Pharmacokinetics of ceftriaxone in pediatric patients with meningitis.
ABSTRACT Pharmacokinetics of ceftriaxone after a single dose of 50 or 75 mg/kg were determined in 30 pediatric patients with bacterial meningitis. Data for doses of 50 and 75 mg/kg, respectively, were as follows (mean +/- standard deviation): maximum plasma concentrations, 230 +/- 64 and 295 +/- 76 mug/ml; elimination rate constant, 0.14 +/- 0.06 and 0.14 +/- 0.04 h(-1); harmonic elimination half-life, 5.8 +/- 2.8 and 5.4 +/- 2.1 h; plasma clearance, 51 +/- 24 and 55 +/- 18 ml/h per kg; volume of distribution, 382 +/- 129 and 387 +/- 56 ml/kg; mean concentration in cerebrospinal fluid 1 to 6 h after infusion, 5.4 and 6.4 mug/ml. A dosage schedule of 50 mg/kg every 12 h for bacterial meningitis caused by susceptible organisms is suggested for pediatric patients over 7 days of age.
- SourceAvailable from: aac.asm.org[Show abstract] [Hide abstract]
ABSTRACT: Ceftriaxone, a new third-generation cephalosporin, appearstobepromising forthetherapy ofacute bacterial meningitis. The90% MBCs ofceftriaxone against 54 recentcerebrospinal fluid isolates of Streptococcus pneumoniae, Neisseria meningitidis, andHaemophilus influenzae were .0.06 to0.25j.Lg/ml. We examined theefficacy andsafety ofceftriaxone therapy ofmeningitis inBahia, Brazil. Thestudy wasconducted intwophases; inphaseA,ceftriaxone was coadministered withampicillin. Themean cerebrospinal fluid concentrations ofceftriaxone 24hafter an intravenous doseof80mg/kgwere4.2and2.3,ug/ml on days4to 6and10to12oftherapy, respectively. Theseconcentrations were 8-tomore than100-fold greater thanthe 90%MBCs against therelevant pathogens. InphaseB,ceftriaxone (administered oncedaily ata doseof80 mg/kgafter an initial doseof100mg/kg) was compared withconventional dosages ofampicillin and chloramphenicol inaprospective randomized trial of36children andadults withmeningitis. Thegroupswere comparable based on clinical, laboratory, andetiological parameters. Ceftriaxone given oncedaily produced results equivalent tothose obtained withampicillin pluschloramphenicol, asjudged bycurerate, casefatality ratio, resolution withsequelae, typeandseverity ofsequelae, timetosterility ofcerebrospinal fluid, and potentially drug-related adverse effects. Thecerebrospinal fluid bactericidal titers obtained 16to24hafter ceftriaxone dosing were usually 1:512 to>1:2,048 evenlate inthetreatment course,compared withvalues of 1:8to1:32inpatients receiving ampicillin pluschloramphenicol. Ceftriaxone clearly deserves further evaluation forthetherapy ofmeningitis; theoptimal dose, dosing frequency (every 12hor every24h),and duration oftherapy remaintobedetermined.
- [Show abstract] [Hide abstract]
ABSTRACT: The adequate management of central nervous system (CNS) infections requires that antimicrobial agents penetrate the blood-brain barrier (BBB) and achieve concentrations in the CNS adequate for eradication of the infecting pathogen. This review details the currently available literature on the pharmacokinetics (PK) of antibacterials in the CNS of children. Clinical trials affirm that the physicochemical properties of a drug remain one of the most important factors dictating penetration of antimicrobial agents into the CNS, irrespective of the population being treated (i.e. small, lipophilic drugs with low protein binding exhibit the best translocation across the BBB). These same physicochemical characteristics determine the primary disposition pathways of the drug, and by extension the magnitude and duration of circulating drug concentrations in the plasma, a second major driving force behind achievable CNS drug concentrations. Notably, these disposition pathways can be expected to change during the normal process of growth and development. Finally, CNS drug penetration is influenced by the nature and extent of the infection (i.e. the presence of meningeal inflammation). Aminoglycosides have poor CNS penetration when administered intravenously. Intrathecal gentamicin has been studied in children with more promising results, often exceeding the minimum inhibitory concentration. There are very limited data with intrathecal tobramycin in children. However, in the few patients that have been studied, the CSF concentrations were highly variable. Penicillins generally have good CNS penetration. Aqueous penicillin G reaches greater concentrations than procaine or benzathine penicillin. Concentrations remain detectable for ≥12 h. Of the aminopenicillins, both ampicillin and parenteral amoxicillin reach adequate CNS concentrations; however, orally administered amoxicillin resulted in much lower concentrations. Nafcillin and piperacillin are the final two penicillins with pediatric data: their penetration is erratic at best. Cephalosporins vary greatly in regard to their CSF penetration. Few first- and second-generation cephalosporins are able to reach higher CSF concentrations. Cefuroxime is the only exception and is usually avoided due to its adverse effects and slower sterilization of the CSF than third-generation agents. Ceftriaxone, cefotaxime, ceftazidime, cefixime and cefepime have been studied in children and are all able to adequately penetrate the CSF. As with penicillins, concentrations are greatest in the presence of meningeal inflammation. Meropenem and imipenem are the only carbapenems with pediatric data. Imipenem reaches higher CSF concentrations; however, meropenem is preferred due to its lower incidence of seizures. Aztreonam has also demonstrated favorable penetration but only one study has been completed in children. Both chloramphenicol and sulfamethoxazole/trimethoprim (cotrimoxazole) penetrate into the CNS well; however, significant toxicities limit their use. The small size and minimal protein binding of fosfomycin contribute to its favorable CNS PK. Although rarely used, it achieves higher concentrations in the presence of inflammation and accumulation is possible. Linezolid reaches high CSF concentrations; however, more frequent dosing might be required in infants due to their increased elimination. Metronidazole also has very limited information but it demonstrated favorable results similar to adult data; CSF concentrations even exceeded plasma concentrations at certain time points. Rifampin (rifampicin) demonstrated good CNS penetration after oral administration. Vancomycin demonstrates poor CNS penetration after intravenous administration. When combined with intraventricular therapy, CNS concentrations are much greater. Of the antituberculosis agents, isoniazid, pyrazinamide and streptomycin have been studied in children. Isoniazid and pyrazinamide have favorable CSF penetration. Streptomycin appears to produce unpredictable CSF levels. No pediatric-specific data are available for clindamycin, daptomycin, macrolides, tetracyclines, and fluoroquinolones. Daptomycin, fluoroquinolones, and tetracyclines have demonstrated favorable CNS penetration in adults; however, data are limited due to their potential pediatric-specific toxicities and newness within the marketplace. Macrolides and clindamycin have demonstrated poor CNS penetration in adults and thus have not been studied in pediatrics.Paediatric Drugs 03/2013; · 1.72 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Salmonellosis is one of the most common causes of food-borne disease in the United States. Increasing antimicrobial resistance and corresponding increases in virulence present serious challenges. Currently, empirical therapy for invasive Salmonella enterica infection includes either ceftriaxone or ciprofloxacin (E. L. Hohmann, Clin. Infect. Dis. 32:263-269, 2001). The bla(CMY-2) gene confers resistance to ceftriaxone, the antimicrobial of choice for pediatric patients with invasive Salmonella enterica infections, making these infections especially dangerous (J. M. Whichard et al., Emerg. Infect. Dis. 11:1464-1466, 2005). We hypothesized that bla(CMY-2)-positive Salmonella enterica would exhibit increased MICs to multiple antimicrobial agents and increased resistance gene expression following exposure to ceftriaxone using a protocol that simulated a patient treatment in vitro. Seven Salmonella enterica strains survived a simulated patient treatment in vitro and, following treatment, exhibited a significantly increased ceftriaxone MIC. Not only would these isolates be less responsive to further ceftriaxone treatment, but because the bla(CMY-2) genes are commonly located on large, multidrug-resistant plasmids, increased expression of the bla(CMY-2) gene may be associated with increased expression of other drug resistance genes located on the plasmid (N. D. Hanson and C. C. Sanders, Curr. Pharm. Des. 5:881-894, 1999). The results of this study demonstrate that a simulated patient treatment with ceftriaxone can alter the expression of antimicrobial resistance genes, including bla(CMY-2) and floR in S. enterica serovar Typhimurium and S. enterica serovar Newport. Additionally, we have shown increased MICs following a simulated patient treatment with ceftriaxone for tetracycline, amikacin, ceftriaxone, and cefepime, all of which have resistance genes commonly located on CMY-2 plasmids. The increases in resistance observed are significant and may have a negative impact on both public health and antimicrobial resistance of Salmonella enterica.Applied and Environmental Microbiology 09/2012; 78(22):8062-6. · 3.95 Impact Factor
Vol. 23, No. 2
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 1983, p. 191-194
Copyright 0 1983, American Society forMicrobiology
Pharmacokinetics of Ceftriaxone in Pediatric Patients With
RUSSELL W. STEELE,'* LINDA B. EYRE,1 ROBERT W. BRADSHER,2 ROBERT E. WEINFELD,3
INDRAVADAN H. PATEL,3 AND JONATHAN SPICEHANDLER3
Departments ofPediatrics' and Medicine,2 University ofArkansasfor Medical Sciences andArkansas
Children's Hospital, Little Rock, Arkansas 72201, and Department ofMedical Research and
Pharmacokinetics andBiopharmaceutics, Hoffmann-La Roche Inc., Nutley, NewJersey 071103
Received 10 August 1982/Accepted 18 November 1982
Pharmacokinetics of ceftriaxone after a single dose of 50 or 75 mg/kg were
determined in 30 pediatric patients with bacterial meningitis. Data for doses of 50
and 75 mg/kg, respectively, were as follows (mean
maximum plasma concentrations, 230 ± 64 and 295 ± 76 ,ug/ml; elimination rate
constant, 0.14 ± 0.06 and 0.14 ± 0.04 h-1; harmonic elimination half-life, 5.8 +
2.8 and 5.4 ± 2.1 h; plasma clearance, 51 ± 24 and 55 ± 18 mI/h per kg; volume of
distribution, 382 ± 129 and 387 ± 56 ml/kg; mean concentration in cerebrospinal
fluid 1 to 6 h after infusion, 5.4 and 6.4 ,ug/ml. A dosage schedule of 50 mg/kg
every 12 h for bacterial meningitis caused by susceptible organisms is suggested
for pediatric patients over 7 days of age.
± standard deviation):
Newer 1-lactam antibiotics have been consid-
ered as an alternative to the current therapy for
bacterial meningitis. There are features unique
to these agents which make them particularly
attractive, primarily their excellent penetration
into cerebrospinal fluid (CSF), a broad spectrum
of bactericidal activity including most enteric
organisms and 3-lactamase-producing Haemo-
philus influenzae, and relatively rare toxicity.
Ceftriaxone offers additional advantages over
other 3-lactam antibiotics in its activity against
group B streptococci and relatively long half-
The present study was designed to examine
ceftriaxone pharmacokinetics after a single in-
travenous dose. Safety and tolerance were also
MATERIAULS AND METHODS
Patients and study deign. The study population
included five full-term neonates, 8 to 21 days, and 25
infants, aged 6 weeks to 2 years, who were receiving
conventional therapy for documented bacterial menin-
gitis at Arkansas Children's Hospital, Little Rock.
Written informed consent was obtained from the par-
ents of all participants. Between days 2 and 5 of
therapy, when infection was judged to be under ade-
quate control, and without alteration of the antimicro-
bial regimen, a single dose ofceftriaxone was adminis-
tered intravenously over a 10-min period. The study
was randomized so that halfofthe patients received 50
mg/kg and halfreceived 75 mg/kg for this one infusion.
Plasma samples were obtainedjust before infusion and
at 15, 30, and 60 min and 2, 4, 6, and 10 h after
infusion. A lumbar puncture was performed 1 to 6 h
after drug administration, and a sample of CSF was
obtained for analysis of ceftriaxone concentration.
Susceptibility studies. Mean inhibitory concentra-
tions (MICs) of ceftriaxone for each pathogen were
determined by standard microtiter broth dilution (6).
An inoculum of 105 organisms per ml in logarithmic
growth phase was introduced into wells containing
appropriate nutrients for that organism and serial
dilutions of ceftriaxone.
Cftriaxone concentrations. Plasma and CSF con-
centrations of ceftriaxone were analyzed by high-
pressure liquid chromatographic techniques (9). To
monitor ceftriaxone levels on a daily basis for patients
receiving this investigational antibiotic, microbiologi-
cal methodology was employed; briefly, this was a
standard agar well diffusion assay in which susceptible
Escherichia coli is used after dilution of the specimen
with pooled plasma (1).
Pharmacokinetic determinations. The elimination
rate constant, 1, was determined from the regression
line of the log plasma concentrations versus time by
the NONLIN computer program (8). Serum half-life,
tV2, was calculated from the equation: t1/2 = 0.693/,B.
Successive trapezoidal approximations and extrapola-
tion were used to calculate the area under the serum
concentration-time curve from time zero to infinity.
Plasma clearance(Clp)was derived from the equation:
Clp = dose/area under the serum concentration-time
curve. The volume ofdistribution, Vd, was determined
from the equation: Vd =dose/(Clp x 1) (10).
Clinical and laboratory studies. Patients were care-
fully monitored for adverse reactions during infusion
by one of the investigators and followed during the
duration of hospitalization. In addition, laboratory
parameters for bone marrow, renal, or hepatic toxicity
were obtained preinfusion and at 2 and 4 days. These
included CBC, blood urea nitrogen, creatinine, urinal-
STEELE ET AL.
TABLE 1. Organisms recovered from 30 patients
with bacterial meningitis
Group B streptoccoci
ysis, serum glutamic oxalacetic transaminase, and
serum glutamic pyruvic transaminase.
along with their susceptibilities to ceftriaxone,
as determined by MICs, are included in Table 1.
Predictably, the organisms most frequently iso-
lated from infants were H. influenzae. All recov-
ered organisms except two isolates of Listeria
monocytogenes and one Bacillus sp. were sus-
ceptible to ceftriaxone at concentrations well
below the range of those achieveable in CSF;
these three resistant organisms were recovered
from neonates. Two CSF isolates of Staphylo-
coccus aureus from infants with ventriculoperi-
toneal shunts, previously placed for hydroceph-
alus, were susceptible at 2 and 4 ,ug/ml.
Results for the five neonates, all over 7 days
of age, were not different from those for infants
in the present study, so determinations were
combined for analysis. Pharmacokinetic data are
summarized in Table 2 and Fig. 1.
from these 30 cases,
ANTIMICROB. AGENTS CHEMOTHER.
were usually 10 to 100 times greater than the
MIC for recovered bacteria. The measured lev-
els of ceftriaxone in the two infants with S.
aureus were two- to threefold higher than the
MIC for those organisms. Other exceptions in-
cluded three resistant organisms already de-
Ceftriaxone administered intravenously over
a 10-min period was well tolerated by infants and
neonates, with no local or systemic reactions
observed. There were no changes in laboratory
parameters used to assess bone marrow, renal,
or hepatic toxicity.
CSF drug concentrations are presented in
Table 2 simply as the mean for all samples
obtained; the wide variation in the time that CSF
was obtained (1 to 6 h) prevents a full statistical
analysis of penetration into CSF for these study
subjects. The CSF-to-plasma concentration ra-
tio ranged from 1.8 to 24.6% after a single dose.
Results for individual patients are presented in
Fig. 2. Mean values expressed as apercentage of
plasma levels were as follows for the 50-mg/kg
dose: 4.8% at 2 h, 11.8% at 3 h, 3.5% at 4 h,
14.6% at 5 h, and 10.0%o at 6 h. For the 75-mg/kg
dose, the percent penetration was 6.2% at 2 h,
7.7% at 3 h, 4.8% at 4 h, 3.5% at 5 h, and 12.9%
at 6 h.
Previously published studies have demon-
strated the in vitro activity ofceftriaxone against
a wide variety of gram-positive and gram-nega-
tive bacteria (5, 7, 14). Pertinent to consider-
ations of meningitis therapy are susceptibilities
of the three major etiological agents causing
disease in infants and those two most commonly
associated with infection in neonates. The con-
centration (in micrograms per milliliter) of cef-
triaxone inhibiting 90%o of clinical isolates in
vitro were as follows: H. influenzae, <0.004;
pneumoniae, 0.03; E. coli, 0.12; and group B
Subsequent studies in a rabbit meningitis
model (11) demonstrated penetration into the
CSF at a concentration that was >7% of the
TABLE 2. Ceftriaxone pharmacokinetics for infants and children
0.14 ± 0.06
5.8 ± 2.8
51 + 24
0.14 ± 0.04
5.4 + 2.1
Elimition rate constant;t7p,elimination half-life,Clp,plasma clearance; Vd, volume of distribution.
Values are expressed as means + standard deviation.
382 ± 129
230 ± 64
PHARMACOKINETICS OF CEFTRIAXONE
Hours After Dose
FIG. 1. Dose and mean plasma concentration-time
curves + standard deviation after a single intravenous
infusion of ceftriaxone.
concomitant serum levels. Compared with other
P-lactamantibiotics, ceftriaxone exhibited the
longest half-life and duration of bactericidal ac-
tivity and was the most effective in reducing
bacterial counts of E. coli and group B strepto-
coccus type III test strains in CSF.
Initial pharmacokinetic data in normal adult
volunteers indicated an elimination half-life of
approximately 8 h (2, 13). Similar studies in five
infants and five young children demonstrated a
slightly lower half-life at 6.5 h (12).
Preliminary studies for the treatment ofbacte-
rial meningitis in neonates, infants, and children
have been published (4). Clinical efficacy and
tolerance studies in adults with serious bacterial
infections have recently been published and
have established ceftriaxone as an agent with a
high degree of efficacy and a low incidence of
toxicity (3, 7). These reports support its selec-
tion as single drug therapy for a variety of
The present studies have focused on aspects
of meningitis therapy in children primarily to
establish dosage recommendations for future
treatment protocols and to examine CSF drug
relative to susceptibility of invading
pathogens. A tentative dosage schedule of 100
mg/kg given in two intravenous infusions every
24 h is suggested. Preliminary results in a recent-
ly completed comparative clinical trial of cef-
triaxone versus standard therapy for bacterial
meningitis have confirmed these recommenda-
tions (R. W. Steele and R. W. Bradsher, Pro-
gram Abstr. Intersci. Conf. Antimicrob. Agents
Chemother. 22nd, Atlantic City, N.J., abstr. no.
Most important for the treatment ofmeningitis
are data concerning penetration of antibiotics
into CSF. CSF levels 5 to 10% of concomitant
plasma concentrations are comparable to those
previously reported in animal models (11) and
human studies (4). These CSF levels exceeded
the MIC for common pathogens by at least 10-
fold; this appears to be the most critical deter-
mining factor for success of therapy.
These and other studies indicate that ceftriax-
one would not be effective for meningitis caused
by L. monocytogenes or enterococci and must
be considered of questionable value for the
treatment of Pseudomonas aeruginosa and S.
aureus meningitis. When any ofthese pathogens
are initially suspected, ceftriaxone should be
used in combination with other agents pending
results of cultures and susceptibility tests.
Repeated measurement of antibiotic levels is
important in monitoring the adequacy of antimi-
crobial therapy. In the present studies, a simple
microbiological assay was comparable to high-
pressure liquid chromatographic methodology
for assaying serum and CSF concentrations of
drug. Thus, more ready application in the usual
clinical setting of a medical center is ensured.
In summary, we found that ceftriaxone pene-
trated into the CSF of infants and neonates to a
Hours after Ds
FIG. 2. CSF concentrations of ceftriaxone at vari-
ous times after a single intravenous dose of 50 mg/kg
(0) or 75 mg/kg (0) in 30 pediatric patients with
VOL. 23, 1983
ANTIMICROB. AGENTS CHEMOTHER.
degree that should provide adequate levels to
treat the usual bacterial causes of meningitis.
The measured plasma half-life was longer than
those of other cephalosporins and investigation-
al P-lactam antibiotics, ensuring a greater dura-
tion of bactericidal activity for individual doses.
These initial pharmacokinetic data establish a
tentative dosage schedule of50 mg/kg every 12 h
for the treatment of meningitis in pediatric pa-
tients over 7 days of age.
The authors wish to express their deepest appreciation to
Elizabeth Robinson and Penni Jacobs for editorial assistance
and to the house officers at Arkansas Children's Hospital for
management of patients.
1. Bennett, J. V., J. L. Brodie, E. J. Benner, and W. M. M.
Kirby. 1966. Simplified, accurate method for antibiotic
assay of clinical specimens. Appl. Microbiol. 14:170-177.
2. Beskdd, G., J. G. Chrstenso, R. Cleelad, W. De Loren-
zo, and P. W. Trown. 1981. In vivo activity ofceftriaxone
(Ro 13-9904), a new broad-spectrum semisynthetic cepha-
losporin. Antimicrob. Agents Chemother. 20:159-167.
3. Braddhr, R. W. 1982. Ceftriaxone (Ro 13-9904) therapy
of serious infection. Antimicrob. Agents Chemother.
4. Cados, M., F. Denis, H. Fells, ad I. Diop. 1981. Treat-
ment of purulent meningitis with a new cephalosporin-
Rocephin (Ro 13-9904). Clinical bacteriological observa-
tions in 24 cases. Chemotherapy 27(Suppl. 1):57-61.
5. Ecksboff, T. C., ad J. Ebret. 1981. Comparative in vitro
studies of Ro 13-9904, a new cephalosporin derivative.
Antimicrob. Agents Chemother. 19:435-442.
6. Gavan, T. L., and A. L. Barry. 1980. Microdilution test
procedures, p. 459-462. In E. H. Lennette, A. Balows,
W. J. Hausler, Jr., and J. P. Truant (ed.), Manual for
clinical microbiology. American Society for Microbiolo-
gy, Washington, D.C.
7. Gnann, J. W., Jr., W. E. Goetter, A. M. Elliot, and C. G.
Cobbs. 1982. Ceftriaxone: In vitro studies and clinical
evaluation. Antimicrob. Agents Chemother. 22:1-9.
8. Metzler, C. M., G. L.Elfrng,and A. J. McEwen. 1974. A
package of computer programs for pharmacokinetic mod-
eling. Biometrics 30:562-563.
9. Patel, L. H., S. Chen, M. Parsonnet, M. R. HaclRnan,
M. A. Brooks, J. Konlkoff, and S. A. Kaplan. 1981. Phar-
macokinetics of ceftriaxone
Agents Chemother. 20:634-41.
10. Ribcbel, W. A. Handbook of Basic Pharmacokinetics.
Drug Intelligence Publications, Inc. 1976, p. 1%, 235, and
310, Hamilton, Illinois. 11.
11. Schaad, U. B., G. H. McCracken, C. A. Loock, and M. L.
Thomas. 1981. Pharmacokinetics and bacteriologic effica-
cy of moxalactam, cefotaxime, cefoperazone, and roce-
phin in experimental bacterial meningitis. J. Infect. Dis.
12. Schaad, U. B., and K. Stoeckel. 1982. Single-dose pharma-
cokinetics of ceftriaxone in infants and young children.
Antimicrob. Agents Chemother. 21:248-253.
13. Seddon, M., R. Wie, A. P. GDett, and R.Uvlngtoe.
1980. Pharmacokinetics of Ro 13-9904, a broad-spectrum
cephalosporin. Antimicrob. Agents Chemother. 18:240-
14. Shelton, S., J. D. Neson, and G. H. McCracken, Jr. 1980.
In vitro susceptibility ofgram-negative bacilli from pediat-
ric patients to moxalactam, cefotaxime, Ro 13-9904, and
other cephalosporins. Antimicrob. Agents Chemother.
in humans. Antimicrob.
STEELE ET AL.