Pharmacokinetics of ceftriaxone in pediatric patients with meningitis.

Antimicrobial Agents and Chemotherapy (Impact Factor: 4.57). 03/1983; 23(2):191-4. DOI: 10.1128/AAC.23.2.191
Source: PubMed

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: 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
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    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


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