Ceftriaxone for Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Ceftriaxone for Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: Canada
Condition: Bacteremia, Bacterial Endocarditis Prevention (Bacterial Endocarditis Prophylaxis), Bacterial Infection, Bone infection (Osteomyelitis), Bronchitis, Chancroid, Conjunctivitis, Endocarditis, Endometritis, Eye Conditions, Epiglottitis, Epididymitis, Sexually Transmitted, Epididymitis, Non-Specific, Gastroenteritis, Gonococcal Infection, Uncomplicated, Gonococcal Infection, Disseminated, Intraabdominal Infection, Joint Infection, Kidney Infections (Pyelonephritis), Lyme Disease, Neurologic, Lyme Disease, Carditis, Lyme Disease, Arthritis, Lyme Disease, Meningitis, Meningococcal Meningitis Prophylaxis, Neurosyphilis, Otitis Media, Pelvic Inflammatory Disease, Peritonitis, Pneumonia, Prostatitis, Proctitis, Salmonella Enteric Fever, Salmonella Gastroenteritis, Sepsis, Septicemia, Shigellosis, Skin and Structure Infection, Skin or Soft Tissue Infection, Syphilis, Early, Surgical Prophylaxis, STD Prophylaxis, Typhoid Fever, Urinary Tract Infection
Class: Miscellaneous antibiotics, Third generation cephalosporins
Form: Intramuscular (IM), Intravenous (IV), Powder
Ingredients: ceftriaxone sodium

Pharmaceutical Information

Drug Substance

Proper name:ceftriaxone sodium
Chemical name:(6R,7R)-7-[2-(2-Amino-4-thiazolyl)glyoxylamido]-8-oxo-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-car-boxylic acid, 72-(Z)-(O-methyloxime), disodium salt, ses-quaterhydrate
Molecular formula:C18H16N8Na2O7S3 •3.5H2O
Molecular mass:661.61
Structural formula:


Physicochemical properties:Ceftriaxone sodium is a white to pale yellow crystalline powder, soluble in water and methanol, insoluble in other common solvents.

Composition

SmartPak bags and vials of Ceftriaxone for Injection, USP contain ceftriaxone sodium (expressed in terms of anhydrous free acid). The sodium content of each gram of ceftriaxone sodium is approximately 83 mg (3.6 mEq sodium ion). The pH of freshly constituted solutions usually ranges from 6 to 8. Solutions are yellowish in colour.

Constitution

Vials

For Intramuscular Use

Constitute ceftriaxone sodium powder with the appropriate diluent:

  • Sterile Water for Injection
  • 9% Sodium Chloride Injection
  • 5% Dextrose Injection
  • Bacteriostatic Water for Injection
  • 1% Lidocaine Hydrochloride Injection

Constitute as follows:

Regular Volume Constitution Table (IM)*
Vial SizeVolume to be Added
to Vial (mL)
Approximate Available
Volume (mL)
Approximate Average
Concentration (g/mL)
0.25 g0.91.00.25
0.5 g1.72.00.25
1.0 g3.34.00.25
2.0 g6.68.00.25

*Shake well until dissolved

Low Volume Constitution Table (IM)*
Vial SizeVolume to be Added
to Vial (mL)
Approximate Available
Volume (mL)
Approximate Average
Concentration (g/mL)
0.25 gNot recommended for this vial size.
0.5 g1.11.40.35
1.0 g2.22.80.35
2.0 g4.45.60.35

*Shake well until dissolved.

Note: Solutions prepared for intramuscular use or any solution containing Lidocaine or Bacteriostatic Water for Injection should never be administered intravenously.

For Intravenous Use

Constitute only with Sterile Water for Injection.

Constitute as follows:

Constitution Table for Bulk Pharmacy Vial**
Vial SizeVolume to be Added
to Vial (mL)
Approximate Available
Volume (mL)
Approximate Average
Concentration (g/mL)
0.25 g2.42.50.1
0.5 g4.85.00.1
1.0 g9.610.10.1
2.0 g19.220.50.1

**Shake well until dissolved. The prepared solution may be further diluted to the desired volume with any of the “Solutions for IV Infusion” listed below.

Solutions for IV Infusion

  • 9% Sodium Chloride Injection
  • 5% Dextrose Injection
  • 5% Dextrose and 0.9% Sodium Chloride Injection

Pharmacy Bulk Vial Constitution for Preparation of Intravenous Infusion Solutions

The closure of the pharmacy bulk vial shall be penetrated only one time after constitution, using a suitable sterile transfer device or dispensing set which allows measured dispensing for the contents. THE USE OF PHARMACY BULK VIALS IS RESTRICTED TO HOSPITALS WITH A RECOGNIZED INTRAVENOUS ADMIXTURE PROGRAM.

Constitution Table for Bulk Pharmacy Vial
Vial SizeVolume to be Added
to Vial (mL)
Approximate Available
Volume (mL)
Approximate Average
Concentration (g/mL)
10 g951010.1

Shake well until dissolved. Withdraw the required amount and dilute with one of the “Solutions for IV Infusion”. Any unused solution remaining within a period of 8 hours should be discarded.

Directions for Proper Use of Smartpak Pharmacy Bulk Package

Not for direct infusion. The Pharmacy Bulk Package is for use in the hospital pharmacy admixture service only in a suitable work area, such as a laminar flow hood. Using aseptic technique, the container closure may be penetrated only one time using a suitable sterile dispensing set or transfer device that allows measured dispensing of the contents. Use of a syringe and needle is not recommended as it may cause leakage. The withdrawal of container contents should be accomplished without delay. However, should this not be possible, a maximum time of 8 HOURS from initial port closure entries is permitted to complete fluid transfer operations. This time limit should begin with the introduction of the solvent or diluent into the Pharmacy Bulk Package.

Instructions for Constitution

Visually examine outer (natural foil) bag for damage. IF THE SEAL IS BROKEN OR DAMAGE IS OBSERVED, DO NOT OPEN THE OUTER BAG. STERILITY OF THE INNER BAG SURFACE MAY BE COMPROMISED. DISCARD BOTH BAGS IMMEDIATELY. DO NOT USE THE INNER BAG IF PARTICULATE OR FOREIGN MATTER IS PRESENT, IF THE DRY POWDER IS DARK YELLOW OR BROWN, IF THE SEALS ARE NOT INTACT, OR IF THERE IS ANY OTHER DAMAGE TO THE BAG. IN SUCH CASE, DISCARD THE BAG IMMEDIATELY. Remove the translucent unthreaded cap from the constitution (smaller) port and discard it. Follow the above “Directions for Proper Use of a Pharmacy Bulk Package” and proceed to constitute the powder through the constitution (smaller) port, using Sterile Water for Injection. Mix gently by picking up the bag and gently moving from side to side until dissolution is complete, approximately 15 minutes, and hang the bag from the eyelets support.

If a pump is used, the following general procedure is recommended:

  1. Attach a sterile spike to the outlet (unspiked) end of a new sterile transfer tube set, and insert spike into spike port of the bag of Sterile Water for Injection to be used to constitute the SmartPak Pharmacy Bulk Package.
  2. Attach the inlet (attached spike) end of the tube set to the Transfer Port of the SmartPak Pharmacy Bulk Package.
  3. Reverse the pump to transfer Sterile Water for Injection into the SmartPak Pharmacy Bulk Package.
  4. After completing the transfer of Sterile Water for Injection, remove the spike from the bag of Sterile Water for Injection, and disconnect the spike from this end of the tube set.
  5. Replace this spike with a transfer needle, and insert this needle into the Constitution Port of the SmartPak Pharmacy Bulk Package.
  6. Using the pump, circulate the constituted drug through the tube set and SmartPak Pharmacy Bulk Package to thoroughly mix (about 15 minutes for the 100 gram container).
  7. After solution is complete, remove the transfer needle from the Constitution Port of the SmartPak Pharmacy Bulk Package, and replace it with a syringe filling adaptor.
  8. Hang the bag from the eyelets support. Constituted solution can now be transferred using a pump from the SmartPak Pharmacy Bulk Package, through the tube set in the Transfer Port, into syringes via the syringe filling adaptor.

It should be noted that the spike placed into the SmartPak Pharmacy Bulk Package in Step 1 is NEVER removed during this procedure and that the Constitution Port is self-sealing.

Solutions should be allowed to stand after dissolution to allow any foaming to dissipate in order to permit visual inspection for completed solubilization. CAUTION: TO AVOID POSSIBLE LEAKAGE CAUSED BY THE HEAVY WEIGHT OF THE ADDED WATER, DO NOT SHAKE VIGOROUSLY OR PULL STRONGLY ON THE BAG.

AFTER INITIAL ENTRY, USE ENTIRE CONTENTS OF THE PHARMACY BULK PACKAGE PROMPTLY; ANY UNUSED PORTION MUST BE DISCARDED WITHIN 8 HOURS.

Prior to administration, parenteral drug products should be inspected visually for clarity, particulate matter, precipitation, discolouration, and leakage whenever solution and container permit. Do not use the product if the mixture (solution) shows haziness, particulate matter, discolouration, or leakage.

SmartPak Pharmacy Bulk Package Dilution Table
SmartPak Bag SizeAmount of Sterile Water for Injection *Approximate Concentration
100 g950 mL100 mg/mL (1 g/10 mL)

* Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to constitute ceftriaxone. Particulate formation can result. Sterile Water for Injection is the only recommended diluent.

Dispensing Constituted Ceftriaxone/Instructions for Filling Empty Syringes

Unscrew the clear threaded cap from the Transfer (larger) Port and discard it. Using this Transfer Port, fill sterile empty syringes, using a new transfer device. Syringes may be filled using aseptic technique following the usual practice of the institution. Such practices may range from the use of a three -way stopcock to the use of a peristaltic pump. If constituted to 100 mg/mL, dispense 5 mL for 500 mg or 10 mL for 1 g.

AFTER INITIAL ENTRY, USE ENTIRE CONTENTS OF THE PHARMACY BULK PACKAGE PROMPTLY; ANY UNUSED PORTION MUST BE DISCARDED WITHIN 8 HOURS.

Prior to administration, parenteral drug products should be inspected visually for clarity, particulate matter, precipitation, discolouration, and leakage whenever solution and container permit. Do not use the product if the mixture (solution) shows haziness, particulate matter, discolouration, or leakage.

Special Instructions

PROPER PROCEDURE FOR CONSTITUTION AND DISPENSING OF THE SMARTPAK PHARMACY BULK PACKAGE

Entire procedure to be performed under Laminar Flow Hood using Aseptic Technique.


CONSTITUTION PHASE MIXING PHASE DISPENSING PHASE
1. Remove translucent constitution port cap by pulling.
2. Insert new transfer device for constitution.
3. Add appropriate volume of Sterile Water for Injection.
4. Disconnect transfer device from Sterile Water for Injection container, and replace the spike or needle with appropriate new transfer adaptor.
5. See Package Insert for further details.
1. Mix gently: either recirculate via a tubing loop or by picking up the bag and gently moving it from side to side until dissolution is completed (15 to 25 minutes) and foam, if any, dissipates.
2. Check for particulate matter, leaks and discolouration (dark yellow or brown).
3. If any of the above are found, discard bag immediately.
4. If satisfactory, hang bag, using the eyelets.
5. See Package Insert for further details.
1. Unscrew clear transfer port cap.
2. Insert new transfer device.
3. Transfer dose into sterile empty syringe.
4. Properly label syringes.
5. See Package Insert for further details.

Storage and Stability Recommendations

Ceftriaxone sodium sterile powder should be stored at a controlled room temperature (between 15 °C and 30 °C) and protected from light.

Constituted Solutions - Stability and Storage Recommendations

  1. For Intramuscular Use

    Solutions should be constituted immediately before use. If storage is required, these solutions may be stored under refrigeration (2 °C − 8 °C) and should be used within 48 hours.

  2. For IV Bolus Injection (without further dilution)

    Constituted solutions should be administered within 24 hours when stored at room temperature and within 72 hours when refrigerated (2 °C − 8 °C).

  3. For IV Infusion

    Further diluted constituted solutions should be administered within 24 hours when stored at room temperature.

    1. Solutions further diluted with 0.9% Sodium Chloride Injection, or with 5% Dextrose Injection should be administered within 72 hours when stored under refrigeration (2 °C − 8 °C).
    2. Solutions further diluted with Dextrose and Sodium Chloride Injection as diluent should not be refrigerated. These solutions are not physically compatible when refrigerated.
  4. Extended Use of Intravenous Admixtures

    Although intravenous admixtures may often be physically and chemically stable for longer periods, DUE TO MICROBIOLOGICAL CONSIDERATIONS, THEY ARE USUALLY RECOMMENDED FOR USE WITHIN A MAXIMUM OF 24 HOURS AT ROOM TEMPERATURE OR 72 HOURS WHEN REFRIGERATED (2 °C − 8 °C). Hospitals and institutions that have recognized admixture programs and use validated aseptic techniques for preparation of intravenous solutions may extend the storage times for ceftriaxone sodium admixtures with 0.9% Sodium Chloride Injection or 5% Dextrose Injection in polyvinyl chloride infusion containers, in concentrations of 3 - 40 mg/mL, to seven days when stored under refrigeration (2 °C − 8 °C).

    WARNING: As with all parenteral drug products, intravenous admixtures should be visually inspected prior to administration, whenever solution and container permit. Solutions showing any evidence of haziness or cloudiness, particulate matter, precipitation, discolouration or leakage should not be used.

  5. Frozen IV Infusion Solutions

    Hospitals and institutions that have recognized admixture programs and use validated aseptic techniques for preparation of intravenous solutions may freeze and store ceftriaxone sodium i.v. infusion solutions when prepared in accordance with the following instructions.

    IV infusion solutions prepared from constituted ceftriaxone sodium further diluted with 5% Dextrose Injection or 0.9% Sodium Chloride Injection, in flexible polyvinylchloride infusion containers, in concentrations up to 40 mg ceftriaxone per mL, may be stored between -10 °C to -20 °C for periods up to three months.

    The frozen solutions should be thawed in a refrigerator (2 °C − 8 °C) for 24 hours or longer to ensure the solution is completely thawed. The solution should subsequently be used within 24 hours when stored at room temperature or seven days when stored under refrigeration (2 °C − 8 °C).

    After thawing, check for leaks by squeezing the bag firmly. If leaks are found, discard the container as sterility may be impaired. Do not use unless the solution is clear and seals/outlet ports are intact. Ceftriaxone solutions range from light yellow to amber in colour. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration whenever the solution and container permit.

    DO NOT REFREEZE the previously frozen ceftriaxone i.v. infusion solutions.

Stability of Constituted SmartPak Bags

AFTER INITIAL ENTRY, USE ENTIRE CONTENTS OF THE PHARMACY BULK PACKAGE PROMPTLY; ANY UNUSED PORTION MUST BE DISCARDED WITHIN 8 HOURS.

Stability of Filled Syringes

In those situations in which the drug has been constituted to 100 mg/mL with Sterile Water for Injection and transferred into empty BD plastic syringes, but not immediately administered to the patient, the BD plastic syringes may be stored under the following conditions:

  1. 24 hours at room temperature
  2. 72 hours under refrigeration, 2 °C to 8 °C (36 °F to 46 °F), if immediately refrigerated after transfer.

Prior to administration, parenteral drug products should be inspected visually for particulate matter, precipitation, discolouration, and leakage whenever solution and container permit. Do not use the product if the mixture (solution) shows haziness, particulate matter, discolouration, or leakage.

Incompatibility

Ceftriaxone sodium should not be added to solutions containing calcium such as Hartmann’s solution and Ringer’s solution (see CONTRAINDICATIONS and WARNINGS).

Ceftriaxone sodium should not be physically mixed with other antimicrobial agents, vancomycin, amsacrine, or fluconazole.

Ceftriaxone sodium should not be added to blood products, protein hydrolysates or amino acids.

Availability of Dosage Forms

  • 10 mL vials containing sterile powder ceftriaxone sodium equivalent to 0.25 g of ceftriaxone, packaged in 25 vials per carton.
  • 10 mL or 15 mL vials containing sterile powder ceftriaxone sodium equivalent to 0.5 g of ceftriaxone, packaged in 25 vials per carton or 10 vials per carton, respectively.
  • 10 mL or 15 mL vials containing sterile powder ceftriaxone sodium equivalent to 1 g of ceftriaxone, packaged in 25 vials per carton or 10 vials per carton, respectively.
  • 20 mL vials containing sterile powder ceftriaxone sodium equivalent to 2 g of ceftriaxone, packaged in 10 vials per carton.
  • 100 mL Pharmacy Bulk Package vials containing ceftriaxone sodium equivalent to 10 grams of ceftriaxone packaged individually.

    The availability of the pharmacy bulk vial is restricted to hospitals with a recognized intravenous admixture programme.

  • 100 grams SmartPak “Pharmacy Bulk Package” containing sterile powder ceftriaxone sodium equivalent to 100 grams of ceftriaxone.

Vial stoppers do not contain natural rubber latex.

Microbiology

The in vitro activity of ceftriaxone against various gram positive and gram negative organisms is presented in Table 1.

Table 1
Cumulative Percentage of Clinical Isolates Inhibited at < Indicated Concentrations of Ceftriaxone (mg/L)*
Microorganisms (No. of Isolates)0.00780.0160.0310.06250.1250.250.501.02.048163264128
Aerobes Gram Negative
Acinetobacter anitratum (28) 113996100
Acinetobacter calcoaceticus (50) 2 6 1224326696100
Acinetobacter lwoffi (10) 10 40 50
Citrobacter freundii (21) 53362 677195
Enterobacter aerogenes (17) 24477182 8894 100
Enterobacter cloacae (40) 52850556575 90 93
Escherichia coli (47) 666889498100
Haemophilus influenzae (16)8694 100
Klebsiella oxytoca (21) 5090
Klebsiella species (49) 5090
Klebsiella pneumoniae (56) 54186100
Neisseria gonorrhea (10)**90100
Neisseria meningitidis (22)**596877100
Proteus inconstans (5) 2080 100
Proteus mirabilis (40)6095100
Proteus morganii (40)1843587585 909398 100
Proteus rettgeri (12)425875 92 100
Proteus vulgaris (29)3 143152728690 97 100
Pseudomonas aeruginosa (64) 52852739597
Pseudomonas cepacia (7) 144371100
Pseudomonas fluorescens (8) 2575
Pseudomonas maltophilia (9) 1122 6778100
Pseudomonas putida (9) 113378100
Salmonella species (18) 50
Salmonella typhi (30)** 3743100
Shigella (11)** 9 5573 82100
Serratia marcescens (45) 4203847586264789698
Aerobes Gram Positive
Staphylococcus aureus (34) 158591 97
Staphylococcus epidermidis (22) 9233650688295
Streptococcus agalacticae (25) 4896100
Streptococcus pneumoniae (88)2639558090100
Streptococcus pyogenes (15) 100
Anaerobes Gram Negative
Bacteroides SP. (56) 245132955718491
Fusobacterium SP. (8) 13 2538 5063
Anaerobes Gram Positive
Clostridium SP. (10) 102050 6070 80100
Peptococcus SP. (15) 334753 6673100
Peptostreptococcus SP. (8) 13 5088100

* The inoculum size ranged from 103 to 106 cells/mL.

** The inoculum size was not reported.

Methicillin resistant staphylococci and most strains of enterococci, Streptococcus faecalis, Group D streptococci, Clostridium difficile and Listeria monocytogenes are resistant to ceftriaxone.

The MBC/MIC ratio for a selected group of organisms is shown in Table 2.

Table 2
The MBC/MIC Ratio of Ceftriaxone for Randomly Selected Susceptible Isolates
Microorganisms (No. of Strains)Mean MBC/MIC Ratio
Citrobacter freundii (6)2.00
Enterobacter cloacae (8)2.75
Escherichia coli (8)1.38
Klebsiella pneumoniae (8)1.13
Proteus mirabilis (8)2.88
Proteus morganii (5)

(Morganella morganii)
1.00
Pseudomonas aeruginosa (8)5.25
Serratia marcescens (8)1.13

The effect of inoculum size on the activity of ceftriaxone was dependent upon the strain examined. Increases in inocula size from 103 to 105 CFU/mL had little if any effect on either MIC or MBC for a number of bacterial strains including beta-lactamase producers. However, a 100-fold increase in inocula size from 105 to 107 CFU/mL resulted in 8- to 533-fold increases in MICs and > 32- to 4267-fold increases in MBCs for P. aeruginosa, S. marcescens, and P. vulgaris, and 125- to 8333-fold increases in MICs and > 8- to 8333-fold increases in MBCs for beta-lactamase producers. A 10-fold increase in inocula size from 107 to 108 CFU/mL was accompanied by 64- to 1000-fold increases in MICs for S. marcescens and P. vulgaris.

The effects of pH in the range of 6 through 8 are shown in Table 3.

Table 3
Effect of pH on the In Vitro Activity of Ceftriaxone
Organisms
(No. of Strains)
MIC (mg/mL) at Indicated pH
pH 8pH 7pH 6
S. aureus (2)3.13 - 6.253.130.78
S. epidermidis (1)1.563.131.56
S. pyogenes (1)0.025≤ 0.012≤ 0.012
E. coli (3)≤ 0.012 - 0.100.025 - 0.10≤ 0.012 - 0.20
K. pneumoniae (1)0.050.050.05
S. typhimurium (2)0.025 - 0.100.05 - 0.200.05 - 0.20
S. marcescens (1)1.560.780.20
E. cloacae (1)1.5612.525.0
P. vulgaris (3)≤ 0.012 - 0.025≤ 0.012≤ 0.012 - 0.025
P. rettgeri (1)0.0250.101.56
P. mirabilis (1)≤ 0.0120.025≤ 0.012
P. aeruginosa (2)3.13 - 12.53.13 - 12.56.25 - 12.5

Heart Infusion Agar

Inoculum: 106 cells/mL

The MICs of laboratory strains of S. aureus, E. coli, P. mirabilis, P. vulgaris and S. marcescens were within one dilution of each other when measured in the following media: Nutrient agar, DST agar, antibiotic medium No. 1 and Mueller-Hinton agar. For P. aeruginosa, however, ceftriaxone was 2- to 8-fold more active in Nutrient agar than in the other media.

The effect of human serum on the MICs and the MBCs of various bacteria are shown in Table 4.

Table 4
The Effect of Serum on the MIC and MBC of Ceftriaxone (mg/L)
Organisms
(No. of Strains)
Isosensitest BrothIsosensitest Broth +25%
Human Serum
Isosensitest Broth +75%
Human Serum
MICMBCMICMBCMICMBC
E. coli (2)0.060.060.06 - 0.120.06 - 0.120.12 - 0.250.25
K. pneumoniae (2)0.060.060.250.250.50.5
P. mirabilis (1)0.0080.0150.0150.030.060.06
P. vulgaris (1)0.060.250.250.250.52.0
P. aeruginosa (2)4.0 - 32.04.0 - 32.04.0 - 64.016.0 - 64.08.0 - 64.064.0 - 128.0
S. aureus (2)2.04.04.0 - 16.08.0 - 16.08.0 - 16.016.0 - 32.0

The relative rates of hydrolysis of ceftriaxone by various beta-lactamases are shown in Table 5.

Table 5
Beta-Lactamase SourcesTypes of
Beta-lactamase1
Richmond-Sykes
Classifications
Relative Rate of
Hydrolysis2
Escherichia coli3PenV0.1
Klebsiella pneumoniaeCepha111A6
Enterobacter cloacae4Cepha1A11
Citrobacter freundii4Cepha-21
Serratia marcescensCepha1A0
Morganella morganii4Cepha1A10
Proteus vulgaris4Cepha1C25
Shigella sonnei3Pen-0.2
Pseudomonas aeruginosa3PenV0
Pseudomonas aeruginosaCepha1D36
Bacteroides fragilis4Cepha-128
Staphylococcus aureus4Pen-0
Bacillus cereusBoth-16

1 Pen: primarily penicillin substrate; Cepha: primarily cephalosporin substrate; Both: both types.

2 Rate in relation to cephaloridine (100%), except for S. aureus and B. cereus, which are based upon hydrolysis of penicillin G (100%).

3 Plasmid mediated.

4 Induced with cephalothin.

Development of Resistance

The acquisition of resistance to ceftriaxone was studied in vitro in eight strains of E. coli. MIC values were determined before and after five passages through sub-lethal doses of ceftriaxone. As shown in Table 6, the increases in resistance to ceftriaxone ranged from 2 to > 1024-fold.

Table 6
Effect of Five Passages Through Media Containing Ceftriaxone on
the Susceptibility of Beta-lactam Sensitive and Resistant E. coli Strains
StrainsMIC (mg/mL)MIC
Increase
(Fold)
Original Susceptibility to Beta-lactams
Pre-transferPost-transferCefazolinAmpicillin
NIHJ0.10.22S1S
IW4310.0250.3916SS
IU5860.050.24SR2(C)3
IW4320.125.0256SR(C)
IW4340.13.1332RR(C)
IV 570.225.0128RR(C)
IV 840.78100.0128RR(C)
IU5810.2> 100.0≥ 1024RR(R) 4

1 S = Sensitive

2 R = Resistant

3 (C) = Chromosome-mediated resistance

4 (R) = R-plasmid-mediated resistance

Interaction With Other Antibiotics

Combinations of ceftriaxone with aminoglycosides resulted in synergistic effects (i.e., at least a 4-fold decrease in the MICs of both antibiotics) against many strains of Pseudomonasaeruginosa and Streptococcus faecalis in vitro (Table 7), even when the organisms were resistant to the individual antibiotics. A combination of ceftriaxone with cefoxitin produced either synergy or antagonism depending on the species and strain (Table 8).

In in vivo studies, synergy was very infrequently observed against Pseudomonas aeruginosa with gentamicin (0 of 8 strains at ratios of ceftriaxone:aminoglycoside of 1:1 or 1:8), tobramycin (1 of 8 strains at 1:1 and 0 of 8 at 1:8) and amikacin (0 of 6 strains at 1:1 and 2 of 6 at 1:8). Synergy was not observed against S. faecalis with either gentamicin or amikacin. Antagonism between ceftriaxone and cefoxitin was observed for 5 of 5 strains of Pseudomonas aeruginosa.

Table 7
In Vitro Interaction Between Ceftriaxone and Aminoglycosides
AminoglycosidesOrganismsSensitivityNo. of StrainsNumberd (%) of Strains at Indicated Ratio of Ceftriaxone:Aminoglycoside
    Optimum Ratio Synergy8:1 Ratio Synergy
Gentamicin                P. aeruginosasens*2017(85)11(55)
P. aeruginosaresisa73(43)1(14)
P. aeruginosaresisb63(50)0
P. aeruginosaresisc32(67)0
S. faecalisresisb1-0
S. faecalisresisc9-9(100)
E. colisens3-0
S. typhimuriumsens2-0
Prot. mirabilissens1-0
Prot. vulgarissens2-0
Prot. morganiisens1-0
Prot. rettgerisens1-0
Klebs. pneum.sens2-0
Ent. cloacaesens1-0
Ent. cloacaeresisa2-0
S. marcescenssens3-2(67)
Staph. aureussens2-0
Tobramycin               P. aeruginosasens2015(75)5(25)
P. aeruginosaresisa109(90)9(20)
P. aeruginosaresisb64(67)0
S. faecalisresisb1-0
S. faecalisresisc9-9(100)
E. colisens3-0
S. typhimuriumsens2-0
Prot. mirabilissens1-0
Prot. vulgarissens1-0
Prot. morganiisens1-0
Prot. rettgerisens1-0
Klebs. pneum.sens2-0
Ent. cloacaesens3-0
S. marcescenssens1-0
S. marcescensresisb2-0
Staph. aureussens1-0
Amikacin            P. aeruginosasens2316(70)13(57)
P. aeruginosaresisa1311(85)6(46)
E. colisens3-0
S. typhimuriumsens2-0
Prot. mirabilissens1-0
Prot. vulgarissens2-0
Prot. morganiisens1-0
Prot. rettgerisens1-0
Klebs. pneum.sens2-0
Ent. cloacaesens1-0
Ent. cloacaeresisa2-0
S. marcescenssens3-0
Staph. aureussens2-0

sens* The organisms were classified as either sensitive or of intermediate sensitivity towards both antibiotics. For ceftriaxone, this was < 50 mg/L; for gentamicin, < 6.3 mg/L; for tobramycin, < 6.3 mg/L and for amikacin, < 12.5 mg/L.

a The organism(s) was (were) resistant to ceftriaxone.

b The organism(s) was (were) resistant to the aminoglycoside studied.

c The organism(s) was (were) resistant to ceftriaxone and the aminoglycoside studied.

d The number of strains does not necessarily match the total number of strains tested. This is because no interaction was observed for some strains.

- No data.

Table 8
In Vitro Interaction Between Ceftriaxone and Cefoxitin
OrganismsNo. of StrainsNumber* (%) if Strains at Ratio of 1:1
SynergyAntagonism
P. aeruginosa12011(92)
Enterob. cloacae704(57)
P. morganii101(100)
S. marcescens302(67)
Citr. freundii202(100)
Bact. fragilis1413(93)0
Strep. faecalis1919(100)0

* The number of strains does not necessarily match the total number of strains tested. This is because no interaction was observed for some strains.

Susceptibility Test

The standard disc susceptibility test (modified Kirby-Bauer method) using the 30 μg ceftriaxone sodium disc and dilution susceptibility tests should be interpreted according to the criteria in Table 9.

Table 9
Zone Diameter (30 µg Ceftriaxone Disc)Approximate MIC Correlation
Susceptible≥ 18 mm≤ 16 mg/L
Moderately Susceptible14 - 17 mm32 mg/L
Resistant≤ 13 mm≥ 64 mg/L

Ceftriaxone has been shown by in vitro tests to be active against certain strains found to be resistant when other beta-lactam discs are used. It is therefore recommended that only the ceftriaxone sodium disc (containing 30 μg ceftriaxone) be used when conducting susceptibility tests. Similarly, the ceftriaxone sodium disc should not be used for testing susceptibility to other cephalosporins.

The zone diameters produced by a 30 μg ceftriaxone disc and the MICs determined by ceftriaxone dilution susceptibility testing for recommended reference strains are provided in Table 10.

Table 10
Reference StrainsZone DiameterMIC
E. coli (ATCC 25922)29 - 35 mm0.016 - 0.5 mg/L
S. aureus (ATCC 25923)22 - 28 mm1 - 2 mg/L
P. aeruginosa (ATCC 27853)17 - 23 mm8 - 64 mg/L

Disc or dilution susceptibility testing may not be appropriate for Pseudomonas species because of a 40 and 31 percent incidence of false susceptible results respectively.

Pharmacology

Animal Pharmacology

Ceftriaxone, at a maximum dose of 1000 mg/kg, had no appreciable effect on:

  1. the heart, circulation or the autonomic nervous system in anesthetised and unanesthetised dogs, anesthetised cats and conscious spontaneously hypertensive rats;
  2. respiration, in unanesthetised dogs, anesthetised cats and conscious rabbits;
  3. the gastrointestinal tract in mice;
  4. the central nervous system in mice and rats.

In rats (during saline induced diuresis) and in dogs, ceftriaxone, at a maximum dose of 300 mg/kg, had no effect on urinary excretion except for one study where sodium retention in one strain of rat was observed (Na/K ratio 1.1 - 1.4).

In drug interaction studies in rats, ceftriaxone, given in doses of 200 mg/kg, potentiated the immunosuppressant activity of dexamethasone and cyclophosphamide and antagonised the diuretic effect of furosemide. In mice treated with leptazol, ceftriaxone, given s.c. in doses of 200 mg/kg, significantly decreased the anticonvulsant activity of 6 mg/kg i.p. doses of diazepam but not of 0.75, 1.5 or 3 mg/kg i.p. doses.

Ceftriaxone demonstrated no immunomodulating properties in mice and no antigenic activity in rats and guinea pigs.

Intravenous administration of ceftriaxone to groups of dogs at doses of 150 and 400 mg/kg/day resulted in the formation of some gritty and occasionally clotted concretions in the gallbladder. The concretions consisted mostly of a calcium salt of ceftriaxone (see TOXICOLOGY).

Human Pharmacology

Pharmacokinetics

A number of standard abbreviations and terms have been used throughout this section. They are identified and defined below:

C- plasma concentration (max - maximum, min - minimum, ave - average steady state)
AUC- area under the plasma concentration-time curve
Clp- systemic (plasma) clearance
ClR- renal clearance
Vd(ß)- volume of distribution
t1/2(ß)- half-life of elimination
fu- fraction of the dose excreted in the urine
T- total drug (bound plus unbound or free drug)
F- unbound or free drug
accumulation (ratio)- the ratio of minimum steady state plasma concentration at 12 hours after the last dose to minimum plasma concentration at 12 hours after the first do>
predicted accumulation (ratio)- calculated as a function of t1/2(ß)
concentration units- mg/L is equivalent to μg/mL

The pharmacokinetics of ceftriaxone are distinguished by: (1) saturable plasma protein binding within the therapeutic range (the free fraction of ceftriaxone remaining relatively constant at approximately 5 to 10 percent at ceftriaxone plasma concentrations of less than 200 μg/mL, and increasing to approximately 40 percent at 650 μg/mL), (2) no active secretion by renal tubules, and (3) approximately 55 percent renal elimination and 45 percent excretion through the biliary pathway.

Ceftriaxone plasma protein binding is dependent upon total drug concentration. The free fractions of ceftriaxone at total ceftriaxone concentrations of 4 - 68, 94 - 188, and 653 µg/mL are 4 - 5, 8, and 42 percent respectively. As a result, the pharmacokinetics of total plasma ceftriaxone are non-linear. This is demonstrated by a less than proportional increase in area under the curve [AUCT(o-∞)] with increase in dose and dose-dependent increases in volume of distribution [VdT(β)], systemic plasma clearance (ClTp) and renal clearance (ClTR). In contrast, the pharmacokinetics of free ceftriaxone are linear.

The renal clearance of free ceftriaxone is slightly less than the glomerular filtration rate. Probenecid does not influence the clearance of ceftriaxone. At doses of 500 mg or more, renal clearance based on total ceftriaxone (ClTR) decreases with time. In contrast, renal clearance based on free ceftriaxone (ClFR) remains relatively constant with time regardless of the dose. This phenomenon is due to increased ceftriaxone protein binding as plasma concentrations decrease during elimination.

Following a single intravenous dose of 14C-ceftriaxone to two male subjects (23 and 27 years old), the following urinary and fecal excretion profile of radioactivity was observed:

Table 11
Time Intervals (hr)Percent of Total Radioactivity Administered
UrineFecesTotal
0 - 2453, 4729, 1482,
0 - 4859, 5139, 4098,
0 - 10061, 5241, 49102,

Excretion of the radioactivity was complete by 100 hours with 90 percent of the dose being excreted during the first 48 hours. Ninety-two percent of the radioactivity recovered in the urine and approximately ten percent of the radioactivity recovered in the feces was accounted for by unchanged ceftriaxone. Relatively high concentrations of unchanged ceftriaxone are found in the bile. This may suggest that ceftriaxone is inactivated by the intestinal flora rather than by the liver.

On multiple dosing, the fraction of ceftriaxone excreted unchanged in the urine (fu) and the terminal elimination half-life [t1/2(ß )] remain unchanged regardless of the dose. However, area under the curve (AUCT) decreases by 12 and 15 percent and volume of distribution [Vd T(ß)] and systemic plasma clearance (ClTp) increase by 14 and 20 percent, and 12 and 15 percent after multiple-doses of 1000 and 2000 mg at 12-hour intervals, respectively. These parameters are not altered with multiple-doses of 500 mg at 12-hour intervals. The changes observed at the higher doses are possibly due to the non-linear plasma protein binding of ceftriaxone.

Intravenous Administration

Bolus Injection Over 5 Minutes

Single-dose

Ceftriaxone, constituted with saline, was administered as a single-dose bolus injection over 5 minutes to six healthy male volunteers (mean age 25 years) in four doses: 150, 500, 1500, and 3000 mg. The total ceftriaxone plasma concentration- time profile for each dose, in a single representative subject, is shown in Figure 1. The total drug concentration time profiles could each be described by a biexponential equation.


Mean urinary recoveries of unchanged drug over 48 or 52 hours were 58.6 ± 6.6, 64.3 ± 7.3, 65.0 ± 4.3 and 66.6 ± 9.0 percent for the 150, 500, 1500, and 3000 mg doses respectively. Mean urinary ceftriaxone concentrations for various collection intervals are shown in Table 12.

Table 12
Urinary Concentrations of Ceftriaxone After Single-dose Bolus Injections
Time Interval (hr)Mean Urinary Ceftriaxone Concentrations (µg/mL)*
Dose (mg)
1505001500
0 - 2189 ± 89894 ± 4213483 ± 951
2 - 4113 ± 64453 ± 2491530 ± 680
4 - 6102 ± 40360 ± 1191093 ± 150
6 - 884 ± 11329 ± 76833 ± 263
8 - 1047 ± 19195 ± 66314 ± 188
10 - 1243 ± 20117 ± 41323 ± 175
12 - 2428 ± 1082 ± 30158 ± 50

* Ceftriaxone urinary concentrations for the 3000 mg dose were not reported.

Various pharmacokinetic parameters were determined and mean values are reported in Table 13.

Table 13
Pharmacokinetics of Ceftriaxone After Single-dose Bolus Injections
Pharmacokinetic
Parameters
Dose (mg)
50010002000
AUCT(0-∞) (µg • hr/mL)551 ± 91 11006 ± 1181703 ± 203
VdT(β) (L)8.8 ± 1.229.2 ± 1.0510.3 ± 1.01
tT½ (β) (hour)6.5 ± 0.726.2 ± 0.765.9 ± 0.69
ClTp (mL/min) 15.5 ± 2.416.8 ± 2.119.8 ± 2.5
ClTR (mL/min) (0 - 2 hr)7.3 ± 1.39.0 ± 1.615.3 ± 3.9

* 0 - 48 hr for 150, 500, 1500 mg doses and 0 - 52 hr for the 3000 mg dose

** 0 - 2 hr for 150, 500, 1500 mg doses and 0 - 1 hr for the 3000 mg dose

Infusion Over 30 Minutes

Single Dose

Ceftriaxone, in 100 mL of saline, was administered as a single-dose infusion at a constant rate over 30 minutes to twelve normal volunteers (ten males and two females, mean age 35 years) in three doses: 500, 1000, and 2000 mg. The mean total ceftriaxone plasma concentration-time profile for each dose is shown in Figure 2. The total drug concentration-time profiles were biphasic and were fitted to a linear two-compartment model.


Mean urinary recoveries of unchanged drug over 48 hours were 41 ± 8, 39 ± 5, and 43 ± 10 percent for the 500, 1000, and 2000 mg doses respectively. Mean urinary ceftriaxone concentrations for various collection intervals are shown in Table 14.

Table 14
Urinary Concentrations of Ceftriaxone After Single-dose Infusions
Time Interval (hr)Mean Urinary Ceftriaxone Concentrations (µg/mL)
Dose (mg)
50010002000
0- 2526 ± 303995 ± 7342692 ± 1403
2- 4366 ± 203855 ± 6151976 ± 1047
4- 8142 ± 63293 ± 163757 ± 437
8 - 1287 ± 45147 ± 66274 ± 119
12- 2470 ± 25132 ± 47198 ± 93

A number of pharmacokinetic parameters were determined and the mean values are reported in Table 15.

Table 15
Pharmacokinetics of Ceftriaxone After Single-dose Infusions
Pharmacokinetic Parameters Dose (mg)
50010002000
AUCT(0-∞) (µg • hr/mL)551 ± 911006 ± 1181703 ± 203
VdT(β) (L)8.8 ± 1.229.2 ± 1.0510.3 ± 1.01
tT½ ( β) (hour)6.5 ± 0.726.2 ± 0.765.9 ± 0.69
ClTp (mL/min)15.5 ± 2.416.8 ± 2.119.8 ± 2.5
ClTR (mL/min) (0 - 2 hr)7.3 ± 1.39.0 ± 1.615.3 ± 3.9

Multiple Doses

Seven 500, 1000 or 2000 mg doses of ceftriaxone were administered at 12 -hour intervals to normal volunteers as constant rate infusions over 30-minute periods. The 500 and 1000 mg doses were each administered to twelve males (mean ages 29 and 31 years respectively) and the 2000 mg doses to eleven males and one female (mean age 33 years). Total ceftriaxone plasma Cmax, Cmin, and Cave values are reported in Table 16.

Table 16
Total Ceftriaxone Plasma Cmax, Cmin, and Cave Values After
Multiple-dose Infusions
Dose (mg)Cmax (µg/mL)Cmin (µg/mL)Cave (µg/mL)
500First Dose79 ± 11.515 ± 4.5--
Last Dose101 ± 12.720 ± 5.541 ± 7
1000 First Dose145 ± 11 30 ± 6 --
Last Dose168 ± 25 35 ± 9.2 72 ± 13
2000First Dose255 ± 41 45 ± 11 --
Last Dose280 ± 39 59 ± 21 118 ± 19

Plasma drug concentrations attained steady-state by Day 4. The accumulation of ceftriaxone in plasma after the 500, 1000 and 2000 mg doses was 35, 20, and 21 percent respectively. The predicted accumulation was 40 percent.

Intramuscular Administration

The bioavailability of ceftriaxone by the intramuscular route is approximately 100 percent.

Single Dose

Ceftriaxone, constituted with either water or 1% lidocaine, was administered intramuscularly in a single 500 mg dose to six normal male volunteers (mean age 36 years). The mean total ceftriaxone plasma concentration-time profile for each diluent is shown in Figure 3.


Over 72 hours, 225 ± 40 and 229 ± 26 mg of unchanged ceftriaxone were recovered in the urine after the administration of the water and 1% lidocaine preparations respectively. Mean urinary ceftriaxone concentrations for various collection intervals are shown in Table 17.

Table 17
Urinary Concentrations of Ceftriaxone After
a Single 500 mg Intramuscular Dose
Time Interval (hr)Mean Urinary Ceftriaxone Concentrations (µg/mL)
Diluent
Water1% Lidocaine
0 - 2176 ± 129176 ± 135
2 - 4223 ± 156215 ± 124
4 - 6213 ± 93298 ± 111
6 - 8198 ± 96216 ± 83
8 - 2499 ± 44111 ± 43

A number of pharmacokinetic parameters were determined and the mean values are reported in Table 18. No significant differences were found between the mean pharmacokinetic parameters of the two preparations.

Table 18
Pharmacokinetics of Ceftriaxone After a Single 500 mg Intramuscular Dose
Pharmacokinetic Parameters Diluent
Water1% Lidocaine
Cmax (µg/mL)67.0 ± 9.755.8 ± 4.5
AUCT(0-∞) (µg • hr/mL)709 ± 58728 ± 63
tT½ (β) (hour)8.5 ± 0.78.4 ± 0.5
ClTR (0 - 8 hr) (mL/min)6.9 ± 0.56.6 ± 0.5

Multiple Doses

Seven 500 or 1000 mg doses of ceftriaxone, constituted with 1% lidocaine, were administered intramuscularly at 12-hour intervals to twelve healthy volunteers (ten males and two females, mean age 36 years). Total ceftriaxone plasma Cmax, Cmin, and Cave values are reported in Table 19.

Table 19
Total Ceftriaxone Plasma Cmax, Cmin and Cave Values After
Multiple Intramuscular Doses
Dose (mg)Cmax (µg/mL)Cmin (µg/mL)Cave (µg/mL)
500 First Dose49 ± 1116 ± 5--
Last Dose65± 824 ± 646 ± 6
1000 First Dose81 ± 1229 ± 7--
Last Dose114 ± 1639 ± 870 ± 10

Maximum ceftriaxone plasma concentrations were reached 0.75 to 3 hours (mean 1.7 hours) after drug administration. Steady-state plasma concentrations were apparent after the third dose of both dosage regimens, and minimum steady state plasma concentrations were maintained. The observed mean accumulation ratios were 1.36 and 1.29 after the multiple administration of 500 and 1000 mg of ceftriaxone respectively. These values were not significantly different from the 1.40 and 1.36 predicted mean accumulation ratios.

Effect of Age on Pharmacokinetics

A representative total ceftriaxone plasma concentration-time profile for an infant (7 months old) and for a child (5.8 years old), each given a single 50 mg/kg dose of ceftriaxone by intravenous injection over 5 minutes, is presented in Figure 4.


A summary of the age-associated changes in ceftriaxone pharmacokinetics is presented in Table 20. Renal and hepatic functions were normal for age on the basis of clinical laboratory findings in these subjects. Ceftriaxone sodium was administered intravenously as a bolus over 2 to 5 minutes or as a 30-minute infusion. The age-associated changes in half-life appear to result from changes in systemic clearance.

Table 20
Pharmacokinetic Parameters (Mean ± SD) Based on Total Ceftriaxone Plasma Concentration at Various Ages
Subjects and Underlying
Condition
nMean Ceftriaxone
Dosage (mg/kg)
Aget½(ß)
(hr)
VdT (ß) (L/kg)ClTp (mL/min/kg)fu (%)
NEONATES
Respiratory distress
syndrome (20)*,
meningitis or bacteremia (4)*
24501 - 8 d18.6 ± 6.90.5 ± 0.150.34 ± 0.1372 ± 20
NEONATES
Meningitis or
bacteremia
10869 - 30 d9.7 ± 3.90.65 ± 0.280.93 ± 0.6675 ± 21
INFANTS
Meningitis or
bacteremia (9)*, viral infection
or epilepsy (2)*
1150 (2)* or 95 (9)*1 - 12 m7.2 ± 3.20.54 ± 0.250.93 ± 0.4055 ± 20
CHILDREN
Viral infection or
epilepsy
5502 - 6 y6.6 ± 0.60.40 ± 0.080.71 ± 0.1552 ± 4.7
ADULTS
Healthy volunteers
5013, 14, 25 or 2718 - 49 y7.3 ± 1.60.16 ± 0.030.24 ± 0.0644 ± 9.8
ELDERLY
Healthy volunteers
914 or 2750 - 74 y8.3 ± 2.20.15 ± 0.020.23 ± 0.0739 ± 11
ELDERLY
Healthy volunteers (1)*,
bronchitis (10)*
1114 (1)* or 24 (10)*75 - 92 y14.2 ± 2.90.15 ± 0.030.14 ± 0.04--

Effect of Renal Impairment on Pharmacokinetics

Twelve functionally anephric patients (six males and six females, mean age 54 years, creatinine clearance < 10 mL/min) received single 150, 500, and 1500 mg doses of ceftriaxone sodium intravenously over 5 minutes. Ten of the twelve patients had non -renal clearance values of free drug similar to healthy subjects. Pharmacokinetic parameters for these ten patients are presented in Table 21. Minor increases were observed in mean elimination half-lives in comparison to normal subjects.

Table 21
Pharmacokinetic
Parameters
150 mg
(n = 4)
500 mg
(n = 2)
1500 mg
(n = 4)
tT1/2(β) (hr)12.4 ± 1.8 77.7, 10.3 111.8 ± 2.4
tF1/2(β) (hr)12.1 ± 1.8 77.4, 10.0 99.1 ± 1.0
VdT(β) (L)9.9 ± 1.9 99.7, 12.6 113.0 ± 2.3
VdF(β) (L)115.8 ± 35.2 669.4, 136.9 886.6 ± 17.7
ClTp(mL/min)9.3 ± 2.1 114.5, 14.1 112.9 ± 1.8
ClFp(mL/min) 1109.7 ± 22.4 1108.1, 158.8 1119.7 ± 32.5

Two of the patients exhibited decreased non -renal clearance values indicating an impairment of their biliary elimination pathway which was not obvious from standard liver function tests. Pharmacokinetic parameters for these two patients are presented in Table 22. More severe prolongations of their elimination half-lives were observed as well as decreases in total body clearance.

Table 22
Pharmacokinetic
Parameters
500 mg
(n = 2)
tT1/2 (ß) (hr)20.0, 34.8
tF1/2(β) (hr)18.4, 32.0
VdT(β) (L)9.5, 13.3
VdF(β) (L)79.0, 78.1
ClTp (mL/min)5.5, 4.4
ClFp (mL/min)49.3, 27.9

Peritoneal dialysis did not remove ceftriaxone and hemodialysis was not very efficient at removing the drug.

Effect of Hepatic Dysfunction on Pharmacokinetics

The pharmacokinetics of total ceftriaxone were investigated in eight patients with liver disease (five males and three females, mean age 46 years) after a single 1000 mg intravenous dose. The half-life of ceftriaxone was within the range for normal subjects regardless of the type of liver disease. In the two patients suffering from decompensated liver cirrhosis with ascites, area under the curve was decreased and total body clearance and volume of distribution were significantly increased (Table 23). In the remaining six patients, these parameters were similar to normal.

Table 23
Liver Disease
(n)
Fatty Liver (2), Compensated Liver
Cirrhosis (2), Liver Fibrosis (1),
Liver Damage with Intrahepatic
Cholestasis (1)
Decompensated
Liver Cirrhosis with
Ascites (2)
Pharmacokinetic Parameter
AUCT(0-∞) (µg • hr/mL)

1160 ± 217

597 ± 49
ClTp (mL/min)14.9 ± 3.228.1 ± 2.3
VdT(β) (L)10.9 ± 0.821.9 ± 3.7
tT½ (β) (hour)8.8 ± 2.19.0 ± 0.8
fu (%)61.7 ± 16.974.8 ± 3.5

Tissue and Body Fluids Ceftriaxone Concentration

Blister Fluid

Penetration of ceftriaxone into blister fluid is rapid. Pertinent pharmacokinetic parameters, for total ceftriaxone, in plasma and in blister fluid are presented in Table 24. Elimination of ceftriaxone from blister fluid is slightly slower than from plasma.

Table 24
Plasma and Blister Fluid Pharmacokinetic Parameters
Subjects (Healthy Volunteers)Dosage (mg)RoutePlasmaBlister Fluid
nSexAge
(yr)
AUCT
(µg·hr/mL)
t T½
(hr)
Cmax
(µg/mL)
Cmin
(µg/mL)
AUCT
(µg·hr/mL)
tT½
(hr)
6M21-37Single Dose
500
IV610±1228.8±1.732.7±7.0--569±13410.4±2.7
126 M
6 F
19-24Multiple Dose
1000 q 12 h
for 5 days.
First Dose
Last Dose
IV1218±301
1076±169
1987±280
1940±253
36.0±10.6
67.0±22.0
13.6±7.5
39.8±14.2
448±159
513±213
8.3±2.9
15.0±4.1
Multiple Dose
2000 q 24 h
for 5 days.
First Dose
Last Dose
IV1987±280
1940±253
6.5±0.9
7.2±1.0
38.6±10.1
68.9±19.7
14.5±8.3
27.1±7.9
767±460
1002±285
11.5±5.7
12.8±8.0

Cerebrospinal Fluid

Seven infants (4.5 to 15.6 months old) and one child (4.3 years old) received a 50 mg/kg dose of ceftriaxone and eight infants (3.1 to 9.8 months old) received a 75 mg/kg dose, by intravenous injection over five minutes. The pediatric patients had bacterial meningitis or ventriculitis. On average, 3 hours after administration, mean ceftriaxone cerebrospinal fluid concentrations were 4.5 ± 3.5 and 6.0 ± 3.9 µg/mL after the 50 and 75 mg/kg ceftriaxone doses respectively.

Ceftriaxone sodium was administered as a single intramuscular injection to one hundred and eight patients, presenting with purulent meningitis. The patients were divided into three groups based on dose. The average (± SD) doses administered in the three groups were 21 ± 2.6, 36 ± 2.4 and 52 ± 1.1 mg/kg. Sixty-two patients were between 10 days and 2 years old, eighteen were between 2 and 9 years old, nine were between 10 and 19 years old and nineteen were between 20 and 83 years old. There were sixty-one males and forty-seven females. CSF concentrations of ceftriaxone were lower than serum concentrations. The mean ceftriaxone concentrations at different times are shown in Table 25. A distinction is made between results for purulent meningitis, as a function of whether bacteriology was positive or negative.

At doses equal to or greater than 35 mg/kg, mean spinal ceftriaxone concentrations were consistently higher than 2 µg/mL for the 24 hours following the single intramuscular injection.

Table 25
Ceftriaxone Concentrations in CSF After Intramuscular Injection in 108 Patients
Culture
of CSF
Dose of
Ceftriaxone
mg/kg
(No. of
Patients)
Ceftriaxone Concentration in CSF (µg/mL)
(No. of Assays)
Hour 2 Hour 6 Hour 12 Hour 24
Positive21 ± 2.6 (23)3.70 ± 1.78 (13)3.17 ± 1.34 (13)2.44 ± 1.33 (13)1.70 ± 1.52 (6)
36 ± 2.4 (14)3.36 ± 2.36 (6)5.72 ± 3.25 (10)2.68 ± 2.59 (7)2.25 ± 1.54 (11)
52 ± 1.1 (49)5.66 ± 2.60 (16)6.80 ± 1.76 (26)5.62 ± 6.48 (4)2.65 ± 1.67 (18)
Negative41.7 (22)2.94 ± 4.48 (5)3.21 ± 2.25 (10)4.55 ± 7.35 (5)1.64 ± 1.45 (18)

Hepatic Bile

Ceftriaxone concentrations were measured in samples of bile obtained from eight patients (five females and three males, mean age 64 years) undergoing surgery for chronic cholecystitis with cholelithiasis (n = 5) or other biliary diseases (n = 3). Ceftriaxone sodium was administered at a dosage of 500 mg i.v. q 12 h for 7 days. Bile samples were obtained daily through a T-tube at various intervals after dosing. Ceftriaxone was detected in all specimens. Two patients had ceftriaxone bile concentrations consistently < 16 µg/mL while the remaining six patients had concentrations ranging from 35 to as high as 924 µg/mL.

The total calcium concentrations in the hepatic bile were also measured. The calculated ionic products of calcium and ceftriaxone ranged from 0.51 to 3.5 x 10-6. The threshold value for precipitation of the calcium salt of ceftriaxone is 3.16 x 10-4.

Gallbladder Bile

Seven patients (four females and three males, average age 49 ± 16 years) with relatively normal hepatic enzyme levels were given five doses (five patients) or three doses (two patients) of ceftriaxone sodium i.v. at a dosage of 2 g q12h. The last injection was given 0.1 to 5.3 (mean 2.7) hours before cholecystectomy. The concentrations of ceftriaxone in the gallbladder bile for all seven patients at the time of the operation ranged from 2970 to 5884 µg/mL. The mean total calcium concentration in the gallbladder bile was 5.1 ± 1.3 mmol/L. The calculated ionic product ranged from 2.4 x 10-5 to 6.2 x 10-5.

Interaction of Ceftriaxone and Calcium In Vitro

Two in vitro studies, one using adult plasma and the other neonatal plasma from umbilical cord blood, were carried out to assess the interaction of ceftriaxone and calcium. Ceftriaxone concentrations of 0.1 – 1 mM (55 – 555 µg/ml) were incubated for 2 hours with calcium concentrations of 2 – 12 mM (80 – 480 µg/ml). Recovery of ceftriaxone from plasma was statistically significantly reduced at calcium concentrations of 6 mM (240 µg/ml) or higher in adult plasma and 4 mM (160 µg/ml) or higher in neonatal plasma. These measures included total free and protein bound ceftriaxone and calcium. The difference observed in the assays may be reflective of ceftriaxone-calcium precipitations.

Toxicology

Acute Toxicity

The acute toxicity of ceftriaxone was determined in mice, rats and rabbits.

Table 26
Acute Toxicity of Ceftriaxone
RouteSpeciesStrainsSexLD50 mg/kg (95% confidence limit)Signs
IV Mice CFI M1840 (1750 - 1930)salivation, respiratory depression, tremors
F2150 (1940 - 2420)
ICR-SLC M3000 (2778 - 3240)transient tremor, staggering gait, irregular
respiration, accelerated respiration,
sedation, systemic convulsions
F2800 (2617 - 2996)
Rats Sprague
Dawley-
CD
M, F2240 (2040 - 2500)ataxia, cyanosis, respiratory depression,
salivation, Straub reaction, tonic extensor
SpragueDawleyM, F2175 (2033 - 2327)Systemic stiffness, tonic spasms, dyspnea, staggering gait, irregular respiration, sedation, ataxic walking, cecum enlargement in most animals
Neonatal Rats*CDM, F1900 (1600 - 3100)loss of righting reflex, respiratory
depression, cyanosis, gasping, thrashing
RabbitsNew
Zealand
White
M, F240 (69 - 700)decreased motor activity, respiratory
depression, diarrhea, general debilitated
condition, irritation of large intestine,
thymus congestiyocardial pallor or
hemorrhage
SC MiceIRC-SLCM, F> 5000none reported
Rats Sprague
Dawley
M, F > 5000 sedation, anorexia, ataxia, analgesia,
irregular respiration, convulsions, cecum
enlargement
POMice IRC-SLC M, F > 10000 none reported
Rats Sprague
Dawley
M, F > 10000 cecum enlargement
IPNeonatal
Rats **
CDM, F > 2000 pallor

* 14 days old

** > 24 hours old

In an intravenous pyramiding dose study in Swiss beagle dogs (one of each sex), daily doses of 100, 200, 400, 800, 1600, 2 x 1600 (12 hours between dosing) and 3 x 1600 mg/kg (8 hours between dosing) of ceftriaxone were administered. The 400 mg/kg dose and higher doses caused some transient screaming, whimpering, gasping for breath and in one case a few clonic convulsions. The symptoms could be largely avoided by slow i.v. administration. Reversible staggering gait, some dizziness and lassitude were observed at all 1600 mg/kg doses. Some elevations in SGPT (up to 12-fold in one dog) and alkaline phosphatase were observed. At autopsy, the gallbladder of both dogs were vastly contracted but contained no concretion-like material.

In another intravenous study in four beagle dogs (two/sex), pyramiding doses of 3.6, 12, 36, 120, 360 and 1200 mg/kg of ceftriaxone were administered at 1 to 2-day intervals. Drug-related signs and symptoms were retching, emesis, head shaking, ear scratching, erythema, edema around the eyes and snout, and sporadic panting and licking. Most of these were observed in one animal which may have been atypically responsive to the drug. Following the 1200 mg/kg dose, SGPT was increased by about 10 and 3.5-fold in two dogs. A grey-white, amorphous, non-gritty sediment was seen in the gallbladder of three dogs at autopsy, 25 days after the last dose.

Multiple-dose Toxicity Studies

Rats

In a 2-week intravenous administration study, groups of eight male Füllinsdorf rats were administered 0, 25 or 60 mg/kg/day of ceftriaxone. Body weight gain was slightly depressed by 9.2 and 20.1 percent in the 25 and 60 mg/kg/day groups respectively. The average weight of the thyroid glands was increased in the treated groups by 11 to 14 percent in comparison to the control animals. A 50 percent reduction in plasma bilirubin in the treated rats was reported along with a decrease in the number of leucocytes.

In a 4-week intravenous study, groups of twenty-four rats (twelve/sex) were administered 0, 25, 125 or 600 mg/kg/day of ceftriaxone. Local and general tolerance were good except that the rapid injection of 600 mg/kg/day resulted in slight and transient giddiness, apathy, lassitude and deep breathing. Some alopecia was noted in two males and four females in the high-dose group and one male in the middle- dose group. Body weight gain was reduced by about 7 percent in the males of the 600 mg/kg/day group. Compared to control rats, urine volumes at week 4 of the study were reduced by 18.5 and 40.0 percent in rats treated with 125 and 600 mg/kg/day respectively. At week 4, one rat of each sex, in the 600 mg/kg/day group developed seizures and convulsions immediately after injection, and died. At autopsy, all rats in the 125 and 600 mg/kg/day groups showed a marked enlargement of the cecum. There were 18 and 10 percent increases in male and female absolute adrenal gland weights respectively in the high-dose group. The average absolute liver weight was decreased by 10 and 17 percent in males in the 125 and 600 mg/kg/day groups respectively.

Sprague-Dawley rats (sixteen/sex/dose) were administered 0, 100, 350 or 1225 mg/kg ceftriaxone i.v. daily for 13 weeks after which six rats/sex/dose were observed during a 5-week recovery period. Because of severe damage at the injection site in the 1225 mg/kg/day group, surviving rats were either sacrificed on day 42 or observed during a 4-week recovery period. In the high-dose group, transient staggering gait and accelerated respiration were observed. Convulsions and dyspnea followed by death were observed in two females in this group after 31 to 35 days of dosing. Hematology and blood chemistry changes in comparison to control rats were reported in the 1225 mg/kg/day group only and included: increases in both sexes in MCV and MCH of 12 to 13 and 14 percent respectively and, an increase in serum sodium and decreases in Hb, PCV and RBC count of 2, 2.5, 3.3, and 14 percent respectively in females. All these changes became normal during the recovery period. During autopsy, vascular occlusion at the injection site was observed in the 350 and 1225 mg/kg/day groups. Cecum enlargement was noted in most treated rats, but returned to normal during the recovery period. In the

1225 mg/kg/day group, half of the animals (both sexes) exhibited a slight petechial bleeding scattered in the subcapsular parts of the thymus. This was not observed in the recovery group animals.

Dogs

In a 2-week study, male Füllinsdorf beagles (two/group) were administered intravenously 0, 25 or 60 mg/kg/day of ceftriaxone for 2 weeks. The average body weight gains were 8, 4, and

2 percent in the control, low- and high-dose groups respectively. Slight dose-related decreases in serum gamma- globulin and potassium along with slight dose-related increases in total bilirubin, serum albumin and albumin/globulin ratio were reported.

In a 4-week study, groups of beagle dogs (two or three/sex/dose) were administered intravenously 0, 25, 150 or 400 mg/kg/day of ceftriaxone. Injection of the drug induced some initial vomiting in one dog in the middle- dose group and in all dogs in the high-dose group. Rectal temperature was slightly raised in the high-dosed dogs at the end of the study. In the treated groups, there was about a 10 percent reduction in lymphocyte count in the middle- and high-dose groups after four weeks administration. After four weeks administration, SGPT was elevated by 4.3- , 6.4- , and 29-fold and alkaline phosphatase was elevated by 2.7- , 1.9- , and 3.2-fold in one dog in the middle-dose group and two dogs in the high-dose group respectively. At autopsy five of six middle-dose dogs and all high-dose dogs had some gritty and occasionally clotted concretions in their gallbladder consisting predominantly of the calcium salt of ceftriaxone. The bile of the high-dose dogs was normal except for an almost doubled content of bile acids and a 50 percent reduction in iron content. Histologically, perivascular hemorrhage, periarteritis or periphlebitis were noted at the injection site. The centrilobular liver cells showed a slightly increased tendency to cloudy swelling and some limited proliferation of pseudo biliary ducts with the higher dose.

In a 4½-week study, groups of four Füllinsdorf beagle dogs (two/sex/group) were administered ceftriaxone intravenously at dosages of 0, 50 mg/kg/day, 50 mg/kg twice daily, 50 mg/kg three times daily or 75 mg/kg three times daily. Changes in some hematological parameters and liver function tests, although statistically significant, were not considered outside the normal ranges or drug-related. At autopsy, gallbladder concrements containing 30 - 40 percent of the calcium salt of ceftriaxone were found in two of the four dogs in the 50 mg/kg twice and three times daily groups. This was also found in three of the four dogs in the 75 mg/kg three times daily group. Dogs in the 50 mg/kg/day, as well as one dog in each of the other ceftriaxone treated groups, had flaky, mucous precipitate in the gallbladder containing 3 percent or less of the calcium salt of ceftriaxone. Histologically, some minor centrilobular liver cell swelling was observed and polarising crystals in the lumen of the gallbladder were observed in one dog in the 50 mg/kg three times daily group and in three dogs in the 75 mg/kg three times daily group.

In a 5-week study, groups of eight beagle dogs (four/sex/group) were administered ceftriaxone intravenously at doses of 0, 60, 120, or 240 mg/kg/day. One animal/sex/group was then allowed to recover for 4 weeks. The dogs were fed three times daily. Occasional vomiting was reported in all groups studied including the control animals. In the 120 and 240 mg/kg/day groups, dose-independent statistically insignificant decreases in the average platelet counts (27 and 41 percent in males and females respectively) were reported at the end of the 5- week treatment period. Sporadic elevations in alkaline phosphatase and transaminases were observed for some of the treated animals (approximately 1½ to 2-fold). No evidence of precipitation in the gallbladder was reported.

In another 5-week study, ceftriaxone was administered i.v. in doses of 200 or 400 mg/kg/day to groups of two male and two female beagles. Precipitates were found in the bile of three of the four dogs sacrificed at the end of the dosing period, but in none of the four sacrificed after a 5-week recovery period. The one dog having no precipitation after 5 weeks of treatment (with 400 mg/kg/day) had eaten soon after each injection. Analysis showed the precipitate contained ceftriaxone (0.32 - 0.57 µmol/mg) and calcium (0.25 - 0.47 µmol/mg). The calcium concentrations in the bile were slightly decreased in the treated dogs (0.30 - 0.37 mg/mL compared with 0.38 - 0.39 mg/mL in controls).

To investigate the association of precipitate formation with eating habits, ceftriaxone was given as single i.v. doses of 200 or 450 mg/kg to beagles, 3 hours before autopsy. Precipitates in the bile were found in all the dogs given the drug after a 24-hour fast, but in none of those fed just before or just after injection. The bile volume and the calcium concentration in the gallbladder bile were almost twice as high and the concentration of ceftriaxone in the gallbladder bile (excluding the precipitates) was over 5 times higher in the fasting dogs.

In an in vitro study, mixing the bile from the fasting dogs with an equal volume of either a 10 or 5 percent solution of ceftriaxone in dog serum at 37°C led to precipitation within 10 or 24 hours respectively. No precipitate formed, however, in the bile from the fed dogs under the same conditions, even at the ceftriaxone concentration of 10 percent.

Further long-term intravenous studies in beagle dogs showed that ceftriaxone doses of 60, 120 or 240 mg/kg/day administered for 5 weeks to dogs (three/sex/dose), fed three times a day, were not associated with bile precipitate. However, when ceftriaxone was administered to dogs for 13 weeks, under the same feeding conditions as in the preceding 5-week study, bile precipitates were observed in three of the three male and two of the three female dogs treated with 240 mg/kg/day. Almost all the precipitate disappeared from the gallbladder after the 5-week recovery period. No bile precipitate was found in the dogs treated with 120 mg/kg/day or less.

Baboons

In a 29-day toxicity study, groups of four baboons (two/sex/group) were administered intravenously 0, 25, 150 or 400 mg/kg/day of ceftriaxone. Diarrhea was a frequent finding in the treated animals. Occasional vomiting was observed. Urinary N-acetylglucosaminidase was statistically significantly increased in the 400 mg/kg/day group. Plasma urea concentrations were statistically significantly increased in this high-dose group, but remained within normal range. No drug-related histological changes or gallbladder precipitates were observed.

Groups of baboons (three/sex/dose) were given ceftriaxone i.v. in doses of 0, 30, 150, 400 or 700 mg/kg daily for 26 weeks. Early in the study, emesis and soft stools or diarrhea were noted, particularly at doses of 150 mg/kg daily or greater. Late in the study, sclerosis of the veins used for injection was seen in some animals in the 400 and 700 mg/kg/day groups. Other drug-related findings in some animals in the 700 mg/kg/day group were lethargy, decreased activity, pale oral mucosa or facial colour, unthrifty and hunched appearance, sunken eyes, body sores, tremors, weight loss, dehydration and a sweet body odour. Treatment-related hematological changes included decreases in platelet counts particularly in females (up to 51 percent), sporadic increases in reticulocyte counts and transient prolongation of clotting times. The less than

15 percent decreases in hematocrit, hemoglobin and erythrocyte counts found early in the study in the highest dosed group largely returned to normal by the end of the study. The mean SGPT (serum ALT) values were increased by 2 or 3-fold in all treated males at week 4, but were subsequently normal. One male in the highest dose group gradually deteriorated with signs of uremia and was sacrificed at week 20. All other animals were autopsied after 26 weeks of treatment. Increases in absolute kidney weight of 12, 38 and 42 percent were noted in females dosed at 400 mg/kg/day and in males and females dosed at 700 mg/kg/day respectively. Nephropathy was found in the 150, 400 and 700 mg/kg/day groups. In the animals treated with 150 mg/kg/day, it was minimal (greenish-brown granular pigment in regenerative tubular epithelium) . At the two highest dose levels, the nephropathy ranged from minimal to moderately severe with necrosis, microliths and regeneration of the renal tubuli. Secondary to the nephropathy, there was thymic atrophy in four animals and decreased bone marrow cellularity in two. In the gallbladder, no precipitation was found in the baboons given 30 or 150 mg/kg/day. Soft or granular deposits were found in the gallbladders of some animals treated with 400 or 700 mg/kg/day.

Microscopic choleliths and/or amorphous material were also noted in the lumen in most males of the two highest dose groups.

Fertility and Reproduction Study

Groups of Sprague-Dawley rats (twenty-two/sex/dose) received 0, 100, 350 or 700 mg/kg ceftriaxone i.v. daily. The males were dosed for at least 60 days prior to and during mating and the females for at least 14 days prior to mating and throughout gestation and lactation. The delivery was natural in twelve females per group and by Cesarian section in the others. Copulation, fertilization and pregnancy were not impaired. There was a tendency to cecal enlargement in all treated groups.

No adverse effects were found on the numbers or relative proportions of corpora lutea and implantations, or on the resorption rate or fetal weight. No visceral or skeletal abnormalities were found in the fetuses from either the control or the treated animals.

In the dams which delivered normally, no adverse effects were seen during lactation or on the numbers of implantation sites and live births. The gestation, viability and lactation indices were not affected, and neonatal body weight at birth and throughout lactation was normal. The general appearance, behaviour and sensory function of all the offspring were normal during the suckling period and at autopsy.

Teratology Studies

Mice

Groups of thirty female Füllinsdorf albino mice were given 0, 100, 250 or 625 mg/kg ceftriaxone i.v. daily from day 7 to day 16 of gestation. About twenty animals per group were sacrificed on day 19 and the remainder allowed to deliver normally and rear their young.

In the groups that were sacrificed on day 19, the incidence of 14 ribs was much greater (18 fetuses all from one litter) in the high-dose group than in the control group (2 fetuses). In the groups that were permitted to deliver normally, the percentage of resorptions per implantation appeared to increase in a dose-related manner: 6.5, 10.5, 11.1, 17.8 percent at doses of 0, 100, 250, 625 mg/kg/day respectively. The pups showed a uniform increase in body weight during the lactation period. No indications of any embryotoxic or teratogenic effect (except for exencephaly observed in one fetus at the lowest dosage group) of the drug were found.

Rats

Groups of thirty female Sprague-Dawley rats were given 0, 100, 350 or 700 mg/kg ceftriaxone i.v. daily from day 7 to day 17 of gestation. Twenty animals per group were sacrificed on day 21 and the remaining ten were allowed to deliver normally.

No dams died during gestation or lactation. There were no drug-related differences in average litter size, resorption rate or fetal body weight between the control and treated groups. The drug produced no external, visceral or skeletal abnormalities in the fetuses.

Rabbits

Groups of seven to twelve rabbits were given 0, 20 or 100 mg/kg ceftriaxone i.v. daily from day 7 to day 19 of gestation. The drug was poorly tolerated by the dams, death occurring in 50 and 30 percent of the dams in the high- and low-dose groups respectively. Diarrhea was seen in most of the dams (heavy in all high- dose animals). All animals in the high-dose group experienced vaginal bleeding. The number of resorptions was significantly increased: 100 percent of implantations at the high dose and 50.6 percent at the low dose. Examination of surviving fetuses (low-dose group) provided no evidence of any teratogenic effect of the drug.

Monkeys

Ceftriaxone was given i.v. in a dose of 100 mg/kg/day to ten Cynomolgus monkeys (group A) from day 21 to day 31 of gestation and to nine (group B) from day 32 to day 45 of gestation. A control group (nine animals) received the vehicle from day 21 to day 45 of gestation. Fetuses were delivered by Cesarian section on day 100 ± 1 of gestation and immediately examined for abnormalities.

Abortion occurred in two control monkeys, one in group A and two in group B. Mild diarrhea occurred in two animals in each of the treatment groups. The body weights of the fetuses from group B (average of approximately 99 grams) were decreased in comparison to controls (average of approximately 108 grams). All other findings were normal and there were no fetal malformations.

Perinatal and Postnatal Study

Groups of twenty female Sprague-Dawley rats were given ceftriaxone i.v. in doses of 0, 100, 350 and 700 mg/kg/day from day 17 of gestation and throughout lactation. All were allowed to give birth naturally.

No maternal deaths occurred. Body weight gain and food intake were slightly diminished in all treated dams during gestation but not during lactation. Parturition occurred normally. At autopsy, cecal enlargement was seen in all treated dams. The average numbers of implantations and of live and dead births were similar in all groups. Neonatal viability, body weight, appearance, behaviour and sensory function were not affected by the drug. No notable external, visceral or skeletal anomalies were seen.

During the 8-week observation period after weaning, no notable effects were seen on mean body weight, emotional behaviour, learning ability, fertility or reproductive performance of the F1 rats.

Mutagenicity Studies

In the Ames test, ceftriaxone did not induce mutations in various Salmonella typhimurium strains at concentrations up to 100 ng/plate either with or without activation by a rat liver homogenate fraction. Higher concentrations were bactericidal to these strains.

In the micronucleus test, groups of three mice/sex/dose were given 18, 84.0 or 420.0 mg/kg ceftriaxone i.v. 30 and 6 hours before sacrifice. No drug-related increases in micronuclei were found. Hence, under the conditions used, the drug does not induce chromosome breaks or mitotic non-disjunctions in mouse bone marrow cells.

In a third study, lymphoblasts obtained from human peripheral blood lymphocytes were exposed in vitro to ceftriaxone at a concentration of 0.2, 2 or 20 mg/mL culture medium for 24 hours. No increase in chromosome aberrations was observed with the first two concentrations. The highest concentration could not be evaluated since it was toxic to the cells.

Other Studies

Tolerance Studies

Intramuscular route

Female albino rats were given 0.2 mL of freshly prepared injections of ceftriaxone in water into the rectus femoris muscle of a hind leg. The increases in SGOT levels 24 hours after administration were 44 and 58 percent for 119 and 289 mg/mL solutions of ceftriaxone respectively.

New Zealand white rabbits received 0.1 or 1.0 mL injections of a low concentration (10 mg/mL) or a high concentration (600 mg added to 1.7 mL) of ceftriaxone in water, or distilled water into the sacrospinalis muscle. While 0.1 mL of the low concentration was not more irritating than the vehicle, 0.1 mL of the high concentration and 1.0 mL of both concentrations produced significant muscle irritation estimated in terms of swelling, edema, hemorrhage and necrosis. The irritation appeared to be dependent upon both volume and dose.

Intramuscular injection of a 100 mg/mL solution of ceftriaxone in a dose of 100 mg/kg caused a 4-fold rise in plasma SGOT in one dog and a 47 percent increase in another. Slight pain occurred during injection in both animals.

Intravenous route

An aqueous solution containing 100 mg/mL ceftriaxone was diluted 1, 3 or 7-fold with normal saline solution and incubated with citrated whole canine blood for 5 minutes. No hemolysis occurred.

Injection of 0.5 mL of ceftriaxone disodium aqueous solution (100 mg/mL) into the rabbit ear vein was well tolerated.

A 10 mg/mL solution of ceftriaxone in water was administered i.v. to dogs (0.4 mL/kg) at a rate of 1.25 mL/min. Analysis of plasma for hemoglobin just before and 1 minute after infusion did not reveal any detectable hemolysis. Gross examination of the injection sites 24 hours later did not reveal any venous irritation. In another study in dogs, a 40 mg/mL solution of ceftriaxone in 5% dextrose solution was infused i.v. at the same rate to achieve a dose of 16 mg/kg (0.4 mL/kg). No appreciable hemolysis and no venous irritation were found.

Intrathecal route

Cerebrospinal fluid (3 mL in one dog and 2 mL in seven dogs) was withdrawn from Swiss beagle dogs (four males and four females) anaesthetised with pentobarbital and replaced by ceftriaxone solution (100 mg/mL) or isotonic saline. The 3 mL replacement dose was too toxic. Injection of ceftriaxone (2 mL) immediately resulted in depression of breathing followed by temporary apnea (2 - 3 minutes), significant tachycardia, opisthotonus and tetanic convulsions. After 24 hours, convulsions and central nervous disorders were still present and the CSF contained increased protein and mono- and polynucleated cells. At autopsy, the brain was normal, but the subarachnoid space was dilated with infiltration of polymorphonuclear leucocytes and edema. No abnormal findings were observed in control dogs given saline.

Nephrotoxicity

Male rabbits (three/dose) were administered single s.c. injections of 100, 200 or 400 mg/kg ceftriaxone. No drug-related renal changes were reported but a 4 - 5 percent loss of body weight was observed.

Another study was carried out comparing ceftriaxone, cephaloridine and cefoxitin at single-doses of 30, 300 or 1000 mg/kg in rabbits. Slight to moderate focal or multi-focal necrosis of kidney tubular epithelium was observed in rabbits dosed with 1000 mg/kg of ceftriaxone.