Pharmacokinetics of ceftriaxone in neonates and infants with meningitis

PEDIATRIC P H A R M A C O L O G Y A N D THERAPEUTICS

Pharmacokinetics of ceftriaxone in neonates and infants with meningitis The pharmacokinetics of ceftriaxone was studied in the plasma, urine, and cerebrospinal fluid of seven neonates and seven infants with meningitis. In addition, plasma and urine data were obtained in five neonates and one infant receiving ceftriaxone for other serious infections. All neonates younger than 14 days received daily doses of 50 mg/kg ceftriaxone; all other patients but two received 100 mg/kg. The average weight-corrected values for total body clearance (Clr), volume of distribution (Vd~), and biologic half-life (t89 were 0.37 ml/min/kg, 0.45 L/kg, and 16.2 hours in neonates younger than 1 week; 0.77 ml/min/kg, 0.48 L/kg, and 9.2 hours ih neonates older than 1 week; and 1.03 ml/min/kg, 0.39 L/kg, and 7.1 hours in older infants, respectively. There was a significant difference in Clr and t89 between the neonates younger and both neonates older than 1 week, and infants. The Vd~ was not significantly different among the three age groups. The average renal clearance in neonates younger than 1 week (0.28 ml/min/kg was 70%, in neonates older than 1 week (0.54 ml/min/kg) was 77%, and in older infants (0.49 ml/min/kg) was 47% of Clr, indicating that nonrenal elimination was less developed in neonates. The quantitation of CSF diffusion of ceftriaxone was assessed by comparison of the areas under the CSF and plasma concentration-time curve. The mean ceftriaxone penetration into the CSF in neonates and infants with bacterial meningitis was 17%. on the other hand, penetration in patients with aseptic meningitis amounted to only 4%. Mean ceftriaxOne concentrations in the CSF in patients with bacterial meningitis were 2.8 mg/L after 24 hours, exceeding by many times the minimum inhibitory concentration of the common meningitis pathogens at this time. (J PEDIATR 105:475, 1984)

Ernst Martini M.D., Jeffrey R. Koup, Pharm.D., Urs Paravicini, M.D., and Klaus Stoeckei, Ph.D. Z u r i c h a n d B a s e l , S w i t z e r l a n d , a n d Seattle, Washington

COMPARATIVE EXPERIMENTAL and clinical studies have demonstrated ceftriaxone, a broad-spectrum/3-1actamase-resistant cephalosporin, to be active against both aerobic and anaerobic gram-positive and gram-negative pathogens? -3 In vitro and in vivo studies have proved its efficacy against the three major organigms causing bacterial meningitis, Haemophilus influenzae type b, Strept ococcus pneumoniae, and Neisseria menlngitidis. 4-8 Good

From the Department of Pediatrics, University of Zurich; the Department of Pharmacy Practice, University of Washington; and the Biological Pharmaceutical Research Department, F. Hoffmann-La Roche & Co., Ltd., Basel. Submitted for publication July 26, 1983; accepted March 2, 1984. Reprint requests." Ernst Martin, M.D., Department of Pediatrics, University of Zurich, Steinweisstrasse 75, CH-8032 Zurich, Switzerland.

penetration into the cerebrospinal fluid results in concentrations far in excess of the minimal inhibitory concentrations of isolated organisms, 9-~3 In addition, ceftriaxone has pharmacokinetic properties that offer an advantage ovei" other cephalosporins. The AUC CIT CIR Vd~s

Area under curve Total body clearance Renal clearance Volume of distribution at steady state

elimination half-life in adults is between 6.5 and 8.6 hours,t3, ~5 whereas values of 6.0 to 7.4 are reported in children, 16 between 3.7 and 7.7 in infants, ~~ ~6 and 5.2 tO 8.4 hours in neonates. H, ~7 Some of the pharmaeokinetic parameters reported to date in neonates and infants may b e unreliable, because the d~ita from which they have been Calculated were collected over a period of less than or at TheJournalofPEDIATRICS

475

476

Martin et al.

The Journal of Pediatrics September 1984

200. 100-

~

50:

~ E~

10

~-8

5

3

6

9

12

15

18

21

24

27

30

33

36

Time (hours)

Fig. 1. Plasma (o) and CSF (A) concentrations as a function of time in a neonate (patient 7) after 50 mg/kg ceftriaxone. Multiple CSF samples were obtained via open ventricular drainage.

most equal to one single elimination half-life of the drug.t~ ~ Based on the reported pharmacokinetic data and the excellent antimicrobial activity, we administered single dail3) doses of ceftriaxone as the only antibacterial agent in our pediatric patients with purulent meningitis. METHODS Seven neonates (patients 4 through 10) and seven infants (patients i4 through 20) ranging in age from 9 to 30 days and from 3 to 9 months, respectively, received single daily doses of ceftriaxone for treatment of purulent meningitis. In addition, eeftriaxone was given to five neonates (age 1 to 16 days; patients 1, 2, 3, 11, 12, the latter three born prematurely) and one infant (patient !3) for suspectedbacteremia. The study protocol was approved b y the local Institutional Ethical Committee, and informed consent was obtained from the parents. All but one of the patients 'were studied during the first 24 hours after initiation of ceftriaxone therapy. In two neonates additional blood samples were collected during the treatment period. In one neonate (patien t 7) an open ventricular drainage tube was installed upon transfer to our hospital, because of obstructive hydrocephalus subsequent to intraventricular hemorrhage. Because this infant continued to have positive CSF cultures during amoxicillin and chloramphenicol therapy for purulent Escherichia coli meningitis-ventriculitis, medication was changed to ceftriaxone. It was therefore possible to collect serial CSF samples over 24 hours (Fig. 1). Single daily doses of ceftriaxone were infused over 5 minutes in all infants for a period of 6 to 10 days. Newborn and preterm infants with a postnatal age of <14 days received doses of 50 mg/kg every 24 hours, whereas 100 mg/kg was given to the older neonates, except patient 7, who was given 50 mg/kg. The CSF of patient 10 could not

be sterilized within 24 hours, and the dose was raised to 100 m g / k g after the first day of therapy. Older infants received 100 mg/kg ceftriaxone once daily, except patient 13. Serial blood samples were collected through central or peripheral venous catheters immediately before dosing and at 1, 4, 8, 12, 18, and 24 hours after termination of the infusion. In infants without an intravenous device to allow repeated blood collection, at least three samples were taken, at 1 or 4, 12, and 24 hours. The blood samples were centrifuged, and the plasma stored at - 2 0 ~ C until assayed. In 19 of the 20 patients the total urine output was collected over the first 24 hours at 4- to 6-hour intervals, and the samples were stored at - 2 0 ~ C. Repeated lumbar punctures were performed i n all 14 children with purulent meningitis at 4 and 24 hours after the first dose of ceftriaxone. In seven patients an additional CSF sample was obtained at 12 hours. Ceftriaxone was analyzed in plasma, urine, and CSF using high-performance liquid chromatography. TM Pharmacokinetie data analysis. A one-compartment open pharmacokinetic model wtth linear disposition characteristics was suitable for the analysis of the plasma concentration time data in three neonates after the 50 mg/kg dose. All other data were individuaily fitted by means of nonlinear; least-squares analysis to the general biexponential equation: Ct -- A e -"t + Be -~t

(1)

using the N O N L ! N ~9computer program. The areas under th e plasma concentration versus time curves (AUCo to co) and the first moment curves (AUMCo ~oco) were calculated using the log trapezoidal rule? ~ These A U C and A U M C values were then used to Calculate total body clearance and volume of distribution at steady state:

Volume 105 Number 3

Ceftriaxone in meningitis

C1 T =

Doseiv AUC X Body weight

AUMC Vd,~ = DosewAUCZX Body weight

(2) (3)

1.0-

1.8-

0.9-

16-

0.8-

14-

16- - -

12-

14-

1.0-

12-

0,70,6-

$

-

(4)

A AUCcsF . . . . tq

|

0

~

- ~ 0.6-

i

9

--A I

NN1

Ni~2

I IF

0.2-

9

I

NN1

9

9

9

--A

9

108-

9

6. 4-

0.49

18"

NN2

I

IF

I"

NN1

I

!

NIq2

IF

I

Fig. 2. Steady-state volume of distribution (Vdss), total body clearance (Clr) and elimination half-life (tl/2) in both neonatal groups (NNi <7 days, NN2 >7 day) and in infants (IF). _ _ , Average values; _ _ A, average adult parameters (corrected for weight).

A k,

(5)

Urine excretion data and AUC from the plasma concentration curve from 0 to 24 hours were used to calculate individual renal clearance values: C1R

0.1-

9

0.8~

0,302-

Because only two or three CSF samples could be obtained from all the other patients during a 24-hour period, the indMdual CSF data were fitted using equation 4, but assuming the CSF elimination rate constant 1~ equaled the /3 values obtained from the patients' plasma data. This procedure made it possible to estimate parameters A and k. and therefore the AUCcsF from time Zero to infinity:

9

0.50.4-

=

2ol84tTr

1.21.1-

The CSF concentration time data in patient 7 were analyzed using a one-compartment open model with firstorder absorption2~ CcsF Ae-Xd~ Ae-~'

CIT (ml/min/kg)

i Vdss (l/kg)

477

X o to 24 -

(6)

AUCo ,o 24 RESULTS Plasma. Plasma samples for pharmacokinetic analysis were obtained in 12 neonates and in eight older infants after the first dose of ceftriaxone,, in one neonate als0 during the course of therapy, and in two neonates after the last close at completion of therapy, yielding a total of 23 pharmacokinetic profiles in 20 patients. The individual plasma concentrations at 1, 12, and 24 hours, together with the individual pharmacokinetic parameters and their respective mean values, are presented in Table I. With the exception of patients 2 and 4, neonates younger than 7 days showed the longest biologic half-lives (Table I). Patient 4 died within 12 hours of unresP0nsive Circulatory shock. We excluded his values from averages and statistical evaluations, because renal and liver dysfunction were very likely present. The remaining neonates were divided into two groups, group 1 containing all neonates younger than 1 week, and group 2 those older than 1 week. Comparing the mean values between both neonatal groups as well as older infants using the Mann-Whitney rank sum test, 2~ a significant difference in CIT (P < 0.01) and t89 (P < 0.05) was observed between neonatal group 1 (C1T 0.368 ml/min/kg, t89 16.2 hours) and both neonatal group 2 (C1T 0.768 ml/min/kg, t89 9.2 hours ) and infants (C1T 1.03 ml/min/kg, tl/2 7.1 hours). No significant difference (P > 0.05) was seen between neonatal group 2 and infants.

Differences in Yd, (0.19 to 0.62 L/kg) never reached the level of significance between [he three groups (Fig. 2). The average adult values for Cl~r, Vd~s, and tlA corrected for body weight (A) are shown in Fig. 2. Approximate average plasma concentration values for neonates and older infants at 1, 12, and 24 hours were obtained by correcting the Observed plasma concentrations to a standard dose of either 50 mg/kg (neonates) or 100 mg/kg (infants). Because ceftriaxone exhibits concentration-dependent protein binding, 22 the total plasma concentration will not exactly double on doubling the dose. Thus the d0wn-correction (patients 2, 5, 6, 8, and 10) tends to underestimate the true plasma concentrations. On the other hand, an up-correction predicts values higher than actually observed; therefore, data in patient 13 were omitted from averaging. The respective, mean(-+ 1 SD) values of the dose,corrected plasma concentrations for neonatal groups ! and 2 were i 2 4 + 14 mg/L and 168 _+ 11 mg/L at 1 to 2 hours; 59 _+ 3 m g / L and 36_+ 1:2 mg/L at 12 hours; arid 34_+ 16 mg/L and i 5 -+ 7 mg/L at 24 hours. The Values for the infants were 212 + 33 mg/L at 172 hours; 49 _+ 39 m g / L at 12 hours, and 13 _+ 15 m g / L at 24 hours. Cerebrospinal fluid. The concentration-time profiles of ceftriaxone in the CSF and plasma of patient 7 with open ventricular drainage (Fig. 1) were characterized by a rapid rise with a maximum value of 14.6 m g / L at 4.5 hours after dosing, and a subsequent decay in parallel to the plasma concentration versus time curve. This study was done on day 12 of treatment. The CSF concentrations at 4, 12, and 24 hours, the area under the CSF concentration versus time Curves, and the area ratios (CSF/plasma) are shown in Table II. There was a significant difference (rank sum test 2,) in the

478

Martin et al.

The Journal of Pediatrics September 1984

Table I. Individual plasma concentrations at 1, 12, a n d 24 hours a n d p h a r m a c o k i n e t i c p a r a m e t e r s in neonates and infants

Patient Neonates Age <1 week 1

3 11 12 Group average Age >1 week 2 4* 5 6 7 8 9~ 10"~

Age

Weigh t (kg)

Dose (mg/kg)

Cpl hr (mg/L)

Cp12hr (mg/L)

Cp24hr (mg/L)

Clr (ml/kg/min)

Days

1

3.5 2.3 1.9 1.2

50 50 50 50

117 108 130 141

76 60 58 43

52 ND 30 20

0.238 0.386 0.389 0.460 0.368

16 27 16 30 20 24 10 17 9 11 12

3.3 4.1 3.4 2.7 3.8 4.5 1.5 1.7 2.3 2.2 2.2

100 100 100 100 50 144 50 50 50 100 100

225 262 248 230 150 295 80 104 32 100 110

97 140 73 43 59~ 80 43 50 13 ND ND

48 -33 15 8 30 18 25 8

0.482 0.293 0.561 0.806 0.635 0.850 0.627 0.573 2.440 1.460 1.420 0.768

3.4 5.4 7.0 8.4 8.4 7.6 7.0 7.0

50 93 100 100 100 100 100 114

308 220 170 227 260 225 184 209

ND 65 25 32 41 128 27 20

12w 14 4 7 10 46 7 4

4

1 1

10 8

GrOup average In~nts 13 14 15 16 17 18 19 20 Group average

Months 1.5 3.0 6.0 8.5 7.0 9.0 6.0 9.0

0.605 0.884 1.460 1.110 0.736 0.449 1.360 1.610 1.03

*Omitted from average and statistical evaluations. tCpat 8 hours after dose. ~Duplicate observations; average used to calculate means and for statistical evaluations. Cp, ceftriaxone plasma concentrations; ND, not determined. w at 17 hours after dose. percentage of p e n e t r a t i o n of ceftriaxone into the C S F (17.0% versus 4.1%) calculated as the area ratio ( C S F / plasma) when patients With bacterial and aseptic meningitis were c o m p a r e d ( T a b l e II). Urine. In infants, the average renal clearance 0.485 m l / k g / m i n accounted for 47.1% of C1T, whereas the values of 0.282 m l / m i n / k g in neonatal group 1 and 0.539 m l / m i n / k g in neonatal group 2 represented 77% and 70% of the respective C1T values. T h e percent of total clearance values (accounted for by renal clearance) between neon~ates and infants were statistical significant ( P < 0.05) by M a n n - W h i t n e y r a n k sum test. 2~ However, no significant differences could be shown for C1R data in the t h r e e groups.

DISCUSSION T h e weight-corrected average total body clearance and the m e a n volume Of distribt~tion a t steady state for ceftriaxone are two to four times higher t h a n values seen in adults 22 (Fig. 2). O u r values for Vds~ and Clr in neonates and older infants are in a g r e e m e n t with those of others, 11,~6 a l t h o u g h higher values have been r e p o r t e d ) ~,17 T h e Clr in neonates younger t h a n 1 week of age (0.368 m l / k g / m i n ) was h a l f t h a t in older neonates (0.768 m l / k g / m i n ) and only one third of the value observed in older infants (1.03 m l / k g / m i n ) . Therefore the clearance values were significantly smaller in the very young neonates c o m p a r e d with the older neonates and infants. T h e calculated Vds~ vaiues in older infants were not significantly different from those

Volume 105 Number 3

Ceftriaxone in meningitis

~(hr-')

tl/2 (h~

Vd,s (L/kg)

C~ (m~kg/min)

AUC (mg/L) • hr

0,035 0.053 0.050 0.039 0.044

19.8 13.1 13.9 17.8 16.2

0.40 0.43 0.43 0.53 0.45

0.272 0.237 0.400 0.217 0.282

3501 2161 2141 I810

0.053 0.040 0.066 0.089 0.126 0.071 0.063 0.056 0.110 0.113 0. t28 0.084

13.1 17.3 10.5 7.8 5.5 9.8 11.0 12.4 6.3 6.1 5.4 9.2

0.51 0.43 0.41 0.35 0.28 0.57 0.58 0.61 1.26 0.70 0.60 0.48

0.280 0.173 0.534 0.772 -0.780 0.327 -2.310 --0.539

3454 5680 2964 2068 1311 2839 1329 1453 341 1141 1174

0.135 0.045 0.161 0.128 0.113 0.067 0.119 0.150 0.115

5.1 15.3 4.3 5.4 6.0 10.0 5.8 4.6 7.1

0.19 0.62 0.38 0.42 0.26 0.37 0.54 0.37 0.394

0.395 0.220 0.711 0.525 0.549 0.212 0.773 0.497 0.485

1392 1755 1140 1505 2265 3747 1225 1182

in neonates. As a consequence of these differences, the average half-life in the neonates younger than 7 days postnatal age was significantly longer (16.2 hours) than was seen in older neonates (9.2 hours) and older infants (7.1 hours). This is in contrast to the half-life value of 4 hours reported by Del Rio et al. ~~ Although it seems reasonable to compare the pharmacokinetic parameters based on unbound drug, because in adt~lts CIT and Vdss for total drug are concentration dependent] z' we were not able to measure the protein binding of ceftriaxone because of the small quantity of blood obtainable in this population. The slightly larger Vds~ observed in neonates could result from lower plasma protein binding or from the increased extracellular fluid volume per kg body weight in these patients. The observed trend toward a larger contribution of renal clearance to the total clearance in neonates (77% and 70% in the neonatal groups, respectively) compared with infants

479

Remarks

Circulatory shock

Circulatory shock

Phenobarbital therapy preceding ceftriaxone

Same After After After

child 7 days later dose 1 dose 3 dose 4

(47.1%) may indicate that the nonrenal, (i.e., hepatic) eliminating processes are less developed in neonates than is renal function. ,In one neonate, the Vdss and C1T were estimated three times during the course of his illness. At the beginning, both Vds~ and C1T had almost twice the value as later in the disease, whereas the half-life did not change significantly. It is possible that fluid retention resulting from inappropriate secretion of antidiuretic hormone caused the change in Vd~, We believe that C S F penetration calculations based on a single time point concentration ratio of a drug in C S F to that in plasma are of limited value and in fact are often misleading. Concentration ratio calculated this way changes over time and can result in values well above 1.0 at low plasma concentrations; this could lead to an estimate of penetration of more than 100%. 23 Therefore we attempted to calculate the penetration of ceftriaxone into

M a r t i n et al.

480

The Journal o f Pediatrics September 1984

Table II. Individual C S F concentrations, areas u n d e r the C S F concentration vs time curves, and area ratios ( C S F / p l a s m a ) in neonates and infants with bacterial a n d aseptic meningitis

Palien t

Age

Bacterial meningitis 4 27 d 7 20 d 8 24 d 9 10 d 10 9d 19 6.0 mo 20 9.0 mo 15 6.0 mo 16 8.5 mo Group average Aseptic meningitis 5 16 d 6 30 d 14

17 18 Group average

3.0 mo

7.0 mo 9.0 mo

Dose (mg/kg)

C4 hr (mg/L)

C~2br (mg/L)

C24hr (mg/L)

A UC (mg/L/h r)

Area ratio* (%)

100 50 144 50 50 100 114 100 100

31.6 14.6 24.5 5.0 22.0 25.0 15.4 21.1 5.6 18.3

57.8] 7.2 9.5 13.4 -12.7 4.8 -3.2 8.5

-2.2 4.2 3.3 3.4 4.5 1.7 2.0 1.4 2.8

-195 390 175 321 395 168 279 84 251

-14.9 13.7 13.0 94.1 :~ 3Z2 14.2 24.5 6.4 17.0

100 100 93 100 100

8.5 5.9 2.0 2.8 3.0 4.4

---

3.2 2.1 0.5 1.1 1.9 1.8

192 130 44 55 95 103

6.5 6.3 2.5 2.5 2.5 4.1

--

2.0 ---

*Penetration into CSF. "~Diedof circulatory shock after 12 hours; sample taken immediately post mortem; not included in mean. :]:Died alter 5 days; not included in mean.

the C S F by c o m p a r i n g the respective A U C s (Table II). The m e a n CcsF of 18.3 m g / L (5.0 to 32 m g / L ) at 4 hours and of 2.8 m g / L (1.4 to 4.5 r a g / L ) at 24 hours exceed the MICg0 for c o m m o n meningitis pathogens by several hundred times. These concentration values are higher t h a n those reported ~~ after 8- or 12-hour dosage regimens. The average protein concentration in the C S F was 4.9 g m / L (range 1.2 to 6.8 g m / L ) . Ethical reasons prohibited the collection of sufficient C S F to assess the degree of protein binding. I f we assume t h a t the " p r o t e i n " composition of t h e C S F (percent a l b u m i n ) is similar to t h a t of plasma ,and t h a t the a l b u m i n present has binding characteristics similar to t h a t of adult albumin, it can be calculated 22 t h a t approximately 40% of the total C S F concentration is u n b o u n d or free when C S F protein equals 5 g m / L . Thus a m u c h larger free fraction is expected in the CSF, where a l b u m i n concentrations are m u c h lower t h a n in plasma, where free fraction varies between 4% and 15% (in adults). In a recently completed study, 25,26 32 of 33 (97%) children with p u r u l e n t meningitis h a d a satisfactory bacteriologic response. Twenty-seven (82%) experienced complete clinical cure, whereas three (9%) had severe neurologic sequelae and three (9%) died between 6 hours a n d 5 days after initiation of therapy. W i t h i n 12 hours after the first dose of ceftriaxone, 13 of 15 (87%) repeat spinal taps were sterile, whereas Del Rio et al. 27 reported 12 of 21 cultures were sterile.

Based on these results, the long half-life, a n d the good C S F penetration of ceftriaxone, combined with the efficacy a n d safety of the drug, a regimen of 50 to 100 m g / k g / 2 4 hr (4 g m m a x i m u m ) for the t r e a t m e n t of serious infections, including meningitis, seems appropriate. F u r t h e r studies are needed to allow definite dosage recommendations. In areas where Listeria monocytogenes is prevalent, a c o m b i n a t i o n of ceftriaxone and ampicillin m a y be advisable for initial therapy of neonatal meningitis until culture results are available. REFERENCES

1. Neu HC, Meropol N J, Fu KP: Antibacterial activity of ceftriaxone (Ro 13-9904), a fl-lactamase-stable cephalosporin. Antimicrob Agents Chemother 19:414, 1981. 2. Verbist L, Verhaegen J: In vitro activity of Ro 13-9904, a new fl-[actamase-stable cephalosporin. Antimicrob Agents Chemother 19:222, 1981. 3. Shannon K, King A, Warren C, Phillips I: In vitro antibacterial activity and susceptibility of the cephalosporin Ro 139904 to beta-la~ctamases. Antimicrob Agents Chemother 18:292, 1980. 4. Beam TR, Cochrane DW, Raab TA, Mylotte JM: Comparison of ceftriaxone, moxalactam and penicillin in treatment of experimental pneumococcal meningitis. Abstract 986, 12th International Congress of Chemotherapy, Florence, 1981. 5. Aronoff SC, Reed MD, O'Brien CA, Blumer JL: Comparison of the efficacy and safety of ceftriaxone to ampicillin/ chloramphenicol in the treatment of childhood meningitis. J Antimicrob C hemother 13:143, 1984.

Volume 105 Number 3

6. Shelton S, Nelson JD, McCracken GH: In vitro susceptibility of gram-negative bacilli from pediatric patients to moxalactam, cefotaxime, Ro 13-9904, and other cephalosporins. Antimicrob Agents Chemother 18:476, 1980. 7. McCracken GH, Nelson JD, Grimm LD: Pharmacokinetics and bacteriological efficacy of cefoperazone, cefuroxime, ceftriaxone, and moxalactam in experimental Streptococcus pneumoniae and Haemophilus influenzae meningitis. Antimicrob Agents Chemother 21:262, 1982. 8. Connor EM, Melick C, Yogev R: Comparison of Roccphin ( R o t 3-9904), moxalactam, and ch[oramphenicol in ampicillin-resistant H. influenzae bacteremia and meningitis in infant rats, Abstract 391, 21st Interscience Conference on Antimicrobial Agents and Chemotherapy (1CAAC), Chicago, 1981. 9. Schaad UB, McCracken GH, Loock CA, Thomas ML: Pharmacokinetics and bacteriologic efficacy of moxalactam, cefotaxime, cefoperazone, and Rocephin in experimental bacterial meningitis. J Infect Dis 143:156, 1981. 10. Del Rio M, McCracken GH, Nelson JD, Chrane D, Shelton S: Pharmacokinetics and cerebrospinal fluid bactericidal activity of ceftriaxone in the treatment of pediatric patients with bacterial meningitis. Antimicrob Agents Chemother 22:622, 1982. 1I. Steele RW, Eyre LB, Bradsher RW, Weinfeld RE, Patel IH, Spicehandler J: Pharmacokinetics of ceftriaxone in pediatric patients with meningitis. Antimicrob Agents Chemother 23:191, 1983. 12. Chadwick EG, Yogev R, Shulman ST, Weinfeld RE, Patel 1H: Single-dose ceftriaxone pharmacokinetics in pediatric patients with central nervous system infections. J PEDIATR 102:134, 1983. 13. Stoeckel K: Pharmacokinetics of Rocephin, a highly active new cephalosporin with an exceptionally long biological half-life. Chemotherapy 27(suppl 1):42, 1981. 14. Chadwick EG, Connor EM, Shulmann ST, Yogev R: Efficacy of ceftriaxone in treatment of serious childhood infections. J PEOIATR 103:141, 1983.

Ceftriaxone in meningitis

48 1

15. Patel IH, Miller K, Weinfeld R, Spicehandler J: Multiple intravenous dose pharmacokinetics of ceftriaxone in man. Chemotherapy 27(suppl 1):47, 1981. 16. Schaad UB, Stoeckel K: Single-dose pharmacokinetics of ceftriaxone in infants and young children. Antimicrob Agents Chemother 21:248, 1982. 17. McCracken GH, Siegel JD, Threlkeld N, Thomas M: Cetriaxone pharmacokinetics in newborn infants. Antimicrob Agents Chemother 23:341, 1983. 18. Trautmann KH, Haefelfinger P: Determination of Ro 139904 in plasma, urine and bile by means of ion-pair reversedphase chromatography. J High Resolution Chromatogr Commun 4:54, 1981. 19. Metzler CM, Elfring GK, McEwen A J: A package of computer programs for pharmacokinetic modeling. Biometrics 30:562, 1974. 20. Gibaldi M, Perrier D: Pharmacokinetics, ed 2. New York, 1982, Marcel Dekker, p 409. 2l. Snedecor GW, Cochran WG: Statistical methods, ed 6. Ames, la., 1967, Iowa State University Press, pp 130-131. 22. Stoeckel K, McNamara P J, Brandt R, Plozza-Nottebrock H, Ziegler WH: Effects of concentration-dependent plasma protein binding on ceftriaxone kinetics. Clin Pharmacol Ther 29:650, 1981. 23. Dettli L, Spring P, Lomar AV: Ueber die Pharmakokinetik tier Cephalosporinc im Liquor cerebrospinalis. Infection 4(suppl 3):S195, 1976. 24. Latif R, Dajani AS: Ceftriaxone diffusion into cerebrospinal fluid of children with meningitis. Antimicrob Agents Chemother 23:46, 1983. 25. Martin E: Once-daily administration of ceftriaxone in the treatment of meningitis and other serious infections in children. Eur J Clin Microbiol 2:509, 1983. 26. Martin E: Ceftriaxone for meningitis. Lancet 2:43, 1983. 27. Del Rio M, Chrane D, Shelton S, McCracken GH, Nelson JD: Ceftriaxone versus ampicillin and chloramphenicol for the treatment of bacterial meningitis in children. Lancet 2:1241, 1983.