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.
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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.
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ABSTRACT: Due to normal growth and development, hospitalised paediatric patients with infection require unique consideration of immune function and drug disposition. Specifically, antibacterial and antifungal pharmacokinetics are influenced by volume of distribution, drug binding and elimination, which are a reflection of changing extracellular fluid volume, quantity and quality of plasma proteins, and renal and hepatic function. However, there is a paucity of data in paediatric patients addressing these issues and many empiric treatment practices are based on adult data. The penicillins and cephalosporins continue to be a mainstay of therapy because of their broad spectrum of activity, clinical efficacy and favourable tolerability profile. These antibacterials rapidly reach peak serum concentrations and readily diffuse into body tissues. Good penetration into the cerebrospinal fluid (CSF) has made the third-generation cephalosporins the agents of choice for the treatment of bacterial meningitis. These drugs are excreted primarily by the kidney. The carbapenems are broad-spectrum β-lactam antibacterials which can potentially replace combination regimens. Vancomycin is a glycopeptide antibacterial with gram-positive activity useful for the treatment of resistant infections, or for those patients allergic to penicillins and cephalosporins. Volume of distribution is affected by age, gender, and body-weight. It diffuses well across serous membranes and inflamed meninges. Vancomycin is excreted by the kidneys and is not removed by dialysis. The aminoglycosides continue to serve a useful role in the treatment of gram-negative, enterococcal and mycobacterial infections. Their volume of distribution approximates extracellular space. These drugs are also excreted renally and are removed by haemodialysis. Passage across the blood-brain barrier is poor, even in the face of meningeal inflammation. Low pH found in abscess conditions impairs function. Toxicity needs to be considered. Macrolide antibacterials are frequently used in the treatment of respiratory infections. Parenteral erythromycin can cause phlebitis, which limits its use. Parenteral azithromycin is better tolerated but paediatric pharmacokinetic data are lacking. Clindamycin is frequently used when anaerobic infections are suspected. Good oral absorption makes it a good choice for step-down therapy in intra-abdominal and skeletal infections. The use of quinolones in paediatrics has been restricted and most information available is in cystic fibrosis patients. High oral bioavailability is also important for step-down therapy. Amphotericin B has been the cornerstone of antifungal treatment in hospitalised patients. Its metabolism is poorly understood. The half-life increases with time and can be as long as 15 days after prolonged therapy. Oral absorption is poor. The azole antifungals are being used increasingly. Fluconazole is well tolerated, with high bioavailability and good penetration into the CSF. Itraconazole has greater activity against aspergillus, blastomycosis, histoplasmosis and sporotrichosis, although it’s pharmacological and toxicity profiles are not as favourable.Paediatric Drugs 01/2001; 3(10):733-761. · 1.72 Impact Factor
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ABSTRACT: Most clinical reports deal with series of patients or single cases under widely different circumstances as to the nature of infection, the duration and mode of chemotherapy, the means of drug concentration assessment, and the expression and interpretation of results. It is generally accepted that the penetration of β-lactamines, aminoglycosides and vancomycin into the CSF is increased in the presence of infection, and this is confirmed in the results of most animal and human studies. Fluoroquinolones, cotrimoxazole, chloramphenicol, metronidazole, penetrate well into normal meninges. Finally, the reports reviewed above provide data used in predicting the likelihood of attaining adequate CSF levels with any particular antibiotic regimen, for bacterial infection of the CNS. However, the fact that levels can be assessed in the CSF does necessarily mean that drugs are effective in the treatment of the disease. Clinical studies are necessary to provide evidence as to the efficacy of each of the agents in meningitis.Medecine Et Maladies Infectieuses - MED MAL INFEC. 01/1996; 26:1032-1043.
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.
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STEELE ET AL.