Ticarcillin-Clavulanic Acid Pharmacokinetics in Preterm

ANTiMIROBLAL AGENTS AND HEMOTHERAPY, Sept. 199, p. -8 Vol. 38, No. 9 66-8/9/$.+ opyright 199, American Society for Microbiology Ticarcillin-lavulanic Acid Pharmacokinetics in Preterm Neonates with Presumed Sepsis AARON H. BURSTEIN,'* LANE E. WYBLE, PETER GAL,3' PHILIP R. DIAZ,3' J. LAURENE RANSOM, RITA Q. ARLOS, AND ALAN FORREST' Division of Neuropharnnacology, Dent Neurologic Institute, Millard Fillmore Hospital, Buffalo, New York 191; Department of Pediatrics, University of South Florida ollege of Medicine, Tampa, Florida 3366; Greensboro Area Health Education enter, The Moses H. one Memorial Hospital3 and The Women's Hospital of Greensboro, Greensboro, North arolina; and enter for linical Pharmacy Research, School of Pharmacy, The State University of New York at Buffalo, Buffalo, New York 165 Received 1 January 199/Returned for modification 1 April 199/Accepted 6 June 199 The objective of the reported study was to characterize the pharmacokinetics of ticarcillin and clavulanic acid in premature low-birth-weight (less than, g) neonates with presumed sepsis. Eleven infants received 1 courses of ticarcillin-clavulanic acid at 75 mg/kg of body weight intravenously every 1 h. Blood samples were collected at.5, 1.5,, and 8 h following the infusion of the initial dose. The concentrations of ticarcillin and clavulanic acid were determined by a microbiologic assay. Median (interpatient coeflicients of variation) values for the volume of the central compartment, total steady-state volume, distributional clearance, total clearance, and terminal elimination half-life for ticarcillin were.3 liter/kg (1%),.6 liter/kg (8%),.1 liter/h/kg (7%),.7 liter/h/kg (7%), and. h (5%), respectively. For clavulanic acid the parameters were.8 liter/kg (3%),.36 liter/kg (3%), 11 liters/h/kg (36%),.1 liters/h/kg (7%), and 1.95 h (%Yo), respectively. Our results suggest that the current dosing recommendations of 75 mg/kg every 1 h risk subtherapeutic clavulanic acid concentrations, and that 5 mg/kg every 6 h is a more rational dosing strategy. Bacterial infections are a common complication in the management of premature newborns in the intensive care nursery. Initial infections are often managed with ampicillin and gentamicin, while subsequent infections require antibiotics which cover gram-positive as well as gram-negative organisms. The antibiotics of choice in the Neonatal Intensive are Unit of The Women's Hospital of Greensboro have been vancomycin and ticarcillin-clavulanic acid. Unfortunately, few published data that can be used to describe the pharmacokinetics of ticarcillin and clavulanic acid in low-birth-weight premature neonates are available. Dosing guidelines in neonates are largely empiric and are founded on the pharmacokinetic data available for ticarcillin in newborns. urrent published guidelines recommend a ticarcillin dose of 75 mg/kg of body weight every 1 h until the infant is greater than weeks of postnatal age (13). The present study focused on obtaining pharmacokinetic parameters for both ticarcillin and clavulanic acid in small preterm neonates and developing dosing guidelines specifically for this patient population. MATERIALS AND METHODS The study was approved by the Institutional Review Board of the Moses H. one Memorial Hospital and the Women's Hospital of Greensboro, Greensboro, N.. Prior to enrollment of the patients, informed consent was obtained from the infants' parents or legal guardians. Neonates with documented or suspected sepsis were considered eligible for inclusion in the study if they were less than 36 weeks of gestational age as estimated on the basis of the method of Ballard et al. (3), weighed less than, g at birth, * orresponding author. Mailing address: Division of Neuropharmacology, Dent Neurologic Institute, Millard Fillmore Hospital, 3 Gates ircle, Buffalo, NY 19. Phone: (7) 887-799. Fax: (7) 887-5193. and had received a course of at least 3 days of ampicillin and gentamicin for the treatment of sepsis. Prior courses of antibiotics were separated from the study treatment by a minimum of days. Eleven patients (seven males, four females) were enrolled in the study. Baseline chemistries, complete blood counts with differentials including platelets, and samples of blood and/or urine for culture were obtained. In addition, clinical evaluation, measurement of length and weight, and determination of gestational age were performed. Follow-up chemistries and complete blood counts with differentials including platelets were repeated daily while the infant was clinically acutely ill and at a minimum of twice weekly thereafter. Ticarcillin-clavulanic acid (lot 559; SmithKline Beecham Pharmaceuticals) was administered at a dose of 75 mg/kg over 15 min by using a syringe pump (model 11; Medfusion). The preparation administered was the commercially available product, which contains a 3-to-1 ratio of ticarcillin (7.5 mg/kg) to clavulanic acid (.5 mg/kg). Following administration, the intravenous access site was flushed with 1 ml of.9% Nal. Following infusion of the initial dose of ticarcillin-clavulanic acid ( h), blood samples were collected at.5, 1.5,, and 8 h from an umbilical artery catheter, when available, or from a capillary heel prick. Samples were immediately centrifuged for 1 min at > 1,75 rpm and the serum was harvested, placed in polypropylene vials, and frozen at -7 until analyzed by the Research and Development Laboratories of SmithKline Beecham Pharmaceuticals. Twelve courses of therapy were studied. Analysis of serum samples for ticarcillin and clavulanic acid concentrations was performed using a slightly modified version of the agar diffusion method described by Staniforth et al. (1). Ticarcillin concentrations in serum were determined by using Pseudomonas aeruginosa NT 171 as the test organism and antibiotic medium (Difco Laboratories). The assay was linear Downloaded from http://aac.asm.org/ on November 1, 18 by guest

VOL. 38, 199 TIARILLIN-LAVULANI AID PHARMAOKINETIS 5 over the concentration range of 1.6 to 1 mg/liters. Withinday coefficients of variation (Vs) associated with the assay were 3.8 and 1.9% at the low and high ends of this concentration range, respectively. Between-day Vs were less than 1%. The lower detection limit for ticarcillin was 1.6 mg/liter. Analysis for clavulanic acid concentrations in serum was conducted by using Kiebsiella pneumoniae NT 118 as the test organism and nutrient agar (Oxoid). The assay was linear over the concentration range of.8 to 5 mg/liter. Within-day Vs associated with the low and high ends of the clavulanic acid concentration range were.7 and 1.3%, respectively. Between-day Vs were less than 1%. The lower detection limit was.78 mg/liter. Iterative two-stage analysis done with the computer software package Adapt II (6) was performed to fit candidate models to the serum concentration-time data. A description of this technique is provided elsewhere (11). Model discrimination was by Akaike's Information riterion (1). The serum concentration-time data reported by Fricke et al. (1) were initially fit by a linear, two-compartment open model to determine estimates of the maximum a posteriori (MAP)- Bayesian estimators for the volume of the central compartment, volume of the peripheral compartment, distributional clearance (Ld), and total clearance (L) for both ticarcillin and clavulanic acid. These results were then used as initial MAP-Bayesian estimators for the subsequent iterative twostage analysis of our data. Modeling incorporated a residual variance model, in which the standard deviations of the observations were linearly related to the fitted values. The parameters estimated for both ticarcillin and clavulanic acid included the volume of distribution in the central compartment (Vc), volume of distribution in the peripheral compartment (V) L, and Ld. The volume of distribution at steady state (V-{) and the terminal elimination half-life (t1l) were calculated on the basis of the following parameters: k = Ld/V, kpc = Ld/Vp, kel = L/Vc,B3= (kel + kcp + k S)/Y -/(kei+ k + kpc)/ - kel 1kpcg t1/ =.693/,B, and V%s = Vc + Vp, where kcp and kpc are intercompartmental rate constants and kel is the elimination rate constant, and 13 is the elimination rate constant. omparison of Vc, Vr, Ld, L, and t11 between ticarcillin and clavulanic acid was performed by Wilcoxin's rank sum test. Statistical significance was defined as a P value of <.5. TABLE 1. Subject demographics Subject Gestational Postnatal Postconceptional Wt (g) age (wk) age (days) age (wk) 1 9.7 8 3.8 879 3. 3.6,11 3 31. 11 3.6 1,193 3. 7 31. 1, 5 3. 117 8.7 1,659 6a 3. 6 3.9 767 6b 3. 19 3.7 79 7 9. 1 3.8 99 8 9. 1 3.8 683 9 3. 3.6 1,5 1 3. 3.6 1,36 11 3. 18 3. 1,8 Median 3. 9 3.5 1,5 summary of the data for individual patients is provided in Table. Upon comparison of the pharmacokinetic parameters for clavulanic acid with those determined for ticarcillin, RESULTS Treatment was well tolerated by all subjects, with no significant adverse experiences or laboratory abnormalities being attributed to the administration of the ticarcillin-clavulanic acid combination. Subject demographics are summarized in Table 1. The pharmacokinetics of ticarcillin and clavulanic acid were best described by a linear, open two-compartment model. Figures 1A and A display the measured concentrations of ticarcillin and clavulanic acid in serum, respectively, following administration of the initial dose of tiarcillin-clavulanic acid. The area under the curve was variable, with a mean (range) of - 1,78 mg * h/kg/liter (559 to 3,57 mg h/kg/liter) for ticarcillin and 1 mg * h/kg/liter (6 to mg * h/kg/liter) for clavulanic acid. The median (interpatient V) for L, Ld, Vc, Vs, and t1, for ticarcillin were.7 liter/h/kg (7%),.1 liter/h/kg (7%),.3 liter/kg (1%),.6 liter/kg (8%), and. h (5%), respectively. For clavulanic acid, the parameters were as follows:.1 liter/h/kg (7%), 11 liter/h/kg (36%),.8 liter/kg (3%),.36 liter/kg (3%), and 1.95 h (%), respectively. A statistically significant differences were found. Larger V, (P <.5), L (P <.1), and Ld (P <.1) were found for clavulanic acid. The t11 of ticarcillin was approximately twofold longer (P <.1). No difference was found upon comparison of the ticarcillin V., with that of clavulanic acid (P >.5). Simulations of the ticarcillin and clavulanic acid concentrations at steady state were performed for the 1 individual treatment courses. The recommended dosage of 75 mg/kg every 1 h resulted in mean (range) peak and trough ticarcillin concentrations of 976 mg/liter (753 to 1,917 mg/liter) and mg/liter (.8 to 91 mg/liter), respectively (Fig. 1B). The concurrent peak and trough clavulanic acid concentrations were 6.8 mg/liter (.9 to 13 mg/liter) and.6 mg/liter (. to.9 mg/liter), respectively (Fig. B). This is in contrast to the mean (range) peak and trough concentrations on a regimen of 5 mg/kg every 6 h of 71 mg/liter (5 to 1,33 mg/liter) and 11 mg/liter (1.5 to 17 mg/liter) for ticarcillin (Fig. 1) and 5. mg/liter (.1 to 9.6 mg/liter) and.88 mg/liter (.57 to.6 mg/liter) for clavulanic acid (Fig. ). Use of a regimen of 75 mg/kg every 1 h would expose 1 of 1 (83%) subjects to serum ticarcillin concentrations below the upper limit of sensitivity, i.e., mg/liter. If the dosage of 5 mg/kg every 6 h is used, this is reduced to 3 of 1 (5%) subjects. lavulanic acid concentrations were less than mg/liter for a mean (range) of 65.5% (33 to 91.7%) of the dosing interval when the dosage of 75 mg/kg every 1 h was used, whereas they were less than mg/liter for 9.1% ( to 1%) of the dosing interval when the dosage of 5 mg/kg every 6 h was used. DISUSSION The sampling strategy used in our study was sparse and empiric. Retrospective analysis by optimal sampling theory (5, 6, 8) suggests that partitioning between V, and Vp as well as values of Ld are poorly identifiable for both ticarcillin and clavulanic acid. Vs, and L are well identified. The optimal four sampling times for this population are approximately,.75,, and 9 h following the completion of dose administration. In comparison with the optimal sampling times, the actual sampling times (.5, 1.5,, and 8 h following administration) provided larger theoretical Vs for partitioning between Vc and V and for values of Ld, but a similar information content on vafues of Vs. and L. Downloaded from http://aac.asm.org/ on November 1, 18 by guest

6 BURSTEIN ET AL. ANTIMIROB. AGENTS HEMOTHER. A B 1 - c 1 ) -j 1I 1i 1 1I 1 1 6 8 1 6 8 1 1 1 3 5 6 Time (hours) FIG. 1. Ticarcillin serum concentration-time profiles for individual subjects observed following administration of the initial 75-mg/kg Mae (A) and simulated for every 1-h dose of 75 mg/kg (B) and simulated for every 6-h dose of 5 mg of ticarcillin-clavulanic acid (Timentin) per kg. The horizontal lines represent the upper ( mg/liter) and lower ( mg/liter) limits for organism susceptibility to ticarcillin. The pharmacokinetic parameters that we determined were consistent with those reported by other investigators (9, 1) in infants closer to full term than ours,, Fayed et al. (9) reported a mean ± standard deviation t1, for ticarcillin of.5 ± 3. h and for clavulanic acid of ± 1.6 h. Their sample consisted of newborn infants with a mean gestational age of 3.7 weeks (range, 5 to 39 weeks) and a mean birth weight of 1,7 g (ranige, 895 to 3,9 g) (9). Fricke et al. (1), in their sample of seven preterm infants with a mean birth weight of,377 g (range, 1,915 to,65 g) and a mean gestational age of 35 weeks (range, 3 to 36 weeks), found a mean ± standard deviation Vs, and t1 for ticarcillin of.338 ±.35 liter/kg and. ±.5 h, respectively and for clavulanic acid of.1 +.9 liter/kg and.56 +.18 h, respectively. Additionally, the pharmacokinetics of ticarcillin and clavulanic acid were available for one patient with a gestational age of 3 weeks and a birth weight of 1, g. The Vss and t1l for ticarcillin were.515 liter/kg and h, respectively, and those for clavulanic acid were.1 liter/kg and.5 h, respectively, in that subject (1). Although it was not surprising, the more rapid clearance of clavulanic acid in comparison with that of ticarcillin is of concern. Ticarcillin, with its primarily renal route of elimination, would be expected to exhibit diminished clearance in this population, which possesses relatively immature kidneys and tubular secretory capacity (). In contrast, clavulanic acid is eliminated primarily through nonrenal mechanisms (7), with these mechanisms generally being more mature than renal 1 1' function in this population. The more rapid clearance and shorter t11 of clavulanic acid potentially leave ticarcillin susceptible to destruction by,-lactamase during that portion of the dosing interval when.clavulanic acid concentrations are negligible. This concern arises in cases in which ticarcillinclavulanic acid-susceptible, ticarcillin-resistant organisms are suspected and/or isolated. As a result of the different clearances of ticarcillin and clavulanic acid, questions arise as to the appropriate method for dosing ticarcillin-clavulanic acid in this population. Of particular interest is the issue of the appropriate target concentrations of clavulanic acid necessary for the adequate inhibition of 1-lactamase. To determine this optimal concentration, a knowledge of the turnover number, or the number of clavulanic acid molecules required to inactivate a single,-lactamase molecule, is required for each type of,-lactamase that may be clinically encountered. Bush et al. (), in thbir evaluation of the kinetic interaction of tazobactam with,b-lactamases, additionally determined the number of turnovers required for inactivation of numerous,-lactamase enzymes in the presence of clavulanic acid. This value varies among the different enzymes, ranging from a value of 1 for P1 enzymes to >5, for P99 and ra enzymes. Alterations in the amino acid profiles of the different 1-lactamase enzymes are considered to be responsible for the variability in turnover numbers. The investigators concluded, on the basis of the tazobactam data, that the enzymes tested demonstrated reversible reactions upon incubation with ta- Downloaded from http://aac.asm.org/ on November 1, 18 by guest

VOL. 38, 199 TIARILLIN-LAVULANI AID PHARMAOKINETIS 7 1 A 1 B 1 E 8 1 1 a a) 6 8 6 c 6 8 1 6 8 1 1 1 3 5 6 Time (hours) FIG.. lavulanic acid serum concentration-time profiles for individual subjects observed following administration of the initial 75-mg/kg dose (A) and simulated for every 1-h dose of 75 mg/kg and simulated for every 6-h dose of 5 mg of ticarcillin-clavulanic acid (Timentin) per kg. The horizontal line represents the minimum therapeutic concentration of clavulanic acid ( mg/liter). zobactam. The degree of reversibility of inhibition was related to the turnover number for tazobactam relative to the individual enzymes. Because this value varied across enzymes, the investigators concluded that successful inhibition of all,b-lactamases requires the presence of a minimum maintained concentration of tazobactam. While the investigators described above failed to extend their conclusion to clavulanic acid, a previous investigation (1) supports the extrapolation of this conclusion. Those investigators found that incubation of various concentrations of clavulanic acid with,-lactamase from an Escherichia coli TABLE. Ticarcillin and clavulanic acid pharmacokinetics Ticarcillin RTEM strain resulted in various degrees of enzyme inhibition. As the ratio of clavulanic acid to enzyme was increased there was a concomitant increase in the extent of irreversible inhibition of the P-lactamase enzyme. However, at all but the highest ratio of inhibitor to enzyme (15:1) a variable recovery of enzyme activity was demonstrated. At a molar ratio of 15, complete inhibition was observed. Recovery of enzyme activity appeared to begin upon complete utilization of the available clavulanic acid. It may be hypothesized that, similar to the conclusions for tazobactam (), maintenance of a minimum concentration of clavulanic acid is warranted. lavulanic acid Subject V V. Ld L t/ V. V. Ld L t1/ (liter/kg) (liter/kg) (liter/h/kg) (liter/h/kg) (h) (liter/kg) (liter/kg) (liter/h/kg) (liter/h/kg) (h) 1.3.37.35. 6.5..3 11.8.57 3.7.13.5.1.8 9.5.33. 1.9.8 3.6 3..51.1.13 6.1.7.6 1.9.36 1..31.31.19.77 3.7..6.8. 1. 5.1..3.81 1..3.39 11.5.5 1.1 6a.3.3.38.5 5..3.55 11..1 1.8 6b.3.18.51.38 3.5.7.35 1.1.1 1.8 7.5.1.7...5.3 11..1.3 8.9.6.3.9..1.19 1.1.63.1 9.31.1.68.1 3..1.8 5.89.83.3 1.3.6..37 5.3.7.35 11..1. 11.9.1..5 3..8.36 11.5.1 1.8 Median.3.6.1.7..8.36 11..1. Minimum.13.1.1.1 1..1.19.8.57 1.1 Maximum.3.51.68.13 9.5.7.6 1.9. 3.7 Downloaded from http://aac.asm.org/ on November 1, 18 by guest

8 BURSTEIN ET AL. ANTIMIROB. AGENTS HEMOTHER. One proposed dosing strategy is such that in vivo concentrations are maintained above a certain finite concentration throughout the entire dosing interval. This value has generally been considered to be mg/liter because typical measures of MIs for organisms use a fixed -mg/liter concentration of clavulanic acid (15). In the presence of a fixed -mg/liter concentration of clavulanic acid, P-lactamase-producing strains of Staphylococcus aureus, Staphylococcus epidermidis, Branhamella catarrhalis, Haemophilus influenzae, Neisseria gonorrhoeae, E. coli, Kiebsiella species, and Bacteroides species exhibit increased susceptibilities to ticarcillin in comparison with their susceptibilities when they are exposed to ticarcillin alone (15). Since the need for persistent concentrations of clavulanic acid cannot be excluded, we believe a more conservative dosing strategy, maintaining a clavulanic acid concentration of greater than mg/liter, is the most effective approach, provided that excessive concentrations of ticarcillin in serum can be avoided. The main toxicity of ticarcillin appears to be inhibition of platelet adhesion when ticarcillin is present at levels of approximately 1, mg/liter. No clear reason for concern for concentrations less than this is apparent, although platelet adhesion may theoretically be inhibited at lower concentrations in premature infants. Following administration of the initial dose studied, the majority of our subjects exhibited clavulanic acid concentrations of less than mg/liter prior to the 8-h sampling time. At the extreme, two subjects exhibited concentrations of clavulanic acid of less than mg/liter as early as 1.5 to h following administration of the single dose. These low concentrations would continue to be a problem at steady state. Using the pharmacokinetic parameters determined for our individual subjects, we have simulated various dosing regimens, predicting the expected concentration-time data. Simulations were performed by assuming that the ratio of ticarcillin to clavulanic acid administered could not be modified. On the basis of those simulations, we suggest a dosage of 5 mg of ticarcillin-clavulanic acid per kg administered every 6 h. Figures 1 and display the simulated steady-state profiles of concentrations in serum for ticarcillin and clavulanic acid associated with this regimen. While providing an additional 5 mg of ticarcillin-clavulanic acid per kg daily, with the resultant increases in the areas under the curve for ticarcillin and clavulanic acid, maximal concentrations would be expected to be less than those provided with 75 mg/kg dosed every 1 h. While this regimen leaves a number of individuals with subtherapeutic concentrations of clavulanic acid, it provides therapeutic concentrations for a greater percentage of the dosing interval. Use of the doses of ticarcillin-clavulanic acid that were predicted to provide therapeutic steady-state concentrations of clavulanic acid throughout the entire dosing interval runs the risk of providing excessive, and potentially toxic, maximal concentrations of ticarcillin. The pharmacokinetics of ticarcillin and clavulanic acid after administration to our subjects were similar to those after administration to older, more mature infants in earlier studies (9, 1). Because of the finding of significantly larger clearances and shorter t1/ values of clavulanic acid in comparison with those of ticarcillin, there is a risk that the concentrations of clavulanic acid may become subtherapeutic, thereby warranting revision of current dosing practices. On the basis of the pharmacokinetics of these agents in our small number of subjects, an alternative dosing recommendation on the basis of the assumption that a minimum concentration of clavulanic acid of,ug/ml will provide a favorable turnover number is the administration of 5 mg of ticarcillin-clavulanic acid per kg every 6 h. Further studies are necessary to validate prospectively the adequacy of this regimen, assess the clinical impact, and develop criteria to more adequately optimize dosing regimens. AKNOWLEDGMENT The assistance of SmithKline Beecham Pharmaceuticals in the determination of ticarcillin and clavulanic acid concentrations is acknowledged. REFERENES 1. Akaike, H. 1976. An information criterion (AI). Math Sci. 1:5-9.. Assael, B. M. 198. Pharmacokinetics and drug distribution during post natal development. Pharmacol. Ther. 18:159-197. 3. Ballard, J. L, K. K. Novak, and M. Driver. 1979. A simplified score for assessment of fetal maturation of newly born infants. J. 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J. lin. Pharmacol. Ther. Toxicol. :13-19. 15. Sutherland, R, A. S. Beale, R J. Boon, K. E. Griflin, B. Slocombe, D. H. Stokes, and A. RK White. 1985. Antibacterial activity of ticarcillin in the presence of clavulanate potassium. Am. J. Med. 79(Suppl. 5B):13-. Downloaded from http://aac.asm.org/ on November 1, 18 by guest