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Clinical pharmacology of ticarcillin in the newborn infant: Relation to age, gestational age, and weight
474
September 1975 The Journal o f P E D I A T R I C S
Clinical pharmacology of ticarcillin in the newborn infant: Relation to age, gestational age, and weight Ticarcillin, a new penicillin derivative with greater in vitro activity against Pseudomonas than carbenicillin, was given as a single dose of 50 mg/kg intramuscularly on 61 occasions to 54 neonates and young infants. The serum concentrations and rate of elimination varied considerably depending upon gestational age, chronological age, and body weight. Peak serum concentrations depended principal~ upon the volume of distribution which approximated the extracellular fluid volume of the neonate. The plasma clearance and serum half-life of the drug were determined. From these pharmacokinetic data appropriate groupings according to age and body weight were made and dosages and intervals of administration predicted for clinical trials of efficacy with repeated doses.
John D. Nelson, M.D.,* Sharon Shelton, B.S., and Helen Kusmiesz, R.N., Dallas, T e x a s
TIcARCILLIN is a new semisynthetic penicillin with many similarities to carbenicillin. It is a disodium salt of c~-carboxy-3-thienylmethyl penicillin, whereas carbenicillin has a benzyl ring in place of the thienylmethyl structure'.-~ and its pharmacology is almost identical to that of carbenicillin. -~.3 It has essentially the same range of antimicrobial activity as carbenicillin, but it has greater in vitro activity against Pseudomonas aeruginosa, 4-7 with minimal inhibitory concentrations of ticarcillin one-half or less those of carbenicillin and also with greater antiPseudomonas activity in serum. ~ Limited clinical experience in adults suggests that ticarcillin dosages (20 g m / day), one-half to two-thirds of the usual carbenicillin dosages (30-40 gm/day), may he effective for Pseudomonas infections? The drug has not been evaluated in infants. This study was performed to determine the basic clinical pharmacology of ticarcillin in the neonate, anticipating its possible future use for treatment of Pseudomonas or indol-positive Proteus infections. To provide maximum safety to the infant, our standard approach for the investigation of new antibiotics is to substitute one dose of the experimental drug for the analogous drug the From the Department of Pediatrics, University of Texas Southwestern Medical School at Dallas. *Reprint address: 5323 Har~y Hines Bld., Dallas, Texas 75235.
Vol. 87, No. 3, pp. 474-479
baby is receiving for treatment of suspected bacterial infection. From the basic pharmacokinetic data gathered after this single dose, predictions can be made of dosage and intervals of doses for later study of efficacy with repeated antibiotic administration. Abbreviation used EGA: estimated gestational age
MATERIALS AND METHODS Patients studied and treatment. All infants studied were in the newborn nurseries or infant ward of Parkland Memorial Hospital, Dallas, and were receiving a penicillin drug (ampicillin or penicillin G) and kanamycin for treatment of possible bacterial infection. Infants with meningitis were excluded. Signed, informed consent was obtained from the mother. Three to five infants were studied in each of the following weight and age groups: < 1,500 gm, 1,500-2,000 gm, 2,000-2,500 gm, and > 2,500 gm; 1-3 days, 4-7 days, 8-14 days, and 15 days or older. Ticarcillin was given as a single intramuscular injection of 50 mg/kg in the anterolateral thigh. Antibiotic assay and methods of analysis. Serum specimens were collected by heel stick 1/2, 1, 2, 4, and 8 hours after the dose. Serum was stored frozen at - 20 ~ C until assayed. Assays were done within three days of collection. The method for ticarcillin assay was identical to our
Volume 87 Number 3 micromethod for carbenicillin9 but used the ticarcillin laboratory standard. It was determined that concentrations of kanamycin as high as 50/~g/ml present in serum specimens did not influence the ticarcillin assay results. Kanamycin concentrations were measured after inactivation of ticarcillin with penicillinase and all were less than 35/~g/ml. 1~Penicillin and ampicillin have no effect on the assay organism. The regression line of serum concentrations was calculated by least mean squares, omitting values before the highest concentration was achieved. The log of 2 divided by the slope of the line was expressed as the serum halflife of ticarcillin. Volume of distribution of ticarcillin was calculated by assuming that the area under the concentration time curve represented a series of trapezoids. The dosage of ticarcillin in milligrams per kilogram body weight was divided by the area under the curve multiplied by the elimination rate constant (0.693 divided by the calculated serum halflife). The resulting figure multiplied by 1,000 gave the volume of distribution in milliliters per kilogram body weight." Plasma clearance was calculated by dividing the total dosage of drug by the area under the concentration time curve and multiplied by 1,000/60 to express the rate in milliliters per minute." Plasma clearance rate was not corrected for body surface area. RESULTS Sixty-one doses of ticarcillin were given to 54 infants. The number of studies in relation to age and weight groups analyzed is shown in Table I. All 14 infants over 2 weeks of age were under one month except one baby of 35 days, one of 6 weeks, two of 7 weeks, and one infant 8 months of age. The estimated gestational age was 32 weeks or less in 9 infants, from 33-35 weeks in 21, from 3638 weeks in 13, and over 38 weeks in 18 infants. The actual dosage administered ranged from 44.9 to 54.8 mg/kg, but in 54 cases it was within _+ 2 of 50 rag/ kg. The mean concentration-time curves and serum halflives for the various age groups are plotted in Fig. 1. Infants in the first week of life had higher peak serum concentrations and delayed excretion compared with older babies. Peak values for individual babies usually occurred after 1 hour but occasional infants had peak ticarcillin serum concentrations 2 hours after the dose. In eight infants serum specimens were also collected 1V2 hours after the dose to make sure we were not missing a peak between 1 and 2 hours. In two of these the concentrations at 1Vz hours were higher than the 1 hour value but in the remaining six they were lower. It was
Pharmacology of ticarcillin in the neonate
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Fig. 1. Mean ticarcillin concentration time curves by age groups and the calculated mean serum half-life (T1A) in hours. Table I. Distribution of 61 ticarcillin concentration time curve studies in 54 infants according to age and weight
Body weight (gin)
Age (days) 1-3 I
4-7 I 8-14 I >>_15 Totals
< 1,500 1,500-2,000 2,000-2,500 >2,500
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therefore decided that the additional serum specimen was not necessary. For the four age groups the mean peak concentrations at one hour were 72, 78, 68, and 62/xg/ml, respectively. Values after eight hours were 19, 15, 8, and 3 izg/ml, respectively. In Fig. 2 the means and ranges of serum half-life are depicted in relation to the three variables: EGA, body weight, and chronologic age. Babies of the youngest gestational or chronologic ages or least body weight had average serum half-lives of 3~A to 4 hours and this progressively declined to 11/2 to 2 hours in the most mature, oldest or largest infants. EGA had an influence on the ticarcillin serum half-life in the various age and weight categories but there was much variability (Table II). A more consistent, orderly progression of half-life values was obtained with analysis of age and weight groupings, as shown in the lower part of Fig. 3. Within each age group there was a progressive decline in serum half-life from the smallest to the largest infants, and a similar progressive shortening of serum
476
Nelson, Shelton, and Kusmiesz
The Journal of Pediatrics September 1975
BY BODY W E I G H T 7
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Table II. Influence of gestational age upon ticarcillin serum half-life at various ages and weights
Estimated
....
3
Age (days)
Body weight (gin)
gestational 1,500- 2,000age 1-3 4-7 8-14 >--15 <1,500 2,000 2,500 >2,500 _<32 5s-]S 36-5G TERM WEEKS ESTIMATED GESTATIONAL AGE 7
<1500
t5002000>2500 2000 2500 BOGY WEIGHT (g)
BY AGE (1 VALUE 6,3)
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0.9 2.2 2.4 1.8
*Mean ticarcillinserum half-life in hours.
5 T1/2
--<32 wk 3.7* 4.5 5.0 1.1 33-35 wk 3.7 3.3 2.6 2.1 36-38 wk 3.8 2.3 2.0 2.0 Term 2.5 2.0 1.6 1.5
4
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Table III. Ticarcillin plasma clearance rate related to age and weight
2
1-3
4-7 8-14 DAYS OF AGE
I
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Fig. 2. Means and ranges of ticarcillin serum half-life (T89 in hours according to three variables. The dotted line in the 8-to 14day age group represents the range to one discrepant value of 6.3 hours which was omitted in computation of the mean. half-life was seen within each weight group from the youngest to the oldest. These changes in serum half-life with increasing age and weight were due to the rapidly changing plasma clearance rates, shown in Table Ilk Penicillins are excreted by both glomerular and tubular renal mechanisms but, as we have demonstrated previously with carbenicillin, 1='ampicillin, ~:' and penicillin G , " the increased rate of excretion in the newborn infant correlates principally with improving glomerular function. It was considered possible that continuing absorption of drug from the intramuscular site might influence the serum concentrations at 2 hours and result in an erroneously prolonged serum half-life since the entire curve was used for calculations. Absorption can be considered complete at twice the time of peak concentration." Therefore, the 4- and 8-hour values are valid points uninfluenced by continuing absorption. Half-lives were calculated from the 4- and 8-hour serum concentrations and compared with those computed for the entire curve. Although there was variability due to the inherent lesser reliability of two-point curves, the average difference was only 3.6 minutes. Another means of checking the influence of continuing absorption on serum concentration is to compare concentration time curves in a patient receiving the same dosage intramuscularly and as a brief intravenous infusion. This was not done with ticarcillin but in the case of carbenicillin, which has similar pharmacokinetics, we showed that only the ~A hour and 1 hour values were different; the 2-, 4-, and 8-hour values and,
Age (days)
Body weight [ <1,500 1,500-2,000 2,000-2,500 >2,500
I 2.01" 3.13 4.18 6.03
2.15 4.16 6.17 7.47
2.55 5.06 7.07 13.93
-4.62 10.24 18.86
*Milliliter per minute. thus, serum half-lives were virtually identical in individual patients receiving the drug by the different routes on successive d a y s / The variation in peak serum ticarcillin concentrations attained in relation to age previously seen in Fig. 1 was more strikingly demonstrated and became explicable when body weight groupings were analyzed (Fig. 3). The differences were greatest in infants weighing more than 2,500 gm in whom those over a week o f age had peak serum concentrations of 51 and 58/~g/ml compared with levels of 81 and 85/xg/ml in those in the first week of life. The influence of age on peak serum concentrations was progressively less in the lower weight groups and negligible in infants under 1,500 gm. Another difference in peak serum concentrations is depicted in Fig. 3. The highest levels occurred during the first week of life in babies weighing over 2,000 gin, but the opposite was true of infants under 2,000 gm. It is possible that a difference in the rate of absorption could contribute to this observed difference in peak levels. These variations in peak serum concentrations of the drug can also be explained by the changing volumes of distribution shown in Table IV. Infants over 2,000 gm had a smaller volume of fluid in which the same dosage of drug was distributed than babies under 2,000 gm; hence, the serum concentration was greater in the larger infants. With increasing age there was increase in the volume of distribution among
Volume 87 Number 3
Pharmacology of ticarcillin in the neonate
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Fig. 3. Influence of body weight and age upon peak serum concentrations and serum half-life (T89 of ticarcillin. Table IV. Calculated volume of distribution of ticarcillin according to weight and age
Age (days) Body weight (gm)
1-3
4-7
8-14
->15
<1,500 1,500-2,000 2,000-2,500 >2,500
545* 556 499 423
520 579 520 438
528 463 490 559
481 573 601
*Milliliter per kilogram body weight. the larger babies with a resultant decrease in peak serum concentration of ticarcillin. The opposite sequence occurred in small infants. Volumes of distribution were also analyzed in relation to E G A with similar but less consistent results. The more immature babies tended to have larger volumes o f distribution than term babies. The means and ranges of ticarcillin serum concentrations in low-birth-weight infants and larger ones are given in Table V. DISCUSSION The newborn infant pharmacokinetically is in a state of flux. It is clear from this evaluation o f ticarcillin and from studies of other penicillins 1:-1'~ that, for any given dosage of antibiotic, wide ranges of serum concentrations and rates of elimination occur depending upon individual physiology reflected by maturity and size. With ticarcillin a 50 m g / k g dose given intramuscularly resulted in m e a n peak serum concentrations from 51 to 85 /zg/ml in the
Table V. Serum concentrations of ticarcillin according to weight and age
Weight and age categories
Hours after dose l/2
1
<2,000 gm body weight 1- 3 53.4* 6%7 days (42- 89) (54-100) 4- 7 64.4 77.0 days (54- 81) (60-105) 8 - 14 64.6 73.0 days (56- 82) (58- 93) ->15 days 80.6 82.5 (51-103) (52-108) >2,000 gm body weight 1- 3 66.9 79.2 days (53- 84) (60- 88) 4- 7 76.4 80.9 days (60- 94) (65- 89) 8 - 14 55.1 60.9 days (42- 68) (42- 72) -->15 days 53.3 53.3 (39- 82) (37- 83)
I
2 1 4 67.4 (53- 89) 67.2 (45-100) 63.1 (48- 78) 64.1 (39-100)
47.9 (36-59) 44.0 (32-63) 39.0 (23-53) 34.9 (21-64)
21.5 (5-34) 20.3 (0-34) 12.8 (0-18) 8.4 (5-14)
74.8 (59- 85) 65.3 (56- 81) 48.3 (32- 65) 35.3 (15- 55)
45.4 (32-52) 26.7 (10-48) 21.2 (11-39) 12.0 (3-25)
14.7 (11-18) 8.2 (0-15) 3.6 (0-11) 1.4 (0-6)
*Mean (range) of ticarcillin concentration in/~g/ml. various age and weight groups and 8 hour trough values from 1.2 to 24/~g/ml. Any attempt to make a r e c o m m e n dation for dosage and intervals of drug administration for all babies from newly born to a month of age that does not take into account physiologic variations is fraught with the double hazards of ineffectually low serum concentrations in some and accumulation to toxic concentrations in others.
478
Nelson, Shelton, and Kusmiesz
If dosage calculated for body weight is kept constant, the highest level achieved in serum depends upon the route of administration, the rate of absorption, the volume of body fluid in which it is distributed, the rate of metabolism to antibiotically inactive compounds, and the rate of excretion. When the rate of absorption from muscle is rapid, as it is with ticarcillin, the rate of excretion has a negligible effect on the peak serum concentration, but if the drug is inadvertently deposited subcutaneously, absorption is slower and the amount excreted during the absorption period has a proportionately greater effect on the ultimate serum concentration. Volume of distribution exerts the most profound effect on peak serum concentration in the case of ticarcillin. Low-birth-weight babies have a larger plasma volume 1~ and extracellular fluid volume TM than term infants and, among the low-birth-weight babies, those with intrauterine growth retardation have a somewhat larger extracellular fluid volume than infants whose weight is appropriate for gestational age. TM Thus, in the small babies the same dosage of ticarcillin is distributed in a larger space and this dilutional effect results in a lower serum concentration of antibiotic than in term infants. The total extracellular fluid volume of term babies has been variously measured in the range of 350-400 ml/ kg. 17-1~'The observed ticarcillin volume of distribution of 423 mg/kg is only slightly more than this and suggests that the antibiotic is mainly present in extracellular fluid rather than intracellular water. (Volume of distribution is not synonymous with volume of body fluid compartments; it is an artificial figure useful only for pharmacokinetic calculations and concepts.) During the first hours of life in term babies there is an increase in extracellular water '~ and, if this process continues in subsequent days, it could account for the progressive decrease in ticarcillin serum concentrations and concomitant increasing volume of distribution observed with increasing age. In the low-birth-weight babies the change in volume of distribution was reversed suggesting that, because they are born with an expanded extracellular water space, they have a tendency to diminish this with increasing age to amounts approximating those of term infants. However, we are not aware of sequential studies of changing body fluid compartments in the first month of life so this is speculative. It is possible that the observed changes in volume of distribution of ticarcillin were due to differing penetrability of the drug to the intracellular space. Regardless of the mechanism the clinical relevance of this observation is that effects of antibiotic overdosage given repeatedly to term babies would be mitigated by their tendency to progressively lower serum concentra-
The Journal of Pediatrics September i975
tions with increasing age. However, in low-birth-weight babies the reverse is true and repeated administration of unnecessarily large dosage could result in accumulation in serum to toxic concentrations. Fortunately, they are protected somewhat because magnitude of the volume of distribution changes is less in small babies than in term infants. The rate of elimination of ticarcillin determines the intervals of administration. Although urine concentrations were not measured in this study, we know from previous experience with other penicillinsl~-" that the principal determinant of elimination rate is renal function. The calculated plasma clearances of ticarcillin thus correlate with renal function and serum half-life. As was the case with carbenicillin1~ 2,000 gm body weight is a more appropriate dividing line for consideration of dosage and intervals of administration than the more traditional 2,500 gm. Infants in the 2,000 to 2,500 gm category behave pharmacologically more like the larger babies than the smaller ones in all respects: serum halflife, plasma clearance rate, volume of distribution, peak serum concentrations, and sequential changes with increasing age. We have s!ressed the pharmacologic variability of babies in the first month of life but obviously it is not feasible or rational to have 16 different dosage recommendations for the four age and weight groups. Furthermore, such precision in dosage is not warranted because desired peak and trough serum concentrations are derived from imprecise, pragmatic considerations. From these basic pharmacologic data certain clinically useful groupings can be made and predictions of dosage and intervals of administration can be made. For therapeutic trials higher sermn concentrations than those obtained with 50 mg/kg would probably be sought. By doubling the dosage to 100 mg/kg one could predict that average peak serum concentrations would be approximately 150/~g/ml. Levels of 40 to 50/~g/ml would arbitrarily be chosen as desirable trough levels. Aiming for these values in a baby under one week of age who has a ticarcillin serum half-life of 4 hours, as an example, it is simple to calculate dosage and interval of administration. The peak concentration of 150 t~g/ml would be achieved 1 hour after an injection of 100 mg/kg. By 8 hours later two serum half-lives would have lapsed, one-fourth of the antibiotic would remain in the baby, and the serum concentration would be 45/~g/ml. (It would not reach 37.5/xg/ml until 9 hours after the dose because of the 1 hour lag initially during absorption.) Giving a subsequent dose of 75 mg/kg 8 hours after the first injection would result in a serum concentration of 150 /~g/ml once again 1 hour later. Similar calculations can be made for the other groups.
Volume 87 Number 3
To maintain peak serum concentrations of 150 txg/ml and trough levels of 40-50/~g/ml with repeated administration of ticarcillin the following regimens should be appropriate: (1) All infants are given an initial injection of 100 mg/kg. (2) Subsequent dosages for babies under 2,000 gm in the first week of life are 75 m g / k g at 8-hour intervals (225 m g / k g / d a y ) . (3) For the small babies over one week of age and for babies over 2,000 gm in the first 2 weeks of life 75 m g / k g is given every 4 or 6 hours (300-450 m g / k g / d a y ) . (4) After 2 weeks of age the larger babies are given 100 m g / k g every 4 hours (600 m g / k g / d a y ) . If renal function is normal, these predicted dosages should provide the desired serum concentrations without the risks of excessively high or undesirably low serum concentrations. When a similar approach was taken with evaluation of carbenicillin in the neonate, predictions based on the initial single-dose study 9 turned out to be appropriate when clinical trials of repeated administration were conducted. 12 We r e c o m m e n d this two-phase approach for evaluation of any new antibiotic as a means o f gaining information on dosage and efficacy while providing maximum safety to the infant. The authors appreciate the cooperative attitude of the directors of the nurseries, Jacob Kay, M.D., and Charles Rosenfeld, M.D., and of the nurses, house staff, and parents which made this study possible.
Pharmacology o f ticarcillin in the neonate
5.
6.
7.
8.
9.
10. 11. 12.
13.
14.
REFERENCES
1. Acred P, Hunter PA, Mizen L, and Robinson GN: aCarboxy-3-thienylmethylpenicillin (BRL 2288), a new semisynthetic penicillin: In vivo evaluation, Antimicrob Agents Chemother-1970, pp 396-401, 1971. 2. Rodriguez V, Inagaki J, and Bodey GP: Clinical pharmacology of ticarcillin (a-carboxyl-3-thienylmethylpenicillin, BRL-2288), Antimicrob Agents Chemother 4:31, 1973. 3. Sutherland R, and Wise PJ: a-Carboxy-3-thienylmethylpenicillin (BRL 2288), a new semisynthetic penicillin: Absorption and excretion in man, Antimicrob Agents Chemother-1970, pp 402-406, 1971. 4. Adler JL, Burke JP, Wilcox C, and FinIand M: Suscepti-
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bility of Proteus species and Pseudomonas aeruginosa to penicillins and cephalosporins, Antimicrob Agents Chemother-1970, pp 63-67, 1971. Sutherland R, Burnett J, and Robinson GN: c~-Carboxy-3thienylmethylpenicillin (BRL 2288), a new semisynthetic penicillin: In vitro evaluation, Antimicrob Agents Chemoffier-1970, pp 390-395, 1971. Neu HC, and Winshell EB: Semisynthetic penicillin 6-[D (-)-a-carboxy-3-thienylaeetamido] penicillanic acid active against Pseudomonas in vitro, Appl Microbiol 21:66, 1971. Bodey GP, and Deerhake B: In vitro studies of a-carboxyl3-thienylmethyl penicillin, a new semisynthetic penicillin, Appl Microbiol 21:61, 1971. Rodriguez V, Bodey GP, Horikoshi N, Inagaki J, and McCredie, KB: Ticarcillin therapy of infections, Antimic~_ob Agents Chemother 4:427, 1973. Morehead CK, Shelton S, Kusmiesz H, and Nelson JD: Pharmacokinetics of carbenicillin in neonates of normal and low birth weight, Antimicrob Agents Chemother 2:267, 1972. Howard JB, and McCraeken GH Jr: Reappraisal of kanamycin usage in neonates, J PEmATR 86:949, 1975. Dost FH: Grundlagen der Pharmacokinetic, Stuttgart, 1967, Georg Thieme Verlag pp 155-190. Nelson JD, and McCracken GH Jr: Clinical pharmacology of carbenicillin and gentamicin in the neonate and comparative efficacy with ampieillin and gentamicin, Pediatrics 52:801, 1973. Kaplan JM, McCracken GH Jr, Horton LJ, Thomas ML, and Davis N: Pharmacologic studies in neonates given large dosages of ampicillin, J PEDIATR84:571, 1974. McCracken GH Jr, Ginsburg C, Chrane D, Thomas ML, and Horton LJ: Clinical pharmacology of penicillin in newborn infants, J PEmATR 82:692, 1973. Cassady G: Plasma volume studies in low birth weight infants, Pediatrics 38:1020, 1966. Cassady G: Bromide space studies in infants of low birth weight, Pediatr Res 4:14, 1970. Fink CW, and Cheek DB: The corrected bromide space (extracellular volume) in the newborn, Pediatrics 26:397, 1960. Cassady G: Effect of caesarian section on neonatal body water spaces, N Engl J Med 285:887, 1971. Finley SC, and Hare RS: Bromide space in infants and children, Am J Dis Child 98:749, 1959.
September 1975 The Journal o f P E D I A T R I C S
Clinical pharmacology of ticarcillin in the newborn infant: Relation to age, gestational age, and weight Ticarcillin, a new penicillin derivative with greater in vitro activity against Pseudomonas than carbenicillin, was given as a single dose of 50 mg/kg intramuscularly on 61 occasions to 54 neonates and young infants. The serum concentrations and rate of elimination varied considerably depending upon gestational age, chronological age, and body weight. Peak serum concentrations depended principal~ upon the volume of distribution which approximated the extracellular fluid volume of the neonate. The plasma clearance and serum half-life of the drug were determined. From these pharmacokinetic data appropriate groupings according to age and body weight were made and dosages and intervals of administration predicted for clinical trials of efficacy with repeated doses.
John D. Nelson, M.D.,* Sharon Shelton, B.S., and Helen Kusmiesz, R.N., Dallas, T e x a s
TIcARCILLIN is a new semisynthetic penicillin with many similarities to carbenicillin. It is a disodium salt of c~-carboxy-3-thienylmethyl penicillin, whereas carbenicillin has a benzyl ring in place of the thienylmethyl structure'.-~ and its pharmacology is almost identical to that of carbenicillin. -~.3 It has essentially the same range of antimicrobial activity as carbenicillin, but it has greater in vitro activity against Pseudomonas aeruginosa, 4-7 with minimal inhibitory concentrations of ticarcillin one-half or less those of carbenicillin and also with greater antiPseudomonas activity in serum. ~ Limited clinical experience in adults suggests that ticarcillin dosages (20 g m / day), one-half to two-thirds of the usual carbenicillin dosages (30-40 gm/day), may he effective for Pseudomonas infections? The drug has not been evaluated in infants. This study was performed to determine the basic clinical pharmacology of ticarcillin in the neonate, anticipating its possible future use for treatment of Pseudomonas or indol-positive Proteus infections. To provide maximum safety to the infant, our standard approach for the investigation of new antibiotics is to substitute one dose of the experimental drug for the analogous drug the From the Department of Pediatrics, University of Texas Southwestern Medical School at Dallas. *Reprint address: 5323 Har~y Hines Bld., Dallas, Texas 75235.
Vol. 87, No. 3, pp. 474-479
baby is receiving for treatment of suspected bacterial infection. From the basic pharmacokinetic data gathered after this single dose, predictions can be made of dosage and intervals of doses for later study of efficacy with repeated antibiotic administration. Abbreviation used EGA: estimated gestational age
MATERIALS AND METHODS Patients studied and treatment. All infants studied were in the newborn nurseries or infant ward of Parkland Memorial Hospital, Dallas, and were receiving a penicillin drug (ampicillin or penicillin G) and kanamycin for treatment of possible bacterial infection. Infants with meningitis were excluded. Signed, informed consent was obtained from the mother. Three to five infants were studied in each of the following weight and age groups: < 1,500 gm, 1,500-2,000 gm, 2,000-2,500 gm, and > 2,500 gm; 1-3 days, 4-7 days, 8-14 days, and 15 days or older. Ticarcillin was given as a single intramuscular injection of 50 mg/kg in the anterolateral thigh. Antibiotic assay and methods of analysis. Serum specimens were collected by heel stick 1/2, 1, 2, 4, and 8 hours after the dose. Serum was stored frozen at - 20 ~ C until assayed. Assays were done within three days of collection. The method for ticarcillin assay was identical to our
Volume 87 Number 3 micromethod for carbenicillin9 but used the ticarcillin laboratory standard. It was determined that concentrations of kanamycin as high as 50/~g/ml present in serum specimens did not influence the ticarcillin assay results. Kanamycin concentrations were measured after inactivation of ticarcillin with penicillinase and all were less than 35/~g/ml. 1~Penicillin and ampicillin have no effect on the assay organism. The regression line of serum concentrations was calculated by least mean squares, omitting values before the highest concentration was achieved. The log of 2 divided by the slope of the line was expressed as the serum halflife of ticarcillin. Volume of distribution of ticarcillin was calculated by assuming that the area under the concentration time curve represented a series of trapezoids. The dosage of ticarcillin in milligrams per kilogram body weight was divided by the area under the curve multiplied by the elimination rate constant (0.693 divided by the calculated serum halflife). The resulting figure multiplied by 1,000 gave the volume of distribution in milliliters per kilogram body weight." Plasma clearance was calculated by dividing the total dosage of drug by the area under the concentration time curve and multiplied by 1,000/60 to express the rate in milliliters per minute." Plasma clearance rate was not corrected for body surface area. RESULTS Sixty-one doses of ticarcillin were given to 54 infants. The number of studies in relation to age and weight groups analyzed is shown in Table I. All 14 infants over 2 weeks of age were under one month except one baby of 35 days, one of 6 weeks, two of 7 weeks, and one infant 8 months of age. The estimated gestational age was 32 weeks or less in 9 infants, from 33-35 weeks in 21, from 3638 weeks in 13, and over 38 weeks in 18 infants. The actual dosage administered ranged from 44.9 to 54.8 mg/kg, but in 54 cases it was within _+ 2 of 50 rag/ kg. The mean concentration-time curves and serum halflives for the various age groups are plotted in Fig. 1. Infants in the first week of life had higher peak serum concentrations and delayed excretion compared with older babies. Peak values for individual babies usually occurred after 1 hour but occasional infants had peak ticarcillin serum concentrations 2 hours after the dose. In eight infants serum specimens were also collected 1V2 hours after the dose to make sure we were not missing a peak between 1 and 2 hours. In two of these the concentrations at 1Vz hours were higher than the 1 hour value but in the remaining six they were lower. It was
Pharmacology of ticarcillin in the neonate
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Fig. 1. Mean ticarcillin concentration time curves by age groups and the calculated mean serum half-life (T1A) in hours. Table I. Distribution of 61 ticarcillin concentration time curve studies in 54 infants according to age and weight
Body weight (gin)
Age (days) 1-3 I
4-7 I 8-14 I >>_15 Totals
< 1,500 1,500-2,000 2,000-2,500 >2,500
4 4 4 3
5 5 4 4
5 3 2 4
0 4 3 7
14 16 13 18
Totals
15
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61
therefore decided that the additional serum specimen was not necessary. For the four age groups the mean peak concentrations at one hour were 72, 78, 68, and 62/xg/ml, respectively. Values after eight hours were 19, 15, 8, and 3 izg/ml, respectively. In Fig. 2 the means and ranges of serum half-life are depicted in relation to the three variables: EGA, body weight, and chronologic age. Babies of the youngest gestational or chronologic ages or least body weight had average serum half-lives of 3~A to 4 hours and this progressively declined to 11/2 to 2 hours in the most mature, oldest or largest infants. EGA had an influence on the ticarcillin serum half-life in the various age and weight categories but there was much variability (Table II). A more consistent, orderly progression of half-life values was obtained with analysis of age and weight groupings, as shown in the lower part of Fig. 3. Within each age group there was a progressive decline in serum half-life from the smallest to the largest infants, and a similar progressive shortening of serum
476
Nelson, Shelton, and Kusmiesz
The Journal of Pediatrics September 1975
BY BODY W E I G H T 7
y~/2
5
(hrs}
4
7
4
Table II. Influence of gestational age upon ticarcillin serum half-life at various ages and weights
Estimated
....
3
Age (days)
Body weight (gin)
gestational 1,500- 2,000age 1-3 4-7 8-14 >--15 <1,500 2,000 2,500 >2,500 _<32 5s-]S 36-5G TERM WEEKS ESTIMATED GESTATIONAL AGE 7
<1500
t5002000>2500 2000 2500 BOGY WEIGHT (g)
BY AGE (1 VALUE 6,3)
6
4.7 3.4 --
1.9 2.9 3.3 2.0
1.4 2.1 2.3 2.2
0.9 2.2 2.4 1.8
*Mean ticarcillinserum half-life in hours.
5 T1/2
--<32 wk 3.7* 4.5 5.0 1.1 33-35 wk 3.7 3.3 2.6 2.1 36-38 wk 3.8 2.3 2.0 2.0 Term 2.5 2.0 1.6 1.5
4
- RANGE
3
Table III. Ticarcillin plasma clearance rate related to age and weight
2
1-3
4-7 8-14 DAYS OF AGE
I
->15
Fig. 2. Means and ranges of ticarcillin serum half-life (T89 in hours according to three variables. The dotted line in the 8-to 14day age group represents the range to one discrepant value of 6.3 hours which was omitted in computation of the mean. half-life was seen within each weight group from the youngest to the oldest. These changes in serum half-life with increasing age and weight were due to the rapidly changing plasma clearance rates, shown in Table Ilk Penicillins are excreted by both glomerular and tubular renal mechanisms but, as we have demonstrated previously with carbenicillin, 1='ampicillin, ~:' and penicillin G , " the increased rate of excretion in the newborn infant correlates principally with improving glomerular function. It was considered possible that continuing absorption of drug from the intramuscular site might influence the serum concentrations at 2 hours and result in an erroneously prolonged serum half-life since the entire curve was used for calculations. Absorption can be considered complete at twice the time of peak concentration." Therefore, the 4- and 8-hour values are valid points uninfluenced by continuing absorption. Half-lives were calculated from the 4- and 8-hour serum concentrations and compared with those computed for the entire curve. Although there was variability due to the inherent lesser reliability of two-point curves, the average difference was only 3.6 minutes. Another means of checking the influence of continuing absorption on serum concentration is to compare concentration time curves in a patient receiving the same dosage intramuscularly and as a brief intravenous infusion. This was not done with ticarcillin but in the case of carbenicillin, which has similar pharmacokinetics, we showed that only the ~A hour and 1 hour values were different; the 2-, 4-, and 8-hour values and,
Age (days)
Body weight [ <1,500 1,500-2,000 2,000-2,500 >2,500
I 2.01" 3.13 4.18 6.03
2.15 4.16 6.17 7.47
2.55 5.06 7.07 13.93
-4.62 10.24 18.86
*Milliliter per minute. thus, serum half-lives were virtually identical in individual patients receiving the drug by the different routes on successive d a y s / The variation in peak serum ticarcillin concentrations attained in relation to age previously seen in Fig. 1 was more strikingly demonstrated and became explicable when body weight groupings were analyzed (Fig. 3). The differences were greatest in infants weighing more than 2,500 gm in whom those over a week o f age had peak serum concentrations of 51 and 58/~g/ml compared with levels of 81 and 85/xg/ml in those in the first week of life. The influence of age on peak serum concentrations was progressively less in the lower weight groups and negligible in infants under 1,500 gm. Another difference in peak serum concentrations is depicted in Fig. 3. The highest levels occurred during the first week of life in babies weighing over 2,000 gin, but the opposite was true of infants under 2,000 gm. It is possible that a difference in the rate of absorption could contribute to this observed difference in peak levels. These variations in peak serum concentrations of the drug can also be explained by the changing volumes of distribution shown in Table IV. Infants over 2,000 gm had a smaller volume of fluid in which the same dosage of drug was distributed than babies under 2,000 gm; hence, the serum concentration was greater in the larger infants. With increasing age there was increase in the volume of distribution among
Volume 87 Number 3
Pharmacology of ticarcillin in the neonate
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Age (days) Body weight (gm)
1-3
4-7
8-14
->15
<1,500 1,500-2,000 2,000-2,500 >2,500
545* 556 499 423
520 579 520 438
528 463 490 559
481 573 601
*Milliliter per kilogram body weight. the larger babies with a resultant decrease in peak serum concentration of ticarcillin. The opposite sequence occurred in small infants. Volumes of distribution were also analyzed in relation to E G A with similar but less consistent results. The more immature babies tended to have larger volumes o f distribution than term babies. The means and ranges of ticarcillin serum concentrations in low-birth-weight infants and larger ones are given in Table V. DISCUSSION The newborn infant pharmacokinetically is in a state of flux. It is clear from this evaluation o f ticarcillin and from studies of other penicillins 1:-1'~ that, for any given dosage of antibiotic, wide ranges of serum concentrations and rates of elimination occur depending upon individual physiology reflected by maturity and size. With ticarcillin a 50 m g / k g dose given intramuscularly resulted in m e a n peak serum concentrations from 51 to 85 /zg/ml in the
Table V. Serum concentrations of ticarcillin according to weight and age
Weight and age categories
Hours after dose l/2
1
<2,000 gm body weight 1- 3 53.4* 6%7 days (42- 89) (54-100) 4- 7 64.4 77.0 days (54- 81) (60-105) 8 - 14 64.6 73.0 days (56- 82) (58- 93) ->15 days 80.6 82.5 (51-103) (52-108) >2,000 gm body weight 1- 3 66.9 79.2 days (53- 84) (60- 88) 4- 7 76.4 80.9 days (60- 94) (65- 89) 8 - 14 55.1 60.9 days (42- 68) (42- 72) -->15 days 53.3 53.3 (39- 82) (37- 83)
I
2 1 4 67.4 (53- 89) 67.2 (45-100) 63.1 (48- 78) 64.1 (39-100)
47.9 (36-59) 44.0 (32-63) 39.0 (23-53) 34.9 (21-64)
21.5 (5-34) 20.3 (0-34) 12.8 (0-18) 8.4 (5-14)
74.8 (59- 85) 65.3 (56- 81) 48.3 (32- 65) 35.3 (15- 55)
45.4 (32-52) 26.7 (10-48) 21.2 (11-39) 12.0 (3-25)
14.7 (11-18) 8.2 (0-15) 3.6 (0-11) 1.4 (0-6)
*Mean (range) of ticarcillin concentration in/~g/ml. various age and weight groups and 8 hour trough values from 1.2 to 24/~g/ml. Any attempt to make a r e c o m m e n dation for dosage and intervals of drug administration for all babies from newly born to a month of age that does not take into account physiologic variations is fraught with the double hazards of ineffectually low serum concentrations in some and accumulation to toxic concentrations in others.
478
Nelson, Shelton, and Kusmiesz
If dosage calculated for body weight is kept constant, the highest level achieved in serum depends upon the route of administration, the rate of absorption, the volume of body fluid in which it is distributed, the rate of metabolism to antibiotically inactive compounds, and the rate of excretion. When the rate of absorption from muscle is rapid, as it is with ticarcillin, the rate of excretion has a negligible effect on the peak serum concentration, but if the drug is inadvertently deposited subcutaneously, absorption is slower and the amount excreted during the absorption period has a proportionately greater effect on the ultimate serum concentration. Volume of distribution exerts the most profound effect on peak serum concentration in the case of ticarcillin. Low-birth-weight babies have a larger plasma volume 1~ and extracellular fluid volume TM than term infants and, among the low-birth-weight babies, those with intrauterine growth retardation have a somewhat larger extracellular fluid volume than infants whose weight is appropriate for gestational age. TM Thus, in the small babies the same dosage of ticarcillin is distributed in a larger space and this dilutional effect results in a lower serum concentration of antibiotic than in term infants. The total extracellular fluid volume of term babies has been variously measured in the range of 350-400 ml/ kg. 17-1~'The observed ticarcillin volume of distribution of 423 mg/kg is only slightly more than this and suggests that the antibiotic is mainly present in extracellular fluid rather than intracellular water. (Volume of distribution is not synonymous with volume of body fluid compartments; it is an artificial figure useful only for pharmacokinetic calculations and concepts.) During the first hours of life in term babies there is an increase in extracellular water '~ and, if this process continues in subsequent days, it could account for the progressive decrease in ticarcillin serum concentrations and concomitant increasing volume of distribution observed with increasing age. In the low-birth-weight babies the change in volume of distribution was reversed suggesting that, because they are born with an expanded extracellular water space, they have a tendency to diminish this with increasing age to amounts approximating those of term infants. However, we are not aware of sequential studies of changing body fluid compartments in the first month of life so this is speculative. It is possible that the observed changes in volume of distribution of ticarcillin were due to differing penetrability of the drug to the intracellular space. Regardless of the mechanism the clinical relevance of this observation is that effects of antibiotic overdosage given repeatedly to term babies would be mitigated by their tendency to progressively lower serum concentra-
The Journal of Pediatrics September i975
tions with increasing age. However, in low-birth-weight babies the reverse is true and repeated administration of unnecessarily large dosage could result in accumulation in serum to toxic concentrations. Fortunately, they are protected somewhat because magnitude of the volume of distribution changes is less in small babies than in term infants. The rate of elimination of ticarcillin determines the intervals of administration. Although urine concentrations were not measured in this study, we know from previous experience with other penicillinsl~-" that the principal determinant of elimination rate is renal function. The calculated plasma clearances of ticarcillin thus correlate with renal function and serum half-life. As was the case with carbenicillin1~ 2,000 gm body weight is a more appropriate dividing line for consideration of dosage and intervals of administration than the more traditional 2,500 gm. Infants in the 2,000 to 2,500 gm category behave pharmacologically more like the larger babies than the smaller ones in all respects: serum halflife, plasma clearance rate, volume of distribution, peak serum concentrations, and sequential changes with increasing age. We have s!ressed the pharmacologic variability of babies in the first month of life but obviously it is not feasible or rational to have 16 different dosage recommendations for the four age and weight groups. Furthermore, such precision in dosage is not warranted because desired peak and trough serum concentrations are derived from imprecise, pragmatic considerations. From these basic pharmacologic data certain clinically useful groupings can be made and predictions of dosage and intervals of administration can be made. For therapeutic trials higher sermn concentrations than those obtained with 50 mg/kg would probably be sought. By doubling the dosage to 100 mg/kg one could predict that average peak serum concentrations would be approximately 150/~g/ml. Levels of 40 to 50/~g/ml would arbitrarily be chosen as desirable trough levels. Aiming for these values in a baby under one week of age who has a ticarcillin serum half-life of 4 hours, as an example, it is simple to calculate dosage and interval of administration. The peak concentration of 150 t~g/ml would be achieved 1 hour after an injection of 100 mg/kg. By 8 hours later two serum half-lives would have lapsed, one-fourth of the antibiotic would remain in the baby, and the serum concentration would be 45/~g/ml. (It would not reach 37.5/xg/ml until 9 hours after the dose because of the 1 hour lag initially during absorption.) Giving a subsequent dose of 75 mg/kg 8 hours after the first injection would result in a serum concentration of 150 /~g/ml once again 1 hour later. Similar calculations can be made for the other groups.
Volume 87 Number 3
To maintain peak serum concentrations of 150 txg/ml and trough levels of 40-50/~g/ml with repeated administration of ticarcillin the following regimens should be appropriate: (1) All infants are given an initial injection of 100 mg/kg. (2) Subsequent dosages for babies under 2,000 gm in the first week of life are 75 m g / k g at 8-hour intervals (225 m g / k g / d a y ) . (3) For the small babies over one week of age and for babies over 2,000 gm in the first 2 weeks of life 75 m g / k g is given every 4 or 6 hours (300-450 m g / k g / d a y ) . (4) After 2 weeks of age the larger babies are given 100 m g / k g every 4 hours (600 m g / k g / d a y ) . If renal function is normal, these predicted dosages should provide the desired serum concentrations without the risks of excessively high or undesirably low serum concentrations. When a similar approach was taken with evaluation of carbenicillin in the neonate, predictions based on the initial single-dose study 9 turned out to be appropriate when clinical trials of repeated administration were conducted. 12 We r e c o m m e n d this two-phase approach for evaluation of any new antibiotic as a means o f gaining information on dosage and efficacy while providing maximum safety to the infant. The authors appreciate the cooperative attitude of the directors of the nurseries, Jacob Kay, M.D., and Charles Rosenfeld, M.D., and of the nurses, house staff, and parents which made this study possible.
Pharmacology o f ticarcillin in the neonate
5.
6.
7.
8.
9.
10. 11. 12.
13.
14.
REFERENCES
1. Acred P, Hunter PA, Mizen L, and Robinson GN: aCarboxy-3-thienylmethylpenicillin (BRL 2288), a new semisynthetic penicillin: In vivo evaluation, Antimicrob Agents Chemother-1970, pp 396-401, 1971. 2. Rodriguez V, Inagaki J, and Bodey GP: Clinical pharmacology of ticarcillin (a-carboxyl-3-thienylmethylpenicillin, BRL-2288), Antimicrob Agents Chemother 4:31, 1973. 3. Sutherland R, and Wise PJ: a-Carboxy-3-thienylmethylpenicillin (BRL 2288), a new semisynthetic penicillin: Absorption and excretion in man, Antimicrob Agents Chemother-1970, pp 402-406, 1971. 4. Adler JL, Burke JP, Wilcox C, and FinIand M: Suscepti-
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bility of Proteus species and Pseudomonas aeruginosa to penicillins and cephalosporins, Antimicrob Agents Chemother-1970, pp 63-67, 1971. Sutherland R, Burnett J, and Robinson GN: c~-Carboxy-3thienylmethylpenicillin (BRL 2288), a new semisynthetic penicillin: In vitro evaluation, Antimicrob Agents Chemoffier-1970, pp 390-395, 1971. Neu HC, and Winshell EB: Semisynthetic penicillin 6-[D (-)-a-carboxy-3-thienylaeetamido] penicillanic acid active against Pseudomonas in vitro, Appl Microbiol 21:66, 1971. Bodey GP, and Deerhake B: In vitro studies of a-carboxyl3-thienylmethyl penicillin, a new semisynthetic penicillin, Appl Microbiol 21:61, 1971. Rodriguez V, Bodey GP, Horikoshi N, Inagaki J, and McCredie, KB: Ticarcillin therapy of infections, Antimic~_ob Agents Chemother 4:427, 1973. Morehead CK, Shelton S, Kusmiesz H, and Nelson JD: Pharmacokinetics of carbenicillin in neonates of normal and low birth weight, Antimicrob Agents Chemother 2:267, 1972. Howard JB, and McCraeken GH Jr: Reappraisal of kanamycin usage in neonates, J PEmATR 86:949, 1975. Dost FH: Grundlagen der Pharmacokinetic, Stuttgart, 1967, Georg Thieme Verlag pp 155-190. Nelson JD, and McCracken GH Jr: Clinical pharmacology of carbenicillin and gentamicin in the neonate and comparative efficacy with ampieillin and gentamicin, Pediatrics 52:801, 1973. Kaplan JM, McCracken GH Jr, Horton LJ, Thomas ML, and Davis N: Pharmacologic studies in neonates given large dosages of ampicillin, J PEDIATR84:571, 1974. McCracken GH Jr, Ginsburg C, Chrane D, Thomas ML, and Horton LJ: Clinical pharmacology of penicillin in newborn infants, J PEmATR 82:692, 1973. Cassady G: Plasma volume studies in low birth weight infants, Pediatrics 38:1020, 1966. Cassady G: Bromide space studies in infants of low birth weight, Pediatr Res 4:14, 1970. Fink CW, and Cheek DB: The corrected bromide space (extracellular volume) in the newborn, Pediatrics 26:397, 1960. Cassady G: Effect of caesarian section on neonatal body water spaces, N Engl J Med 285:887, 1971. Finley SC, and Hare RS: Bromide space in infants and children, Am J Dis Child 98:749, 1959.