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Rocephin (Ceftriaxone Sodium) - Description and Clinical Pharmacology

 
 



ROCEPHIN®
(ceftriaxone sodium)
FOR INJECTION

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Rocephin and other antibacterial drugs, Rocephin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

Rocephin is a sterile, semisynthetic, broad-spectrum cephalosporin antibiotic for intravenous or intramuscular administration. Ceftriaxone sodium is (6 R,7 R)-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-carboxylic acid, 72-(Z)-(O -methyloxime), disodium salt, sesquaterhydrate.

The chemical formula of ceftriaxone sodium is C18H16N8Na2O7S3•3.5H2O. It has a calculated molecular weight of 661.59 and the following structural formula:

Rocephin is a white to yellowish-orange crystalline powder which is readily soluble in water, sparingly soluble in methanol and very slightly soluble in ethanol. The pH of a 1% aqueous solution is approximately 6.7. The color of Rocephin solutions ranges from light yellow to amber, depending on the length of storage, concentration and diluent used.

Rocephin contains approximately 83 mg (3.6 mEq) of sodium per gram of ceftriaxone activity.

CLINICAL PHARMACOLOGY

Average plasma concentrations of ceftriaxone following a single 30-minute intravenous (IV) infusion of a 0.5, 1 or 2 gm dose and intramuscular (IM) administration of a single 0.5 (250 mg/mL or 350 mg/mL concentrations) or 1 gm dose in healthy subjects are presented in Table 1.

Table 1 Ceftriaxone Plasma Concentrations After Single Dose Administration
Dose/RouteAverage Plasma Concentrations (µg/mL)
 0.5 hr1 hr2 hr4 hr6 hr8 hr12 hr16 hr24 hr
ND = Not determined.
0.5 gm IV 1 82594837292315105
0.5 gm IM                  
  250 mg/mL22333835302616ND5
0.5 gm IM                  
  350 mg/mL20323834312416ND5
1 gm IV1511118867534328189
1 gm IM40687668564429NDND
2 gm IV2571921541178974463115

1 IV doses were infused at a constant rate over 30 minutes.

Ceftriaxone was completely absorbed following IM administration with mean maximum plasma concentrations occurring between 2 and 3 hours postdosing. Multiple IV or IM doses ranging from 0.5 to 2 gm 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
Dose/RouteAverage Urinary Concentrations (µg/mL)
  0-2 hr2-4 hr4-8 hr8-12 hr12-24 hr24-48 hr
ND = Not determined.
0.5 gm IV526366142877015
0.5 gm IM1154253081279628
1 gm IV99585529314713232
1 gm IM504628418237NDND
2 gm 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 gm IV dose, average concentrations of ceftriaxone, determined from 1 to 3 hours after dosing, were 581 µg/mL in the gallbladder bile, 788 µg/mL in the common duct bile, 898µg/mL in the cystic duct bile, 78.2 µg/gm in the gallbladder wall and 62.1 µg/mL in the concurrent plasma.

Over a 0.15 to 3 gm 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 µg/mL to a value of 85% bound at 300 µg/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 (µg/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 (µg/mL)5.66.4
  Range (µg/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 gm 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

Pharmacokinetics in the Middle Ear Fluid

In one study, total ceftriaxone concentrations (bound and unbound) were measured in middle ear fluid obtained during the insertion of tympanostomy tubes in 42 pediatric patients with otitis media. Sampling times were from 1 to 50 hours after a single intramuscular injection of 50 mg/kg of ceftriaxone. Mean (± SD) ceftriaxone levels in the middle ear reached a peak of 35 (± 12) µg/mL at 24 hours, and remained at 19 (± 7) µg/mL at 48 hours. Based on middle ear fluid ceftriaxone concentrations in the 23 to 25 hour and the 46 to 50 hour sampling time intervals, a half-life of 25 hours was calculated. Ceftriaxone is highly bound to plasma proteins. The extent of binding to proteins in the middle ear fluid is unknown.

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.

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 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 is also active against many strains of Pseudomonas aeruginosa.

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

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. Most strains of Group D streptococci and enterococci, eg, 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 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 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
Citrobacter freundii
Providencia
species (including Providencia rettgeri)
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 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) 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 (µg/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:

Microorganism ATCC ® # MIC (µg/mL)
Escherichia coli 259220.03 - 0.12
Staphylococcus aureus 292131 - 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 aeruginosa 278538 - 32
Haemophilus influenzae 492470.06 - 0.25
Neisseria gonorrhoeae 492260.004 - 0.015
Streptococcus pneumoniae 496190.03 - 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 µg 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 µg 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 µg/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 µg ceftriaxone disc should provide the following zone diameters in these laboratory test quality control strains:3

Microorganism ATCC ® # Zone Diameter Ranges (mm)
Escherichia coli 2592229 - 35
Staphylococcus aureus 2592322 - 28
Pseudomonas aeruginosa 2785317 - 23
Haemophilus influenzae 4924731 - 39
Neisseria gonorrhoeae 4922639 - 51
Streptococcus pneumoniae 4961930 - 35

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to ceftriaxone 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 powder should provide the following MIC values for the indicated standardized anaerobic dilution4 testing method:

Method Microorganism ATCC ® # MIC (µg/mL)
ATCC® is a registered trademark of the American Type Culture Collection.
Agar Bacteroides fragilis 2528532 - 128
   Bacteroides thetaiotaomicron 2974164 - 256
Broth Bacteroides thetaiotaomicron 2974132 - 128

ANIMAL PHARMACOLOGY

Concretions consisting of the precipitated calcium salt of ceftriaxone have been found in the gallbladder bile of dogs and baboons treated with ceftriaxone.

These appeared as a gritty sediment in dogs that received 100 mg/kg/day for 4 weeks. A similar phenomenon has been observed in baboons but only after a protracted dosing period (6 months) at higher dose levels (335 mg/kg/day or more). The likelihood of this occurrence in humans is considered to be low, since ceftriaxone has a greater plasma half-life in humans, the calcium salt of ceftriaxone is more soluble in human gallbladder bile and the calcium content of human gallbladder bile is relatively low.

CLINICAL STUDIES

Clinical Trials in Pediatric Patients With Acute Bacterial Otitis Media

In two adequate and well-controlled US clinical trials a single IM dose of ceftriaxone was compared with a 10 day course of oral antibiotic in pediatric patients between the ages of 3 months and 6 years. The clinical cure rates and statistical outcome appear in the table below:

Clinical Efficacy in Evaluable Population
Study DayCeftriaxone
Single Dose
Comparator –
10 Days of
Oral Therapy
95%
Confidence
Interval
Statistical
Outcome
Study 1 – USamoxicillin/clavulanate
1474% (220/296)82% (247/302)(-14.4%, -0.5%)Ceftriaxone is lower
than control at
2858% (167/288)67% (200/297)(-17.5%, -1.2%)study day 14 and
28.
Study 2 - US5TMP-SMZ
1454% (113/210)60% (124/206)(-16.4%, 3.6%)Ceftriaxone is
equivalent to
2835% (73/206)45% (93/205)(-19.9%, 0.0%)control at study day
14 and 28.

An open-label bacteriologic study of ceftriaxone without a comparator enrolled 108 pediatric patients, 79 of whom had positive baseline cultures for one or more of the common pathogens. The results of this study are tabulated as follows:

Week 2 and 4 Bacteriologic Eradication Rates in the Per Protocol Analysis in the Roche Bacteriologic Study by pathogen:

  Study Day
13-15
  Study Day
30+2
  
OrganismNo.
Analyzed
No.
Erad. (%)
No.
Analyzed
No.
Erad. (%)
Streptococcus pneumoniae 3832 (84)3525 (71)
Haemophilus influenzae 3328 (85)3122 (71)
Moraxella catarrhalis 1512 (80)159 (60)

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