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Rocephin

Rocephin

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/Route Average Plasma Concentrations (μg/mL)
0.5 hr 1 hr 2 hr 4 hr 6 hr 8 hr 12 hr 16 hr 24 hr
0.5 gm IV * 82 59 48 37 29 23 15 10 5
0.5 gm IM 250 mg/mL 22 33 38 35 30 26 16 ND 5
0.5 gm IM 350 mg/mL 20 32 38 34 31 24 16 ND 5
1 gm IV * 151 111 88 67 53 43 28 18 9
1 gm IM 40 68 76 68 56 44 29 ND ND
2 gm IV * 257 192 154 117 89 74 46 31 15
*IV doses were infused at a constant rate over 30 minutes.
ND = Not determined.

Ceftriaxone was completely absorbed following IM administration with mean maximum plasma concentrations occurring between 2 and 3 hours post-dose. 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 shown in Table 2.

Table 2 : Urinary Concentrations of Ceftriaxone After Single Dose Administration

Dose/Route Average Urinary Concentrations (μg/mL)
0-2 hr 2-4 hr 4-8 hr 8-12 hr 12-24 hr 24-48 hr
0.5 gm IV 526 366 142 87 70 15
0.5 gm IM 115 425 308 127 96 28
1 gm IV 995 855 293 147 132 32
1 gm IM 504 628 418 237 ND ND
2 gm IV 2692 1976 757 274 198 40
ND = Not determined.

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

Compared to that in healthy adult subjects, the pharmacokinetics of ceftriaxone 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 six of 26 dialysis patients, the elimination rate of ceftriaxone was markedly reduced.

Table 4 : Average Pharmacokinetic Parameters of Ceftriaxone in Humans

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

The elimination of ceftriaxone is not altered when Rocephin (ceftriaxone) is co-administered with probenecid.

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.

Interaction with Calcium

Two in vitro studies, one using adult plasma and the other neonatal plasma from umbilical cord blood have been carried out to assess interaction of ceftriaxone and calcium. Ceftriaxone concentrations up to 1 mM (in excess of concentrations achieved in vivo following administration of 2 grams ceftriaxone infused over 30 minutes) were used in combination with calcium concentrations up to 12 mM (48 mg/dL). Recovery of ceftriaxone from plasma was reduced with calcium concentrations of 6 mM (24 mg/dL) or higher in adult plasma or 4 mM (16 mg/dL) or higher in neonatal plasma. This may be reflective of ceftriaxonecalcium precipitation.

Microbiology

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

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

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

Aerobic gram-negative 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 resistant to multiple 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 ≤ 1 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. For details of susceptibility test methodologies, the most recent documents of the Clinical and Laboratory Standards Institute (CLSI) for antimicrobial susceptibility testing1-3 should be consulted.

The MIC values for aerobic organisms should be interpreted according to the following criteria:

For Enterobacteriaceae:

MIC (μg/mL) Interpretation
≤ 1 (S) Susceptible
2 (I) Intermediate
≥ 4 (R) Resistant

The following interpretive criteria 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 criteria 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 following interpretive criteria4 should be used when testing Neisseria meningitidis on Mueller-Hinton agar with 5% defribrinated sheep blood.

MIC (μg/mL) Interpretation
≤ 0.12 (S) Susceptible

The absence of resistant neisserial 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.

When testing Staphylococcus aureus (methicillin-susceptible, MSSA) the following interpretive criteria should be applied:

MIC (μg/mL) Interpretation
≤ 4 (S) Susceptible
8 (I) Intermediate
≥ 16 (R) Resistant

For staphylococcal infections, a daily dose of 2 to 4 grams should be administered to achieve > 90% target attainment (see DOSAGE AND ADMINISTRATION).

The following interpretive criteria should be used when testing Streptococcus pneumoniae using Mueller-Hinton broth with 2 to 5% lysed horse blood:

Meningitis:

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

Non-meningitis infections:

MIC (μg/mL) Interpretation
≤ 1 (S) Susceptible
2 (I) Intermediate
≥ 4 (R) Resistant

For β-hemolytic streptococci the following interpretive criteria should be used when testing on cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood:

MIC (μg/mL) Interpretation
≤ 0.5 (S) Susceptible

For the Viridians Group streptococci the following interpretive criteria should be applied:

MIC (μg/mL) Interpretation
≤ 1 (S) Susceptible
2 (I) Intermediate
≥ 4 (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 values:

Microorganism ATCC® # MIC ( g/mL)
Escherichia coli 25922 0.030.12
Staphylococcus aureus 29213 18*
Pseudomonas aeruginosa 27853 864
Haemophilus influenzae 49247 0.060.25
Neisseria gonorrhoeae 49226 0.0040.015
Streptococcus pneumoniae 49619 0.030.12
* A bimodal distribution of MICs results at the extremes of the acceptable range should be suspect and control validity should be verified with data from other control strains.

 

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

For Enterobacteriaceae:

Zone Diameter (mm) Interpretation
≥ 23 (S) Susceptible
20-22 (I) Intermediate
≤ 19 (R) Resistant

When testing Haemophilus influenzae on Haemophilus Test Media (HTM), the following interpretive criteria should be used:

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 criteria should be used when testing Neisseria gonorrhoeae when using GC agar base and 1% defined growth supplement:

Zone Diameter (mm) Interpretation
35 (S) Susceptible

For Neisseria meningitidis, the following disc diffusion criteria apply:5

Zone Diameter (mm) Interpretation
≥ 34 (S) Susceptible

For Staphylococcus aureus (methicillin-susceptible, MSSA), the following interpretive criteria apply:

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

The following interpretive criteria should be used when testing β-hemolytic streptococci using Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO2:

Zone Diameter (mm) Interpretation
≥ 24 (S) Susceptible

For the Viridians Group streptococci the following criteria apply:

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 25922 2935
Staphylococcus aureus 29213 2228
Pseudomonas aeruginosa 27853 1723
Haemophilus influenzae 49247 3139
Neisseria gonorrhoeae 49226 3951
Streptococcus pneumoniae 49619 3035

Anaerobic Susceptibility Testing by Agar Dilution: For anaerobic bacteria, the susceptibility to ceftriaxone as MICs can be determined by standardized test methods.6 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 dilution6 testing method:

Method Microorganism ATCC® # MIC ( g/mL)
Agar Bacteroides fragilis 25285 32128
  Bacteroides thetaiotaomicron 29741 64256

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 Day Ceftriaxone Single Dose Comparator –10 Days of Oral Therapy 95% Confidence Interval Statistical Outcome
Study 1 – US amoxicillin/clavulanate Ceftriaxone is lower than control at study day 14 and 28.
14 74% (220/296) 82% (247/302) (-14.4%, -0.5%)
28 58% (167/288) 67% (200/297) (-17.5%, -1.2%)
Study 2US 7 TMP-SMZ Ceftriaxone is equivalent to control at study day 14 and 28.
14 54% (113/210) 60% (124/206) (-16.4%, 3.6%)
28 35% (73/206) 45% (93/205) (-19.9%, 0.0%)
7 Barnett ED, Teele DW, Klein JO, et al. Comparison of Ceftriaxone and Trimethoprim-Sulfamethoxazole for Acute Otitis Media. Pediatrics. Vol. 99, No. 1, January 1997.

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:

Organism Study Day 13-15 Study Day 30+2
No. Analyzed No. Erad. (%) No. Analyzed No. Erad. (%)
Streptococcus pneumoniae 38 32 (84) 35 25 (71)
Haemophilus influenzae 33 28 (85) 31 22 (71)
Moraxella catarrhalis 15 12 (80) 15 9 (60)

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved StandardEighth Edition. CLSI document M07-A8. CLSI, 940 West Valley Road, Suite 1400, Wayne, PA 19087, 2009.

2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twentieth Informational Supplement. CLSI document M100-S20. CLSI, 940 West Valley Road, Suite 1400, Wayne, PA 19087, 2010.

3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved StandardTenth Edition. CLSI document M02-A10. CLSI, 940 West Valley Road, Suite 1400, Wayne, PA 19087, 2009.

4. Burgess DS, Frei CR, Lewis II JS, et al. The contribution of pharmacokinetic-pharmacodynamic modeling with Monte Carlo simulation to the development of susceptibility breakpoints for Neisseria meningitidis. Clin Microbiol Infect. 2007;13:33-39.

5. Jorgensen JH, Crawford SA, Fulcher LC, et al. Multilaboratory evaluation of disk diffusion antimicrobial susceptibility testing of Neisseria meningitidis isolates. J Clin Microbiol. 2006;44(5):1744-1754.

6. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard Seventh Edition. CLSI document M11-A7. CLSI, 940 West Valley Road, Suite 1400, Wayne, PA 19087, 2007.

Last reviewed on RxList: 12/21/2010
This monograph has been modified to include the generic and brand name in many instances.

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