5, 2, 3, 4, 5, or 6 hours after intravenous administration), and ceftriaxone (1, 2, 4, 6, 12, or 24 hours after intravenous administration) in serum and cerebrospinal fluid were measured using a micro agar diffusion bioassay. Results demonstrate that penicillin G sodium concentrations in cerebrospinal fluid were above minimum inhibitory concentration after five hours, but below the limit of determination in 60% after six hours. All ceftriaxone results in cerebrospinal fluid - even after 24 hours - were above minimum inhibitory concentration. Penicillin G sodium serum values ranged from 46.6 to 0.1µ,g/ml (1 to 6 hours post dose) and ceftriaxone serum values from 261 to 5 µ,g/ml (1 to 24 hours post dose ). The role of administration intervals in antibiotic therapy of neuroborreliosis in children is discussed. KEYWORDS neuroborreliosis, antibiotic therapy, cerebrospinal fiuid, ceftria.xone, penicillin INTRODUCTION Since Lyme Borreliosis (LB) is known to be a self limiting disease in some cases, the efficacy of antibiotic treatment cannot be discussed by looking at the clinical outcome of patients alone. Penicillin G sodium and ceftriaxone, a broad-spectrum b-lactamase- resistant third generation cephalosporine, are demon- acta dermatovenerologica A.P A. Vol 5, 96, No 3-4 strated to be active against Borrelia burgdo,feri (Bb) in vitro (1-5). Although it is a bacterial agent, Bb spirochetes cause an aseptic type of meningitis. A low-capacity, facilitated diffusion system at the blood-brain barrier and a transport from cerebrospinal fluid (CSF) back into blood via· the choroid plexus have been described for penicillin G sodium and ceftriaxone in case of inflamed menin- 169 Treatment of neuroborreliosis in childhood Penici/lin G in CSF 0,30 µg/ml 0,25 - 0,20 0,15 0,10 0,05 · 0,00 -+------~------------- 0 2 3 4 5 6 hours after administration Figure 1. Penicillin G sodium concentrations in cerebrospinal fiuid (CSF) on day 10 of therapy. ges (6). Less is known about CSF penetration and pharmacokinetics of both substances in case of an aseptic meningitis in which antibiotics have to penetrate an intact blood-brain barrier. Therefore, concentrations of antibiotics are supposed to be lower. Since results of quantitative determinations of both antibiotic substances in CSF of children are very limited, pharmacokinetics of these substances in case of intact blood-brain barrier were studied by our group. PATIENTS AND METHODS Inclusion criteria over a 3-year period were: - children with aseptic meningitis, with probable or definite central nervous system infection caused by Bb, Ceftriaxone in CSF 10 µg/ml 0+-----+---+--+--+--+---+----- 0 2 4 6 8 10 12 14 16 18 20 22 24 hours after administration neuropsychiatric group, MMM95 Figure 2. Ceftriaxone concentrations in cerebrospinal fiuid (CSF) on day 10 of therapy. 170 300 serum ceftriaxone (µg/ml) 250 200 150 100 50 . ... .. . . .. o __ • .... ··-· ·-·-;•-="'-·-----+----+----+-----< 0,0 0,5 1,0 1,5 2,0 2,5 3,0 CSF ceftriaxone (µg/ml) Figure 3. Correlation of ceftriaxone concentrations in serum and cerebrospinal fiuid (CSF). - intact blood-brain barrier, investigated by the method of Reiber (7), - treatment with 4 x 80,000-120,000 I.U. penicillin G sodium/kg/day, or 1 x 50-90 mg ceftriaxone/kg/day for 14 days intravenously, and - availability of paired CSF and serum samples on day ten ot treatment to measure concentration of both antibiotics. 75 children (median age 96 months, range 10 to 176 months) with probable or definite neuroborreliosis were treated at random with penicillin G sodium or ceftriaxone intravenously. On day ten of therapy paired serum and CSF samples were taken from each patient to control the course of the disease and the effect of antibiotic therapy. On this occasion these samples taken randomly 1, or 1.5, or 2, or 3, or 4, or 5, or 6 hours after intravenous administration (penicillin), and 1, or 2, or 4, or 6, or 12, or 24 hours after intravenous administration ( ceftriaxone ), respectively, were analyzed with a micro agar diffusion bioassay as a standard procedure (8). RESULTS The data in figure 1 demonstrate that 5 hours after administration of penicillin, the concentrations were above the minimum inhibitory concentration (MIC) of 0.005 µ,g/ml (3) in all cases. However, six hours after administration - which means . exactly before giving teh next dose - concentration in 60% was fallen already below the determination limit - which may mean below its MIC. acta dermatovenerologica A.P.A. Vol 5, 96, No 3-4 Treatment of neuroborreliosis in childhood !~ I 40 l 35 ~ 30 - 25 -t- 1 20 t serum penicillin (µg/ml) 15 -~: •• • • 1 O - • 5 ~ • • • o --~ • , • • • • • 0,00 0,05 0,10 0,15 0,20 0,25 CSF penicillin (µg/ml) 0,30 Figure 4: Correlation of penicillin G sodium concen- trations in serum and cerebrospinal fiuid (CSF). Figure 2 shows all ceftriaxone levels in CSF to be above the MIC for Bb, which was reported to be 0.01 to 0.04 µ,g/ml (2,5). In our study the elimination half-life of ceftriaxone was measured to be 9.7 hours. Penicillin G sodium serum values ranged from 46.6 to 0.1µ,g /ml (1 to 6 hours post dose), and ceftriaxone serum values from 261 to 5 µ,g /ml (1 to 24 hours post dose ). Thus, a good correlation between CSF and serum levels of both antibiotic substances are demonstrated (Figures 3 and 4). DISCUSSION Drugs administered for the treatment of LB have to be active against Bb in vitro which is undoubtedly the case for penicillin G sodium and ceftriaxone. Since 72 to 96 hours of an effective antibiotic concentration are necessary to eradicate 99% of the Bb spirochetes (5), effective therapy needs continuos levels of the antibiotic substances above its MIC. Moreover, penetration of antibiotics through blood- brain barrier is important not only for neuroborreliosis but also for early forms of the disease (i.e. derma- toborreliosis) as early dissemination of the infectious agent has been demonstrated (9). The presented data give clear evidence for such a good penetration of both antibiotics through blood-brain barrier even in case of aseptic meningitis in which the blood- brain barrier is fully intact. CSF concentrations above its MIC are demonstrated for both antibiotics. The long half life of ceftriaxone when given once a day guarantees therapeutic levels even after 24 hours. Penicillin G sodium was already below determination limit in 60% of our patients. This may indicate that penicillin G sodium with its short half life is not available continuously in CSF and thus, eradication of Bb could be insufficient in some cases. Further measurements of concentrations of penicillin in CSF samples will be necessary to determine whether it should be given at intervals of 6 hours or preferably 5 hours in the treatment of neuroborreliosis in children to guarantee continuous therapeutic levels in the CSF. REFERENCES l. Preac-Mursic V, Wilske B, Schierz G. European Borrelia burgdo,feri isolated from humans and ticks: culture conditions and antibiotic susceptibility. Zbl Bakt Hyg A 1986; 263: 112-18. 2. Johnson SE, Klein GC, Schmid GP, Feeley JC. Susceptibility of the Lyme disease spirochete to seven antimicrobial agents. Yale J Biol Med 1984; 57: 549-53. 3. Berger BK, Kaplan MH, Rothenberg IR, Barbour AG. Isolation and characterization of the Lyme disease spirochete from the skin of patients with erythema chronicum migrans. J Am Acad Dermatol 1985; 13: 444-49. acta dennatovenerologica A .P.A. Vol 5, 96, No 3-4 4. Mursic VP, Wilske B, Schierz G et al. In vitro and in vivo susceptibility of Borrelia burgdo,feri. Eur J Ciin Microbiol 1987; 6: 424-26. 5. Luft BJ, Halperin JJ, Volkman DJ, Dattwyler RJ. New chemotherapeutic approaches in the treatment of Lyme disease. Ann NY Acad Sci 1988; 539: 93- 102. 6. Spector R. Ceftriaxone transport through the blood brain barrier. J Infect Dis 1987; 156: 209-11. 7. Reiber H . The discrimination between different blood CSF barrier dysfunctions and inflammatory reactions of the central nervous system by a recent evaluation graph for the protein profile of cerebro- spinal fluid. J Neurol 1980; 224: 89-99. 171 Treatment of neuroborreliosis in childhood 8. Georgopoulos A. A simple micro agar diffusion method for the determination of antibiotic concen- trations in blood and other body fluids. Zbl Bakt Hyg 1978; 242: 287-93. 9. Coyle PK, Dattwyler RJ, Dykhuisen D et al. Rapid dissemination of B. burgdorferi from skin to central nervous system in early Lyme disease. Book of abstracts, VIIth International Congress on Lyme Borreliosis, San Francisco, CA (1996) p168. 172 AUTHORS' ADDRESSES Michael M. Millner, MD, associate professor, Karl Franzens-University of Graz, Department of Pediatrics, Neuropsychiatric Group, Auenbruggerplatz 30, A-8036 Graz, Austria Gabriela H. Thalhammer, MD, same address acta dennatovenerologica A.P.A. Vol 5, 96, No 3-4