Drug Information for CefTRIaxONE for injection and Dextrose Injection (B. Braun Medical Inc.): CLINICAL PHARMACOLOGY

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  • Average plasma concentrations of ceftriaxone following a single 30-minute intravenous (IV) infusion of a 0.5, 1 or 2 g dose in healthy subjects are presented in Table 1.

    TABLE 1. Ceftriaxone Plasma Concentrations After Single Dose Administration
    Average Plasma Concentrations (mcg/mL)
    Dose/Route0.5 hr1 hr2 hr4 hr6 hr8 hr12 hr16 hr24 hr
    0.5 g IVIV doses were infused at a constant rate over 30 minutes.82594837292315105
    1 g IV1511118867534328189
    2 g IV2571921541178974463115

    Multiple IV doses ranging from 0.5 to 2 g at 12- to 24-hour intervals resulted in 15% to 36% accumulation of ceftriaxone above single dose values.

    Ceftriaxone concentrations in urine are high, as shown in Table 2.

    TABLE 2. Urinary Concentrations of Ceftriaxone After Single Dose Administration
    Average Urinary Concentrations (mcg/mL)
    Dose/Route0–2 hr2–4 hr4–8 hr8–12 hr12–24 hr24–48 hr
    0.5 g IV526366142877015
    1 g IV99585529314713232
    2 g IV2692197675727419840

    Thirty-three percent to 67% of a ceftriaxone dose was excreted in the urine as unchanged drug and the remainder was secreted in the bile and ultimately found in the feces as microbiologically inactive compounds. After a 1 g IV dose, average concentrations of ceftriaxone, determined from 1 to 3 hours after dosing, were 581 mcg/mL in the gallbladder bile, 788 mcg/mL in the common duct bile, 898 mcg/mL in the cystic duct bile, 78.2 mcg/g in the gallbladder wall and 62.1 mcg/mL in the concurrent plasma.

    Over a 0.15 to 3 g dose range in healthy adult subjects, the values of elimination half-life ranged from 5.8 to 8.7 hours; apparent volume of distribution from 5.78 to 13.5 L; plasma clearance from 0.58 to 1.45 L/hour; and renal clearance from 0.32 to 0.73 L/hour. Ceftriaxone is reversibly bound to human plasma proteins, and the binding decreased from a value of 95% bound at plasma concentrations of <25 mcg/mL to a value of 85% bound at 300 mcg/mL. Ceftriaxone crosses the blood placenta barrier.

    The average values of maximum plasma concentration, elimination half-life, plasma clearance and volume of distribution after a 50 mg/kg IV dose and after a 75 mg/kg IV dose in pediatric patients suffering from bacterial meningitis are shown in Table 3. Ceftriaxone penetrated the inflamed meninges of infants and pediatric patients; CSF concentrations after a 50 mg/kg IV dose and after a 75 mg/kg IV dose are also shown in Table 3.

    TABLE 3. Average Pharmacokinetic Parameters of Ceftriaxone in Pediatric Patients With Meningitis
    50 mg/kg IV75 mg/kg IV
    Maximum Plasma Concentrations (mcg/mL)216275
    Elimination Half-life (hr)4.64.3
    Plasma Clearance (mL/hr/kg)4960
    Volume of Distribution (mL/kg)338373
    CSF Concentration – inflamed meninges (mcg/mL)5.66.4
    Range (mcg/mL)1.3 – 18.51.3 – 44
    Time after dose (hr)3.7 (±1.6)3.3 (±1.4)

    Compared to that in healthy adult subjects, the pharmacokinetics of ceftriaxone were only minimally altered in elderly subjects and in patients with renal impairment or hepatic dysfunction (Table 4); therefore, dosage adjustments are not necessary for these patients with ceftriaxone dosages up to 2 g per day. Ceftriaxone was not removed to any significant extent from the plasma by hemodialysis. In 6 of 26 dialysis patients, the elimination rate of ceftriaxone was markedly reduced, suggesting that plasma concentrations of ceftriaxone should be monitored in these patients to determine if dosage adjustments are necessary.

    TABLE 4. Average Pharmacokinetic Parameters of Ceftriaxone in Humans
    Subject GroupElimination Half-Life (hr)Plasma Clearance (L/hr)Volume of Distribution (L)
    Healthy Subjects5.8–8.70.58–1.455.8–13.5
    Elderly Subjects (mean age, 70.5 yr)8.90.8310.7
    Patients with Renal Impairment
    Hemodialysis Patients (0–5 mL/min) Creatinine clearance.14.70.6513.7
    Severe (5–15 mL/min)15.70.5612.5
    Moderate (16–30 mL/min)11.40.7211.8
    Mild (31–60 mL/min)12.40.7013.3
    Patients With Liver Disease8.81.113.6
  • Microbiology

  • The bactericidal activity of ceftriaxone results from inhibition of cell wall synthesis. Ceftriaxone has a high degree of stability in the presence of beta-lactamases, both penicillinases and cephalosporinases, of gram-negative and gram-positive bacteria.

    In an in vitro study antagonistic effects have been observed with the combination of chloramphenicol and ceftriaxone.

    Ceftriaxone has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections described in the INDICATIONS AND USAGE section.

    Aerobic gram-negative microorganismsAcinetobacter calcoaceticusEnterobacter aerogenesEnterobacter cloacaeEscherichia coliHaemophilus influenzae (including ampicillin-resistant and beta-lactamase producing strains) Haemophilus parainfluenzaeKlebsiella oxytocaKlebsiella pneumoniaeMoraxella catarrhalis (including beta-lactamase producing strains) Morganella morganiiNeisseria gonorrhoeae (including penicillinase- and nonpenicillinase-producing strains) Neisseria meningitidisProteus mirabilisProteus vulgarisSerratia marcescens

    Ceftriaxone is also active against many strains of Pseudomonas aeruginosa.

    NOTE: Many strains of the above organisms that are multiply resistant to other antibiotics, e.g., penicillins, cephalosporins, and aminoglycosides, are susceptible to ceftriaxone.

    Aerobic gram-positive microorganismsStaphylococcus aureus (including penicillinase-producing strains) Staphylococcus epidermidisStreptococcus pneumoniaeStreptococcus pyogenesViridans group streptococci

    NOTE: Methicillin-resistant staphylococci are resistant to cephalosporins, including ceftriaxone. Most strains of Group D streptococci and enterococci, e.g., Enterococcus (Streptococcus) faecalis, are resistant.

    Anaerobic microorganismsBacteroides fragilisClostridium speciesPeptostreptococcus species

    NOTE: Most strains of Clostridium difficile are resistant.

    The following in vitro data are available, but their clinical significance is unknown. Ceftriaxone exhibits in vitro minimal inhibitory concentrations (MICs) of ≤8 mcg/mL or less against most strains of the following microorganisms, however, the safety and effectiveness of ceftriaxone in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

    Aerobic gram-negative microorganismsCitrobacter diversusCitrobacter freundiiProvidencia species (including Providencia rettgeri) Salmonella species (including Salmonella typhi) Shigella species

    Aerobic gram-positive microorganismsStreptococcus agalactiae

    Anaerobic microorganismsPrevotella (Bacteroides) biviusPorphyromonas (Bacteroides) melaninogenicus

  • Dilution Techniques

  • Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure.1 Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ceftriaxone powder. The MIC values should be interpreted according to the following criteria2 for aerobic organisms other than Haemophilus spp, Neisseria gonorrhoeae, and Streptococcus spp, including Streptococcus pneumoniae:

    MIC (mcg/mL)Interpretation
    ≤8(S) Susceptible
    16–32(I) Intermediate
    ≥64(R) Resistant

    The following interpretive criteria2 should be used when testing Haemophilus species using Haemophilus Test Media (HTM).

    MIC (mcg/mL)Interpretation
    ≤2(S) Susceptible

    The absence of resistant strains precludes defining any categories other than "Susceptible". Strains yielding results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing.

    The following interpretive criteria2 should be used when testing Neisseria gonorrhoeae when using GC agar base and 1% defined growth supplement.

    MIC (mcg/mL)Interpretation
    ≤0.25(S) Susceptible

    The absence of resistant strains precludes defining any categories other than "Susceptible". Strains yielding results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing.

    The following interpretive criteria2 should be used when testing Streptococcus spp including Streptococcus pneumoniae using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.

    MIC (mcg/mL)Interpretation
    ≤0.5(S) Susceptible
    1(I) Intermediate
    ≥2(R) Resistant

    A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the results should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of the drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

    Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standardized ceftriaxone powder should provide the following MIC values2:

    MicroorganismATCC®#MIC (mcg/mL)
    Escherichia coli259220.03 – 0.12
    Staphylococcus aureus292131 – 8A bimodal distribution of MICs results at the extremes of the acceptable range should be suspect and control validity should be verified with data from other control strains.
    Pseudomonas aeruginosa278538 – 32
    Haemophilus influenzae492470.06 – 0.25
    Neisseria gonorrhoeae492260.004 – 0.015
    Streptococcus pneumoniae496190.03 – 0.12
  • Diffusion Techniques

  • Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure3 requires the use of standardized inoculum concentrations. This procedure uses paper discs impregnated with 30 mcg of ceftriaxone to test the susceptibility of microorganisms to ceftriaxone.

    Reports from the laboratory providing results of the standard single-disc susceptibility test with a 30 mcg ceftriaxone disc should be interpreted according to the following criteria for aerobic organisms other than Haemophilus spp, Neisseria gonorrhoeae, and Streptococcus spp:

    Zone Diameter (mm)Interpretation
    ≥21(S) Susceptible
    14 – 20(I) Intermediate
    ≤13(R) Resistant

    The following interpretive criteria3 should be used when testing Haemophilus species when using Haemophilus Test Media (HTM).

    Zone Diameter (mm)Interpretation
    ≥26(S) Susceptible

    The absence of resistant strains precludes defining any categories other than "Susceptible". Strains yielding results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing.

    The following interpretive criteria3 should be used when testing Neisseria gonorrhoeae when using GC agar base and 1% defined growth supplement.

    Zone Diameter (mm)Interpretation
    ≥35(S) Susceptible

    The absence of resistant strains precludes defining any categories other than "Susceptible". Strains yielding results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing.

    The following interpretive criteria3 should be used when testing Streptococcus spp other than Streptococcus pneumoniae when using Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.

    Zone Diameter (mm)Interpretation
    ≥27(S) Susceptible
    25–26(I) Intermediate
    ≤24(R) Resistant

    Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disc test with the MIC for ceftriaxone.

    Disc diffusion interpretive criteria for ceftriaxone discs against Streptococcus pneumoniae are not available, however, isolates of pneumococci with oxacillin zone diameters of >20 mm are susceptible (MIC ≤0.06 mcg/mL) to penicillin and can be considered susceptible to ceftriaxone. Streptococcus pneumoniae isolates should not be reported as penicillin (ceftriaxone) resistant or intermediate based solely on an oxacillin zone diameter of ≤19 mm. The ceftriaxone MIC should be determined for those isolates with oxacillin zone diameters ≤19 mm.

    As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30 mcg ceftriaxone disc should provide the following zone diameters in these laboratory test quality control strains3:

    MicroorganismATCC®#Zone Diameter Ranges (mm)
    Escherichia coli2592229 – 35
    Staphylococcus aureus2592322 – 28
    Pseudomonas aeruginosa2785317 – 23
    Haemophilus influenzae4924731 – 39
    Neisseria gonorrhoeae4922639 – 51
    Streptococcus pneumoniae4961930 – 35
  • Anaerobic Techniques

  • For anaerobic bacteria, the susceptibility to ceftriaxone as MICs can be determined by standardized test methods4. The MIC values obtained should be interpreted according to the following criteria:

    MIC (mcg/mL)Interpretation
    ≤16(S) Susceptible
    32(I) Intermediate
    ≥64(R) Resistant

    As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized ceftriaxone powder should provide the following MIC values for the indicated standardized anaerobic dilution4 testing method:

    MethodMicroorganismATCC®#MIC (mcg/mL)
    AgarBacteroides fragilis2528532 – 128
    Bacteroides thetaiotaomicron2974164 – 256
    BrothBacteroides thetaiotaomicron2974132 – 128
  • Drug Information Provided by National Library of Medicine (NLM).
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