Ceftriaxone (Page 2 of 7)

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) mcg/mL at 24 hours, and remained at 19 (± 7) mcg/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 ceftriaxone-calcium 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.

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, e.g., Enterococcus (Streptococcus) faecalis, are resistant.

Anaerobic microorganisms:

Bacteroides fragilis

Clostridium species

Peptostreptococcus species

NOTE: Most strains of Clostridium difficile are resistant.

in vitro data are available, but their clinical significance is unknown. Ceftriaxone exhibits in vitro minimal inhibitory concentrations (MICs) of ≤1 mcg/mL or less against most strains of the following microorganisms, however, the safety and effectiveness of ceftriaxone in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-negative 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 (mcg/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 (mcg/mL)Interpretation

≤2 (S) Susceptible

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

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

MIC (mcg/mL)Interpretation

≤0.25 (S) Susceptible

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

MIC (mcg/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 (mcg/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 (mcg/mL)Interpretation

≤0.5 (S) Susceptible

1 (I) Intermediate

≥2 (R) Resistant

Non-meningitis infections:

MIC (mcg/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 (mcg/mL)Interpretation

≤0.5 (S) Susceptible

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

MIC (mcg/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:

MicroorganismATCC® #MIC (mcg/mL)

Escherichia coli 25922 0.03 — 0.12

Staphylococcus aureus 29213 1 — 8*

Pseudomonas aeruginosa 27853 8 — 64

Haemophilus influenzae 49247 0.06 — 0.25

Neisseria gonorrhoeae 49226 0.004 — 0.015

Streptococcus pneumoniae 49619 0.03 — 0.12

* A bimodal distribution of MICs results at the extremes of the acceptable range should be suspect and control validity should be verified with data from other control strains.

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

Reports from the laboratory providing results of the standard single-disc susceptibility test with a 30 mcg ceftriaxone disc should be interpreted according to the following criteria for aerobic organisms:

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 mcg/mL) to penicillin and can be considered susceptible to ceftriaxone. Streptococcus pneumoniae isolates should not be reported as penicillin (ceftriaxone) resistant or intermediate based solely on an oxacillin zone diameter of ≤19 mm. The ceftriaxone MIC should be determined for those isolates with oxacillin zone diameters ≤19 mm.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30 mcg ceftriaxone disc should provide the following zone diameters in these laboratory test quality control strains:3

MicroorganismATCC® #Zone Diameter Ranges (mm)

Escherichia coli 25922 29 — 35

Staphylococcus aureus 29213 22 — 28

Pseudomonas aeruginosa 27853 17 — 23

Haemophilus influenzae 49247 31 — 39

Neisseria gonorrhoeae 49226 39 — 51

Streptococcus pneumoniae 49619 30 — 35

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 (mcg/mL)Interpretation

≤16 (S) Susceptible

32 (I) Intermediate

≥64 (R) Resistant

As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized ceftriaxone powder should provide the following MIC values for the indicated standardized anaerobic dilution6 testing method:

MethodMicroorganismATCC® #MIC (mcg/mL)

Agar Bacteroides fragilis 25285 32 — 128

Bacteroides thetaiotaomicron 29741 64 — 256

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