Ceftriaxone Sodium Dailymed

To Reduce The Development Of Drug-resistant Bacteria And Maintain The Effectiveness Of Ceftriaxone For Injection And Other Antibacterial Drugs, Ceftriaxone For Injection Should Be Used Only To Treat Or Prevent Infections That Are Proven Or Strongly Suspected To Be Caused By Bacteria.

Description

Ceftriaxone sodium is a sterile, semisynthetic, broad-spectrum cephalosporin antibiotic for intravenous or intramuscular administration. Ceftriaxone sodium is (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-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:

Ceftriaxone sodium 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 ceftriaxone sodium solutions ranges from light yellow to amber, depending on the length of storage, concentration and diluent used.

Ceftriaxone sodium 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/Route	Average Plasma Concentrations (mcg/mL)
	0.5 hr	1 hr	2 hr	4 hr	6 hr	8 hr	12 hr	16 hr	24 hr
0.5 gm IVIV doses were infused at a constant rate over 30 minutes.	82	59	48	37	29	23	15	10	5
0.5 gm IM
250 mg/mL	22	33	38	35	30	26	16	NDNot Determined	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

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 (mcg/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

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 mcg/mL in the gallbladder bile, 788 mcg/mL in the common duct bile, 898 mcg/mL in the cystic duct bile, 78.2 mcg/gm in the gallbladder wall and 62.1 mcg/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 mcg/mL to a value of 85% bound at 300 mcg/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 (mcg/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 (mcg/mL)	5.6	6.4
Range (mcg/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)	PlasmaClearance (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)Creatinine clearance.	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	0.7	13.3
Patients With Liver Disease	8.8	1.1	13.6

The elimination of ceftriaxone is not altered when 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) 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.

NOTE: Many strains of the above organisms that are resistant to multiple antibiotics, e.g., 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, e.g., 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 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

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
National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard-Fifth Edition. NCCLS document M7-A5 (ISBN 1-56238-309-9). NCCLS, Wayne, PA 19087-1898, 2000.
. 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 criteria
National Committee for Clinical Laboratory Standards, Supplemental Tables.  NCCLS document M100-S10 (M7) (ISBN 1 - 56238-309-9).  NCCLS, Wayne, PA 19087-1898, 2000.
for aerobic organisms other than Haemophilus spp, Neisseria gonorrhoeae, and Streptococcus spp, including Streptococcus pneumoniae:

MIC (mcg/mL)	Interpretation
≤ 8	(S) Susceptible
16-32	(I) Intermediate
≥ 64	(R) Resistant

The following interpretive criteria
National Committee for Clinical Laboratory Standards, Supplemental Tables.  NCCLS document M100-S10 (M7) (ISBN 1 - 56238-309-9).  NCCLS, Wayne, PA 19087-1898, 2000.
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
National Committee for Clinical Laboratory Standards, Supplemental Tables.  NCCLS document M100-S10 (M7) (ISBN 1 - 56238-309-9).  NCCLS, Wayne, PA 19087-1898, 2000.
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 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
National Committee for Clinical Laboratory Standards, Supplemental Tables.  NCCLS document M100-S10 (M7) (ISBN 1 - 56238-309-9).  NCCLS, Wayne, PA 19087-1898, 2000.
should be used when testing Streptococcus spp including Streptococcus pneumoniae using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.

MIC (mcg/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 values:
National Committee for Clinical Laboratory Standards, Supplemental Tables.  NCCLS document M100-S10 (M7) (ISBN 1 - 56238-309-9).  NCCLS, Wayne, PA 19087-1898, 2000.

Microorganism	ATCC® #	MIC (mcg/mL)
Escherichia coli	25922	0.03-0.12
Staphylococcus aureus	29213	1- 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	27853	8-32
Haemophilus influenzae	49247	0.06 - 0.25
Neisseria gonorrhoeae	49226	0.004-0.015
Streptococcus pneumoniae	49619	0.03 -0.12

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure
National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disc Susceptibility Tests; Approved Standard - Seventh Edition. NCCLS document M2-A7 (ISBN 1-56238-393-0). NCCLS, Wayne, PA 19087-1898, 2000.
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 other than Haemophilus spp, Neisseria gonorrhoeae, and Streptoccocus spp:

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

The following interpretive criteria
National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disc Susceptibility Tests; Approved Standard - Seventh Edition. NCCLS document M2-A7 (ISBN 1-56238-393-0). NCCLS, Wayne, PA 19087-1898, 2000.
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 criteria
National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disc Susceptibility Tests; Approved Standard - Seventh Edition. NCCLS document M2-A7 (ISBN 1-56238-393-0). NCCLS, Wayne, PA 19087-1898, 2000.
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 criteria
National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disc Susceptibility Tests; Approved Standard - Seventh Edition. NCCLS document M2-A7 (ISBN 1-56238-393-0). NCCLS, Wayne, PA 19087-1898, 2000.
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 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:
National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disc Susceptibility Tests; Approved Standard - Seventh Edition. NCCLS document M2-A7 (ISBN 1-56238-393-0). NCCLS, Wayne, PA 19087-1898, 2000.

Microorganism	ATCC® #	Zone Diameter Ranges (mm)
Escherichia coli	25922	29-35
Staphylococcus aureus	25923	22-28
Pseudomonas aeruginosa	27853	17-23
Haemophilus influenzae	49247	31-39
Neisseria gonorrhoeae	49226	39-51
Streptococcus pneumoniae	49619	30-35

For anaerobic bacteria, the susceptibility to ceftriaxone as MICs can be determined by standardized test methods.
National Committee for Clinical Laboratory Standards, Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard-Fourth Edition. NCCLS document M11-A4 (ISBN 1-56238-210-1). NCCLS, Wayne, PA 19087-1898, 1997.
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 microorganism 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 dilution
National Committee for Clinical Laboratory Standards, Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard-Fourth Edition. NCCLS document M11-A4 (ISBN 1-56238-210-1). NCCLS, Wayne, PA 19087-1898, 1997.
testing method:

Method	Microorganism	ATCC ® #	MIC (mcg/mL)
Agar	Bacteroides fragilis	25285	32 -128
	Bacteroides thetaiotaomicron	29741	64 -256
Broth	Bacteroides thetaiotaomicron	29741	32 -128

ATCC^® is a registered trademark of the American Type Culture Collection.