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.
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.
Ceftriaxone is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Ceftriaxone has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of Gram-negative and Gram-positive bacteria.
Mechanism of Resistance
Resistance to ceftriaxone is primarily through hydrolysis by beta-lactamase, alteration of penicillin-binding proteins (PBPs), and decreased permeability.
Interaction with Other Antimicrobials:
In an in vitro study antagonistic effects have been observed with the combination of chloramphenicol and ceftriaxone.
• Gram-negative bacteria
• Gram-positive bacteria
Viridans group streptococci
• Anaerobic bacteria
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ceftriaxone. However, the efficacy of ceftriaxone in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.
• Gram-negative bacteria
Providencia species (including Providencia rettgeri)
Salmonella species (including Salmonella typhi)
• Gram-positive bacteria
• Anaerobic bacteria
Porphyromonas (Bacteroides) melaninogenicus
Prevotella (Bacteroides) bivius
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.
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 test method 1,3. The MIC values should be interpreted according to criteria provided in Table 5.
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.2,3. This procedure uses paper disks impregnated with 30 mcg ceftriaxone to test the susceptibility of microorganisms to ceftriaxone. The disk diffusion interpretive criteria are provided in Table 5.
For anaerobic bacteria, the susceptibility to ceftriaxone as MICs can be determined by a standardized agar test method 3,4. The MIC values obtained should be interpreted according to the criteria provided in Table 5.
|Pathogen||Minimum Inhibitory Concentrations ( mcg / mL )||Disk Diffusion Zone Diameters ( mm )|
|( S ) Susceptible||( I ) Intermediate||( R ) Resistant||( S ) Susceptible||( I ) Intermediate||( R ) Resistant|
|Enterobacteriaceae *||≤ 1||2||≥4||≥ 23||20 to 22||≤19|
|Haemophilus influenzae † , ‡||≤2||–||–||≥26||–||–|
|Neisseria gonorrhoeae *||≤ 0.25||–||–||≥ 35||–||–|
|Neisseria meningitidis ‡||≤ 0.12||–||–||≥ 34||–||–|
|Streptococcus pneumoniae §meningitis isolates||≤ 0.5||1||≥ 2||–||–||–|
|Streptococcus pneumoniae §non-meningitis isolates||≤1||2||≥4||–||–||–|
|Streptococcus species beta-hemolytic group ‡||≤0.5||–||–||≥ 24||–||–|
|Viridans group streptococci||≤ 1||2||≥ 4||≥27||25 to 26||≤24|
|Anaerobic bacteria (agar method)||≤1||2||≥4||–||–||–|
A report of Susceptible indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration at the site of infection. A report of Intermediate indicates that the result 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 a high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test 1,2,3,4. Standard ceftriaxone powder should provide the following range of MIC values noted in Table 6. For the diffusion technique using the 30 mcg disk, the criteria in Table 6 should be achieved.
|QC Strain||Minimum Inhibitory Concentrations ( mcg / mL )||Disk Diffusion Zone diameters ( mm )|
|Escherichia coli ATCC 25922||0.03 to 0.12||29 to 35|
|Staphylococcus aureus ATCC 25923||———-||22 to 28|
|Staphylococcus aureus ATCC 29213||1 to 8||———|
|Haemophilus influenzae ATCC 49247||0.06 to 0.25||31 to 39|
|Neisseria gonorrhoeae ATCC 49226||0.004 to 0.015||39 to 51|
|Pseudomonas aeruginosa ATCC 27853||8 to 64||17 to 23|
|Streptococcus pneumoniae ATCC 49619||0.03 to 0.12||30 to 35|
|Bacteroides fragilis ATCC 25285 (agar method)||32 to 128||———|
|Bacteroides thetaiotaomicron ATCC 29741 (agar method)||64 to 256||———|
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