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Ceftriaxone

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Ceftriaxone

CLINICAL PHARMACOLOGY

Average plasma concentrations of ceftriaxone (ceftriaxone sodium and dextrose injection ) 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 (ceftriaxone sodium and dextrose injection ) Plasma Concentrations After Single Dose Administration


Dose/Route Average Plasma Concentrations (µ/mL)
  0.5 hr 1 hr 2hr 4hr 6hr 8hr 12hr 16 hr 24 hr
0.5 g IV* 82 59 48 37 29 23 15 10 5
1 g IV* 151 111 88 67 53 43 28 18 9
2 g IV* 257 192 154 117 89 74 46 31 15
*IV doses were infused at a constant rate over 30 minutes.

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

Ceftriaxone (ceftriaxone sodium and dextrose injection ) concentrations in urine are high, as shown in Table 2.

TABLE 2. Urinary Concentrations of Ceftriaxone (ceftriaxone sodium and dextrose injection ) After Single Dose Administration


Dose/Route Average Urinary Concentrations (µ/mL)
  0-2 hr 2-4 hr 4-8 hr 8-12 hr 12-24 hr 24-48 hr
0.5 g IV 526 366 142 87 70 15
1 g IV 995 855 293 147 132 32
2g lV 2692 1976 757 274 198 40

Thirty-three percent to 67% of a ceftriaxone (ceftriaxone sodium and dextrose injection ) 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 (ceftriaxone sodium and dextrose injection ) , determined from 1 to 3 hours after dosing, were 581 µg/mL in the gallbladder bile, 788 µglml in the common duct bile, 898 µg/mL in the cystic duct bile, 78.2 µg/g in the gallbladder wall and 62.1 µg/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 (ceftriaxone sodium and dextrose injection ) is reversibly bound to human plasma proteins, and the binding decreased from a value of 95% bound at plasma concentrations of < 25 µg/mL to a value of 85% bound at 300 µg/mL. Ceftriaxone (ceftriaxone sodium and dextrose injection ) 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 (ceftriaxone sodium and dextrose injection ) 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 (ceftriaxone sodium and dextrose injection ) in Pediatric Patients With Meningitis


  50 mg/kg IV 75 mg/kq IV
Maximum Plasma Concentrations (µg/mL) 216 275
Elimination Half-life (hr) 4.6 4.3
Plasma Clearance (mL/hr/kg) 49 60
Volume of Distribution (mL/kg) 338 373
CSF Concentration — inflamed meninges (µg/mL) 5.6 6.4
Range (µ/mL) 1.3-18.5 1.3-44
Time after dose (hr) 3.7 (±1.6) 3.3 (±1.4)

Compared to that in healthy adult subjects, the pharmacokinetics of ceftriaxone (ceftriaxone sodium and dextrose injection ) 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 (ceftriaxone sodium and dextrose injection ) dosages up to 2 g per day. Ceftriaxone (ceftriaxone sodium and dextrose injection ) was not removed to any significant extent from the plasma by hemodialysis. In 6 of 26 dialysis patients, the elimination rate of ceftriaxone (ceftriaxone sodium and dextrose injection ) was markedly reduced, suggesting that plasma concentrations of ceftriaxone (ceftriaxone sodium and dextrose injection ) should be monitored in these patients to determine if dosage adjustments are necessary.

TABLE 4. Average Pharmacokinetic Parameters of Ceftriaxone (ceftriaxone sodium and dextrose injection ) in Humans


Subject Group Elimination
Half-Life
(hr)
Plasma
Clearance
(L/hr)
Volume of
Distribution
(L)
Healthy Subjects 5.8-8.7 0.58-1.45 5.8-13.5
Elderly Subjects (mean age, 70.5 yr) 8.9 0.83 10.7
Patients with Renal Impairment      
  Hemodialysis Patients (0-5 mL/min)* 14.7 0.65 13.7
  Severe (5-15 mL/min) 15.7 0.56 12.5
  Moderate (16-30 mL/min) 11.4 0.72 11.8
  Mild (31-60 mL/min) 12.4 0.70 13.3
Patients With Liver Disease 8.8 1.1 13.6
*Creatinine clearance.

Microbiology

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

Ceftriaxone (ceftriaxone sodium and dextrose injection ) 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 microorganisms

Acinetobacter calcoaceticus
Enterobacter aerogenes

Enterobacter cloacae
Escherichia coli
Haemophilus influenzae
(including ampicillin-resistant and beta-lactamase producing strains)
Haemophilus parainfluenzae

Klebsiella oxytoca

Klebsiella pneumoniae
Moraxella catarrhalis (including beta-lactamase producing strains)
Morganella morganii

Neisseria gonorrhoeae
(including penicillinase- and nonpenicillinase-producing strains)
Neisseria meningitidis

Proteus mirabilis

Proteus vulgaris
Serratia marcescens

Ceftriaxone (ceftriaxone sodium and dextrose injection ) 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 (ceftriaxone sodium and dextrose injection ) .

Aerobic gram-positive microorganisms

Staphylococcus aureus (including penicillinase-producing strains)

Staphylococcus epidermidis
Streptococcus pneumoniae

Streptococcus pyogenes

Viridans group streptococci

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

Anaerobic microorganisms

Bacteroides fragilis
Clostridium species
Peptostreptococcus species

NOTE: Most strains of Clostridium difficile are resistant.

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

Aerobic gram-negative microorganisms

Citrobacter diversus
Citrobacterfreundii

Providencia
species (including Providencia rertgeri)
Salmonella
species (including Salmonella typhi)
Shigella
species

Aerobic gram-positive microorganisms

Streptococcus agalactiae

Anaerobic microorganisms

Prevotella (Bacteroides) bivius
Porphyromonas (Bacteroides) melaninogenicus

Susceptibility Tests

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 (ceftriaxone sodium and dextrose injection ) 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 (µg/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 (µg/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 (µg/mL) Internretation
≤ 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 (µg/mL) Internretation
≤ 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 (ceftriaxone sodium and dextrose injection ) powder should provide the following MIC values:2


Microorganism ATCC® # MIC (µg/mL)
Escherichia coli 25922 0.03-0.12
Staphylococcus aureus 29213 1-8*
Pseudomonas aeruginosa 27853 8-32
Haemophilus influenzae 49247 0.06-0.25
Neisseria gonorrhoeae 49226 0.004-0.015
Streptococcus pneumoniae 49619 0.03-0.12
* A 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.
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 µg of ceftriaxone (ceftriaxone sodium and dextrose injection ) to test the susceptibility of microorganisms to ceftriaxone (ceftriaxone sodium and dextrose injection ) .

Reports from the laboratory providing results of the standard single-disc susceptibility test with a 30 µg ceftriaxone (ceftriaxone sodium and dextrose injection ) 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) Internretation
≥ 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) Internretation
≥ 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 (ceftriaxone sodium and dextrose injection ) .

Disc diffusion interpretive criteria for ceftriaxone (ceftriaxone sodium and dextrose injection ) discs against Streptococcus pneumoniae are not available, however, isolates of pneumococci with oxacillin zone diameters of > 20 mm are susceptible (MIC ≤ 0.06 µg/mL) to penicillin and can be considered susceptible to ceftriaxone (ceftriaxone sodium and dextrose injection ) . Streptococcus pneumoniae isolates should not be reported as penicillin (ceftriaxone (ceftriaxone sodium and dextrose injection ) ) resistant or intermediate based solely on an oxacillin zone diameter of ≤ 19 mm. The ceftriaxone (ceftriaxone sodium and dextrose injection ) 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 µg ceftriaxone (ceftriaxone sodium and dextrose injection ) disc should provide the following zone diameters in these laboratory test quality control strains:3


Microorqanism ATCC®# Zone Diameter Ranaes (mm)
Escherichia coli 25922 29-35
Staphylococcus aureus 25923 22-28
Pseudomonas aeruginosa 27853 17-23
Haemophilus influenzae 49247 31-39
Neisseria gonorrhoeae 49226 39-51
Streptococcus pneumoniae 49619 30-35
Anaerobic Techniques

For anaerobic bacteria, the susceptibility to ceftriaxone (ceftriaxone sodium and dextrose injection ) as MICs can be determined by standardized test methods.4 The MIC values obtained should be interpreted according to the following criteria:


MIC µg/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 (ceftriaxone sodium and dextrose injection ) powder should provide the following MIC values for the indicated standardized anaerobic dilution4 testing method:


Method Microoraanism ATCC®# MIC (µq/mL)
Agar Bacteroides fragilis 25285 32-128
  Bacteroides thetaiotaomicron 29741 64-256
Broth Bacteroides thetaiotaomicron 29741 32-128

REFERENCES

1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard-Fifth Edition. NCCLS document M7-A5 (ISBN 1-56238-309-9). NCCLS, Wayne, PA 19087-1898,2000.

2. National Committee for Clinical Laboratory Standards, Supplemental Tables. NCCLS document M100-S10(M7) (ISBN 1-56238-309-9). NCCLS, Wayne, PA 19087-1898,2000.

3. National Committee fof'Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Teste; Approved Standard-Seventh Edition. NCCLS document M2-A7 (ISBN 1-56238-393-0). NCCLS, Wayne, PA 19087-1898,2000.

4. National Committee for Clinical Laboratory Standards, Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacterial; Approved Standard-Fourth Edition. NCCLS document M11-A4 (ISBN 1-56238-210-1). NCCLS, Wayne, PA 19087-1898,1997.

Last reviewed on RxList: 10/3/2007
This monograph has been modified to include the generic and brand name in many instances.

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